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Hypoxia appears to promote contraction [hypoxic pulmonary vasoconstriction (HPV)] of bovine pulmonary arteries (BPA) through removal of a peroxide-mediated relaxation. This study examines the roles of BPA Nox oxidases and mitochondria in the HPV response. Inhibitors of Nox2 (0.1 mM apocynin and 50 [micro]M gp91-dstat) and mitochondrial electron transport (10 [micro]M antimycin and rotenone) decreased superoxide generation in BPA without affecting contraction to 25 mM KC1 or the HPV response. Transfection of BPA with small inhibitory RNA (siRNA) for Nox2 and Nox4 decreased Nox2 and Nox4 protein expression, respectively, associated with an attenuation of superoxide detection, without affecting 25 mM KC1 contraction. However, Nox4 siRNA, but not Nox2, attenuated HPV in BPA. A Nox4 inhibitor plumbagin (10 [micro]M) increased basal force, decreased superoxide detection and peroxide release, and caused BPA to relax under hypoxia. Although acute removal of peroxide with 0.1 mM ebselen increased 25 mM KC1 contraction and decreased hypoxic contraction, prolonged treatment with ebselen only decreased hypoxic contraction without affecting 25 mM KCI contraction, suggesting basal peroxide levels also maintain a contractile mechanism not removed by acute hypoxia. Organ culture of BPA with transforming growth factor (TGF)-[beta]1 (4 nM) increased Nox4 expression, superoxide, peroxide, and the HPV response. Thus Nox2 and mitochondria are sources for superoxide generation in BPA, which do not appear to influence the HPV response. However, peroxide derived from superoxide generated by Nox4 appears to maintain a basal relaxation in BPA under normoxic conditions, which is removed under hypoxia leading to HPV. Peroxide generated by Nox4 may also function to maintain a contractile mechanism, which is not reversed by acute hypoxia. hydrogen peroxide; hypoxic pulmonary vasoconstriction; mitochondria; Nox oxidase; oxygen sensor doi: 10.1152/ajpheart.01228.2009.

Cutaneous vasodilation associated with whole-body heat stress occurs via withdrawal of adrenergic vasoconstriction and engagement of cholinergic 'active' vasodilation, the latter of which attenuates cutaneous vasoconstrictor responsiveness. However, the precise neurotransmitter(s) responsible for this sympatholytic-like effect remain unknown. In skeletal muscle, ATP inhibits adrenergically mediated vasoconstriction. ATP also may be responsible for attenuating cutaneous vasoconstriction since it is coreleased from cholinergic neurons. The effect of ATP on cutaneous vasoconstrictor responsiveness, however, has not been investigated. Accordingly, this study tested the hypothesis that ATP inhibits adrenergically mediated cutaneous vasoconstriction. To accomplish this objective, four microdialysis probes were inserted in dorsal forearm skin of 11 healthy individuals (mean [+ or -] SD; 35 [+ or -] 11 years). Local temperature at each site was clamped at 34[degrees]C throughout the protocol. Skin blood flow was indexed by laser-Doppler flowmetry and was used to calculate cutaneous vascular conductance (CVC; laser-Doppler-derived flux/mean arterial pressure), which was normalized to peak CVC achieved with sodium nitroprusside infusion combined with local skin heating to ~42[degrees]C. Two membranes were perfused with 30 mM ATP, while the other two membranes were flow matched via administration of 2.8 mM adenosine to serve as control sites. After achieving stable baselines, 1 x [10.sup.-4] M tyramine was administered at all sites, while ATP and adenosine continued to be infused at their respective sites. ATP and adenosine infusion increased CVC from baseline by 35 [+ or -] 26% [CVC.sub.peak] units and by 36 [+ or -] 15% [CVC.sub.peak] units, respectively (P = 0.75). Tyramine decreased CVC similarly (by about one-third) at all sites (P < 0.001 for main effect and P = 0.32 for interaction). These findings indicate that unlike in skeletal muscle, ATP does not attenuate tyramine-stimulated vasoconstriction in human skin. skin blood flow; thermoregulation; cutaneous vasodilation; laser-Doppler flowmetry doi: 10.1152/ajpregu.00846.2009.

Intravenous administration of cell-free Hb induces vasoconstriction and circulatory disorders, presumably because of the intrinsic affinities to endogenous nitric oxide (NO) and carbon monoxide (CO) as vasorelaxation factors and because of the facilitated [O.sub.2] release that might induce autoregulatory vasoconstriction. We examined these gas reactions when Hb-containing solutions of four kinds were perfused through artificial narrow tubes at a practical Hb concentration (10 g/dl). Purified Hb solution, polymerized bovine Hb ([Poly.sub.B]Hb), encapsulated Hb [Hb-vesicles (HbV), 279 nm], and red blood cells (RBCs) were perfused through a gas-permeable narrow tube (25 [micro]m inner diameter) at 1 mm/s centerline velocity. The level of reactions was determined microscopically based on the visible-light absorption spectrum of Hb. When the tube was immersed in NO and CO atmospheres, both NO binding and CO binding of deoxygenated Hb (deoxy-Hb) and [Poly.sub.B]Hb in the tube was faster than those of HbV and RBCs, and HbV and RBCs showed almost identical binding rates. When the tube was immersed in a [N.sub.2] atmosphere, oxygenated Hb and [Poly.sub.B]Hb showed much faster [O.sub.2] release than did HbV and RBCs. [Poly.sub.B]Hb showed a faster reaction than Hb because of the lower [O.sub.2] affinity of [Poly.sub.B]Hb than Hb. The diffusion process of the particles was simulated using Navier-Stokes and Maxwell-Stefan equations. Results clarified that small Hb (6 nm) diffuses laterally and mixes rapidly. However, the large-dimension HbV shows no such rapid diffusion. The purely physicochemical differences in diffusivity of the particles and the resulting reactivity with gas molecules are one factor inducing biological vasoconstriction of Hb-based oxygen carriers. microcirculation; blood substitutes; gas biology; liposome; erythrocytes doi:10.1152/ajpheart.00741.2009

Acute pulmonary embolism (PE) is a life-threatening disease, and several vasoconstrictors, including endothelin-1 (ET-1), play a key role in vasoconstriction and hypoxemia during the development of PE. Rho kinase is activated by various vasoconstrictors resulting in vascular contraction and remodeling. Recent evidence has revealed an important role of Rho kinase in the pathogenesis of systemic and pulmonary vascular diseases. However, contribution of Rho kinase in PE remains unclear. We thus investigated the role of Rho kinase in the PE rat model induced by intrajugular administration of polystyrene microspheres (mean diameter, 26 [micro]m). At 6 h following the administration of microspheres (1.5 ml/kg), right ventricular systolic pressure (RVSP) was higher in the PE than in the control rats (15.8 [+ or -] 1.6 vs. 32.9 [+ or -] 7.5 mmHg). Arterial oxygen tension was lower (92.3 [+ or -] 12.5 vs. 66.0 [+ or -] 17.7 Torr), and alveolar-arterial difference in oxygen partial pressure was higher (3.9 [+ or -] 3.8 vs. 36.5 [+ or -] 26.9 Torr) in the PE rats. Western blotting analysis revealed upregulation and downregulation in expression of vascular cell adhesion molecule-1 and endothelial nitric oxide synthase in lungs from the PE rats, respectively, and radioimmunoassay demonstrated an increase in plasma ET-1 levels. Lung Rho kinase [alpha] expression was greater in the PE rats. At 5 h following administration of microspheres (0.75 ml/kg), intravenous Rho kinase inhibitors HA1077 and Y27632 (3 mg/kg each) attenuated elevation of RVSP (22.0 [+ or -] 3.7, 17.1 [+ or -] 3.2, 14.3 [+ or -] 2.6 mmHg, PE, PE + HA1077, PE + Y27632) and the severity of hypoxemia (66.3 [+ or -] 16.2, 94.9 [+ or -] 23.0, 89.1 [+ or -] 8.5 Torr, PE, PE+HA1077, PE+Y27632) in the PE rats. These results suggest that pulmonary endothelial dysfunction and activation of Rho kinase may contribute to the potentiation of vasoconstriction and hypoxemia in the PE rats. vascular cell adhesion molecule-1; endothelial nitric oxide synthase; endothelin-1; Rho kinase [alpha] doi:10.1152/ajplung.90237.2008.

Endurance training has been associated with increased orthostatic intolerance. The purpose of the present study was to test the hypothesis that endurance training reduces renal vasoconstriction to orthostatic stress. Blood pressure, heart rate, and renal blood flow velocity were measured during a 25-min 60[degrees] head-up tilt (HUT) test before and after 8 wk of endurance training in eight healthy sedentary subjects (26 [+ or -] 1 .yrs). Training elicited a 21 [+ or -] 3% increase in peak oxygen uptake (VO2peak) and a reduction in heart rate at rest of 8 [+ or -] 2 beats/rain. During HUT, heart rate progressively increased (-20 beats/min) over the 25-rain HUT trial both before and after training. Systolic arterial blood pressure during HUT was unchanged with training, whereas diastolic arterial blood pressure was lower at the end of HUT after training. Before training renal blood flow velocity ([DELTA]14 [+ or -] 5 cm/s) and renal vascular conductance ([DELTA]22 [+ or -] 7%) decreased during HUT, whereas after training renal blood flow velocity ([DELTA]2 [+ or -] 5 cm/s) and renal vascular conductance ([DELTA]1 [+ or -] 12%) did not change significantly during HUT. Renal blood flow velocity and vascular conductance responses to HUT did not change in control subjects during the 8-wk period. These results demonstrate that endurance training reduces renal vasoconstriction during an orthostatic challenge and may contribute to training-induced orthostatic intolerance. renal vascular conductance; head-up tilt doi: 10.1152/ajprenal.00447.2009

Am J Physiol Heart Circ Physiol 298: H245-H250, 2010. First published November 6, 2009; doi: 10.1152/ajpheart.00909.2009.--Muscle metaboreflex activation during submaximai dynamic exercise in normal subjects elicits a pressor response primarily due to increased cardiac output (CO). However, when the ability to increase CO is limited, such as in heart failure or during maximal exercise, the muscle metaboreflex-induced increases in arterial pressure occur via peripheral vasoconstriction. How the mechanisms of this pressor response are altered is unknown. We tested the hypothesis that this change in metaboreflex function is dependent on the level of CO. The muscle metaboreflex was activated in dogs during mild dynamic exercise (3.2 km/h) via a partial reduction of hindlimb blood flow. Muscle metaboreflex activation increased CO and arterial pressure, whereas vascular conductance of all areas other than the hindlimbs did not change. CO was then reduced to the same level observed during exercise before the muscle metaboreflex activation via partial occlusion of the inferior and superior vena cavae. Arterial pressure dropped rapidly with the reduction in CO but, subsequently, nearly completely recovered. With the removal of the muscle metaboreflex-induced rise in CO, substantial peripheral vasoconstriction occurred that maintained arterial pressure at the same levels as before CO reduction. Therefore, the muscle metaboreflex function is nearly instantaneously shifted from increased CO to increased vasoconstriction when the muscle metaboreflex-induced rise in CO is removed. We conclude that whether vasoconstriction occurs with muscle metaboreflex depends on whether CO rises. integrative cardiovascular regulation; exercise reflexes; peripheral vascular regulation

The purpose of the study was to determine the interactive effect of aging and forearm muscle heating on renal vascular conductance and muscle sympathetic nerve activity (MSNA) during ischemic isometric handgrip. A tubelined, water-perfused sleeve was used to heat the forearm in 12 young (27 [+ or -] 1 yr) and 9 older (63 [+ or -] 1 yr) subjects. Ischemic isometric handgrip was performed before and after heating. Muscle temperature (intramuscular thermistor) was 34.3 [+ or -] 0.2 and 38.7 [+ or -] 0.1[degrees]C during normothermia and heating, respectively. At rest, heating had no effect on renal blood velocity (Doppler ultrasound) or renal vascular conductance in either group (young, n = 12; older, n = 8). Heating compared with normothermia caused a significantly greater increase in renal vasoconstriction during exercise and postexercise muscle ischemia (PEMI) in both groups. However, the increase in renal vasoconstriction during heating was greater in the older compared with the young subjects (18 [+ or -] 3 vs. 8 [+ or -] 3%). During handgrip, heating elicited greater increases in MSNA responses in the older group (young, n = 12; older, n = 6), whereas no statistical difference was observed between groups during PEMI. In summary, aging augments renal vascular responses to ischemic isometric handgrip during heating of the exercising muscle. The greater renal vasoconstriction was associated with augmented MSNA in the older subjects. kidney; sympathetic; hyperthermia

Hypoxia-induced mitogenic factor (HIMF), also known as 'found in inflammatory zone 1' (FIZZI) or resistin-like molecule-[alpha] (RELM[alpha]), is a profound vasoconstrictor of the pulmonary circulation and a strong mitogenic factor in pulmonary vascular smooth muscle. To further understand the mechanism of these contractile and mitogenic responses, we examined the effect of HIMF on intracellular [Ca.sup.2+] in human pulmonary artery smooth muscle cells (SMC). [Ca.sup.2+] imaging in fluo 4-loaded human pulmonary artery SMC revealed that recombinant murine HIMF increased intracellular [Ca.sup.2+] concentration ([[Ca.sup.2+].sub.i]) in a sustained and oscillatory manner. This increase occurred independent of extracellular [Ca.sup.2+] influx. Pretreatment of human pulmonary artery SMC with U-73122, a specific inhibitor of phosphatidylinositolphospholipase C (PLC) completely prevented the HIMF-induced [Ca.sup.2+] signal. The [[Ca.sup.2+]].sub.i] increase was also abolished by pretreatment with 2-aminoethoxydiphenyl borate (2-APB), an inositol 1,4,5-trisphosphate ([IP.sub.3]) receptor antagonist. Ryanodine pretreatment did not affect initiation of [[Ca.sup.2+]].sub.i] activation or internal release but reduced [[Ca.sup.2+]].sub.i] at the plateau phase. Pretreatment with the G[[alpha].sub.i]-specific inhibitor pertussis toxin and the G[[alpha].sub.s]-specific inhibitor NF449 did not block the [Ca.sup.2+] signal. Knockdown of G[[alpha].sub.q/11] expression did not prevent [Ca.sup.2+] release, but the pattern of [Ca.sup.2+] release changed from the sustained oscillatory transients with prolonged plateau to a series of short [[Ca.sup.2+].sub.i] transients that return to baseline. However, pretreatment with the tyrosine kinase inhibitor genistein completely inhibited the internal [Ca.sup.2+] release. These results demonstrate that HIMF can stimulate intracellular [Ca.sup.2+] release in human pulmonary artery SMC through the PLC signaling pathway in an [IP.sub.3]- and tyrosine phosphorylation-dependent manner and that G[[alpha].sub.q/11] protein-coupled receptor and ryanodine receptor contribute to the increase of [[Ca.sup.2+].sub.i]. resistin-like molecule-[alpha]; inositol 1,4,5-trisphosphate receptor; phospholipase C; tyrosine phosphorylation; pulmonary vascular smooth muscle

Extracorporeal circulation provides critical life support in the face of cardiopulmonary or renal failure, but it also introduces a host of unique morbidities characterized by edema formation, cardiac insufficiency, autonomic dysfunction, and altered vasomotor function. We tested the hypothesis that cyclohexanone (CHX), a solvent used in production of extracorporeal circuits and intravenous (IV) bags, leaches into the contained fluids and can replicate these clinical morbidities. Crystalloid fluid samples from circuits and IV bags were analyzed by gas chromatography-mass spectrometry to provide a range of clinical CHX exposure levels, revealing CHX contamination of sampled fluids (9.63-3,694 [micro]g/l). In vivo rat studies were conducted (n = 49) to investigate the effects of a bolus IV infusion of CHX vs. saline alone on cardiovascular function, baroreflex responsiveness, and edema formation. Cardiovascular function was evaluated by cardiac output, heart rate, stroke volume, vascular resistance, arterial pressure, and ventricular contractility. Baroreflex function was assessed by mean femoral arterial pressure responses to bilateral carotid occlusion. Edema formation was assessed by the ratio of wet to dry organ weights for lungs, liver, kidneys, and skin. CHX infusion led to systemic hypotension; pulmonary hypertension; depressed contractility, heart rate, stroke volume, and cardiac output; and elevated vascular resistance (P < 0.05). Mean arterial pressure responsiveness to carotid occlusion was dampened after CHX infusion (from +17.25 [+ or -] 1.8 to +5.61 [+ or -] 3.2 mmHg; P < 0.05). CHX infusion led to significantly higher wet-to-dry weight ratios vs. saline only (3.8 [+ or -] 0.06 vs. 3.5 [+ or -] 0.05; P < 0.05). CHX can reproduce clinical cardiovascular, neurological, and edema morbidities associated with extracorporeal circulatory treatment. ventricular contractility; autonomic nervous system; vasoconstriction; edema

The fact that endothelium removal increases diameter and compliance in the common carotid artery (CCA) of spontaneously hypertensive rats (SHR) and that improving CCA endothelium-dependent vasorelaxation has been shown to normalize a reduced systolic blood flow through the SHR CCA compared with normotensive Wistar-Kyoto rats (WKY) suggests that endothelial vasomotor dysfunction may be linked to altered large artery hemodynamics in hypertension. The experiments herein were designed to further investigate WKY and SHR CCA hemodynamics and endothelium-dependent vasomotor functions. It was hypothesized that CCA blood flow and conductance would be reduced throughout the cardiac cycle in SHR and that endothelium-dependent contractile activity would impair SHR CCA vasorelaxation. We report that mean, maximal systolic, and diastolic blood flow was reduced in SHR vs. WKY CCA, as was vascular conductance. Pressure was augmented in SHR CCA and accompanied by late systolic flow augmentation so that total flow during systole was indeed no different between strains, possibly explained by earlier lower body wave reflection. While ACh stimulation in isolated precontracted WKY CCA caused a robust nitric oxide (NO)-mediated vasorelaxation, endothelium-dependent, cyclooxygenase (COX)-mediated contractile activity stimulated by high ACh concentration impaired NO- and non-NO/non-COX-mediated vasorelaxation in precontracted SHR CCA. In quiescent CCA, this endothelium-dependent contractile response was COX-1 and thromboxane-prostanoid receptor mediated and modulated by the availability of NO. These data collectively suggest that endothelium-dependent, COX-mediated endoperoxide signaling in the CCA of SHR may elicit vasoconstriction, which could shift the mechanical properties of this conduit artery and contribute to reduced CCA blood flow in vivo. acetylcholine; endothelium-dependent contraction; carotid pressure and flow augmentation; cyclooxygenase; thromboxane-prostanoid receptor

Slow local skin heating (LH) causes vasodilator responses, some of which are dependent on sympathetic nerve function. It is not known, however, how the rate of LH affects either the sympathetic or the nonadrenergic components of the responses to LH and whether the adrenergic effects of LH depend on tonic sympathetic activity or whether LH stimulates transmitter release. In part 1, cutaneous vascular conductance (CVC) responses to slow and fast LH (+0.1[degrees] and +2[degrees]C/min) from 34[degrees] to 40[degrees]C were compared both at control sites and at sites pretreated with bretylium tosylate (BT; blocks transmitter release from adrenergic terminals). We confirmed, as previously found, the axon reflex (AR) response to slow LH to be blocked by BT (P < 0.05). Pretreatment with BT reduced the AR only with fast LH. BT inhibited the peak vasodilation achieved with both rates of LH (P < 0.05). Longer-term LH was associated with a slow fall in CVC, the classical 'die away' phenomenon, at untreated sites (P < 0.05) but not at BT-pretreated sites. Thus the LH-stimulated AR is only partially dependent on intact sympathetic function, and the 'die away' phenomenon is dependent on such function. In part 2, we tested whether the conditions in part 1 (whole body and local skin temperatures of 34[degrees]C) completely suppressed sympathetic nerve activity. The infusion of BT by microdialysis did not change the CVC (P > 0.05), suggesting the absence of tonic activity in those conditions and therefore that the adrenergic components of the responses in part 1 are via the stimulation of the transmitter release by LH. bretylium; norepinephrine release; local control of blood flow; axon reflex; human

Vascular resistance and blood pressure (BP) are reduced during late normal pregnancy (Norm-Preg). In contrast, studies in human preeclampsia and in animal models of hypertension in pregnancy (HTN-Preg) have suggested that localized reduction in uterine perfusion pressure (RUPP) in late pregnancy is associated with increased systemic vascular resistance and BP: however, the vascular mechanisms involved are unclear. Because [Ca.sup.2+] is a major determinant of vascular contraction, we hypothesized that the intracellular free calcium concentration ([[[Ca.sup.2+]].sub.i]) signaling of vasoconstriction is differentially regulated in systemic microvessels during normal and RUPP in late pregnancy. Pressurized mesenteric microvessels from Norm-Preg and RUPP rats were loaded with fura 2 in preparation for simultaneous measurement of diameter and [[[Ca.sup.2+]].sub.i] (presented as fura 2 340/380 ratio). Basal [[[Ca.sup.2+]].sub.i] was lower in RUPP (0.73 [+ or -] 0.03) compared with Norm-Preg rats (0.82 [+ or -] 0.03). Membrane depolarization by 96 mM KCl, phenylephrine (Phe, [10.sup.-5] M), angiotensin II (ANG II, [10.sup.-7] M), or endothelin-1 (ET-1, [10.sup.-7] M) caused an initial peak followed by maintained vasoconstriction and [[[Ca.sup.2+]].sub.i]. KCl caused similar peak vasoconstriction and [[[Ca.sup.2+]].sub.i] in Norm-Preg (45.5 [+ or -] 3.3 and 0.89 [+ or -] 0.02%) and RUPP rats (46.3 [+ or -] 2.1 and 0.87 [+ or -] 0.01%). Maximum vasoconstriction to Phe, ANG II, and ET-1 was not significantly different between Norm-Preg (28.6 [+ or -] 4.8, 32.5 [+ or -] 6.3, and 40 [+ or -] 4.6%, respectively) and RUPP rats (27.8 [+ or -] 5.9, 34.4 [+ or -] 4.3, and 38.8 [+ or -] 4.1%, respectively). In contrast, the initial Phe-, ANG II-, and ET-1-induced 340/380 ratio ([[[Ca.sup.2+]].sub.i]) was reduced in RUPP (0.83 [+ or -] 0.02, 0.82 [+ or -] 0.02, and 0.83 [+ or -] 0.03. respectively) compared with Norm-Preg rats (0.95 [+ or -] 0.04, 0.93 [+ or -] 0.01, and 0.92 [+ or -] 0.02, respectively). Also, the [[[Ca.sup.2+]].sub.i]-vasoconstriction relationship was similar in KCl-treated but shifted to the left in Phe-, ANG II-, and ET-1-treated microvessels of RUPP compared with Norm-Preg rats. The lower agonist-induced [[[Ca.sup.2+]].sub.i] signal of vasoconstriction and the leftward shift in the [[[Ca.sup.2+]].sub.i]-vasoconstriction relationship in microvessels of RUPP compared with Norm-Preg rats suggest activation of [[[Ca.sup.2+]].sub.i] sensitization pathway(s). The similarity in vasoconstriction in RUPP and Norm-Preg rats suggests that such a [[[Ca.sup.2+]].sub.i] sensitization pathway(s) may also provide a feedback effect on [Ca.sup.2+] mobilization/homeostatic mechanisms to protect against excessive vasoconstriction in systemic microvessels during RUPP in late pregnancy. resistance vessels; vascular smooth muscle; intracellular free calcium concentration; preeclampsia

A reduction of heat loss to the environment through increased cutaneous vasoconstrictor (CVC) sympathetic outflow contributes to elevated body temperature during fever. We determined the role of neurons in the dorsomedial hypothalamus (DMH) in increases in CVC sympathetic tone evoked by [PGE.sub.2] into the preoptic area (POA) in chloralose/urethane-anesthetized rats. The frequency of axonal action potentials of CVC sympathetic ganglion cells recorded from the surface of the tail artery was increased by 1.8 Hz following nanoinjections of bicuculline (50 pmol) into the DMH. [PGE.sub.2] nanoinjection into the POA elicited a similar excitation of tail CVC neurons (+2.1 Hz). Subsequent to [PGE.sub.2] into the POA, muscimol (400 pmol/side) into the DMH did not alter the activity of tail CVC neurons. Inhibition of neurons in the rostral raphe pallidus (rRPa) eliminated the spontaneous discharge of tail CVC neurons but only reduced the [PGE.sub.2]-evoked activity. Residual activity was abolished by subsequent muscimol into the rostral ventrolateral medulla. Transections through the neuraxis caudal to the POA increased the activity of tail CVC neurons, which were sustained through transections caudal to DMH. We conclude that while activation of neurons in the DMH is sufficient to activate tail CVC neurons, it is not necessary for their [PGE.sub.2]-evoked activity. These results support a CVC component of increased core temperature elicited by [PGE.sub.2] in POA that arises from relief of a tonic inhibition from neurons in POA of CVC sympathetic premotor neurons in rRPa and is dependent on the excitation of CVC premotor neurons from a site caudal to DMH. rostral raphe pallidus; thermoregulation; fever; dorsomedial hypothalamus; preoptic hypothalamus

Our prior studies indicated that postural fainting relates to splanchnic hypervolemia and thoracic hypovolemia during orthostasis. We hypothesized that thoracic hypovolemia causes excessive sympathetic activation, increased respiratory tidal volume, and fainting involving the pulmonary stretch reflex. We studied 18 patients 13-21 yr old, 11 who fainted within 10 min of upright tilt (fainters) and 7 healthy control subjects. We measured continuous blood pressure and heart rate, respiration by inductance plethysmography, end-tidal carbon dioxide ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]) by capnography, and regional blood flows and blood volumes using impedance plethysmography, and we calculated arterial resistance with patients supine and during 70[degrees] upright tilt. Splanchnic resistance decreased until faint in fainters (44 [+ or -] 8 to 21 [+ or -] 2 mmHg*[l.sup.-1]*[min.sup.-1]) but increased in control subjects (47 [+ or -] 5 to 53 [+ or -] 4 mmHg*[l.sup.-1][min.sup.-1]). Percent change in splanchnic blood volume increased (7.5 [+ or -] 1.0 vs. 3.0 [+ or -] 11.5%, P < 0.05) after the onset of tilt. Upright tilt initially significantly increased thoracic, pelvic, and leg resistance in fainters, which subsequently decreased until faint. In fainters but not control subjects, normalized tidal volume (1 [+ or -] 0.1 to 2.6 [+ or -] 0.2, P < 0.05) and normalized minute ventilation increased throughout tilt (1 [+ or -] 0.2 to 2.1 [+ or -] 0.5, P < 0.05), whereas respiratory rate decreased (19 [+ or -] 1 to 15 [+ or -] 1 breaths/min, P < 0.05). Maximum tidal volume occurred just before fainting. The increase in minute ventilation was inversely proportionate to the decrease in [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]. Our data suggest that excessive splanchnic pooling and thoracic hypovolemia result in increased peripheral resistance and hyperpnea in simple postural faint. Hyperpnea and pulmonary stretch may contribute to the sympathoinhibition that occurs at the time of faint. splanchnic resistance; total peripheral resistance; minute ventilation; regional blood flow

(1) Occupational and Environmental Medicine Program, Department of Environmental and Occupational Health Sciences, (2) Department of Surgery (Vascular Surgery), (3) Department of Medicine, and (4) Department of Psychiatry and Behavioral [...]

Estrogen potentiates vascular reactivity to vasopressin (VP) by enhancing constrictor prostanoid function. To determine the cellular and molecular mechanisms, the effects of estrogen on arachidonic acid metabolism and on the expression of constrictor prostanoid pathway enzymes and endoperoxide/ thromboxane receptor (TP) were determined in the female rat aorta. The release of thromboxane [A.sub.2] (Tx[A.sub.2]) and prostacyclin (PG[I.sub.2]) was measured in male (M), intact-female (Int-F), ovariectomized-female (OvX-F), and OvX + 17[beta]-estradiol-replaced female (OvX + ER-F) rats. The expression of mRNA for cyclooxygenase (COX)- 1, COX-2, thromboxane synthase (TxS), and TP by aortic endothelium (Endo) and vascular smooth muscle (VSM) of these four experimental groups was measured by RT-PCR. The expression of COX-1, COX-2, and TxS proteins by Endo and VSM was also estimated by immunohistochemistry (IHC). Basal release of Tx[A.sub.2] and PG[I.sub.2] was similar in M (18.8 [+ or -] 1.9 and 1,723 [+ or -] 153 pg/mg ring wt/45 min, respectively) and Int-F (20.2 [+ or -] 4.2 and 1,488 [+ or -] 123 pg, respectively) rat aortas. VP stimulated the dose-dependent release of Tx[A.sub.2] and PG[I.sub.2] from both male and female rat aorta. OvX markedly attenuated and ER therapy restored VP-stimulated release of Tx[A.sub.2] and PG[I.sub.2] in female rats. No differences in COX-1 mRNA levels were detected in either Endo or VSM of the four experimental groups (P > 0.1). The expression of both COX-2 and TxS mRNA were significantly higher (P < 0.05) in both Endo and VSM of Int-F and OvX + ER-F, compared with M or OvX-F. Expression of TP mRNA was significantly higher in VSM of Int-F and OvX + ER-F compared with M or OvX-F. IHC revealed the uniform staining of COX-l in VSM of the four experimental groups, whereas staining of COX-2 and TxS was greater in Endo and VSM of Int-F and OvX + ER-F than in OvX-F or M rats. These data reveal that estrogen enhances constrictor prostanoid function in female rat aorta by upregulating the expression of COX-2 and TxS in both Endo and VSM and by upregulating the expression of TP in VSM. arginine vasopressin; endothelium; thromboxane synthase; thromboxane receptor; vascular smooth muscle; vasoconstriction

Approximately 40% of patients with type 2 diabetes present with concurrent hypertension at the time of diabetes diagnosis. Increases in peripheral vascular resistance and correspondingly enhanced vasoconstrictor capacity could have profound implications for the development of hypertension and the progression of insulin resistance to overt diabetes. The purpose of this study was to determine whether skel[ET.sub.A]l muscle arteriolar vasoconstrictor dysfunction precedes or occurs concurrently with the onset of diabetes and hypertension. Male Zucker diabetic fatty (ZDF) rats were studied at 7, 13, and 20 wk of age to represent prediabetic and short-term and long-term diabetic states, respectively. Conscious mean arterial pressure (MAP), fasted plasma insulin and glucose, vasoconstrictor responses, and passive mechanical properties of isolated skel[ET.sub.A]l muscle arterioles were measured in prediabetic, diabetic, and age-matched control rats. Elevated MAP was manifest in short-term diabetes (control 117 [+ or -] l, diabetic 135 [+ or -] 3 mmHg) and persisted with long-term diabetes (control 113 [+ or -] 2, diabetic 135 [+ or -] 3 mmHg). This higher MAP was preceded by augmented arteriolar vasoconstrictor responses to norepinephrine and endothelin-1 and followed by diminished [b[ET.sub.A]]-adrenergic vasodilation and enhanced myogenic constriction in long-term diabetes. Furthermore, we demonstrate that diminished nitric oxide (NO) signaling underlies the increases in vasoconstrictor responsiveness in arterioles from prediabetic and diabetic rats. Arteriolar stiffness was not different between control and prediabetic or diabetic rats at any time point studied. Collectively, these results indicate that increases in vasoconstrictor responsiveness resulting from diminished NO signaling in skel[ET.sub.A]l muscle arterioles precede the development of diabetes and hypertension in ZDF rats. type 2 diabetes; vasoconstriction; nitric oxide; norepinephrine; endothelin-1

Individuals with metabolic syndrome exhibit insulin resistance and an attenuated functional vasodilatory response to exercise. We have shown that impaired functional vasodilation in obese Zucker rats (OZRs) is associated with enhanced thromboxane receptor (TP)mediated vasoconstriction. We hypothesized that insulin resistance, hyperglycemia/hyperlipidemia, and the resultant ROS are responsible for the increased TP-mediated vasoconstriction in OZRs, resulting in impaired functional vasodilation. Eleven-week-old male lean Zucker rats (LZRs) and OZRs were fed normal rat chow or chow containing rosiglitazone (5 mg * [kg.sup.-1] * [day.sup.-1]) for 2 wk. In another set of experiment, LZRs and OZRs were treated with 2 mM tempol (drinking water) for 7-10 days. After the treatments, spinotrapezius muscles were prepared, and arcade arteriolar diameters were measured following muscle stimulation and arachidonic acid (AA) application (10 [micro]M) in the absence and presence of the TP antagonist SQ-29548 (1 [micro]M). OZRs exhibited higher insulin, glucose, triglyceride, and superoxide levels and increased NADPH oxidase activity compared with LZRs. Functional and AA-induced vasodilations were impaired in OZRs. Rosiglitazone treatment improved insulin, glucose, triglyceride, and superoxide levels as well as NADHP oxidase activity in OZRs. Both rosiglitazone and tempol treatment improved vasodilatory responses in OZRs with no effect in LZRs. SQ-29548 treatment improved vasodilatory responses in nontreated OZRs with no effect in LZRs or treated OZRs. These results suggest that insulin resistance and the resultant increased ROS impair functional dilation in OZRs by increasing TP-mediated vasoconstriction. arachidonic acid; prostacyclin; thromboxane; diabetes

An increase in fetoplacental vascular resistance caused by hypoxia is considered one of the key factors of placental hypoperfusion and fetal underuutrition leading to intrauterine growth restriction (IUGR), one of the serious problems in current neonatology. However, although acute hypoxia has been shown to cause fetoplacental vasoconstriction, the effects of more sustained hypoxic exposure are unknown. This study was designed to test the hypothesis that chronic hypoxia elicits elevations in fetoplacental resistance, that this effect is not completely reversible by acute reoxygenation, and that it is accompanied by increased acute vasoconstrictor reactivity of the fetoplacental vasculature. We measured fetoplacental vascular resistance as well as acute vasoconstrictor reactivity in isolated perfused placentae from rats exposed to hypoxia (10% [O.sub.2]) during the last week of a 3-wk pregnancy. We found that chronic hypoxia shifted the relationship between perfusion pressure and flow rate toward higher pressure values (by ~20%). This increased vascular resistance was refractory to a high dose of sodium nitroprusside, implying the involvement of other factors than increased vascular tone. Chronic hypoxia also increased vasoconstrictor responses to angiotensin II (by ~75%) and to acute hypoxic challenges (by >150%). We conclude that chronic prenatal hypoxia causes a sustained elevation of fetoplacental vascular resistance and vasoconstrictor reactivity that are likely to produce placental hypoperfusion and fetal undernutrition in vivo. perfused placenta; pressure-flow relationship; hypoxic fetoplacental vasoconstriction

Toll-like receptors (TLRs) mediate inflammation in sepsis, but their role in sepsisinduced respiratory failure is unknown. Hypoxic pulmonary vasoconstriction (HPV) is a unique vasoconstrictor response that diverts blood flow away from poorly ventilated lung regions. HPV is impaired in sepsis and after challenge with the TLR4 agonist lipopolysaccharide (LPS). Unlike TLR4 agonists, which are present only in Gramnegative bacteria, TLR2 agonists are ubiquitously expressed in all of the major classes of microorganisms that cause sepsis, including both Gram-positive and Gram-negative bacteria and fungi. We tested the hypothesis that (S)-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-N-palmitoyl- (R)-Cys-(S)-Ser(S)-[Lys.sub.4]-OH, trihydrochloride (Pam3Cys), a TLR2 agonist, impairs HPV and compared selected pulmonary and systemic effects of Pam3Cys vs. LPS. HPV was assessed 22 h after challenge with saline, Pam3Cys, or LPS by measuring the increase in the pulmonary vascular resistance of the left lung before and during left lung alveolar hypoxia produced by left mainstem bronchus occlusion (LMBO). Additional endpoints included arterial blood gases during LMBO, hemodynamic parameters, weight loss, temperature, physical appearance, and several markers of lung inflammation. Compared with saline, challenge with Pam3Cys caused profound impairment of HPV, reduced systemic arterial oxygenation during LMBO, weight loss, leukopenia, and lung inflammation. In addition to these effects, LPS-challenged mice had lower rectal temperatures, metabolic acidosis, and were more ill appearing than Pam3Cyschallenged mice. These data indicate that TLR2 activation impairs HPV and induces deleterious systemic effects in mice and suggest that TLR2 pathways may be important in sepsis-induced respiratory failure. hypoxic pulmonary vasoconstriction impairment; lung inflammation; sepsis

Redistribution of blood from the viscera to the peripheral vasculature is the major cardiovascular response designed to restore thermoregulatory homeostasis after an elevation in body core temperature. In this study, we investigated the role of the hypothalamic paraventricular nucleus (PVN) in the reflex decrease in renal blood flow that is induced by hyperthermia, as this brain region is known to play a key role in renal function and may contribute to the central pathways underlying thermoregulatory responses. In anesthetized rats, blood pressure, heart rate, renal blood flow, and tail skin temperature were recorded in response to elevating body core temperature. In the control group, saline was microinjected bilaterally into the PVN; in the second group, muscimol (1 nmol in 100 nl per side) was microinjected to inhibit neuronal activity in the PVN; and in a third group, muscimol was microinjected outside the PVN. Compared with control, microinjection of muscimol into the PVN did not significantly affect the blood pressure or heart rate responses. However, the normal reflex reduction in renal blood flow observed in response to hyperthermia in the control group (~70% from a resting level of 11.5 ml/min) was abolished by the microinjection of muscimol into the PVN (maximum reduction of 8% from a resting of 9.1 ml/min). This effect was specific to the PVN since microinjection of muscimol outside the PVN did not prevent the normal renal blood flow response. The data suggest that the PVN plays an essential role in the reflex decrease in renal blood flow elicited by hyperthermia. hyperthermia

Neuropeptide Y (NPY) is coreleased with norepinephrine and stimulates vasoconstriction, vascular and cardiomyocyte hypertrophy via Y1 receptors (R) and angiogenesis via Y2R. Although circulating NPY is elevated in heart failure, NPY's role remains unclear. Activation of the NPY system was determined in Wistar rats with the aortocaval (A-V) fistula model of high-output heart failure. Plasma NPY levels were elevated in A-V fistula animals (115.7 [+ or -] 15.3 vs. 63.1 [+ or -] 17.4 pM in sham, P < 0.04). Animals either compensated [urinary [Na.sup.+] excretion returning to normal with moderate disease (COMP)] or remained decompensated with severe cardiac and renal failure (urinary [Na.sup.+] excretion Y1 receptor; Y2 receptor; renal blood flow; cardiac hypertrophy

An important role for the enzyme ADP-ribosyl cyclase (ADPR cyclase) and its downstream targets, the ryanodine receptors (RyR), is emerging for a variety of vascular systems. We hypothesized that the ADPR cyclase/RyR pathway contributes to regulation of renal vasomotor tone in vivo. To test this, we continuously measured renal blood flow (RBF) in anesthetized Sprague-Dawley rats. Infusion of the ADPR cyclase inhibitor nicotinamide intrarenally at low doses inhibits angiotensin II (ANG II)- and norepinephrine (NE)-induced vasoconstriction by 72 and 67%, respectively (P < 0.001). RBF studies in rats were extended to mice lacking the predominant form of ADPR cyclase (CD38). Acute renal vasoconstrictor responses to ANG II and NE are impaired by 59 and 52%, respectively, in anesthetized CD38-/- mice compared with wild-type controls (P < 0.05). Intrarenal injection of the RyR activator FK506 decreases RBF by 22% (P > 0.03). Furthermore, RyR inhibition with ruthenium red attenuates ANG II and NE responses by 50 and 59%, respectively (P [less than or equal to] 0.01). Given at higher doses, nicotinamide increases basal RBF by 22% (P > 0.001). Non-receptor-mediated renal vasoconstriction by L-type voltage-gated [Ca.sup.2+] channels is also dependent on ADPR cyclase and RyRs. Nicotinamide and ruthenium red inhibit constriction by the L-type channel agonist BAY K 8644 by 59% (P > 0.02) and 63% (P > 0.001). We conclude that 1) ADPR cyclase activity contributes to regulation of renal vasomotor tone under resting conditions, 2) renal vasoconstriction induced by G protein-coupled receptor agonists ANG II and NE is mediated in part by ADPR cyclase and RyRs, and 3) ADPR cyclase and RyRs participate in L-type channel-mediated renal vasoconstriction in vivo. vascular smooth muscle; intracellular calcium; L-type calcium channels; FK506; CD38

It is now generally accepted that [alpha]-adrenoreceptor-mediated vasoconstriction is attenuated during exercise, but the efficacy of nonadrenergic vasoconstrictor pathways during exercise remains unclear. Thus, in eight young (23 [+ or -] 1 yr), healthy volunteers, we contrasted changes in leg blood flow (ultrasound Doppler) before and during intra-arterial infusion of the [[alpha].sub.1]-adrenoreceptor agonist phenylephrine (PE) with that of the nonadrenergic endothelin A ([ET.sub.A])/[ET.sub.B] receptor agonist ET-1. Heart rate, arterial blood pressure, common femoral artery diameter, and mean blood velocity were measured at rest and during knee-extensor exercise at 20%, 40%, and 60% of maximal work rate ([WR.sub.max]). Drug infusion rates were adjusted for blood flow to maintain comparable doses across all subjects and conditions. At rest, PE infusion (8 ng x [ml.sup.-l] x [min.sup.-1]) provoked a rapid and significant decrease in leg blood flow (-51 [+ or -] 3%) within 2.5 min. Resting ET-1 infusion (40 pg x [ml.sup.-1] x [min.sup.-1]) significantly decreased leg blood flow within 5 min, reaching a maximal vasoconstriction (-34 [+ or -] 3%) after 25-30 min of continuous infusion. Compared with rest, an exercise intensity-dependent attenuation to PE-mediated vasoconstriction was observed (-18 [+ or -] 5%, -7 [+ or -] 2%, and -1 [+ or -] 3% change in leg blood flow at 20%, 40%, and 60% of [WR.sub.max], respectively). Vasoconstriction in response to ET-1 was also blunted in an exercise intensity-dependent manner (-13 [+ or -] 3%, -7 [+ or -] 4%, and 2 [+ or -] 3% change in leg blood flow at 20%, 40%, and 60% of [WR.sub.max], respectively). These findings support a significant contribution of ET-1 and [alpha]-adrenergic receptors in the regulation of skeletal muscle blood flow in the human leg at rest and suggest a similar, intensity-dependent 'lysis' of peripheral ET and [alpha]-adrenergic vasoconstriction during dynamic exercise. endothelial; [alpha]-adrenoreceptor; exercise hyperemia; ultrasound Doppler

Previous investigations have demonstrated a subset of postural tachycardia syndrome (POTS) patients characterized by normal peripheral resistance and blood volume while supine but thoracic hypovolemia and splanchnic blood pooling while upright secondary to splanchnic hyperemia. Such 'normal-flow' POTS patients often demonstrate hypocapnia during orthostatic stress. We studied 20 POTS patients (14-23 yr of age) and compared them with 10 comparably aged healthy volunteers. We measured changes in heart rate, blood pressure, heart rate and blood pressure variability, arm and leg strain-gauge occlusion plethysmography, respiratory impedance plethysmography calibrated against pneumotachography, end-tidal partial pressure of carbon dioxide ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII.]), and impedance plethysmographic indexes of blood volume and blood flow within the thoracic, splanchnic, pelvic (upper leg), and lower leg regional circulations while supine and during upright tilt to 70[degrees]. Ten POTS patients demonstrated significant hyperventilation and hypocapnia (POT[S.sub.HC]) while 10 were normocapnic with minimal increase in postural ventilation, comparable to control. While relative splanchnic hypervolemia and hyperemia occurred in both POTS groups compared with controls, marked enhancement in peripheral vasoconstriction occurred only in POT[S.sub.HC] and was related to thoracic blood flow. Variability indexes suggested enhanced sympathetic activation in POT[S.sub.HC] compared with other subjects. The data suggest enhanced cardiac and peripheral sympathetic excitation in POT[S.sub.HC]. vasoconstriction; hypocapnia; orthostatic intolerance doi:10.1152/ajpheart.01359.2005

It has been proposed that [alpha]-adrenoceptor vasoconstriction in coronary resistance vessels results not from [alpha]-adrenoceptors on coronary smooth muscle but from [alpha]- adrenoceptors on cardiac myocytes that stimulate endothelin (ET) release. The present experiments tested the hypothesis that the [alpha]-adrenoceptor- mediated coronary vasoconstriction that normally occurs during exercise is due to endothelin. In conscious dogs (n = 10), the endothelin [ET.sub.A]/[ET.sub.B] receptor antagonist tezosentan (1 mg/kg iv) increased coronary venous oxygen tension at rest but not during treadmill exercise. This result indicates that basal endothelin levels produce a coronary vasoconstriction at rest that is not observed during the coronary vasodilation during exercise. In contrast, the [alpha]-adrenoceptor antagonist phentolamine increased coronary venous oxygen tension during exercise but not at rest. The difference between the endothelin blockade and [alpha]-adrenoceptor blockade results indicates that [alpha]-adrenoceptor coronary vasoconstriction during exercise is not due to endothelin. However, in anesthetized dogs, bolus intracoronary injections of the [alpha]-adrenoceptor agonist phenylephrine produced reductions in coronary blood flow that were partially antagonized by endothelin receptor blockade with tezosentan. These results are best explained if [alpha]-adrenoceptor-induced endothelin release requires high pharmacological concentrations of catecholamines that are not reached during exercise. coronary blood flow; exercise; tezosentan; dogs; norepinephrine

Elevations in arterial pressure associated with hypertension, micro-gravity, and prolonged bed rest alter cerebrovascular autoregulation in humans. Using head-down tail suspension (HDT) in rats to induce cephalic fluid shifts and elevate arterial pressure, this study tested the hypothesis that 2-wk HDT enhances cerebral artery vasoconstriction and that an enhanced vasoconstriction described in vitro will alter regional cerebral blood flow (CBF) and vascular resistance (CVR) during standing and head-up tilt. To test this hypothesis, basal tone and vasoconstrictor responses to increases in transmural pressure, shear stress, and [K.sup.+] were determined in vitro in middle cerebral arteries (MCAs) from HDT and control rats. All in vitro measurements were done in the presence and absence of the nitric oxide synthase (NOS) inhibitor [N.sup.G]-nitro-L-arginine methyl ester (L-NAME; [10.sup.-5] M) and with endothelium removal. Endothelial NOS (eNOS) mRNA and protein expression levels were measured by RT-PCR and immunoblot, respectively. Regional CBF and CVR were determined with a radiolabeled tracer technique and quantitative autoradiography. Basal tone and all vasoconstrictor responses were greater in MCAs from HDT rats. L-NAME and endothelium removal abolished these differences between groups, and HDT was associated with lower levels of MCA eNOS protein. CBF in select regions was lower and CVR higher during standing and head-up tilt in HDT rats. These results indicate that chronic cephalic fluid shifts enhanced basal tone and vasoconstriction through alterations in the eNOS signaling mechanism. The functional consequence of these vascular alterations with HDT is regional elevations in CVR and corresponding reductions in cerebral perfusion. orthostatic intolerance; cerebral blood flow; hindlimb unloading; middle cerebral artery; vascular remodeling; nitric oxide synthase

Byline: L. G. Fischer (1), H. Freise (1), J.-H. Hilpert (1), D. Wendholt (1), S. Lauer (1), H. Van Aken (1), A. W. Sielenkamper (1) Keywords: Sepsis; Hypoxic pulmonary vasoconstriction; Nitric oxide synthase Abstract: Objective This study assessed modulation of hypoxic pulmonary vasoconstriction (HPV) in isolated perfused rat lungs during sepsis induced by cecal ligation and perforation (CLP) at different times and its relationship to nitric oxide synthases (NOS). Design and setting Prospective controlled trial in a university research laboratory. Subjects 102 male Sprague-Dawley rats. Interventions Groups 1--3 received sham laparotomy 6 h before lung isolation: group 1, only laparotomy group 2, concurrently l-N .sup.6-(1-iminoethyl)-lysine (L-NIL, 3 mg/kg) group 3, concurrently N .sup.[OMEGA]-nitro-l-arginine methylester (L-NAME, 5 mg/kg). Groups 4--6 received CLP 6 h before lung isolation: group 4, only CLP group 5, concurrently L-NIL group 6, concurrently L-NAME. The same experiments were carried out with sham and CLP treatment for 24 h (groups 7--12). Exhaled NO from rats' lungs was measured after anesthesia and tracheostomy. After the pulmonary circuit was isolated and perfused, angiotensin II (0.1 Aug) was injected into the inflow tract. The lungs were ventilated with the hypoxic mixture (HPV, 3% O.sub.2) for 10 min and then again with the normoxic mixture (21% O.sub.2) for an equal period. Changes in perfusion pressure were measured. Endothelial (eNOS) and inducible NOS (iNOS) expression of the lungs was determined. Measurements and results Treatment with L-NAME but not L-NIL increased HPV in sham lungs. HPV was unaltered after CLP 6 h and decreased after CLP 24 h compared to sham. In CLP animals eNOS protein expression was reduced whereas iNOS expression was increased compared to sham animals. Exhaled NO, reflecting NOS activity was twice as high in the CLP 24 h group than in the CLP 6 h group. Conclusions In the CLP sepsis model modulation of HPV was time-dependent. In addition, vasoconstriction to hypoxic stimuli was dependent on NOS activity. Author Affiliation: (1) Department of Anesthesiology and Intensive Care, University of Munster, 48149, Munster, Germany Article History: Registration Date: 25/05/2004 Received Date: 05/08/2003 Accepted Date: 19/05/2004 Online Date: 15/06/2004 Article note: L.G. F. is supported by Innovative Medizinische Forschung Munster, Germany (Fi-1-2000-4)

Previous studies have provided evidence of a non-noradrenergic contributor to reflex cutaneous vasoconstriction in humans but did not identify the transmitter responsible. To test whether neuropeptide Y (NPY) has a role, in two series of experiments we slowly reduced whole body skin temperature ([T.sub.SK]) from 34.5 to 31.7[degrees]C. In protocol 1, Ringer solution and the NPY receptor antagonist BIBP-3226 alone were delivered intradermally via microdialysis. In protocol 2, yohimbine plus propranolol (Yoh + Pro), Yoh + Pro in combination with BIBP-3226, and Ringer solution were delivered to antagonize locally the vasomotor effects of NPY and norepinephrine. Blood flow was measured by laser Doppler flowmetry (LDF). Mean arterial blood pressure (MAP) was monitored at the finger (Finapres). In protocol 1, cutaneous vascular conductance (CVC) fell by 45%, to 55.1 [+ or -] 5.6% of baseline at control sites (P < 0.05). At BIBP-3226-treated sites, CVC fell by 34.1% to 65.9 [+ or -] 5.0% (P < 0.05; P < 0.05 between sites). In protocol 2, during body cooling, CVC at control sites fell by 32.6%, to 67.4 [+ or -] 4.3% of baseline; at sites treated with Yoh + Pro, CVC fell by 18.7%, to 81.3 [+ or -] 4.4% of baseline (P < 0.05 vs. baseline; P < 0.05 vs. control) and did not fall significantly at sites treated with BIBP-3226 + Yoh + Pro (P > 0.05; P < 0.05 vs. other sites). After cooling, exogenous norepinephrine induced vasoconstriction at control sites (P < 0.05) but not at sites treated with Yoh + Pro + BIBP-3226 (P > 0.05). These results indicate that NPY participates in sympathetically mediated cutaneous vasoconstriction in humans during whole body cooling. sympathetic nervous system; cotransmitters; cold stress; skin blood flow

Variants of postural tachycardia syndrome (POTS) are associated with increased ['high-flow' POTS (HFP)], decreased ['low-flow' POTS (LFP)], and normal ['normal-flow' POTS (NFP)] blood flow measured in the lower extremities while subjects were in the supine position. We propose that postural tachycardia is related to thoracic hypovolemia during orthostasis but that the patterns of peripheral blood flow relate to different mechanisms for thoracic hypovolemia. We studied 37 POTS patients aged 14-21 yr: 14 LFP, 15 NFP, and 8 HFP patients and 12 healthy control subjects. Peripheral blood flow was measured in the supine position by venous occlusion strain-gauge plethysmography of the forearm and calf to subgroup patients, Using indocyanine green techniques, we showed decreased cardiac index (CI) and increased total peripheral resistance (TPR) in LFP, increased CI and decreased TPR in HFP, and unchanged CI and TPR in NFP while subjects were supine compared with control subjects. Blood volume tended to be decreased in LFP compared with control subjects. We used impedance plethysmography to assess regional blood volume redistribution during upright tilt. Thoracic blood volume decreased, whereas splanchnic, pelvic, and leg blood volumes increased, for all subjects during orthostasis but were markedly lower than control for all POTS groups. Splanchnic volume was increased in NFP and LFP. Pelvic blood volume was increased in HFP only. Calf volume was increased above control in HFP and LFP. The results support the hypothesis of (at least) three pathophysiologic variants of POTS distinguished by peripheral blood flow related to characteristic changes in regional circulations. The data demonstrate enhanced thoracic hypovolemia during upright tilt and confirm that POTS is related to inadequate cardiac venous return during orthostasis. vasoconstriction; regional blood flow

Cytochrome P-450-4A1 (CYP4A1) is an [omega]-hydroxylase that catalyzes the metabolism of arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE). The goal of this study was to determine the vasomotor consequences of vascular overexpression of CYP4AI. Isolated rat gracilis muscle arterioles transfected ex vivo with an expression plasmid containing CYP4A1 cDNA expressed more CYP4A protein than vessels transfected with the control plasmid. In arterioles pressurized to 80 mmHg, the internal diameter of vessels transfected with CYP4A1 cDNA (55 [+ or -] 3 [micro]m) was surpassed (P < 0.05) by that of vessels transfected with control plasmid (97 [+ or -] 4 [micro]m). Treatment with a CYP4A inhibitor (N-methylsulfonyl-12, 12-dibromododec-11-enamide; DDMS) or with an antagonist of 20-HETE actions [20-hydroxyeicosa-6(Z), 15(Z)-dienoic acid; 20-HEDE] elicited robust dilation of arterioles transfected with CYP4A1 cDNA, whereas the treatment had little or no effect in vessels transfected with control plasmid. Examination of the intraluminal pressure-internal diameter relationship revealed that pressure increments over the range of 40-100 mmHg elicited a more intense (P < 0.05) myogenic constrictor response in arterioles transfected with CYP4A1 cDNA than in those with control plasmid. Arterioles transfected with CYP4A1 cDNA also displayed enhanced sensitivity to the constrictor action of phenylephrine. Treatment with DDMS or 20-HEDE greatly attenuated the constrictor responsiveness to both constrictor stimuli in vessels overexpressing CYP4A1, whereas the treatment had much less effect in control vessels. These data suggest that CYP4A1 overexpression promotes constriction of gracilis muscle arterioles by intensifying the responsiveness of vascular smooth muscle to constrictor stimuli. This effect of CYP4A1 overexpression appears to be mediated by a CYP4A1 product. myogenic vasoconstriction; 20-hydroxyeicosatetraenoic acid; cytochrome P-450 oxygenases; vascular reactivity

During exercise, the sympathetic nervous system is activated, which causes vasoconstriction. The autonomic mechanisms responsible for this vasoconstriction vary based on the particular tissue being studied. Attempts to examine reflex control of the human renal circulation have been difficult because of technical limitations. In this report, the Doppler technique was used to examine renal flow velocity during four muscle contraction paradigms in conscious humans. Flow velocity was divided by mean arterial blood pressure to yield an index of renal vascular resistance (RVR). Fatiguing static handgrip (40% of maximal voluntary contraction) increased RVR by 76%. During posthandgrip circulatory arrest, RVR remained above baseline (2.1 [+ or -] 0.2 vs. 2.8 [+ or -] 0.2 arbitrary units; P < 0.017) but was only 40% of the end-grip RVR value. Voluntary biceps contraction increased RVR within 10 s of initiation of contraction. This effect was not associated with an increase in blood pressure. Finally, involuntary biceps contraction also raised RVR. We conclude that muscle contraction evokes renal vasoconstriction in conscious humans. The characteristic of this response is consistent with a primary role for mechanically sensitive afferents. This statement is based on the small posthandgrip circulatory arrest response and the vasoconstriction that was observed with involuntary biceps contraction. physiology; vasoconstriction; central command; sympathetic nervous system

The purpose of this study was to test the hypothesis that pathways modulating vasoconstriction in rat mesenteric resistance arteries are gender dependent. Net contractile responses to phenylephrine were significantly increased by endothelium disruption in arteries from males but not females. This gender-dependent effect was stimulus specific, because disruption of endothelium increased reactivity to serotonin comparably in arteries from both genders. Ovariectomy unmasked an increase in net [[alpha].sub.1]-adrenergic contractile responsiveness after endothelium disruption, suggesting [[alpha].sub.1]-adrenergic-stimulated production of endothelial vasodilators is suppressed in control females by gonadal sex steroids. Production of modulatory endothelium-derived vasodilators in males is balanced by production of vasoconstricting arachidonic acid metabolites. This was revealed by decreased [[alpha].sub.1]-adrenergic contractile responses in arteries from males after pretreatment with indomethacin or the cyclooxygenase-1 selective inhibitor SC-560. The indomethacin-induced effect persisted after endothelium disruption, indicating smooth muscle as the source of cyclooxygenase-l-derived vasoconstrictors and was attenuated after orchiectomy. This study indicates gender differences in the expression of two pathways modulating [[alpha].sub.1]-adrenergic sensitivity in mesenteric arteries: an endothelium-dependent vasodilator pathway and a balancing smooth muscle cyclooxygenase-l-dependent vasoconstrictor pathway. One consequence of these differences is that endothelial damage produces a selective increase in [[alpha].sub.1]-adrenergic agonist reactivity in arteries from males. vasoconstriction; endothelium; cyclooxygenase; adrenergic receptor agonists; serotonin; gonadectomy

We tested whether the respective angiotensin type 1 (A[T.sub.1]) and 2 (A[T.sub.2]) receptor subtype antagonists losartan and PD-123319 could block the descending vasa recta (DVR) endothelial intracellular calcium concentration ([[Ca.sup.2+]]].sub.i]) suppression induced by ANG II. ANG II partially reversed the increase in [[Ca.sup.2+]].sub.i] generated by cyclopiazonic acid (CPA; [10.sup.-5] M), acetylcholine (ACh; [10.sup.-5] M), dr bradykinin (BK; [10.sup.-7] M). Losartan ([10.sup.-5] M) blocked that effect. When vessels were treated with ANG II before stimulation with BK and ACh, concomitant AT2 receptor blockade with PD-123319 ([10.sup.-8] M) augmented the suppression of endothelial [[Ca.sup.2+]].sub.i] responses. Similarly, pre-activation with the A[T.sub.2] receptor agonist CGP-42112A ([10.sup.-8] M) prevented A[T.sub.1] receptor stimulation with ANG II + PD123319 from suppressing endothelial [[Ca.sup.2+]].sub.i]. In contrast to endothelial [[Ca.sup.2+]].sub.i] suppression by ANG II, pericyte [[[Ca.sup.2+]].sub.i] exhibited typical peak and plateau [[[Ca.sup.2+]].sub.i] responses that were blocked by losartan but not PD-123319. DVR vasoconstriction by ANG II was augmented when A[T.sub.2] receptors were blocked with PD-123319. Similarly, A[T.sub.2] receptor stimulation with CGP-42112A delayed the onset of ANG II-induced constriction. PD-123319 alone ([10.sup.-5] M) showed no A[T.sub.1]-like action to constrict microperfused DVR or increase pericyte [[[Ca.sup.2+]].sub.i]. We conclude that ANG II suppression of endothelial [[[Ca.sup.2+]].sub.i] and stimulation of pericyte [[[Ca.sup.2+]].sub.i] is mediated by A[T.sub.1] or A[T.sub.1]-like receptors. Furthermore, A[T.sub.2] receptor activation opposes ANG II-induced endothelial [[[Ca.sup.2+]].sub.i] suppression and abrogates ANG II-induced DVR vasoconstriction. kidney; vasoconstriction; vasodilation; medulla; blood flow

Although the mechanisms of cirrhosis-induced portal hypertension have been studied extensively, the role of thromboxane [A.sub.2] (TX[A.sub.2]) in the development of portal hypertension has never been explicitly explored. In the present study, we sought to determine the role of TX[A.sub.2] in bile duct ligation (BDL)-induced portal hypertension in Sprague-Dawley rats. After 1 wk of BDL or sham operation, the liver was isolated and perfused with Krebs-Henseleit bicarbonate buffer at a constant flow rate. After 30 min of nonrecirculating perfusion, the buffer was recirculated in a total volume of 100 ml. The perfusate was sampled for the enzyme immunoassay of thromboxane [B.sub.2] (TX[B.sub.2]), the stable metabolite of TX[A.sub.2]. Although recirculation of the buffer caused no significant change in sham-operated rats, it resulted in a marked increase in portal pressure in BDL rats. The increase in portal pressure was found concomitantly with a significant increase of TX[B.sub.2] in the perfusate (sham vs. BDL after 30 min of recirculating perfusion: 1,420 [+ or -] 803 vs. 10,210 [+ or -] 2,950 pg/ml; P < 0.05). Perfusion with a buffer containing indomethacin or gadolinium chloride for inhibition of cyclooxygenase (COX) or Kupffer cells, respectively, substantially blocked the recirculation-induced increases in both portal pressure and TX[B.sub.2] release in BDL group. Hepatic detection of COX gene expression by RT-PCR revealed that COX-2 but not COX-1 was upregulated following BDL, and this upregulation was confirmed at the protein level by Western blot analysis. In conclusion, these results clearly demonstrate that increased hepatic TX[A.sub.2] release into the portal circulation contributes to the increased portal resistance in BDL-induced liver injury, suggesting a role of TX[A.sub.2] in liver fibrosis-induced portal hypertension. Furthermore, the Kupffer cell is likely the source of increased TX[A.sub.2], which is associated with upregulation of the COX-2 enzyme. hepatic fibrosis; vasoconstriction; isolated liver perfusion; cyclooxygenase; portal pressure

Byline: Antonia Tabernero (1), Francis Schneider (2), Maria Assunta Potenza (3), Voahanginirina Fidi-soa Randriamboavonjy (1), Sylvette Chasserot (4), Philippe Wolf (5), Delia Mitolo-Chieppa (3), Jean-Claude Stoclet (1), Ramaroson Andriantsitohaina (1) Keywords: Artery, resistance Cyclooxygenase Human Liver failure, acute Liver, diseases Nitric oxide Vasoconstriction Abstract: Objective. To investigate the expression of inducible cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) and the role of vasodilatory prostanoids and endogenous nitric oxide (NO) in small omental arteries harvested from patients with severe liver diseases. Design. Ex vivo study of resistance arteries. Setting. Intensive care unit. Patients. Twenty patients undergoing liver transplantation for fulminant hepatic failure (FHF, n=6), cirrhogenous viral hepatitis (CH, n=6) and limited hepatocarcinoma (controls, n=8). Interventions. Western blot and immunohistochemical labeling for assessment of COX-2 and iNOS expression and localization and ex vivo vascular reactivity studies. Measurements and results. Significant upregulation of COX-2 and iNOS expressions were detected in arteries from FHF and CH patients with a greater increase in the former than in the latter. Ex vivo contractile responses to norepinephrine and the thromboxane A.sub.2 analog, U46619, were not significantly different between patients with severe liver dysfunction and controls. Exposure to either the NO-synthase inhibitor, N.sup.G-nitro-L-arginine methyl ester (L-NAME), the cyclooxygenase inhibitor, indomethacin, or their combination did not significantly modify contractions of agonists in controls and CH patients. In FHF, the specific COX-2 inhibitor, N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (1 Aum/l), but not L-NAME, significantly enhanced the maximal effect (p Conclusions. COX-2 and iNOS are upregulated in omental arteries from patients with cirrhogenous hepatitis and fulminant hepatic failure. Whereas neither NO nor vasodilatory prostaglandins seem to play a major role in counteracting arterial contractility of arteries from control patients, COX-2 derivatives are involved in lowering the arterial contractility of vessels harvested from FHF patients. Author Affiliation: (1) Laboratoire de Pharmacologie et Physicochimie des Interactions Cellulaires et Moleculaires, CNRS (UMR 7034), Illkirch, France (2) Service de Reanimation Medicale, Centre Hospitalier Universitaire de Hautepierre, Avenue Moliere, 67098, Strasbourg, France (3) Institute of Pharmacology, Medical School, University of Bari, Bari, Italy (4) , CNRS UPR 2356, Strasbourg, France (5) Service de Transplantation, Centre Hospitalier Universitaire de Hautepierre, Strasbourg, France Article History: Received Date: 04/06/2002 Accepted Date: 21/11/2002 Article note: Electronic Publication

Because the precise immunopathological events occurring in appendicitis are not completely understood, possible local production of endothelin-1 (ET-1) in human appendix was investigated. We used immunohistochemistry and in situ hybridization to detect the presence, distribution, and phenotype of ET-1-positive cells and prepro-ET-1 (pp-ET-1)mRNA-expressing cells. ET-1-positive stromal cells and pp-ET-1 mRNA-expressing cells were detected with different distributions and relative frequencies in normal control appendix, histologically normal appendix, and inflamed appendix. Six of 20 histologically normal appendixes from patients with a clinical diagnosis of acute appendicitis had many ET-1-positive stromal cells and high pp-ET-1 mRNA expression, similar to inflamed appendix. Forty percent of the pp-ET-1 mRNA-expressing cells were neutrophils, and the other positive cells were mast cells and macrophages. We suggest that local production of ET-1 by neutrophils and other inflammatory cells could be a molecular sign of focal inflammation in histologically normal appendixes and that ET-1 could be implicated, with other cytokines, in the pathogenesis of appendicitis by inducing appendiceal ischemia through vasoconstriction. appendicitis; in situ hybridization; immunohistochemistry; neutrophils; mast cells

The voltage-dependent and [Ca.sup.2+]-activated [K.sup.+] channel (MaxiK, BK) and the cellular proto-oncogene [pp60.sup.c-Src] (c-Src) are abundant proteins in vascular smooth muscle. The role of MaxiK channels as a vasorelaxing force is well established, but their role in vasoconstriction is unclear. Because Src participates in regulating vasoconstriction, we investigated whether c-Src inhibits MaxiK as a mechanism for agonist-induced vasoconstriction. Functional experiments in human and rat show that inhibitors of Src (Lavendustin A, PP2) but not inactive compounds (Lavendustin B, PP3) induce a pronounced relaxation of coronary or aortic smooth muscle precontracted with 5-hydroxytriptamine, phenylephrine, or Angiotensin II. Iberiotoxin, a MaxiK blocker, antagonizes the relaxation induced by Lavendustin A or PP2, indicating that c-Src inhibits the Iberiotoxin-sensitive component, likely MaxiK channels. In agreement, coronary muscle MaxiK currents were enhanced by Lavendustin A. To investigate the molecular mechanism of c-Src action on MaxiK channels, we transiently expressed its [alpha] subunit, hSlo, with or without c-Src in HEK293T cells. The voltage sensitivity of hSlo was right-shifted by [approximately equal to] 16 mV. hSlo inhibition by c-Src is due to channel direct phosphorylation because: (i) excised patches exposed to protein tyrosine phosphatase (CD45) resulted in a partial reversal of the inhibitory effect by [approximately equal to] 10 mV, and (ii) immunoprecipitated hSlo channels were recognized by an anti-phosphotyrosine Ab. Furthermore, coexpression of hSlo and c-Src demonstrate a striking colocalization in HEK293T cells. We propose that MaxiK channels via direct c-Src-dependent phosphorylation play a significant role supporting vasoconstriction after activation of G protein-coupled receptors by vasoactive substances and neurotransmitters.

Nitric oxide (NO) functions as an endothelium-derived relaxing factor by activating guanylate cyclase to increase cGMP levels. However, NO and related species may also regulate vascular tone by cGMP-independent mechanisms. We hypothesized that naturally occurring NO donors could decrease the pulmonary vascular response to serotonin (5-HT) in the intact lung through chemical interactions with 5-H[T.sub.2] receptors. In isolated rabbit lung preparations and isolated pulmonary artery (PA) rings, 50-250 [micro]M S-nitrosoglutathione (GSNO) inhibited the response to 0.01-10 [micro]M 5-HT. The vasoconstrictor response to 5-HT was mediated by 5-H[T.sub.2] receptors in the lung, since it could be blocked completely by the selective inhibitor ketanserin (10 [micro]M). GSNO inhibited the response to 5-HT by 77% in intact lung and 82% in PA rings. In PA rings, inhibition by GSNO could be reversed by treatment with the thiol reductant dithiothreitol (10 mM). 3-Morpholinosydnonimine (100-500 [micro]M), which releases NO and [O.sup.-.sub.2] simultaneously, also blocked the response to 5-HT. Its chemical effects, however, were distinct from those of GSNO, because 5-HT-mediated vasoconstriction was not restored in isolated rings by dithiothreitol. In the intact lung, neither NO donor altered the vascular response to endothelin, which activates the same second-messenger vasoconstrictor system as 5-HT. These findings, which did not depend on guanylate cyclase, are consistent with chemical modification by NO of the 5-H[T.sub.2] G protein-coupled receptor system to inhibit vasoconstriction, possibly by S-nitrosylation of the receptor or a related protein. This study demonstrates that GSNO can regulate vascular tone in the intact lung by a reversible mechanism involving inhibition of the response to 5-HT. nitric oxide; G protein-coupled receptor

To test the hypothesis that homocysteine induces constrictive vascular remodeling by inactivating peroxisome proliferator-activated receptor (PPAR), aortic endothelial cells (ECs) and smooth muscle cells (SMCs) were isolated. Collagen gels were prepared, and ECs or SMCs ([10.sup.5]) or SMCs + ECs ([10.sup.4]) were incorporated into the gels. To characterize PPAR, agonists of PPAR-[alpha] [ciprofibrate (CF)] and PPAR-[gamma] [15-deoxy-12,14-prostaglandin [J.sub.2] (PG[J.sub.2])] were used. To determine the role of disintegrin metalloproteinase (DMP), cardiac inhibitor of metalloproteinase (CIMP) was used in collagen gels. Gel diameter at 0 h was 14.1 [+ or -] 0.2 mm and was unchanged up to 24 h as measured by a digital micrometer. SMCs reduce gel diameter to 10.5 [+ or -] 0.4 mm at 24 h. Addition of homocysteine to SMCs reduces further the gel diameter to 8.0 [+ or -] 0.2 mm, suggesting that SMCs induce contraction and that the contraction is further enhanced by homocysteine. Addition of ECs and SMCs reduces gel diameter to 12.0 [+ or -] 0.3 mm, suggesting that ECs play a role in collagen contraction. Only PG[J.sub.2], not CF, inhibits SMC contraction. However, both PG[J.sub.2] and CF inhibit contraction of ECs and SMCs + ECs. Addition of anti-DMP blocks SMC- as well as homocysteine-mediated contraction. However, CIMP inhibits only homocysteine-mediated contraction. The results suggest that homocysteine may enhance vascular constrictive remodeling by inactivating PPAR-[alpha] and -[gamma] in ECs and PPAR-[gamma] in SMCs. aorta; arteriosclerosis; hypertension; peroxisome proliferator-activated receptor; fibrate; prostaglandin; endothelial cell; smooth muscle cell

We examined modulation by nitric oxide (NO) of sympathetic neurotransmitter release and vasoconstriction in the isolated pump-perfused rat kidney. Electrical renal nerve stimulation (RNS; 1 and 2 Hz) increased renal perfusion pressure and renal norepinephrine (NE) efflux. Nonselective NO synthase (NOS) inhibitors [[N.sup.[omega]]-nitro-L-arginine methyl ester (L-NAME) or [N.sup.[omega]]-nitro-L-arginine], but not a selective neuronal NO synthase inhibitor (7-nitroindazole sodium salt), suppressed the NE efflux response and enhanced the perfusion pressure response. Pretreatment with L-arginine prevented the effects of L-NAME on the RNS-induced responses. 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), which eliminates NO by oxidizing it to N[O.sub.2], suppressed the NE efflux response, whereas the perfusion pressure response was less susceptible to carboxy-PTIO. 8-Bromoguanosine cGMP suppressed and a guanylate cyclase inhibitor [4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one] enhanced the RNS-induced perfusion pressure response, but neither of these drugs affected the NE efflux response. These results suggest that endogenous NO facilitates the NE release through cGMP-independent mechanisms, NO metabolites formed after N[O.sub.2] rather than NO itself counteract the vasoconstriction, and neuronal NOS does not contribute to these modulatory mechanisms in the sympathetic nervous system of the rat kidney. sympathetic nerves; vasoconstriction; nitric oxide synthase inhibitor; guanylate cyclase inhibitor; nitric oxide scavenger

Exercise capacity and skeletal muscle blood flow during exercise are reduced with advancing age. This reduction in blood flow capacity may be related to increased reactivity of skeletal muscle resistance vessels to vasoconstrictor stimuli. The purpose of this study was to test the hypothesis that aging results in increased vasoconstrictor responses of skeletal muscle resistance arterioles. First-order (1A) arterioles (90-220 [micro]m) from the gastrocnemius and soleus muscles of young (4 mo) and aged (24 mo) Fischer-344 rats were isolated, cannulated, and pressurized via hydrostatic reservoirs. Vasoconstriction in response to increases in norepinephrine (NE; 1 x [10.sup.-9] -1 x [10.sup.-4] M) and KCl (20-100 mM) concentrations and increases in intraluminal pressure (10-130 cm[H.sub.2]O) were evaluated in the absence of flow. Responses to NE and KCl were similar in both soleus and gastrocnemius muscle arterioles from young and aged rats. In contrast, active myogenic responses to changes in intraluminal pressure were diminished in soleus and gastrocnemius arterioles from aged rats. To assess whether alterations in the mechanical properties of resistance arterioles underlie altered myogenic responsiveness, passive diameter responses to pressure and mechanical stiffness were evaluated. There was no effect of age on the structural behavior (passive pressure-diameter relationship) or stiffness of arterioles from either the soleus or gastrocnemius muscles. These results suggest that aging does not result in a nonspecific decrease in vasoconstrictor responsiveness of skeletal muscle arterioles. Rather, aging-induced adaptations of vasoreactivity of resistance arterioles appear to be limited to mechanisms that are uniquely involved in the signaling of the myogenic response. norepinephrine; potassium chloride; orthostatic hypotension; stiffness; myogenic response

P2 receptor-mediated afferent arteriolar vasoconstriction during calcium blockade. Am J Physiol Renal Physiol 282: F245-F255, 2002. First published August 15, 2001; 10.1152/ajprenal. 00038.2001.--Experiments were performed to determine the role of L-type calcium channels on the afferent arteriolar vasoconstrictor response to ATP and UTP. With the use of the blood-perfused juxtamedullary nephron technique, kidneys were perfused at 110 mmHg and the responses of arterioles to [alpha],[beta]-methylene ATP, ATP, and UTP were determined before and during calcium channel blockade with diltiazem, [alpha],[beta]-Methylene ATP (1.0 [micro]M) decreased arteriolar diameter by 8 [+ or -] 1% under control conditions. This response was abolished during calcium channel blockade. In contrast, 10 [micro]M UTP reduced afferent arteriolar diameter to a similar degree before (20 [+ or -] 4%) and during (14 [+ or -] 4%) diltiazem treatment. Additionally, diltiazem completely prevented the vasoconstriction normally observed with ATP concentrations below 10 [micro]M and attenuated the response obtained with 10 [micro]M ATP. These data demonstrate that L-type calcium channels play a significant role in the vasoconstrictor influences of [alpha],[beta]-methylene ATP and ATP but not UTP. The data also suggest that other calcium influx pathways may participate in the vasoconstrictor response evoked by P2 receptor activation. These observations support previous findings that UTP-mediated elevation of intracellular calcium concentration in preglomerular vascular smooth muscle cells relies primarily on calcium release from intracellular pools, whereas ATP-mediated responses involve both voltage-dependent calcium influx, through L-type calcium channels, and the release of calcium from intracellular stores. These results support the argument that P2X and P2Y receptors influence the diameter of afferent arterioles through activation of disparate signal transduction mechanisms. afferent arterioles; calcium channels; cytosolic calcium; renal microcirculation; P2X receptors; P2Y receptors; adenosine 5'-triphosphate; uridine 5'-triphosphate; [alpha],[beta]-methylene adenosine 5'-triphosphate; cadmium

Dynamics of cerebral blood flow regulation explained using a lumped parameter model. Am J Physiol Regulatory Integrative Comp Physiol 282: R611-R622, 2002; 10.1152/ajpregu. 00285.2001.--The dynamic cerebral blood flow response to sudden hypotension during posture change is poorly understood. To better understand the cardiovascular response to hypotension, we used a windkessel model with two resistors and a capacitor to reproduce beat-to-beat changes in middle cerebral artery blood flow velocity (transcranial Doppler measurements) in response to arterial pressure changes measured in the finger (Finapres). The resistors represent lumped systemic and peripheral resistances in the cerebral vasculature, whereas the capacitor represents a lumped systemic compliance. Ten healthy young subjects were studied during posture change from sitting to standing. Dynamic variations of the peripheral and systemic resistances were extracted from the data on a beat-to-beat basis. The model shows an initial increase, followed approximately 10 s later by a decline in cerebrovascular resistance. The model also suggests that the initial increase in cerebrovascular resistance can explain the widening of the cerebral blood flow pulse observed in young subjects. This biphasic change in cerebrovascular resistance is consistent with an initial vasoconstriction, followed by cerebral autoregulatory vasodilation. cerebral autoregulation; arterial modeling

Niwa, Kiyoshi, Valerie A. Porter, Ken Kazama, David Cornfield, George A. Carlson, and Costantino Iadecola. A[beta]-peptides enhance vasoconstriction in cerebral circulation. Am J Physiol Heart Circ Physiol 281: H2417-H2424, 2001.--Amyloid-[beta] (A[beta])-peptides are involved in the pathophysiology of Alzheimer's dementia. We studied the effects of A[beta] on selected constrictor responses of cerebral circulation. Mice were anesthetized (by using urethane-chloralose) and equipped with a cranial window. Arterial pressure and blood gases were monitored and controlled. Cerebral blood flow (CBF) was monitored by a laser Doppler probe. Topical superfusion with A[beta]1-40 (0.1-10 [micro]M), but not with the reverse peptide A[beta]40-1, reduced resting CBF (-29 [+ or -] 4% at 5 [micro]M; P < 0.05) and augmented the reduction in CBF produced by the thromboxane analog U-46619 (+45 [+ or -] 3% at 5 [micro]M; P < 0.05). A[beta]1-40 or A[beta]1-42 did not affect the reduction in CBF produced by hypocapnia. The reduction in resting CBF and the enhancement of vasoconstriction were reversed by treatment with the free radical scavengers superoxide dismutase or manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin. Substitution of the methionine residue in position 35 with norleucine, a mutation that abolishes the ability of A[beta] to produce free radicals, abolished its vascular effects. Nanomolar concentrations of A[beta]1-40 constricted isolated pressurized middle cerebral artery segments with intrinsic tone (-16 [+ or -] 3% at 100 nM; P < 0.05). We conclude that A[beta] acts directly on cerebral arteries to produce vasoconstriction and to enhance selected constrictor responses. The evidence supports the idea that A[beta]-induced production of reactive oxygen species plays a role in this effect. The vascular actions of A[beta] may contribute to the deleterious effects resulting from accumulation of this peptide in Alzheimer's dementia. Alzheimer's disease; cerebral blood flow; reactive oxygen species; laser Doppler flowmetry Received 16 May 2001; accepted in final form 23 August 2001

Johnson, Christopher D., Andrew M. Coney, and Janice M. Marshall. Roles of norepinephrine and ATP in sympathetically evoked vasoconstriction in rat tail and hindlimb in vivo. Am J Physiol Heart Circ Physiol 281: H2432-H2440, 2001.--In anesthetized rats, we characterized the contributions of norepinephrine (NE) and ATP to changes in tail and hindlimb (femoral) vascular resistances (TVR and FVR, respectively) evoked by three patterns of sympathetic stimulation: 1) couplets (2 impulses at 20 Hz), 2) short trains (20 impulses at 20 Hz), and 3) a natural irregular pattern previously recorded from a sympathetic fiber innervating the rat tail artery. All stimuli evoked greater changes in TVR than FVR. Judging from the effects of the [alpha]-adrenoceptor antagonist phentolamine, the purinergic receptor antagonist suramin, or [alpha],[beta]-methylene ATP (which desensitizes P2X receptors), we propose that NE has a major role in the constriction evoked by the couplet, as well as by the short train and by the low- and high-frequency components of the natural pattern, but that considerable synergy occurred between the actions of ATP and NE. This contrasts with previous in vitro studies that indicated that ATP dominates vascular responses evoked by sympathetic stimulation with a few impulses at low frequency and that NE dominates responses to longer trains or at high frequencies. cotransmission; synergy; cutaneous circulation; skeletal muscle circulation Received 4 December 2000; accepted in final form 7 August 2001