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Abstract: Alarin is a recently discovered regulatory peptide with vasoconstrictive properties in murine skin. Control of vasoconstriction/-relaxation is essential for ocular blood flow and hence the eye''s homeostasis, and regulatory peptides are involved in regulation of ocular blood flow. Here we describe the existence and distribution of alarin in the eye of human and potential experimental animals (rat, mouse). Eyes of rat, mouse, and human were prepared for immunohistochemistry against murine and human alarin, respectively. Additionally, double staining experiments for alarin and CD31 were performed in human choroidal flat-mount preparations. For documentation, confocal laser scanning microscopy was used while quantitative real-time-PCR was applied to confirm immunohistochemical data and to detect alarin mRNA expression in human retina and choroid. Alarin-like immunoreactivity (alarin-LI) was detected in corneal epi- and endothelium of human, mouse, and rat, as well as in the conjunctiva of mouse and rat. Alarin-LI was found in the iris of all the species investigated and, in humans, was concentrated around blood vessels. All three species showed distinctive alarin-LI in the non-pigmented epithelium of the ciliary body. In the retina of mouse and rat, maximum signals were detected in the outer nuclear and ganglion cell layer, whereas in humans a strong alarin-LI was found around retinal blood vessels and in intrinsic choroidal neurons (ICN). Quantitative RT-PCR in human confirmed alarin mRNA expression retina and choroid. The existence of alarin in cornea and conjunctiva might indicate a role in immune defense, while its presence in the non-pigmented ciliary epithelium favors an involvement in aqueous humor production. Alarin around blood vessels/in ICN might indicate an involvement in ocular blood flow regulation. Since alarin is found widely distributed in the eyes of species investigated, we were able to establish the basis for further functional experiments. [Copyright &y& Elsevier]

The article explores why aorta treated with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) generated less protein kinase G (PKG) disulfide that is insufficient to induce vasoconstriction. cGMP binding to PKG induces a state that is resistant to disulfide formation. cGMP depletion also sensitizes PKG to oxidation which happens to a lesser extent in aortas than in mesenteries.

The article discusses a study which determined whether tubular-vascular cross-talk has an effect on vasoconstrictor responses to angiotensin II and to determine whether this is altered in the Dahl salt-sensitive (SS) rat. In this study, a novel outer medullary tissue strip preparation in which freshly isolated vasa recta (VR) within VR bundles were perfused with medullary thick ascending limb (mTAL). It concluded that paracrine signaling from mTAL buffers angiotensin II vasoconstriction.

The article discusses a study which determined the role of endothelial nitric oxide synthase (eNOS) in the mother and/or conceptus in uteroplacental changes during pregnancy. During pregnancy, several changes observed include increase in uteroplacental blood flow, reduction in vascular resistance and enlargement and structural organization of the uterine and spiral arteries. A common and serious complication of pregnancy is preeclampsia, which may result if sustaining these changes failed.

A new theory is presented for the origin of spontaneous oscillations in blood vessel diameters that are observed experimentally in the microcirculation. These oscillations, known as vasomotion, involve timevarying contractions of the vascular smooth muscle in the walls of arterioles. It is shown that such oscillations can arise as a result of interactions between the mechanics of the vessel wall and the dynamics of the active contraction of smooth muscle cells in response to circumferential tension in the wall. A theoretical model is developed in which the diameter and the degree of activation in a vessel are dynamic variables. The model includes effects of wall shear stress and oxygen-dependent metabolic signals on smooth muscle activation and is applied to a single vessel and to simplified network structures. The model equations predict limit cycle oscillations for certain ranges of parameters such as wall shear stress, arterial pressure and oxygen consumption rate. Predicted characteristics of the oscillations, including their sensitivity to arterial pressure, are consistent with experimental observations. [ABSTRACT FROM PUBLISHER]

Microcirculatory vessel response to changes in pressure, known as the myogenic response, is a key component of a tissue's ability to regulate blood flow. Experimental studies have not clearly elucidated the mechanical signal in the vessel wall governing steady-state reduction in vessel diameter upon an increase in intraluminal pressure. In this study, a multiscale computational model is constructed from established models of vessel wall mechanics, vascular smooth muscle (VSM) force generation, and VSM Ca2+ handling and electrophysiology to compare the plausibility of vessel wall stress or strain as an effective mechanical signal controlling steady-state vascular contraction in the myogenic response. It is shown that, at the scale of a resistance vessel, wall stress, and not stretch (strain), is the likely physiological signal controlling the steady-state myogenic response. The model is then used to test nine candidate VSM stress-controlled channel variants by fitting two separate sets of steady-state myogenic response data. The channel variants include nonselective cation (NSC), supplementary Ca2+ and Na+, L-type Ca2+, and large conductance Ca2+-activated K+ channels. The nine variants are tested in turn, and model fits suggest that stress control of Ca2+ or Na+ influx through NSC, supplementary Ca2+ or Na+, or L-type Ca2+ channels is sufficient to produce observed steady-state diameter changes with pressure. However, simulations of steady-state VSM membrane potential, cytosolic Ca2+, and Na+ with pressure show only that Na+ influx through NSC channel also generates known trends with increasing pressure, indicating that stress-controlled Na+ influx through NSC is sufficient to generate the myogenic response. [ABSTRACT FROM AUTHOR]

Vasomotion refers to spontaneous oscillation of small vessels observed in many microvascular beds. It is an intrinsic phenomenon unrelated to cardiac rhythm or neural and hormonal regulation. Vasomotion is found to be particularly prominent under conditions of metabolic stress. In spite of a significant existent literature on vasomotion, its physiological and pathophysiological roles are not clear. It is thought that modulation of vasomotion by vasoactive substances released by metabolizing tissue plays a role in ensuring optimal delivery of nutrients to the tissue. Vasomotion rhythms exhibit a great variety of temporal patterns from regular oscillations to chaos. The nature of vasomotion rhythm is believed to be significant to its function, with chaotic vasomotion offering several physiological advantages over regular, periodic vasomotion. In this article, we emphasize that vasomotion is best understood as a network phenomenon. When there is a local metabolic demand in tissue, an ideal vascular response should extend beyond local microvasculature, with coordinated changes over multiple vascular segments. Mechanisms of information transfer over a vessel network have been discussed in the literature. The microvascular system may be regarded as a network of dynamic elements, interacting, either over the vascular anatomical network via gap junctions, or physiologically by exchange of vasoactive substances. Drawing analogies with spatiotemporal patterns in neuronal networks of central nervous system, we ask if properties like synchronization/desynchronization of vasomotors have special significance to microcirculation. Thus the contemporary literature throws up a novel view of microcirculation as a network that exhibits complex, spatiotemporal and informational dynamics. [ABSTRACT FROM AUTHOR]

The cerebrovasculature dilates or constricts in response to acute blood pressure changes to stabilize cerebral blood flow across a range of blood pressures. It is unclear, however, whether such dynamic cerebral autoregulation (dCA) is equally effective in responding to falling versus rising blood pressure. In this study we applied a pharmacological approach to evaluate dCA gain to transient hypotension and hypertension and compared this method with 2 established indices of dCA that do not explicitly differentiate between dCA efficacy and falling versus rising blood pressure. Middle cerebral arterial velocity and blood pressure recordings were made in 26 healthy volunteers randomized to 2 protocols. In 10 subjects, dCA gain to transient hypotension induced with intravenous nitroprusside was compared with dCA gain to transient hypertension induced with intravenous phenylephrine. In 16 subjects, dCA gain to transient hypotension induced with intravenous nitroprusside was compared with the rate of regulation and autoregulatory index derived from transient hypotension induced with the thigh cuff deflation technique. dCA gain to transient hypotension induced with intravenous nitroprusside was unrelated to dCA gain to transient hypertension induced with intravenous phenylephrine (r=0.06; P=0.87) and was consistently greater than dCA gain to transient hypertension induced with intravenous phenylephrine (0.57+/-0.16 versus 0.31+/-0.20 cm/s per millimeter of mercury; P<0.01). However, dCA gain to transient hypotension induced with intravenous nitroprusside was inversely related to the rate of regulation (r=-0.52; P=0.037) and autoregulatory index (r=-0.66; P=0.005). These data indicate that, under our laboratory conditions, dCA appears to be inherently nonlinear with disparate efficacy against rising and falling blood pressure, and dCA gain derived from pharmacologically induced transient hypotension correlates with established nonpharmacological indices of dCA. [ABSTRACT FROM AUTHOR]

Vertebrate red blood cells (RBCs) seem to serve tissue oxygen delivery in two distinct ways. Firstly, ABCs enable the adequate transport of O2 between respiratory surfaces and metabolizing tissues by means of their high intracellular concentration of hemoglobin (Hb), appropriate allosteric interactions between Hb ligand-binding sites, and an adjustable intracellular chemical environment that allows fine-tuning of Hb O2 affinity. Secondly, ABCs may sense tissue O2 requirements via their degree of deoxygenation when they travel through the microcirculation and release vasodilatory compounds that enhance blood flow in hypoxic tissues. This latter function could be important in matching tissue O2 delivery with local O2 demand. Three main mechanisms by which ABCs can regulate their own distribution In the microcirculation have been proposed. These are: (1) deoxygenation-dependent release of ATP from RBCs, which stimulates production of nitric oxide (NO) and other vasodilators in the endothelium; (2) release of vasoactive NO from S-nitroso-Hb upon deoxygenation; and (3) reduction of naturally occurring nitrite to vasoactive NO by deoxygenated Hb. This Commentary inspects all three hypotheses with regard to their mechanisms, experimental evidence in their support and details that remain unresolved. The prime focus is on human/mammalian models, where most evidence for a role of erythrocyte ATP and NO release in blood flow regulation have accumulated. Information from other vertebrate groups is integrated in the analysis and used to discuss the evolutionary origin and general relevance of each hypothesis. [ABSTRACT FROM AUTHOR]

During cycling blood flow is redistributed from physically inactive tissues to working leg muscles. It is unknown how long this situation persists after very intense exercise or whether it differs between intense exhausting and non-exhausting exercise. It is also not known to what extent the redistribution differs between different types of non-active tissues. Therefore nine healthy young men cycled first for 2min at 328 W (non-exhausting exercise, mean). Blood velocity in thigh and arm (ultrasound-doppler), perfusion of forearm skin (non-acral skin) and finger tip (acral skin, with arterio-venous anastomoses) were measured for 30min after exercise (laser-doppler). To be able to study vascular resistance and central circulation, blood pressure (Finometer), heart rate (ECG), and stroke volume (ultrasound-doppler) were measured. Thereafter the subjects cycled at the same power to exhaustion (4min), and the measurements were repeated. After both exercises mean blood pressure was unchanged (≤ 80mm Hg) despite increased cardiac output (≥ + 30% vs. pre-exercise). Blood velocity in the brachial artery was higher during the whole recovery period than at rest ( p≤0.02; no differences between exercises). Blood perfusion of non-acral skin was unchanged from pre-exercise level after 2min of non-exhausting exercise, but it was twice as high after 4min cycling to exhaustion as at rest ( p=0.02). Blood perfusion of acral skin rose after both exercises and did not differ between exhausting and non-exhausting exercise. In conclusion, arm blood flow increases above the pre-exercise level in the recovery period after short-lasting, strenuous exercise. [ABSTRACT FROM AUTHOR]

beta(2)-adrenoceptors are important modulators of vascular tone, particularly in the pulmonary circulation. Because neurohormonal activation occurs in pulmonary arterial hypertension, we have investigated the effect of different adrenergic vasoactive substances on tone regulation in large and small pulmonary arteries, as well as in systemic vessels of mice. We found that the beta(2)-adrenoceptor antagonist ICI 118,551 (ICI) evoked a decrease of vascular tone in large pulmonary arteries and reduced the sensitivity of pulmonary arteries toward different contracting agents, eg, norepinephrine, serotonin, or endothelin. ICI proved to act specifically on pulmonary vessels, because it shifted the dose-response curve of norepinephrine to the right in pulmonary arteries, whereas there was no effect in the aorta. Pharmacological experiments proved that the right shift of the norepinephrine dose-response curve by ICI was mediated via a beta(2)-adrenoceptor/G(i/o) protein-dependent pathway enhancing NO production in the endothelium; these results were corroborated in beta-adrenoceptor and endothelial NO synthase knockout mice where ICI had no effect. ICI increased vascular lumen diameter in lung sections and reduced pulmonary arterial pressure under normoxia and under hypoxia in the isolated perfused lung model. These effects were found to be physiologically relevant, because ICI specifically decreased pulmonary but not systemic blood pressure in vivo. Thus, the beta(2)-adrenoceptor antagonist ICI is a pulmonary arterial-specific vasorelaxant and, therefore, a potentially interesting novel therapeutic agent for the treatment of pulmonary arterial hypertension. [ABSTRACT FROM AUTHOR]

Control of exercising muscle blood flow is a balance between local vasodilatory factors and the increase in global sympathetic vasoconstrictor outflow. Hypoxia has been shown to potentiate the muscle sympathetic nerve response to exercise, potentially limiting the increase in muscle blood flow. Accordingly, we investigated sympathetic restraint to exercising muscle during whole body exercise in hypoxia. Six dogs chronically instrumented with ascending aortic and hindlimb flow probes and a terminal aortic catheter were studied at rest and mild [2.5 miles/h (mph), 5% grade] and moderate (4.0 mph, 10% grade) exercise while breathing room air or hypoxia (Pao2 ~45 mmHg) in the intact control condition and following systemic α-adrenergic blockade (phentolamine). Hypoxia caused an increase in cardiac output (CO), hindlimb flow (FlowL), and blood pressure (BP), while total (CondT) and hindlimb conductance (CondL) were unchanged at rest and mild exercise but increased with moderate exercise. During both mild and moderate exercise, α-blockade in normoxia resulted in significant vasodilation as evidenced by increases in CO (10%), FlowL (17%), CondT (33%), CondL (43%), and a decrease in BP (- 18%), with the increase in CondL greater than the increase in CondT during mild exercise. Compared with the normoxic response, α-blockade in hypoxia during exercise resulted in a. significantly greater increase in CondT (59%) and CondL (74%) and a correspondingly greater decrease in BP (-34%) from baseline. These findings indicate that there is considerable hypoxia-induced sympathetic restraint of muscle blood flow during both mild and moderate exercise, which helps to maintain arterial blood pressure in hypoxia. [ABSTRACT FROM AUTHOR]

Background: Currently visual and tactile clues such as color, mottling, and tissue turgor are used in the operating room for subjective assessments of organ ischemia. Studies have demonstrated that infrared (IR) imaging is a reliable tool to identify perfusion of brain tumors and kidneys during human surgery. Intraoperative IR imaging has the potential for more objective real-time detection and quantitative assessment of organ viability including early ischemia. We hypothesize, by detecting variations of the IR signal, we can assess the degree to which renal surface temperature reflects underlying renal ischemia. To address this hypothesis, IR imaging-derived temperature fluctuations were evaluated during laparotomy in a porcine model (n = 15). These temperature profiles then underwent spectral (frequency) analysis to assess their relationship to well-described oscillations of the microcirculation. Materials and methods: An IR camera was positioned 30–60 cm above the exposed kidneys. Images (3–5 μm wavelength) were collected (1.0/s) at baseline, during warm renal ischemia, and during reperfusion. Dominant frequency (DF) of the tissue temperature fluctuations were determined by a Fourier transformation (spectral) analysis. Results: IR images immediately showed which segments of the kidney were ischemic. DF at ∼0.008 Hz that corresponds to blood flow oscillations was observed in thermal profiles. The oscillations were diminished or disappeared after 25 min of warm ischemia and were recovered with reperfusion in a time-dependent fashion. Oscillations were attenuated substantially in ischemic segments, but not in perfused segments of the kidney. Conclusions: The described oscillations can be measured noninvasively using IR imaging in the operating room, as represented by the DF, and may be an early marker of critical renal ischemia. [Copyright &y& Elsevier]

The autoregulation of blood flow, the maintenance of almost constant blood flow in the face of variations in arterial pressure, is characteristic of many tissue types. Here, contributions to the autoregulation of pressure-dependent, shear stress-dependent, and metabolic vasoactive responses are analyzed using a theoretical model. Seven segments, connected in series, represent classes of vessels: arteries, large arterioles, small arterioles, capillaries, small venules, large venules, and veins. The large and small arterioles respond actively to local changes in pressure and wall shear stress and to the downstream metabolic state communicated via conducted responses. All other segments are considered fixed resistances. The myogenic, shear-dependent, and metabolic responses of the arteriolar segments are represented by a theoretical model based on experimental data from isolated vessels. To assess autoregulation, the predicted flow at an arterial pressure of 130 mmHg is compared with that at 80 mmHg. If the degree of vascular smooth muscle activation is held constant at 0.5, there is a fivefold increase in blood flow. When myogenic variation of tone is included, flow increases by a factor of 1.66 over the same pressure range, indicating weak autoregulation. The inclusion of both myogenic and shear-dependent responses results in an increase in flow by a factor of 2.43. A further addition of the metabolic response produces strong autoregulation with flow increasing by a factor of 1.18 and gives results consistent with experimental observation. The model results indicate that the combined effects of myogenic and metabolic regulation overcome the vasodilatory effect of the shear response and lead to the autoregulation of blood flow. [ABSTRACT FROM AUTHOR]

Exercise hyperemia is attenuated in the elderly, which may be attributed to local vasoregulatory pathways within the skeletal muscle vasculature. Therefore, we sought to determine whether healthy aging is associated with changes in angiotensin II (Ang II) receptor sensitivity through measurements of leg blood flow in resting and exercising skeletal muscle. In 12 (n=6 young, 24+/-1 years; n=6 older, 68+/-3 years) healthy volunteers, we determined changes in leg blood flow (ultrasound Doppler) before and during intra-arterial infusion of Ang II (0.8 ng/mL of leg blood flow per minute). Heart rate, arterial blood pressure, common femoral artery diameter, and mean blood velocity were measured at rest and during knee-extensor exercise at 20% and 40% of the maximal work rate (WR(max)). At rest, Ang II infusion decreased leg blood flow to a greater extent in older (-61+/-8%) subjects compared with younger subjects (-31+/-5%). Compared with rest, Ang II-mediated vasoconstriction (leg blood flow) during exercise was diminished in both older and younger subjects at 20% (older: -7+/-5%; younger: -21+/-2%) and 40% WR(max) (older: -5+/-4%; younger: -9+/-3%). These data identify a clear age-related hypersensitivity to Ang II in the resting leg, which may contribute to the recognized decrement in leg blood flow in this cohort. However, the diminished vasoconstriction to Ang II during exercise suggests that the elevation in Ang II type 1 receptor sensitivity documented at rest does not contribute significantly to the blunted exercise hyperemia experienced with advancing age. [ABSTRACT FROM AUTHOR]

Increased endothelin-1-mediated vasoconstrictor tone has been linked to the etiology of a number of pathologies associated with human aging, including hypertension, congestive heart failure, and coronary artery disease. However, it is currently unclear whether aging, per se, is associated with enhanced endothelin-1 system activity. We hypothesized that endothelin-1 vasoconstrictor activity is greater in healthy older compared with young men and that regular aerobic exercise is an effective intervention for reducing endothelin-1 vasoconstrictor tone in older previously sedentary men. Forearm blood flow (plethysmography) responses to intra-arterial infusion of endothelin-1 (5 pmol/min; for 20 minutes) and selective (BQ-123; 100 nmol/min; for 60 minutes) and nonselective (BQ-123+BQ-788; 100 nmol/min; for 60 minutes) endothelin-1 receptor blockade were determined in 28 healthy, sedentary men: 13 younger (age: 27+/-1 years) and 15 older (age: 62+/-2 years). The vasoconstrictor response to endothelin-1 was significantly blunted ( approximately 65%) in the older versus younger men. In response to BQ-123, resting forearm blood flow increased ( approximately 20%; P<0.05) in the older but not in the younger men. The addition of BQ-788 to BQ-123 did not significantly affect the blood flow responses to BQ-123 in either group. Eight of the 15 older sedentary men completed a 3-month aerobic exercise intervention. After the intervention, the vasoconstrictor response to endothelin-1 was markedly increased (225%; P<0.05), whereas BQ-123 resulted in modest vasoconstriction in the previously sedentary older men. These results demonstrate that endothelin-1-mediated vasoconstrictor tone increases with age in healthy men but can be alleviated with regular aerobic exercise. [ABSTRACT FROM AUTHOR]

The growing incidence and prevalence of the overweight/obese condition across developed economies worldwide has an enormous impact on increasing the risk for the development of impaired glycemic control or insulin resistance and ultimately peripheral vascular disease (PVD) in afflicted individuals. This places an enormous economic and social burden on these societies, in terms of additional health care costs and lost productivity and through a reduction in the quality of life of the individual owing, in part, to the progressive PVD. Characterized by an inability of the vascular systems to adequately perfuse tissues and organs relative to their metabolic demand, PVD is in part a function of a structural remodeling of the microvascular networks such that the density of microvessel and capillaries within tissues is reduced below that under normal conditions, with the potential for profound negative impacts on the processes of mass transport and exchange. The review discusses the severity of the obesity "epidemic" from the perspective of PVD and the effects of the development of the obese, insulin-resistant condition on tissue/organ microvessel density. Additional material is reviewed that addresses ameliorative treatments, primarily exercise training, on blunting microvessel loss in the obese, insulin-resistant individual, and on potential mechanistic contributors that warrant considerable future investigation. [ABSTRACT FROM AUTHOR]

Elevated blood flow (reactive hyperemia) is seen in many organs after a period of blood flow stoppage. This hyperemia is often considered to be due in part to a shift to anaerobic metabolism during tissue hypoxia. The aim of our study was to test this hypothesis in skeletal muscle. For this purpose we measured NADH fluorescence at localized tissue areas in cat sartorius muscle during and after arterial occlusions of 5-300 s. In parallel studies, red blood cell (RBC) velocity was measured in venules. Tissue NADH fluorescence rose significantly with occlusions of 45 s or greater, reaching a maximum of 44% above control at 180 s. Peak RBC velocity rose to four times control as occlusion duration was increased from 5 to 45 s, but hyperemia duration was stable at ~70 s. With occlusions of 45-240s, hyperemia duration increased progressively to 210 s while peak flow was unchanged. However, after 300-s occlusions, peak flow rose to six times above control and hyperemia duration fell to 140s. With occlusions of 45-300 s the time integral both of increased NADH fluorescence and of reduced fluorescence following occlusion release showed a high degree of correlation with the additional hyperemia. We conclude that in this muscle anaerobic vasodilator metabolites are responsible for the increase in reactive hyperemia with arterial occlusions longer than 45 s. Since the durations of reactive hyperemia and reduced fluorescence are substantially different, vasodilator metabolite removal may be due to washout by the bloodstream rather than metabolic uptake. [ABSTRACT FROM AUTHOR]

Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor, which also stimulates insulin release. The aim of the present study was to evaluate whether exogenously administered ET-1 affected pancreatic islet blood flow in vivo in rats and the islet arteriolar reactivity in vitro in mice. Furthermore, we aimed to determine the ET-receptor subtype that was involved in such responses. When applying a microsphere technique for measurements of islet blood perfusion in vivo, we found that ET-1 (5 nmol/kg) consistently and markedly decreased total pancreatic and especially islet blood flow, despite having only minor effects on blood pressure. Neither endothelin A (ETA) receptor (BQ-123) nor endothelin-B (ETB) receptor (BQ-788) antagonists, alone or in combination, could prevent this reduction in blood flow. To avoid confounding interactions in vivo, we also examined the arteriolar vascular reactivity in isolated, perfused mouse islets. In the latter preparation, we demonstrated a dose-dependent constriction in response to ET- 1. Administration of BQ-123 prevented this, whereas BQ-788 induced a right shift in the response. In conclusion, the pancreatic islet vasculature is highly sensitive to exogenous ET-1, which mediates its effect mainly through ETA receptors. [ABSTRACT FROM AUTHOR]

Endothelin 1 mediates coronary vasoconstriction and endothelial dysfunction via endothelin receptor type A (ET(A)) activation. However, the effects of selective endothelin receptor type B (ET(B)) and combined ET(A+B) receptor blockade on coronary vasomotion are unknown. We measured coronary vascular tone and endothelium-dependent and -independent vasomotor function before and after selective infusion of BQ-788 (an ET(B) receptor antagonist) or combined infusion of BQ-788+BQ-123 (an ET(A) antagonist) into unobstructed coronary arteries of 39 patients with coronary atherosclerosis or risk factors undergoing cardiac catheterization. BQ-788 did not affect epicardial diameter but constricted the microcirculation (P<0.0001), increased coronary sinus endothelin, and reduced nitrogen oxide levels. In contrast, BQ-123+BQ-788 dilated epicardial (P<0.0001) and resistance (P=0.022) arteries. Responses to acetylcholine and sodium nitroprusside were unaffected by BQ-788 alone. Epicardial endothelial dysfunction improved after BQ-123+BQ-788 (P=0.007). Coronary microvascular responses to acetylcholine and sodium nitroprusside were unaffected by BQ-123+BQ-788. We conclude that selective ET(B) receptor antagonism causes coronary microvascular constriction, without affecting epicardial tone or endothelial function, via reduced endothelin clearance and NO availability. Combined ET(A+B) blockade dilates coronary conduit and resistance vessels and improves endothelial dysfunction of the epicardial coronary arteries. Thus, endogenous endothelin, predominantly via ET(A) receptor stimulation, contributes to basal constrictor tone and endothelial dysfunction, whereas ET(B) activation mediates vasodilation in human coronaries. Our data suggest that selective ET(A) blockade may have greater therapeutic potential than nonselective agents, particularly for treatment of endothelial dysfunction in atherosclerosis. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that skeletal muscle perfusion is impaired in obese Zucker rats (OZR) under control conditions and with elevated metabolic demand versus responses in lean Zucker rats (LZR). To further our understanding of processes contributing to impaired perfusion, we determined whether hyperernic responses following periods of occlusion were altered in skeletal muscle of OZR versus LZR. In isolated hindlimbs, basal blood flow in OZR was less than in LZR, and total perfusion responses after 30, 90, and 180 s of occlusion were reduced. Treatment of animals with an antioxidant (polythethylene glycol-superoxide dismutase) had no effect on reactive hyperemia, although blockade of α-adrenoreceptors (α1 > α2) improved responses to 30 and 90s of occlusion; responses to 180 s of occlusion were unaltered. Pump perfusion of a dilated distal hindlimb demonstrated that increased volume flow elicited a greater increase in perfusion pressure in OZR versus LZR, suggesting structural contributions to an increased vascular resistance. Responses were comparable for in situ cremaster muscle because reactive hyperemia following serial arteriolar occlusion was attenuated in OZR versus LZR, treatment with polythethylene glycol-superoxide dismutase was ineffective, and hyperemic responses were improved following inhibition of α-adrenoreceptors (α1 > α2). Treatment of cremaster muscle with adenosine (10-3 M) caused flow to increase to a level comparable to that following 180 s of occlusion in both strains, although this level was reduced in OZR versus LZR. These results suggest that increased adrenergic tone may constrain reactive hyperemia in OZR with brief occlusion, although structural increases in vascular resistance can contribute to constrained perfusion after longer periods of occlusion. [ABSTRACT FROM AUTHOR]

As obese Zucker rats (OZR) manifesting the metabolic syndrome exhibit enhanced vascular adrenergic constriction and potentially an enhanced adrenergic activity vs. lean Zucker rats (LZR), this study tested the hypothesis that OZR exhibit an improved tolerance to progressive hemorrhage. Preliminary experiments indicated that, corrected for body mass, total blood volume was reduced in OZR vs. LZR. Anesthetized LZR and OZR had a cremaster muscle prepared for in situ videomicroscopy and had renal, splanchnic, hindlimb, and skeletal muscle perfusion monitored with flow probes. Arterial pressure, arteriolar reactivity to norepinephrine, and tissue/organ perfusion were monitored after either infusion of phentolamine or successive withdrawals of 10% total blood volume. Phentolamine infusion indicated that regional adrenergic tone under control conditions differs substantially between LZR and OZR, whereas with hemorrhage OZR exhibit decompensation in arterial pressure before LZR. Renal, distal hindlimb, and skeletal muscle perfusion decreased more rapidly and to a greater extent in OZR vs. LZR after hemorrhage. In contrast, hemorrhage-induced reductions in splanchnic perfusion in OZR lagged behind those in LZR, although a similar maximum reduction was ultimately attained. With increasing hemorrhage, cremasteric arteriolar tone increased more in OZR than LZR, and this increase in active tone was entirely due to an elevated adrenergic contribution. Norepinephrine-induced arteriolar constriction was greater in OZR vs. LZR under control conditions and during hemorrhage, with arterioles from OZR demonstrating early closure vs. LZR. These results suggest that a combination of reduced blood volume and elevated peripheral adrenergic constriction contribute to impaired hemorrhage tolerance in OZR. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine whether increased expression of heme oxygenase (HO) contributes to impairment of aortic contractile responses after hypoxia through effects on reactivity to endothelin-1 (ET-1). Thoracic aortas from normoxic rats and rats exposed to hypoxia (10% O2) for 16 or 48 h were mounted in organ bath myographs for contractile studies, fixed in paraformaldehyde, or frozen in liquid nitrogen for protein extraction. In rings from normoxic rats, the HO inhibitor tin protoporphyrin IX (SnPP IX, 10 µM) did not alter the response to phenylephrine or ET-1. In rings from rats exposed to 16-h hypoxia, maximum tension generated in response to these agonists was higher in endothelium-intact but not -denuded rings in the presence of SnPP IX. In tings from rats exposed to 48-h hypoxia SnPP IX increased contraction in endothelium-intact but not -denuded rings. In endothelium-intact aortic rings from rats exposed to 16-h hypoxia incubated with endothelin A receptor-specific antagonist BQ-123 (10-7 M), SnPP IX did not alter phenylephrine-induced contraction. Aortic ET-1 protein levels, measured by radioimmunoassay, were increased in rats exposed to hypoxia for 16 and 48 h. Western blotting showed that HO-1 and HO-2 protein were increased after 16 h of hypoxia and returned to near-control levels after 48 h. Increase in HO-1 protein was detected in endothelium-intact and -denuded rings. Removal of endothelium abolished the increase in HO-2 immunoreactivity. Immunohistochemistry localized expression of HO-1 protein to vascular smooth muscle, whereas HO-2 was only detected in endothelium. HO-2 is expressed by aortic endothelial cells early during hypoxic exposure and impairs ET-1-mediated potentiation of contraction to α-adrenoceptor stimulation. [ABSTRACT FROM AUTHOR]

Objectives:Angiotensin II suppression leads to impaired vascular relaxation in normotensive animals on a high-salt diet. The goal of this study was to determine whether normal vascular reactivity could be restored by transferring the chromosomal region carrying the Dahl salt-resistant (R) renin gene into the Dahl salt-sensitive (SS) genetic background in a strain of renin congenic rats (RGRR).Methods:Male RGRR and SS rats were fed low-salt (0.4%) and high-salt (4%) diets for 4 weeks. The responses of cremaster muscle arterioles to acetylcholine (ACh), sodium nitroprusside (SNP), and elevatedPO2were assessed using video microscopy.Results:ACh-induced dilation was significantly enhanced in RGRR on a high-salt diet compared to SS rats, while dilation to the NO donor SNP was similar in both strains. A high-salt diet significantly enhanced arteriolar constriction in response to elevatedPO2, in both SS and RGRR rats.Conclusions:These data suggest that transfer of the chromosomal region containing the renin gene is crucial in the recovery of ACh-induced dilation of arterioles in RGRR rats vs. SS rats, and that factors in the SS genetic background contribute to an enhanced sensitivity to elevatedPO2, independent of genes on chromosome 13. [ABSTRACT FROM AUTHOR]

Boettcher cells lie on the basilar membrane beneath Claudius cells. The cells are considered supporting cells for the organ of Corti, and present only in the lower turn of the cochlea, which responds to high-frequency sound. Boettcher cells interdigitate with each other, and project microvilli into the intercellular space. Their structural specialization suggests that Boettcher cells may play a significant role in the function of the cochlea. Nitric oxide synthase (NOS) has previously been detected in substructures of the cochlea. In the cochlea, it is believed that nitric oxide plays an important role in neurotransmission, blood flow regulation, and induction of cytotoxicity under pathological conditions. Findings concerning detection of NOS on Boettcher cells are rare. We demonstrated here the localization of NOS on Boettcher cells of the rat by immunohistochemistry using polyclonal antibody to NOS. On observation with the light microscope using DAB staining, positive immunostaining to NOS was observed in Boettcher cells. In immunoelectron micrographs, NOS was detected abundantly in the cytoplasm of the interdigitations. This suggests that the interdigitations may play significant roles by using NOS. It follows from this that the nitric oxide (NO) on Boettcher cells may influences neighboring Boettcher cells. The ultrastructure of Boettcher cells suggests that they may be active cells, which perform both secretory and absorptive functions. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the role of Cl− channel activation in prostaglandin F2α-stimulated aortic contraction and in membrane depolarization during stimulation with prostaglandin F2α in an aortic smooth muscle cell line (A7r5). The Cl− channel antagonists 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), indanyloxyacetic acid-94 (IAA-94) and 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS) were found to decrease (P<0.05) the maximum tension generated by rat thoracic aortic segments during stimulation with prostaglandin F2α and to shift the concentration–response relationship to the right. In the presence of Nifedipine and Cesium, rat aorta-derived A7r5 smooth muscle cells demonstrated outwardly rectifying voltage-dependent currents that were inhibited by NPPB, IAA-94 and DIDS. Both inward and outward currents were enhanced (P<0.05) following addition of prostaglandin F2α (4 μmol/l, final concentration) to the bath solution and this increase was completely inhibited by NPPB. In the absence of Cesium, the addition of prostaglandin F2α (4 μmol/l) to the extracellular bath solution either depolarized or hyperpolarized the cell membrane depending on the equilibrium potential for Cl− ions. Our results indicate that altered Cl− conductance is an important mechanism mediating membrane depolarization and contraction of aortic smooth muscle cells during stimulation with prostaglandin F2α. Given the significant role that prostaglandin F2α and its biologically active isomers, the F2 isoprostanes, play in the control of vascular tone during hypoxic and oxidative stress in the systemic circulation, alterations in Cl− channel function and expression may represent an important mechanism in the pathogenesis of abnormal blood flow regulation in disease states. [Copyright &y& Elsevier]

The maturity of pericytes in cerebral neocapillaries induced by two different growth factors: basic fibroblast growth factor (bFGF) and platelet‐derived growth factor (PDGF), was examined using an immunohistochemical staining technique. Cerebral angiogenesis was induced in mice by implanting a sandwich system of bFGF/PDGF gel and nylon‐mesh over the exposed cortex. On 28th day after incubation, a small volume of cerebral tissue with the nylon‐mesh was isolated and stained using tetramethyl rhodamine isothiocyanate (TRITC)‐labeled secondary antibody to the primary antibody against NG[sub 2] proteoglycan and fluorescein isothiocyanate (FITC)‐labeled Griffonia simplicifolia (GS)‐lectin. Using a confocal laser microscopic system, we observed the cerebral neocapillaries on the upper surface of the nylon‐mesh and evaluated the maturity of pericytes stained with NG[sub 2] based on the fluorescence immunohistological images. The pericyte appeared rich in neocapillaries induced by PDGF. It was suggested that pericytes might play a key role in the regulation of blood flow in neovessels. [ABSTRACT FROM AUTHOR]

The vascular supply of the optic nerve has been studied with different methods including corrosion casts both in humans and in other mammals. In man, primates and some other mammals, such as the rat, a distinct central retinal artery accompanies the optic nerve, and runs through the lamina cribosa to reach the optic nerve head. Similarities between human and rat central retinal artery could serve to understand changes in the autonomic perivascular innervation in glaucoma using the rat as an animal model. Nitric oxide, calcitonin gene-related peptide, neuropeptide Y, substance P and vasoactive intestinal peptide have been identified around the monkey central retina artery. Innervation of the rat central artery, however, has not been described in detail. Using immuno- and histochemical methods, the present study investigates the peptidergic, adrenergic and nitrergic innervation of the rat posterior ciliary artery as well as the central retina artery. Numerous nitric oxide positive nerve fibers were visualized posterior and anterior to the lamina cribosa of the optic nerve. They colocalized with NADPH-diaphorase positive fibers, which could also be observed in two of six specimens studied at the level of the optic nerve head. Calcitonin gene-related peptide, tyrosine hydroxylase, and VIP positive fibers were also observed surrounding the vessels of the rat optic nerve. The presence of neuronal nitric oxide/NADPH-diaphorase and vasoactive intestinal peptide positive nerve fibers surrounding the posterior ciliary and central retinal arteries indicates a vasodilator effect in the rat optic nerve. Tyrosine hydroxylase positive innervation indicates the presence of sympathetic activity, and calcitonin gene-related peptide positive fibers indicate sensory innervation by trigeminal primary efferents. [Copyright &y& Elsevier]

We examined whether the formation or the release of the vasodilators adenosine, prostacyclin (PGI[sub 2] ) and potassium (K[sup +] ) increase in skeletal muscle interstitium in response to nitric oxide synthase (NOS) inhibition. Five subjects performed one-legged knee extensor exercise at 30 W without (controls) and with prior N[sup G] -nitro-L-arginine methyl ester (L-NAME) infusion (4 mg/kg, intravenously). Samples from the interstitial fluid were obtained at rest, during exercise and after exercise with the microdialysis technique. Interstitial adenosine in controls increased (p < 0.05) from 0.11 ± 0.03 μmol/l at rest to 0.48 ± 0.06 μmol/l during exercise. Interstitial adenosine during exercise in L-NAME was similar (p > 0.05) to controls. The 6-keto-prostaglandin F1α concentration in controls was 1.17 ± 0.20 ng/ml at rest and increased (p < 0.05) to 1.97 ± 0.30 ng/ml during exercise and was further elevated (p < 0.05) to 2.76 ± 0.38 ng/ml after exercise and these concentrations were not different (p > 0.05) in L-NAME. The interstitial K[sup +] concentration in controls increased (p < 0.05) from 4.1 ± 0.1 mmol/l at rest to 9.5 ± 0.5 mmol/l during exercise. The interstitial K[sup +] concentration during exercise (6.7 ± 0.4 mmol/l) was lower (p < 0.05) in L-NAME than in controls. The present findings demonstrate that the muscle interstitial concentrations of adenosine, PGI[sub 2] and K[sup +] during exercise are not increased with systemic NOS inhibition. Thus, the lack of effect of NOS inhibition on the rate of blood flow to contracting human skeletal muscle does not appear to be due to compensatory formation or release of adenosine, PGI[sub 2] and K[sup +] in the muscle interstitium. The present study also supports a role for PGI[sub 2] in the regulation of blood flow during exercise.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The matching of oxygen supply with demand requires the existence of a mechanism within the tissue capable of both sensing tissue oxygen need and inducing alterations in vascular perfusion necessary to meet that need. Historically, localized sites within the tissue and the vessels themselves have been investigated with the sensor site failing to be determined. Within the last decade, studies have focused on the red blood cell, the efficient carrier of oxygen, as a possible candidate. The red blood cell is clearly capable of sensing oxygen levels, as its extent of haemoglobin desaturation (decrease in oxygen content) is intimately tied with tissue oxygen demand. In addition, numerous studies have indicated that the red blood cell is capable of releasing increased amounts of adenosine 5′-triphosphate (ATP) as oxygen content falls and its haemoglobin becomes desaturated. Within the vasculature, intraluminal ATP has been shown to induce a vasodilator response which is conducted along the vessels resulting in augmentation of tissue perfusion. While details of the red blood cell’s role are still under investigation, evidence presented here supports the intriguing idea that the mobile red blood cell may itself be able to augment blood flow and oxygen delivery wherever and whenever the need might arise. Such a mechanism eliminates the requirement for a diverse network of sensing sites throughout the vasculature and should provide a more efficient means of appropriately matching oxygen supply with demand. [ABSTRACT FROM AUTHOR]

Immunohistochemistry for neuronal nitric oxide synthase (nNOS) and vasoactive intestinal peptide (VIP), and NADPH diaphorase histochemistry, were applied to investigate neurons in the choroid and the ciliary ganglion of the muscovy duck Anis carina. Up to 1000 neurons in the choroid stained for NADPH diaphorase and showed virtually complete colocalization for nNOS immunoreactivity. Almost all of them co-stained for VIP, while about 90% of VIP immunoreactive cell bodies showed colocalization for nNOS. Two-thirds of the neurons were located, mostly singly, at nodes of a widemeshed nerve plexus in the suprachoroid and were only rarely grouped in ganglia of up to 3 neurons. Numerous varicose nNOS/NADPH-diaphorase-positive nerve fibers were seen around large arterial blood vessels. These fibers derived mainly from paravascular cell bodies that represented about one-third of all choroidal neurons and also displayed costaining for nitrergic markers and VIP. Colocalization of nNOS/NADPH-d and VIP could be demonstrated in most of the perivascular fibers, while slightly more VIP-positive axons in the suprachoroid plexus did not costain for nNOS/NADPH-d. Small-caliber blood vessels and those localized in the choriocapillaris were not endowed with VIP/nNOS/NADPH-diaphorase-positive fibers. A few reactive neuronal cell bodies were also found in ciliary nerves, while most ciliary axons were unstained. In the ciliary ganglion a small subpopulation of neurons showed VIP/nNOS/NADPH-diaphorase colocalization. There were also nNOS/ NADPH-d-positive cap-like terminals on ciliary ganglion cells. The presence of VIP/nNOS/NADPH-diaphorase positive neurons and nerve fibers in both the choroid and ciliary ganglion, and in the choroidal perivascular plexus, indicates peripheral nitrergic and VIPergic control of blood flow in the choroid of the duck. [ABSTRACT FROM AUTHOR]

We compared changes in gastric mucosal bloodflow (GMBF) and left gastric artery blood flow (LGABF)in response to pharmacological, physiological, andpathological stimuli. GMBF and LGABF were measured by the hydrogen gas clearance and perivascularultrasonic transit time techniques, respectively, underbaseline conditions and following intravenous infusionof vasopressin or pentagastrin, isovolemic hemodilution, or gastric perfusion with HCl-taurocholate.Blood flow changes following vasopressin or hemodilutionwere significantly larger in the left gastric arterythan in the gastric mucosa. In contrast, the increment in blood flow associated withpentagastrin-stimulated acid secretion was significantlygreater in the gastric mucosa than in the extramuralartery. Barrier disruption with acid-taurocholateinduced similar changes in both measurement sites. The gastrichyperemia induced by either mechanism was significantlyattenuated by blockade of NO synthesis. These datademonstrate that although functional changes in GMBF are primarily supported by changes inblood flow at the extramural gastric arteries, thegastric mucosal microvasculature is also under theinfluence of independent local controlmechanisms. [ABSTRACT FROM AUTHOR]

The effects of different [Ca] in the presence of variable [Na] (100 to 37 mM) on the slow action potentials were studied in isolated rat atria in the presence of 25 mM K plus 10 M isoproterenol. Two modes of electrical stimulation were used, sustained stimulation at 0.5 Hz ('steady-state' mode), and stimulation by a single stimulus after rest periods of 2 to 5 min ('1st response' mode). With the first type of stimulation, and for [Ca] between 0.5 and 10 mM and [Na] between 100 and 65 mM, the slow action potential overshoot increased linearly with the logarithm of the [Ca] (28.4 mV per 10-fold change in [Ca]). However, elevation of [Ca] above 10 mM caused depression of the overshoot. This overshoot depression by high [Ca] was accentuated if [Na] was decreased to 37 mM. With the '1st response' mode of stimulation, the overshoot - log [Ca] relationship was linear within a wider [Ca] range (0.5 to 25 mM), and was less sensitive to further decreases in [Na]. It is suggested that rat atria slow action potentials are generated by selective influx of Ca but not Na, and that the depression of amplitudes observed a high [Ca] and low [Na] is due to a decrease in the Na exchange mechanism which results in a higher [Ca], and not to a decrease in the inward Na current. Adenosine produced a parallel downward displacement of the overshoot to log [Ca] relationship. This adenosine effect was concentration dependent, independent of [Ca] and the frequency of stimulation. In contrast, the effects of 0.4 mM La were dependent on the [Ca] and on the frequency of stimulation. Adenosine also produced a downward shift of the relationship between maximal rate of rise of the slow action potential and membrane resting potential in such a manner that its effects cannot be attributed to changes in inactivation potential of the slow channels. Hence, adenosine and La depress the slow Ca action potentials by two different mechanisms. Adenosine may act by 1) decreasing the number of functional slow channels, 2) decreasing the conductance of the individual channels, or 3) altering the kinetic properties of these channels. La may act by competing with Ca for membrane binding sites. These membrane binding sites appear to be characterized by frequency dependence. [ABSTRACT FROM AUTHOR]

Background Abnormal renal hemodynamic responses to salt-loading are thought to contribute to salt-sensitive (SS) hypertension. However, this is based largely on studies in anesthetized animals, and little data are available in conscious SS and salt-resistant rats. Methods and Results We assessed arterial blood pressure, renal function, and renal blood flow during administration of a 0.4% NaCl and a high-salt (4.0% NaCl) diet in conscious, chronically instrumented 10- to 14-week-old Dahl SS and consomic SS rats in which chromosome 1 from the salt-resistant Brown-Norway strain was introgressed into the genome of the SS strain (SS.BN1). Three weeks of high salt intake significantly increased blood pressure (20%) and exacerbated renal injury in SS rats. In contrast, the increase in blood pressure (5%) was similarly attenuated in Brown-Norway and SS.BN1 rats, and both strains were completely protected against renal injury. In SS.BN1 rats, 1 week of high salt intake was associated with a significant decrease in renal vascular resistance (-8%) and increase in renal blood flow (15%). In contrast, renal vascular resistance failed to decrease, and renal blood flow remained unchanged in SS rats during high salt intake. Finally, urinary sodium excretion and glomerular filtration rate were similar between SS and SS.BN1 rats during 0.4% NaCl and high salt intake. Conclusions Our data support the concept that renal vasodysfunction contributes to blood pressure salt sensitivity in Dahl SS rats, and that genes on rat chromosome 1 play a major role in modulating renal hemodynamic responses to salt loading and salt-induced hypertension.

The energy demands of neurons are met by a constant supply of glucose and oxygen via the cerebral vasculature. The cerebral cortex is perfused by dense, parallel arterioles and venules, consistently in imbalanced ratios. Whether and how arteriole-venule arrangement and ratio affect the efficiency of energy delivery to the cortex has remained an unanswered question. Here, we show by mathematical modeling and analysis of the mapped mouse sensory cortex that the perfusive efficiency of the network is predicted to be limited by low-flow regions produced between pairs of arterioles or pairs of venules. Increasing either arteriole or venule density decreases the size of these low-flow regions, but increases their number, setting an optimal ratio between arterioles and venules that matches closely that observed across mammalian cortical vasculature. Low-flow regions are reshaped in complex ways by changes in vascular conductance, creating geometric challenges for matching cortical perfusion with neuronal activity., Competing Interests: The authors declare no competing interest.

The vascular endothelium senses and integrates numerous inputs to regulate vascular tone. Recent evidence reveals complex signal processing within the endothelium, yet little is known about how endothelium-dependent stimuli interact to regulate blood flow. We tested the hypothesis that combined stimulation of the endothelium with adenosine triphosphate (ATP) and acetylcholine (ACh) elicits greater vasodilation and attenuates α 1 -adrenergic vasoconstriction compared with combination of ATP or ACh with the endothelium-independent dilator sodium nitroprusside (SNP). We assessed forearm vascular conductance (FVC) in young adults (6 women, 7 men) during local intra-arterial infusion of ATP, ACh, or SNP alone and in the following combinations: ATP + ACh, SNP + ACh, and ATP + SNP, wherein the second dilator was coinfused after attaining steady state with the first dilator. By design, each dilator evoked a similar response when infused separately (ΔFVC, ATP: 48 ± 4; ACh: 57 ± 6; SNP: 53 ± 6 mL·min -1 ·100 mmHg -1 ; P ≥ 0.62). Combined infusion of the endothelium-dependent dilators evoked greater vasodilation than combination of either dilator with SNP (ΔFVC from first dilator, ATP + ACh: 45 ± 9 vs. SNP + ACh: 18 ± 7 and ATP + SNP: 26 ± 4 mL·min -1 ·100 mmHg -1 , P < 0.05). Phenylephrine was subsequently infused to evaluate α 1 -adrenergic vasoconstriction. Phenylephrine elicited less vasoconstriction during infusion of ATP or ACh versus SNP (ΔFVC, -25 ± 3 and -29 ± 4 vs. -48 ± 3%; P < 0.05). The vasoconstrictor response to phenylephrine was further diminished during combined infusion of ATP + ACh (-13 ± 3%; P < 0.05 vs. ATP or ACh alone) and was less than that observed when either dilator was combined with SNP (SNP + ACh: -26 ± 3%; ATP + SNP: -31 ± 4%; both P < 0.05 vs. ATP + ACh). We conclude that endothelium-dependent agonists interact to elicit vasodilation and limit α 1 -adrenergic vasoconstriction in humans. NEW & NOTEWORTHY The results of this study highlight the vascular endothelium as a critical site for integration of vasomotor signals in humans. To our knowledge, this is the first study to demonstrate that combined stimulation of the endothelium with ATP and ACh results in enhanced vasodilation compared with combination of either ATP or ACh with an endothelium-independent dilator. Furthermore, we show that ATP and ACh interact to modulate α 1 -adrenergic vasoconstriction in human skeletal muscle in vivo.

Denervation of sensory and sympathetic nerve fibers and reduced blood flow result in decreased bone mineral density (BMD). In this study, we aim to detect the effect of compression of brachial plexus and subclavian vessels on the forearm BMD in patients with thoraric outlet syndrome (TOS). Twenty-three patients with TOS (17 females and 6 males) were enrolled in the study. Thirty-three extremities of the patients with TOS were classified as true neurogenic (1), vascular (15) and disputed neurogenic TOS (17). Thirty upper extremities of 15 age- and sex-matched healthy subjects were evaluated as controls. Electrophysiological testings and Doppler ultrasonography were performed. Comparisons of the dominant and the non-dominant forearm BMD between patients and controls, and between the involved and the non-involved sides in TOS patients revealed no significant differences ( P < 0.05). In conclusion, intermittent compression of brachial plexus and subclavian vessels in patients with disputed and vascular TOS does not seem to affect forearm BMD. Further studies are needed to detect the effect of persistent neurovascular compression in TOS. [ABSTRACT FROM AUTHOR]

With the growing prevalence of obesity and impaired glycemic control, and the correlation between these conditions and an elevated predisposition for the development of vascular disease, research emphases are increasingly being targeted to the mechanistic bases and functional outcomes of these relationships. Given this, the current issue of Microcirculation, presents a series of reviews that summarize knowledge on an array of topics relevant to obesity, insulin resistance, and vascular dysfunction. The first chapters discuss altered patterns of blood flow regulation, vascular reactivity, microvascular density, and vascular wall mechanics. The second grouping details alterations to coronary, renal, and hepatic circulations and the implications of these effects for organ function. Additionally, one article presents knowledge and outlines future research directions for the study of endothelial permeability and barrier function within insulin resistance. The last group of articles discusses the effects of inflammation with obesity and insulin resistance on vascular function, and also details the role of perivascular adipose tissue in contributing to vascular dysfunction. The final review extends this general topic to the effects of the metabolic syndrome on microvascular dysfunction, wherein obesity and impaired glycemic control are contributing elements to a larger constellation of systemic pathologies. The authors hope that this Special Topics Issue will be informative for its readers and will provide a basis for future investigation into microvasculopathy in obesity and insulin-resistance. [ABSTRACT FROM AUTHOR]