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Tributyltin chloride (TBT) is an organotin compound that reduces estrogen levels in female rats. We aimed to investigate the effects of TBT exposure on vascular tonus and vascular remodelling in the resistance arteries of female rats. Rats were treated daily with TBT (500 ng/kg) for 15 days. TBT did not change arterial blood pressure but did modify some morpho-physiological parameters of third-order mesenteric resistance arteries in the following ways: (1) decreased lumen and external diameters; (2) increased wall/lm ratio and wall thickness; (3) decreased distensibility and increased stiffness; (4) increased collagen deposition; and (5) increased pulse wave velocity. TBT exposure increased the phenylephrine-induced contractile response in mesenteric resistance arteries. However, vasodilatation responses induced by acetylcholine and sodium nitroprusside were not modified by TBT. It is suggested that TBT exposure reduces vascular nitric oxide (NO) production, because:(1) L-NAME incubation did not cause a leftward shift in the concentration–response curve for phenylephrine; (2) both eNOS protein expression; (3) in situ NO production were reduced. Incubation with L-NAME; and (4) SOD shifted the phenylephrine response curve to the left in TBT rats. Tiron, catalase, ML-171 and VAS2870 decreased vascular reactivity to phenylephrine only in TBT rats. Moreover, increased superoxide anion production was observed in the mesenteric resistance arteries of TBT rats accompanied by an increase in gp91phox, catalase, AT 1 receptor and total ERK1/2 protein expression. In conclusion, these findings show that TBT induced alterations are most likely due to a reduction of NO production combined with increased O 2 − production derived from NADPH oxidase and ERK1/2 activation. These findings offer further evidence that TBT is an environmental risk factor for cardiovascular disease. [ABSTRACT FROM AUTHOR]

The incidence of hypertension, the major modifiable risk factor for cardiovascular disease, is increasing. Thus, there is a pressing need for the development of new and more effective strategies to prevent and treat hypertension. Development of these relies on a continued evolution of our understanding of the mechanisms which control blood pressure (BP). Resistance arteries are important in the regulation of total peripheral resistance and BP; changes in their structure and function are strongly associated with hypertension. Anti-hypertensives which both reduce BP and reverse changes in resistance arterial structure reduce cardiovascular risk more than therapies which reduce BP alone. Hence, identification of novel potential vascular targets which modify BP is important. Hypertension is a multifactorial disorder which may include a genetic component. Genome wide association studies have identified ATP2B1 , encoding the calcium pump plasma membrane calcium ATPase 1 (PMCA1), as having a strong association with BP and hypertension. Knockdown or reduced PMCA1 expression in mice has confirmed a physiological role for PMCA1 in BP and resistance arterial regulation. Altered expression or inhibition of PMCA4 has also been shown to modulate these parameters. The mechanisms whereby PMCA1 and 4 can modulate vascular function remain to be fully elucidated but may involve regulation of intracellular calcium homeostasis and/or comprise a structural role. However, clear physiological links between PMCA and BP, coupled with experimental studies directly linking PMCA1 and 4 to changes in BP and arterial function, suggest that they may be important targets for the development of new pharmacological modulators of BP. [ABSTRACT FROM AUTHOR]

BACKGROUND Creatine kinase (CK) is a main predictor of blood pressure, and this is thought to largely depend on high resistance artery contractility. We previously reported an association between vascular contractility and CK in normotensive pregnancy, but pregnancy is a strong CK inducer, and data on human hypertension are lacking. Therefore, we further explored CK-dependency of vascular contractility outside the context of pregnancy in normotensive and hypertensive women. METHODS AND RESULTS Nineteen consecutive women, mean age 42 years (SE 1.3), mean systolic/ diastolic blood pressure respectively 142.6 (SE 5.9)/85.6 (3.4) mm Hg (9 hypertensive), donated an omental fat sample during abdominal surgery. We compared vasodilation after the specific CK inhibitor 2,4-dinitro-1-fluorobenzene (DNFB; 10-6 mol/l) to sodium nitroprusside (10-6 mol/l) in isolated resistance arteries using a wire myograph. Additionally, we assessed predictors of vasoconstrictive force. DNFB reduced vascular contractility to 24.3% (SE 4.4), P < 0.001, compared to baseline. Sodium nitroprusside reduced contractility to 89.8% (SE 2.3). Maximum contractile force correlated with DNFB effect as a measure of CK (r = 0.8), and with vessel diameter (r = 0.7). The increase in contractile force was 16.5 mN [9.1-23.9] per unit DNFB effect in univariable and 10.35 mN [2.10-18.60] in multivariable regression analysis. CONCLUSION This study extends on our previous findings in pregnant normotensive women of CK-dependent microvascular contractility, indicating that CK contributes significantly to resistance artery contractility across human normotension and primary hypertension outside the context of pregnancy. Further studies should explore the effect of CK inhibitors on clinical blood pressure. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) was first described as a bioactive molecule through its ability to stimulate soluble guanylate cyclase, but the revelation that NO was the endothelium derived relaxation factor drove the field to its modern state. The wealth of research conducted over the past 30 years has provided us with a picture of how diverse NO signaling can be within the vascular wall, going beyond simple vasodilation to include such roles as signaling through protein S-nitrosation. This expanded view of NO's actions requires highly regulated and compartmentalized production. Importantly, resistance arteries house multiple proteins involved in the production and transduction of NO allowing for efficient movement of the molecule to regulate vascular tone and reactivity. In this review, we focus on the many mechanisms regulating NO production and signaling action in the vascular wall, with a focus on the control of endothelial nitric oxide synthase (eNOS), the enzyme responsible for synthesizing most of the NO within these confines. We also explore how cross talk between the endothelium and smooth muscle in the microcirculation can modulate NO signaling, illustrating that this one small molecule has the capability to produce a plethora of responses. [ABSTRACT FROM AUTHOR]

Prolonged vasoconstrictorstimulated phospholipase C activity can induce arterial constriction, hypertension, and smooth muscle hypertrophy/hyperplasia. Arrestin proteins are recruited by agonist-occupied G protein-coupled receptors to terminate signaling and counteract changes in vascular tone. Here we determine whether the development of hypertension affects arrestin expression in resistance arteries and how such changes alter arterial contractile signaling and function. Arrestin2/3 expression was increased in mesenteric arteries of 12-wk-old spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto (WKY) controls, while no differences in arrestin expression were observed between 6-wk-old SHR and WKY animals. In mesenteric artery myography experiments, high extracellular K+-stimulated contractions were increased in both 6- and 12-wk-old SHR animals. Concentration-response experiments for uridine 5=-triphosphate (UTP) acting through P2Y receptors displayed a leftward shift in 12-wk, but not 6-wk-old animals. Desensitization of UTP-stimulated vessel contractions was increased in 12-wk-old (but not 6-wk-old) SHR animals. Dual IP3/Ca2+ imaging in mesenteric arterial cells showed that desensitization of UTP and endothelin-1 (ET1) responses was enhanced in 12-wk-old (but not 6-wk-old) SHR compared with WKY rats. siRNA-mediated depletion of arrestin2 for UTP and arrestin3 for ET1, reversed the desensitization of PLC signaling. In conclusion, arrestin2 and 3 expression is elevated in resistance arteries during the emergence of the early hypertensive phenotype, which underlies an enhanced ability to desensitize vasoconstrictor signaling and vessel contraction. Such regulatory changes may act to compensate for increased vasoconstrictor-induced vessel contraction. [ABSTRACT FROM AUTHOR]

The author comments on the state-of-the-art including comprehensive meta-analytic data through macro- and microvascular dilator function in primarily endurance-trained athletes and an insight on challenges to the field. Topics cited include suggestion that enhanced arterial dilator function that interacts with increased arterial constrictor function or sympathetic constrictor drive and the contribution of optimal arterial function with regards to exercise performance to maximize blood flow.

Leptin plays a crucial role in blood pressure (BP) regulation, notably in the context of obesity through central sympatho-mediated pressor effects. Leptin also relaxes arteries via endothelial (EC) leptin receptor (LepREC)-mediated increases in nitric oxide (NO) bioavailability. Herein, we investigated whether leptin-mediated increases in NO bioavailability represent a buffering mechanism against leptin-induced sympatho-activation. We tested the direct contribution of LepREC to BP regulation in physiological conditions and in response to chronic leptin infusion using mice deficient in LepREC. LepREC deficiency did not alter baseline metabolic profile nor leptin-induced reduction in adiposity and increases in energy expenditure. LepREC−/− mice demonstrated no increase in baseline BP and heart rate (HR) (MAP: LepREC+/+:94.7 ± 1.6, LepREC−/−:95.1 ± 1.8 mmHg; HR:LepREC+/+:492.4 ± 11.7, LepREC−/−:509.5 ± 13.4 bpm) nor in response to leptin (MAP, LepREC+/+:101.1 ± 1.7, LepREC−/−:101.7 ± 1.8 mmHg; HR, LepREC+/+:535.6 ± 11.1, LepREC−/−:539.3 ± 14.2 bpm). Moreover, baseline neurogenic control of BP and HR was preserved in LepREC−/− mice as well as leptin-mediated increases in sympathetic control of BP and HR and decreases in vagal tone. Remarkably, LepREC deficiency did not alter endothelium-dependent relaxation in resistance vessels, nor NO contribution to vasodilatation. Lastly, leptin induced similar increases in adrenergic contractility in mesenteric arteries from both LepREC+/+ and LepREC−/− mice. Collectively, these results demonstrate that the NO buffering effects of leptin are absent in resistance arteries and do not contribute to BP regulation. We provide further evidence that leptin-mediated hypertension involves increased vascular sympatho-activation and extend these findings by demonstrating for the first time that increased cardiac sympatho-activation and reduced vagal tone also contribute to leptin-mediated hypertension. [Display omitted] • Leptin-induced NO bioavailability is absent in resistance arteries. • Endothelial leptin signaling does not contributes to blood pressure regulation. • Leptin-induced endothelial NO bioavailability is specific to conductance arteries. • Endothelial NO does not buffer leptin-mediated sympatho-activation. • Leptin-induced hypertension involves cardiac sympatho-excitation and reduced vagal tone. [ABSTRACT FROM AUTHOR]

Conducted vasodilation is essential to coordinate vascular resistance along distances to ensure adequate tissue perfusion. We hypothesized that conducted vasodilation of coronary resistance arteries declines with age. Coronary arterioles were dissected from right atrial appendage of patients (n = 27) undergoing cardiac surgery. Arterioles (~100 μm) were cannulated and pressurized (80 mmHg), and developed spontaneous myogenic tone. Conducted vasodilation was initiated by locally administering the endothelium-dependent agonist bradykinin (BK; 100 μM) ejected from a glass micropipette (~3 μm tip opening, positioned in close proximity to the vessel wall). Diameter changes were measured at local and upstream sites (500 and 1,000 μm from the stimulus) with videomicroscopy. Local administration of BK elicited vasodilation, the magnitude of which increased with the duration of stimulus (69 ± 6, 81 ± 6, 90 ± 2%, after 1, 3, and 5 - 100 ms, respectively). BK-induced dilation remained substantial at upstream sites (500 μm: 53 ± 7%; 1,000 μm: 46 ± 9%). The gap junction uncoupler carbenoxolone or 18-α-glycyrrhetinic acid did not affect local responses, but diminished conducted vasodilation. Inhibitors of small/intermediate conductance calcium-activated potassium channels (SKCa/IKCa), apamin and TRAM34, reduced dilations both at local and remote sites. We found that conducted dilation, but not the local response, was significantly reduced in older (≥64 yr) patients. The nitric oxide (NO) synthesis inhibitor Nω-nitro-L-arginine methyl ester did not affect local responses, but markedly reduced conducted dilation in younger (<64 yr) individuals. Collectively, we show that human coronary arterioles exhibit SKCa/IKCa-mediated hyperpolarization spread through gap junctions, which contributes to conducted vasodilation initiated by focal application of BK. We demonstrate that conducted dilation declines with age, likely due to reduced NO availability, which plays a permissive role in propagating longitudinal vasomotor signaling. [ABSTRACT FROM AUTHOR]

Abstract: Through interference with free radicals, the nitroxide tempol potentially increases bioavailability of nitric oxide (NO) and along with modulation of potassium channels reduces blood pressure (BP). We studied whether tempol in pigs lowers BP by mechanisms sensitive to inhibition of NO synthase or large conductance calcium-activated potassium channels (BKCa). The cardiovascular effects of intravenous tempol (25–50mg/kg) were examined in anesthetized pigs with myocardial function being evaluated by echocardiography. While saline-treated animals remained hemodynamically stable, tempol induced fast, dose-dependent and transient reductions in BP lasting 5–10min with a simultaneous impairment of left ventricular contraction. Pretreatment with the NO synthase (NOS) inhibitor N G-nitro-l-arginine methyl ester (l-NAME, 4mg/kg) or a blocker of BKCa (tetraethylammonium (TEA), 100mg/h) increased baseline BP but also enhanced BP reductions to tempol. Isolated myocardial trabeculae subjected to an identical protocol also demonstrated dose-related reductions in contractility to tempol. This effect was not affected by l-NAME, but attenuated by TEA. In isolated mesenteric resistance arteries contracted with noradrenaline, tempol caused small postjunctional l-NAME sensitive relaxations, while neurogenic contractions were inhibited by tempol by TEA-sensitive mechanisms and mechanisms insensitive to TEA and l-NAME. In conclusion intravenous tempol induces fast transient reductions in BP associated with simultaneous reductions in myocardial contraction. Tempol exerts direct negative inotropic effects which are partly sensitive to BKCa-blockade but independent of NOS inhibition. In addition tempol has direct vasodilatory effects despite NOS and potassium channel blockade. The negative inotropic and hypotensive effects raise concerns using tempol, or structurally similar drugs, for intravenous use. [Copyright &y& Elsevier]

Aims High fructose levels are found in diabetes mellitus, associated with high corn syrup diets, and have been claimed to cause hypertension. As the direct effects on conduit and resistance arteries have not been previously reported, we measured these in vivo in the anaesthetized pig with instrumented iliac arteries. Methods Experiments were performed on the iliac artery preparation in the anaesthetized pig: blood flow, diameter and pressure were measured in the iliac. Results The change in diameter of an occluded iliac artery segment filled with hyperfructosemic (15 μ m) blood was 89.5 ± 22.1 μm (mean ± SE), contrasted with 7.7 ± 13.06 μm control ( P = 0.005, paired t-test, n = 6). There was no significant difference when compared with blood containing both hyperfructosemic blood and the nitric oxide synthesis inhibitor, N( G)-nitro- l-arginine methyl ester (250 μg mL−1). Step changes in pressure and flow were achieved by progressive arterial stenosis during control saline and 15 μ m min−1 fructose downstream intra-arterial infusions. Linear regression of the step changes in blood pressure versus the instantaneous step changes in blood flow showed a statistically significant decrease in slope of the conductance ( P < 0.001, analysis of covariance), indicating an increase in instantaneous peripheral vascular resistance. Peripheral autoregulation and conduit artery shear-stress-mediated dilatation were not significantly altered. Conclusion An elevated level of fructose caused dilatation of a conduit artery but constriction of resistance vessels. The latter effect could account, if maintained long-term, for the hypertension claimed to be due to hyperfuctosemia. [ABSTRACT FROM AUTHOR]

Prevention of target organ damage represents the El Dorado for clinicians who treat hypertension. Although many of the cardiovascular sequelae of chronic hypertension are due to large artery atherosclerosis, an equal number are due to small artery dysfunction. These microvascular complications include eye disease (retinopathy), kidney failure, diastolic dysfunction of the heart and small vessel brain disease leading to stroke syndromes, dementia and even depression. Examination of the retinal vasculature represents the only way to reliably derive information regarding small arteries responsible for these diverse pathologies. This review aims to summarise the rapidly accruing evidence indicating that easily observable abnormalities of retinal arteries reflect target organ damage elsewhere in the body of hypertensive patients. In tandem, we also present putative mechanisms by which hypertension and diabetes fundamentally change small artery structure and function and how these processes may lead to target organ damage. [ABSTRACT FROM AUTHOR]

Abstract: Aims: We hypothesized that arachidonic acid produced by anandamide breakdown contributes to the vascular effects of anandamide. Main methods: Isolated, pressurized rat skeletal muscle arteries, which possess spontaneous myogenic tone, were treated with anandamide, arachidonic acid, capsaicin (vanilloid receptor agonist), WIN 55-212-2 (cannabinoid receptor agonist), URB-597 (FAAH inhibitor), baicalein (lipoxygenase inhibitor), PPOH (cytochrome P450 inhibitor), and indomethacin (cyclooxygenase inhibitor). Changes in the arteriolar diameter in response to the various treatments were measured. To assess the effect of anandamide metabolism, anandamide was applied for 20min followed by washout for 40min. This protocol was used to eliminate other, more direct effects of anandamide in order to reveal how anandamide metabolism may influence vasodilation. Key findings: Anandamide at a low dose (1μM) evoked a loss of myogenic tone, while a high dose (30μM) not only attenuated the myogenic response but also evoked acute dilation. Both of these effects were inhibited by the FAAH inhibitor URB-597 and were mimicked by arachidonic acid. The CB1 and CB2 agonist R-WIN 55-212-2 and the vanilloid receptor agonist capsaicin were without effect on the myogenic response. The inhibition of the myogenic response by anandamide was blocked by indomethacin and PPOH, but not by baicalein or removal of the endothelium. FAAH expression in the smooth muscle cells of the blood vessels was confirmed by immunohistochemistry. Significance: Anandamide activates the arachidonic acid pathway in the microvasculature, affecting vascular autoregulation (myogenic response) and local perfusion. [Copyright &y& Elsevier]

Aims The lipid and protein kinase phosphoinositide 3-kinase γ (PI3Kγ) is abundantly expressed in inflammatory cells and in the cardiovascular tissue. In recent years, its role in inflammation and in cardiac function and remodelling has been unravelled, highlighting the beneficial effects of its pharmacological inhibition. Furthermore, a role for PI3Kγ in the regulation of vascular tone has been emphasized. However, the impact of this signalling in the control of blood pressure is still poorly understood. Our study investigated the effect of a selective inhibition of PI3Kγ, obtained by using two independent small molecules, on blood pressure. Moreover, we dissected the molecular mechanisms involved in control of contraction of resistance arteries by PI3Kγ. Methods and results We showed that inhibition of PI3Kγ reduced blood pressure in normotensive and hypertensive mice in a concentration-dependent fashion. This effect was dependent on enhanced vasodilatation, documented in vivo by decreased peripheral vascular resistance, and ex vivo by vasorelaxing effects on isolated resistance vessels. The vasorelaxation induced by PI3Kγ inhibition relied on blunted pressure-induced Akt phosphorylation and a myogenic contractile response. Molecular insights revealed that PI3Kγ inhibition affected smooth muscle L-type calcium channel current density and calcium influx by impairing plasma membrane translocation of the α1C L-type calcium channel subunit responsible for channel open-state probability. Conclusion Overall our findings suggest that PI3Kγ inhibition could be a novel tool to modulate calcium influx in vascular smooth muscle cells, thus relaxing resistance arteries and lowering blood pressure. [ABSTRACT FROM AUTHOR]

Statins can have beneficial cholesterol-independent effects on vascular contractility, which may involve increases in the bioavailability of NO (nitric oxide) as a result of phosphorylation of eNOS (endothelial NO synthase). Although this has been attributed to phosphorylation of Akt (also known as protein kinase B), studies in cultured cells have shown that statins can phosphorylate AMPK (AMP-activated protein kinase); it is unknown whether this has functional effects in intact arteries. Thus we investigated the acute effects of simvastatin on resistance arterial contractile function, evaluating the involvement of NO, Akt and AMPK. Isolated rat mesenteric resistance arteries were mounted on a wire myograph. The effects of incubation (1 and 2 h) with simvastatin (0.1 or 1 μM) on contractile responses were examined in the presence and absence of L-NNA (Nnitro- L-arginine; 10 μM) or mevalonate (1 mM). Effects on eNOS, phospho-eNOS (Ser1177), and total and phospho-Akt and -AMPK protein expression were investigated using Western blotting. The effect of AMPK inhibition (compound C, 10 μM) on eNOS phosphorylation and contractile responses were also studied. Simvastatin (1 μM, 2 h) significantly reduced constriction to U46619 and phenylephrine and enhanced dilations to ACh (acetylcholine) in depolarized, but not in U46619-pre-constricted arteries. These effects were completely and partially prevented by LNNA and mevalonate respectively. Simvastatin increased eNOS and AMPKα phosphorylation, but had no effect on Akt protein expression and phosphorylation after 2 h incubation. Compound C prevented the effects of simvastatin on eNOS phosphorylation and contractility. Thus simvastain can acutely modulate resistance arterial contractile function via mechanisms that involve the AMPK/phospho-eNOS (Ser1177)/NO-dependent pathway. [ABSTRACT FROM AUTHOR]

To study Ca2+ signaling in the endothelium of murine feed arteries, we determined the in vitro stability of endothelial cell (EC) tubes freshly isolated from abdominal muscle feed arteries of male and female C57BL/6 mice (5-9 mo, 25-35 g). We tested the hypothesis that intracellular Ca2+ concentration ([Ca2+]i) responses to muscarinic receptor activation would increase with temperature. Intact EC tubes (length: 1-2 mm, width: 65-80 μm) were isolated using gentle enzymatic digestion with trituration to remove smooth muscle cells. A freshly isolated EC tube was secured in a chamber and superfused at 24 (room temperature), 32, or 37°C. Using fura-2 dye, [Ca2+]i was monitored (ratio of fluorescence at 340- to 380-nm wavelength) at rest and in response to bolus doses of ACh (20 nmol to 200 μmol). The morphological integrity of EC tubes was preserved at 24 and 32°C. Based on the Ca2+ Kd values we determined for fura-2 (174 nM at 24°C and 146 nM at 32°C), resting [Ca2+]i remained stable for 180 min at both 24 and 32°C (27 ± 4 and 34 ± 2 nM, respectively), with peak responses to ACh (20 μmol) increasing from ∼220 nM at 24°C to ∼500 nM at 32°C (P < 0.05). There was no difference in responses to ACh between EC tubes from male versus female mice. When EC tubes were maintained at 37°C (typical in vivo temperature), resting [Ca2+]i increased by ∼30% within 15 min, and gaps formed between individual ECs as they retracted and extruded dye, precluding further study. We conclude that EC tubes enable Ca2+ signaling to be evaluated in the freshly isolated endothelium of murine feed arteries. While Ca2+ responses are enhanced by approximately twofold at 32 versus 24°C, the instability of EC tubes at 37°C precludes their study at typical body temperature. [ABSTRACT FROM AUTHOR]

We investigated an effect of uraemia on structural and functional features of human resistance vasculature. Arteries (≈ 200 μm) isolated from subcutaneous fat biopsies obtained from 35 ESRD (end-stage renal disease) patients starting peritoneal dialysis and 30 matched controls were studied using isolated small artery bioassays. Flow-mediated dilatation was attenuated in ESRD patients compared with controls. NO (nitric oxide) contribution to flow was lacking in ESRD patients, but present in the controls. ADMA (asymmetrical dimethyl L-arginine) levels were higher in the ESRD group compared with the control group. Dilatation in response to acetylcholine was reduced in ESRD patients compared with controls, but response to NO donor was similar. Expression of nitrotyrosine and heat shock proteins 70 and 27, but not 90, was increased in arteries from ESRD patients compared with controls. Arterial remodelling was absent in ESRD patients. There was no difference between the groups in myogenic tone, vascular reactivity or sensitivity to several vasoconstrictors. Arterial distensibility, reflecting passive properties of the vascular wall, was reduced in ESRD patients compared with controls. Exclusion of ESRD patients with diabetes and/or cardiovascular disease from analyses had no influence on the main findings. Thus we propose that uraemia has a strong impact on endothelial function and passive properties of the arterial wall of human peripheral resistance vasculature. The reduced contribution of NO to flow stimulus via enhanced nitrosative stress and higher plasma concentrations of ADMA may suggest potential mechanisms behind endothelial dysfunction in the resistance peripheral circulation in ESRD. [ABSTRACT FROM AUTHOR]

Aims Prolonged P2Y-receptor signalling can cause vasoconstriction leading to hypertension, vascular smooth muscle hypertrophy, and hyperplasia. G protein-coupled receptor signalling is negatively regulated by G protein-coupled receptor kinases (GRKs) and arrestin proteins, preventing prolonged or inappropriate signalling. This study investigates whether GRKs and arrestins regulate uridine 5′-triphosphate (UTP)-stimulated contractile signalling in adult Wistar rat mesenteric arterial smooth muscle cells (MSMCs). Methods and results Mesenteric arteries contracted in response to UTP challenge: When an EC50 UTP concentration (30 µM, 5 min) was added 5 min before (R1) and after (R2) the addition of a maximal UTP concentration (Rmax: 100 µM, 5 min), R2 responses were decreased relative to R1, indicating desensitization. UTP-induced P2Y-receptor desensitization of phospholipase C signalling was studied in isolated MSMCs transfected with an inositol 1,4,5-trisphosphate biosensor and/or loaded with Ca2+-sensitive dyes. A similar protocol (R1/R2 = 10 µM; Rmax = 100 µM, applied for 30 s) revealed markedly reduced R2 when compared with R1 responses. MSMCs were transfected with dominant-negative GRKs or siRNAs targeting specific GRK/arrestins to probe their respective roles in P2Y-receptor desensitization. GRK2 inhibition, but not GRK3, GRK5, or GRK6, attenuated P2Y-receptor desensitization. siRNA-mediated knockdown of arrestin2 attenuated UTP-stimulated P2Y-receptor desensitization, whereas arrestin3 depletion did not. Specific siRNA knockdown of the P2Y2-receptor almost completely abolished UTP-stimulated IP3/Ca2+ signalling, strongly suggesting that our study is specifically characterizing this purinoceptor subtype. Conclusion These new data highlight roles of GRK2 and arrestin2 as important regulators of UTP-stimulated P2Y2-receptor responsiveness in resistance arteries, emphasizing their potential importance in regulating vasoconstrictor signalling pathways implicated in vascular disease. [ABSTRACT FROM AUTHOR]

1. Coordinated oscillations in diameter occur spontaneously in cerebral vessels and depend on the opening of voltage dependent calcium channels. However, the mechanism that induces the initial depolarisation has remained elusive. We investigated the involvement of canonical transient receptor potential (TRPC) channels, which encode nonselective cation channels passing Na+ and Ca2+ currents, by measuring changes in diameter, intracellular Ca2+ and membrane potential in branches of juvenile rat basilar arteries. 2. Removal of extracellular Ca2+ abolished vasomotion and relaxed arteries, but paradoxically produced depolarisation. 3. Decrease in temperature to 24°C or inhibition of phospholipase C (PLC) abolished vasomotion, hyperpolarised and relaxed arteries and decreased intracellular Ca2+. 4. Reduction in the driving force for Na+ through decrease in extracellular Na+ produced similar effects and prevented the depolarisation elicited by removal of extracellular Ca2+. 5. Nonselective TRP channel blockers, SKF96365 and gadolinium, mimicked the effects of inhibition of the PLC pathway. 6. Depolarisation of vessels in which TRP channels were blocked with SKF96365 reinstated vascular tone and vasomotion. 7. Quantitative polymerase chain reaction revealed TRPC1 as the predominantly expressed TRPC subtype. 8. Incubation with a function blocking TRPC1 antibody delayed the onset of vasomotion. 9. We conclude that nonselective cation channels contribute to vasoconstriction and vasomotion of cerebral vessels by providing an Na+-induced depolarisation that activates voltage dependent calcium channels. Our antibody data suggest the involvement of TRPC1 channels that might provide a target for treatment of therapy-refractory vasospasm. [ABSTRACT FROM AUTHOR]

Background/Aims: To identify the relationship between systemic and local hemodynamics, as well as segmental biomechanical properties in a musculocutaneous resistance artery during angiotensin-II hypertension and its recovery. Methods: Rats were infused with angiotensin-II using implanted osmotic minipumps (ALZET 2ML4, 150 ng/kg/min) for 4 weeks. Measurements were made either immediately following infusion or after an additional 4-week recovery period. Parallel controls were created. Segmental geometry and blood flow were determined in vivo on microsurgically exposed segments of the saphenous arterial branch (350 μm). Pressure-radius plots of excised cylindrical segments were recorded by pressure arteriography. Results: Eutrophic hypertensive wall remodeling developed, with reduced passive radius, increased wall thickness, elevated low-stress elastic modulus, reduced norepinephrine contraction, and reduced endothelium-mediated dilation. Relaxed wall geometry fully healed in 4 weeks of recovery, but an increased contractility and a reduced in vivo lumen persisted. Regional hemodynamic resistance correlated positively with systemic arterial pressure and wall thickness in vivo, and negatively with in vivo lumen size throughout these studies. Conclusion: A partial recovery of the biomechanical parameters was found. Healing of eutrophic hypertensive remodeling of the resistance artery wall is a complex biomechanical process, not a simple reversal of the original pathological sequel. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aims: Prolonged endothelin (ET) receptor signalling causes vasoconstriction and can lead to hypertension, vascular smooth muscle hypertrophy, and hyperplasia. Usually, G protein-coupled receptor signalling is negatively regulated by G protein-coupled receptor kinases (GRKs), preventing prolonged or inappropriate signalling. This study investigated whether GRKs regulate ET receptor contractile signalling in adult Wistar rat mesenteric arterial smooth muscle cells (MSMCs). [ABSTRACT FROM PUBLISHER]

Prolonged ouabain administration to normal rats causes sustained blood pressure (BP) elevation. This ouabain-induced hypertension (OH) has been attributed, in part, to the narrowing of third-order resistance arteries (∼320 μm internal diameter) as a result of collagen deposition in the artery media (see Ref. 6). Here we describe the structural and functional properties of fourth-order mesenteric small arteries from control and OH rats, including the effect of low-dose ouabain on myogenic tone in these arteries. Systolic BP in OH rats was 138 ± 3 versus 124 ± 4 mmHg in controls (P < 0.01). Pressurized (70 mmHg) control and OH arteries, with only a single layer of myocytes, both had ∼165-μm internal diameters and ∼20-μm wall thicknesses. Even after fixation, despite vasoconstriction, the diameters and wall thicknesses did not differ between control and OH fourth-order arteries, whereas in third-order arteries, both parameters were significantly smaller in OH than in controls. Myogenic reactivity was significantly augmented in OH fourth-order arteries. Nevertheless, phenylephrine(1 μM) and high K+ -induced vasoconstrictions and acetylcholine-induced vasodilation were comparable in control and OH arteries. Vasoconstrictions induced by 5 μM phenylephrine and by 10 mM caffeine in Ca2+-free media indicated that releasable sarcoplasmic reticulum Ca2+ stores were normal in OH arteries. Importantly, 100 nM ouabain constricted both control and OH arteries by ∼26 μm, indicating that this response was not downregulated in OH rats. This maximal ouabain-induced constriction corresponds to a ∼90% increase in resistance to flow in these small arteries; thus ouabain at EC50 of ∼0.66 nM should raise resistance by ∼35%. We conclude that dynamic constriction in response to circulating nanomolar ouabain in small arteries likely makes a major contribution to the increased vascular tone and BP in OH rats. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus profoundly changes small artery remodeling in response to hypertension. Abnormal increases of both wall thickness and lumen diameter are associated with an increased mortality. Changes to small artery structure in response to blood pressure (BP) in patients with type 1 diabetes mellitus have never been examined. In 1997, 17 patients with type 1 diabetes mellitus and 9 control subjects underwent in vitro assessment of gluteal-fat small arteries using pressure myography. Patients with BP <140/90 mm Hg (systolic BP: 119+/-3 mm Hg; n=12) had normal-resistance artery structure. However, patients with BP >140/90 mm Hg (systolic BP: 152+/-5 mm Hg; n=5) demonstrated vascular hypertrophic remodeling with a significant increase in the medial cross-sectional area and wall thickness. In 2008, 8 of the original 17 diabetic patients returned for a repeat assessment. All 8 of the patients had significantly improved cholesterol (2008: 154+/-9 mg/dL versus 1997: 191+/-9 mg/dL; P=0.01) and low-density lipoprotein cholesterol (2008: 79+/-8 mg/dL versus 1997: 122+/-9 mg/dL; P=0.003) but higher BPs (systolic BP: 2008: 136+/-3 mm Hg versus 1997: 119+/-6 mm Hg; P=0.03). Glycemia was improved (2008: 7.9+/-0.3% versus 1997: 8.9+/-0.6%; P=0.17), but not significantly so. In the small arteries studied, there were significant increases in medial wall thickness and wall:lumen ratio, but cross-sectional area was unchanged, indicating eutrophic remodeling. Collectively, these findings suggest that, with poor metabolic control, small arteries from patients with type 1 diabetes mellitus show hypertrophic growth in response to elevated BP, similar to that seen in type 2 diabetes mellitus. However, metabolic improvements enable eutrophic remodeling to occur in response to an increase in BP. This has only been observed previously in patients without diabetes mellitus. [ABSTRACT FROM AUTHOR]

Recent data have led us to hypothesize that selective activation of endothelial small- and/or intermediate-conductance, calcium-activated potassium channels (SKCa and IKCa channels, respectively) by the opener compounds NS309 and DCEBIO would augment stimulated nitric oxide (NO) synthesis and vasodilation in resistance arteries. Experimentally, ATP-evoked changes in membrane potential, cytosolic Ca2+, and NO synthesis were recorded by patch clamp and microfluorimetry in single human endothelial cells. Agonist-evoked inhibition of myogenic tone in isolated, pressurized arterioles from rat cremaster skeletal muscle was analyzed by video microscopy. NS309 and DCEBIO enhanced ATP-evoked membrane hyperpolarization and cytosolic Ca2+ transients, along with acute NO synthesis in isolated endothelial cells. The acetylcholine-mediated inhibition of myogenic tone (IC50=237 nM) was left-shifted in the presence of NS309 and DCEBIO (10, 100, and 1000 nM) to IC50 values of 101, 78, and 43 nM; endothelial denudation inhibited this drug effect. L-NAME attenuated the acetylcholine-induced inhibition of myogenic tone but did not interfere with NS309 and DCEBIO-evoked vasodilation. Collectively, our data demonstrate that drug-induced enhancement of endothelial SKCa and IKCa channel activities represents a novel cellular mechanism to increase vasodilation of small-resistance arterioles, thereby highlighting these channels as potential therapeutic targets in cardiovascular disease states associated with compromised NO signaling. [ABSTRACT FROM AUTHOR]

This study determines that vascular smooth muscle cell (VSMC) signaling through extracellular signal-regulated kinase (ERK) 1/2-mitogen-activated protein (MAP) kinase, αvβ3-integrin, and transforming growth factor (TGF)-β1 dictates collagen type I network induction in mesenteric resistance arteries (MRA) from Type 1 diabetic (streptozotocin) or hypertensive (HT; ANG II) mice. Isolated MRA were subjected to a pressure-passive-diameter relationship. To delineate cell types and mechanisms, cultured VSMC were prepared from MRA and stimulated with ANG II(100 nM) and high glucose (HG, 22 mM). Pressure-passive-diameter relationship reduction was associated with increased collagen type I deposition in MRA from HT and diabetic mice compared with control. Treatment of HT and diabetic mice with neutralizing TGF-β1 antibody reduced MRA stiffness and collagen type I deposition. Cultured VSMC stimulated with HG or ANG II for 5 min increased ERK1/2-MAP kinase phosphorylation, whereas a 48-h stimulation induced latent TGF-β, αvβ3-integrin, and collagen type I release in the conditioned media. TGF-β1 bioactivity and Smad2 phosphorylation were αvβ-integrin-dependent, since β3-integrin antibody and αvβ3-integrin inhibitor (SB-223245, 10 µM) significantly prevented TGF-β1 bioactivity and Smad2 phosphorylation. Pretreatment of VSMC with ERK1/2-MAP kinase inhibitor (U-0126, 1 µM) reduced αvβ3-integrin, TGF-β1, and collagen type 1 content. Additionally, αvβ3-integrin antibody, SB-223245, TGF-β1-small-intefering RNA (siRNA), and Smad2-siRNA (40 nM) prevented collagen type I network formation in response to ANG II and HG. Together, these data provide evidence that resistance artery fibrosis in Type 1 diabetes and hypertension is a consequence of abnormal collagen type I release by VSMC and involves ERK1/2, αβ3-integrin, and TGF-β1 signaling. This pathway could be a potential target for overcoming small artery complications in diabetes and hypertension. [ABSTRACT FROM AUTHOR]

In the present review, microvascular remodelling refers to alterations in the structure of resistance vessels contributing to elevated systemic vascular resistance in hypertension. We start with some historical aspects, underscoring the importance of Folkow’s contribution made half a century ago. We then move to some basic concepts on the biomechanics of blood vessels, and explicit the definitions proposed by Mulvany for specific forms of remodelling, especially inward eutrophic and inward hypertrophic. The available evidence for the existence of remodelled resistance vessels in hypertension comes next, with relatively more weight given to human, in comparison with animal data. Mechanisms are discussed. The impact of antihypertensive drug treatment on remodelling is described, again with emphasis on human data. Some details are given on the three studies to date which point to remodelling of subcutaneous resistance arteries as an independent predictor of cardiovascular risk in hypertensive patients. We terminate by considering the potential role of remodelling in the pathogenesis of end-organ damage and in the perpetuation of hypertension. [ABSTRACT FROM PUBLISHER]

Abstract: The vasodilator effect of the ethanolic extract of leaves from Hancornia speciosa Gomes (HSE) was evaluated in superior mesenteric artery rings. HSE produced a concentration-dependent vasodilation (IC50=10.8±4.0μg/mL) in arterial rings pre-contracted with phenylephrine, which was completely abolished in endothelium-denuded vessels. Endothelium-dependent vasodilation induced by HSE was strongly reduced by l-NAME (100μM), a nitric oxide (NO) synthase inhibitor, but neither by atropine, a muscarinic receptor antagonist (1μM), nor by indomethacin (10μM), a cyclooxygenase inhibitor. In rings pre-contracted with 80mM KCl, the vasodilator effect of HSE was shifted to the right and was completely abolished in the presence of l-NAME (100μM). Similar effects were obtained in mesenteric rings pre-contracted with phenylephrine in the presence of KCl 25mM alone or in addition to 100μM l-NAME. In addition, BaCl2 (1mM) dramatically reduced the vasodilation induced by HSE. Together, these findings led us to conclude that HSE induces an endothelium-dependent vasodilation in rat mesenteric artery, by a mechanism dependent on NO, on the activation of potassium channels and endothelium-derived hyperpolarizing factor release. Rutin, identified as a major peak in the HPLC fingerprint obtained for HSE, might contribute for the observed vasodilator effect, since it was able to induce an endothelium-dependent vasodilation in rat superior mesenteric arteries. [Copyright &y& Elsevier]

This work aimed to establish the lineage of cells similar to the interstitial cells of Cajal (ICC), the arterial ICC-like (AIL) cells, which have recently been described in resistance arteries, and to study their location in the artery wall. Segments of guinea-pig mesenteric arteries and single AIL cells freshly isolated from them were used. Confocal imaging of immunostained cells or segments and electron microscopy of artery segments were used to test for the presence and cellular localization of selected markers, and to localize AIL cells in intact artery segments. AIL cells were negative for PGP9.5, a neural marker, and for von Willebrand factor (vWF), an endothelial cell marker. They were positive for smooth muscle α-actin and smooth muscle myosin heavy chain (SM-MHC), but expressed only a small amount of smoothelin, a marker of contractile smooth muscle cells (SMC), and of myosin light chain kinase (MLCK), a critical enzyme in the regulation of smooth muscle contraction. Cell isolation in the presence of latrunculin B, an actin polymerization inhibitor, did not cause the disappearance of AIL cells from cell suspension. The fluorescence of basal lamina protein collagen IV was comparable between the AIL cells and the vascular SMCs and the fluorescence of laminin was higher in AIL cells compared to vascular SMCs. Moreover, cells with thin processes were found in the tunica media of small resistance arteries using transmission electron microscopy. The results suggest that AIL cells are immature or phenotypically modulated vascular SMCs constitutively present in resistance arteries. [ABSTRACT FROM AUTHOR]

Hypertension has been associated with changes in endothelial function in both large muscular arteries and small resistance arteries. We evaluated the relationship between blood flow velocity and dilatation of the brachial artery following transient forearm ischemia and acetylcholine-induced relaxation in subcutaneous small arteries and the influence of antihypertensive therapy on both in patients with essential hypertension. Thirty-one previously untreated hypertensive patients were randomized in a double-blind fashion to treatment with either the angiotensin-converting enzyme (ACE) inhibitor perindopril or the beta-blocker atenolol and compared with 17 healthy normotensive controls. Before and after 1 year of treatment, while still on active medication, flow-mediated dilatation (FMD) was measured in the brachial artery using ultrasound while relaxation to acetylcholine in small arteries was tested in vitro in a myograph. FMD correlated inversely to resting brachial artery diameter (r = -0.38, p<0.05). FMD corrected for resting diameter (FMDcorr) was lower in patients (3.0±0.2%) compared with controls (4.2±0.3%, p<0.01). In both patients and controls, FMDcorr was related to flow velocity in a non-linear way with FMDcorr reaching a maximum despite increasing flow velocities, and in the patients, FMDcorr was only reduced at high flow velocities. Furthermore, patients had a reduced acetylcholine-induced relaxation in small arteries (p = 0.04). Perindopril and atenolol reduced blood pressure to similar levels and both drugs improved FMDcorr to a similar degree without any effects on relaxation to acetylcholine in small arteries. The present study demonstrates the role of correcting for differences in baseline diameter during measurements of FMD and a non-linear relationship between flow velocity and FMD in the brachial artery. Furthermore, the results suggest different effects of antihypertensive treatment on endothelial function in large and small arteries. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction is a key event in the pathophysiology of cardiovascular diseases and appears as a strong independent predictor of cardiovascular events. In this context, biological evaluation of endothelial circulating markers can be helpful. However, functional tests using pharmacological stimuli appear more specific for the study of resistance arteries. These methods consist in the evaluation of the endothelium-dependent changes in regional vascular flow in response to local infusion of substances that act through endothelial receptors without modification of systemic arterial pressure and in comparison with a non endothelium-dependent relaxation. Flow is measured by Doppler and intravascular ultrasound in coronary circulation, laser Doppler in skin and by venous occlusion plethysmography in peripheral muscular arteries. Similar studies can be performed ex vivo using isolated resistance arteries obtained from fat subcutaneous biopsies. In addition, other information can be obtained from reactive hyperemia and the study of the flow-mediated dilatation of conduit arteries to enable a selective and comprehensive approach of the heterogeneity of endothelial function in pathophysiology. [ABSTRACT FROM AUTHOR]

1. Alterations in a1-adrenoceptor signalling that result in enhanced contraction in resistance arteries in heart failure are not well characterized. To clarify whether this enhanced constriction is due to Ca2+-dependent or -independent effects, we measured the phenylephrine-induced changes in [Ca2+]i in the presence of a Rho kinase inhibitor or an inositol 1,4,5-trisphosphate (IP3) receptor inhibitor. 2. Heart failure was induced in rats by ligation of the left coronary artery. Changes in the internal diameter of pressurized small femoral arteries were examined using videomicroscopy. Phenylephrine concentration–response curves, constructed in the presence of the Rho kinase inhibitor Y27632 (0.3 mmol/L) or the IP3 receptor inhibitor xestospongin C (0.3 mmol/L), were compared in heart failure rats and sham-operated (control) rats; fura-2 Ca2+ signals were measured in the arteries of both groups. 3. The heart : bodyweight ratio, lung : bodyweight ratio, left ventricular end-diastolic pressure and plasma B-type natriuretic peptide were significantly higher in heart failure rats compared with control rats. Phenylephrine-induced contractile responses and increases in [Ca2+]i were significantly greater in arteries from heart failure rats compared with arteries from control rats. At 0.3 mmol/L, Y27632 selectively inhibited phenylephrine-induced constrictions of heart failure arteries, but had no effect on the increase in [Ca2+]i. 4. Immunohistochemical staining for Rho kinase was greater in heart failure rats compared with control rats. 5. The degree of inhibition of both the phenylephrine-induced constriction and the increase in [Ca2+]i by xestospongin C (0.3 mmol/L) was greater in arteries from heart failure rats than in those from control rats. 6. The increased contractile response to phenylephrine in arteries of heart failure rats results from IP3-dependent increases in [Ca2+]i and from an enhanced Ca2+ sensitivity via a Rho kinase-dependent mechanism. [ABSTRACT FROM AUTHOR]

Halothane, a volatile anaesthetic, produces systemic hypotension and significantly alters organ blood flow. Isometric force was recorded in isolated rat small mesenteric arteries to investigate its action on contractile response to noradrenaline, the sympathetic neurotransmitter. Halothane (1–5%) enhanced contractile response to noradrenaline in the endothelium-intact arteries, but had little influence in the endothelium-denuded arteries. However, halothane consistently inhibited the noradrenaline response in the endothelium-denuded arteries pretreated with ryanodine (10 μM). The enhancement of the contractile response to noradrenaline in the endothelium-intact arteries was unaffected by treatment with NG-nitro L-arginine, tetraethylammonium, apamin, charybdotoxin, indomethacin, diclofenac, nordihydroguaiaretic acid, BQ-123, BQ-788, losartan, ketanserin, or superoxide dismutase. Halothane prolonged vasorelaxation after washout of noradrenaline in the endothelium-denuded arteries. Both ryanodine and vanadate (0.1–0.3 mM), a putative inhibitor of the plasma membrane Ca2+-ATPase, also prolonged the vasorelaxation. Halothane still prolonged the vasorelaxation in the ryanodine-treated arteries, but not in the vanadate-treated arteries. Halothane decreased the pD2 value for the pCa-force relation in the β-escin-permeabilised, endothelium-denuded arteries. Halothane appears to influence contractile response to noradrenaline through multiple actions including endothelium-dependent enhancing, endothelium-independent enhancing, and endothelium-independent inhibitory actions. Nitric oxide, endothelium-derived hyperpolarising factor, cyclooxygenase products, lipoxygenase products, endothelin-1, angiotensin-II, serotonin, and superoxide anions are not involved in the endothelium-dependent enhancement. The endothelium-independent enhancement is presumably due to its ability to stimulate Ca2+ release from the ryanodine-sensitive intracellular stores, while the endothelium-independent inhibition is due, at least in part, to depressed Ca2+-activation of contractile proteins. Halothane may inhibit the plasma membrane Ca2+-ATPase of vascular smooth muscle cells. [ABSTRACT FROM AUTHOR]

Low-threshold concentrations of diadenosine polyphosphates (ApnA: Ap3A, Ap4A, Ap5A, Ap6A) or ATP, which at basal vessel tone induce just measurable vasoconstrictions, induce up to ten times enhanced vasoconstrictions of previously relaxed (by acetylcholine or sodium nitroprusside or 8Br2 cGMP or isoproterenol or levcromakalim) pre-contracted rat mesenteric resistance arteries (MrA) in a microvessel–myograph. These enhanced vasoconstrictions were of similar magnitude for threshold concentrations of all ApnA. Possibly, the low concentrations of ApnA reverse the prior vasorelaxation by inhibiting a common vasorelaxation pathway, but obviously this is not due to inhibition of guanylate cyclase, which has been previously described to be inhibited by ApnA, because the enhanced vasoconstrictions can be observed with guanylate cyclase-independent vasorelaxants (8Br2 cGMP, isoproterenol or levcromakalim), too. The enhanced vasoconstrictions are endothelium-independent because after mechanical vascular de-endothelialization the results were identical. De-endothelialized vessels, which fail to relax by acetylcholine, showed no enhanced ApnA-induced vasoconstrictions, demonstrating that the mere prior vasorelaxation of the vessel is required to provide the enhanced vasoconstriction by ApnA. Furthermore, the enhanced contractility is not based on a potentiation of the phenylephrine contraction because it equally occurs with other agents used for arterial pre-contraction. Systemically applied ApnA considerably decrease arteriovascular resistance, resulting in hypotension. But here it is demonstrated that a preceding vasorelaxation enables the resistance arteries to generate a strong and persistent ApnA-induced vasoconstriction. Thus, in vivo at very low concentrations ApnA may serve to counteract severe conditions of hypotension (e.g., shock syndrome or anaphylaxis) by the constriction of resistance arteries. [ABSTRACT FROM AUTHOR]

The actin-binding protein SM22α marks contractile differentiation in smooth muscle, but its function is unknown. We tested its role in arterial contractility and stretch-sensitive vascular protein synthesis. Active stress in depolarised mesenteric resistance arteries and portal veins was reduced by 40% in SM22α−/− mice. Passive and active arterial circumference–force relationships were shifted leftwards, whereas α1-adrenergic responses were increased. Actin contents were 10–25% lower in vessels from SM22α−/− mice, but protein composition was otherwise similar. Synthesis of SM22α, calponin and α-actin, but not β-actin, was sensitive to stretch. Ablation of SM22α did not affect stretch sensitivity of any of these proteins. Thus, SM22α plays a role in contractility, possibly by affecting actin filament organisation. [Copyright &y& Elsevier]

1: The a1-adrenoceptor subtypes involved in responses to exogenous and neurally released noradrenaline in rat femoral resistance arteries were characterised using a small vessel myograph, with antagonists prazosin (nonsubtype selective), 5-methyl-urapidil (a1A-selective), BMY 7378 (a1D-selective) and the alkylating agent chloroethylclonidine (preferential for a1B-). 2: Prazosin and 5-methyl-urapidil produced rightward shifts of the exogenous noradrenaline concentration - response curve (CRC) with pA2 values of 9.2 and 9.1 respectively, in agreement with the presence of a1A-adrenoceptors. BMY 7378 (1?µM) shifted the noradrenaline CRC with an apparent pKB of 6.7, in agreement with the presence of a1A-, but not a1D-, adrenoceptors. Chloroethylclonidine at 1?µM had no effect and at 10?µM produced only a small reduction (c. 20%) in the maximum response to noradrenaline, indicating little, if any, contribution from a1B-adrenoceptors. 3: Responses of the rat femoral resistance arteries to electrical field stimulation (EFS) at 5-30?Hz for 10?s and 0.05?ms pulse width were principally due to a1-adrenoceptor stimulation. Prazosin and 5-methyl-urapidil inhibited EFS-mediated responses with pIC50s of 9.3 and 8.2, respectively, consistent with the a1A-adrenoceptor being the predominant subtype. Responses to EFS at 10-30?Hz were relatively insensitive to BMY 7378 (pIC50, 6.5-6.7), while responses to 5?Hz were inhibited with a significantly higher pIC50 of 8.02, suggesting the contribution of a1D-adrenoceptors. Chloroethylclonidine had no effect on responses to EFS, ruling out the contribution of an a1B-subtype. 4: In the presence of cocaine, the predominant subtype involved in responses to EFS was the a1A-adrenoceptor, with a contribution from a1D-adrenoceptors at low frequency, as seen in the absence of cocaine. However, there was also a significant increase in the sensitivity to BMY 7378 at higher frequencies, suggesting that a further small a1D-adrenoceptor component may be uncovered in the presence of cocaine. 5: The present study has shown a predominant role of the a1A-adrenoceptor in contractions due to exogenous noradrenaline and to neurally released noradrenaline in rat femoral resistance arteries. a1D-Adrenoceptors are not involved in responses to exogenous noradrenaline but appear to be activated by neurally released noradrenaline at a low frequency of stimulation and at higher frequencies in the presence of neuronal-uptake blockade.British Journal of Pharmacology (2004) 141, 915-924. doi:10.1038/sj.bjp.0705690 [ABSTRACT FROM AUTHOR]

Alteration of resistance artery geometric design is a hallmark of established hypertension. In particular, there is an increased media thickness: lumen diameter ratio. In this review, consideration is given to the methods available for assessment of vascular structure, the terminology used to describe vascular structural changes in hypertension and the possible functional consequences of altered arterial design in the maintenance of the hypertensive state. In light of these considerations, a number of proposals are made concerning quantification strategies and descriptor terminologies. In particular, a simple descriptor terminology is proposed that describes such structural differences but makes no assumptions concerning the underlying processes that account for altered arterial structure in hypertension. Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

1 The mechanism underlying the enhancement by superoxide dismutase (SOD) of endothelium-dependent relaxation was investigated in rabbit mesenteric resistance arteries. 2 SOD (200 U ml -1) increased the production of H2O2 in smooth muscle cells (as indicated by the use of an H2O2-sensitive fluorescent dye). 3 Neither SOD nor catalase (400 U ml-1) modified either the resting membrane potential or the hyperpolarization induced by acetylcholine (ACh, 1 μM) in smooth muscle cells. 4 In arteries constricted with noradrenaline, the endothelium-dependent relaxation induced by ACh (0.01 -1 μM) was enhanced by SOD (200 U ml-1) (P<0.0l). This action of SOD was inhibited by L-NG-nitroarginine (nitric oxide (NO)-synthase inhibitor) but not by either charybdotoxin + apamin (Ca2+-activated-K+-channel blockers) or diclofenac (cyclooxygenase inhibitor). 5 Neither ascorbate (50μM) nor tiron (0.3mM), superoxide scavengers, had any effect on the ACh-induced relaxation, but each attenuated the enhancing effect of SOD on the ACh-induced relaxation. Similarly, catalase (400 U ml-1) inhibited the effect of SOD without changing the ACh-induced relaxation. 6 In endothelium-denuded strips constricted with noradrenaline. SOD enhanced the relaxation induced by the NO donor l-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-l-triazene (NOC-7) (P<0.05). Ascorbate and catalase each attenuated this effect of SOD. 7 H2O2 (I μM) enhanced the relaxation on the noradrenaline contraction induced by NOC-7 and that induced by 8-bromo-cGMP. a membrane-permeable analogue of guanosine 3′.5′ cyclic monophosphate (cGMP). 8 SOD had no effect on cGMP production, whether measured in endothelium-intact strips following an application of ACh (0.1 μM) or in endothelium-denuded strips following an application of NOC-7 (0.1μM). 9 It is suggested that in rabbit mesenteric resistance arteries, SOD increases the ACh-induced. endothelium-dependent relaxation by enhancing the action of NO in the smooth muscle via its H2O2-producing action (rather than via a superoxide-scavenging action). [ABSTRACT FROM AUTHOR]

Besides their diuretic action, loop diuretics may induce a rapid vasodilator effect that contribute to their short-term therapeutic properties. We examined the effects of furosemide (10−6–10−3 mol l−1) in comparison with bumetanide (10−6–10−4 mol l−1) on isolated resistance arteries from rat and guinea pig mesentery and human subcutaneous fat, and investigated the mechanism of the acute direct vasorelaxant action on an isometric microvascular myograph. Both loop diuretics induced concentration-dependent relaxation of resistance vessels irrespective of membrane potential. The maximal effect of furosemide was greatest in rat and least in human arteries. Both diuretics caused a rightward shift in the concentration–response curve to extracellular Ca2+. Incubation with indomethacin (2×10−5 mol l−1) or mechanical removal of the endothelium did not inhibit the loop diuretic-induced relaxation. At high concentrations (10−4–10−3 mol l−1) loop diuretics exert only weak direct relaxant effects on isolated human subcutaneous resistance arteries compared to the vasorelaxant effects in rat and guinea pig mesenteric vessels. [Copyright &y& Elsevier]

The myogenic response in uremic hypertension. Background. The constriction of resistance arteries in response to an increase in transmural pressure, the myogenic response, is thought to be an important determinant of peripheral vascular resistance and therefore of arterial blood pressure. Since raised peripheral resistance is known to occur in uremic hypertension, abnormal myogenic constriction might be responsible. We sought to assess the myogenic response of resistance arteries from the subtotal nephrectomy rat model of uremic hypertension. Methods. Uremic Wistar-Kyoto (WKYU) rats, and sham-operated normotensive (WKYC) and spontaneously hypertensive (SHRC) controls were studied in parallel. Skeletal muscle arteries were mounted on a pressure myograph and allowed to develop myogenic constriction. The active internal diameter was measured at increasing lumen pressures from 20 to 200 mm Hg. Vascular smooth muscle then was relaxed in a calcium free solution containing nitroprusside, and the passive internal diameter measured at the same pressure steps. The ratio of active to passive diameter at any given pressure was used to assess the myogenic response. Results. Myogenic constriction was not increased in either WKYU or SHRC compared to WKYC at pressures up to 180 mm Hg. Conclusions. Increased myogenic tone is not the cause of uremic hypertension. [ABSTRACT FROM AUTHOR]

Objective: Our purpose was to investigate interactions between human chorionic gonadotropin (hCG) and angiotensin II (ANG II) in resistance arteries. Study design: Isolated pre-arteriolar vessels of female Sprague–Dawley rats were prepared from the mesenteric arcade and the mesometrium. Dose–response curves were recorded by means of an video-electronic arteriograph system. Results: (1) hCG dilated mesenteric (MA; EC50: 21±6.9 mU/ml) and uterine (UA; EC50: 256±44.3 mU/ml)) resistance arteries pre-constricted with ANG II. In the presence of glybenclamide (1 μmol/l), the response of MA was reduced by >50%. (2) After application of hCG for 1 h, vasoconstriction by ANG II was significantly attenuated in MA. This effect was dose-dependent and was not observed in UA. Efficacy of ANG II could be restored, when hCG was followed by glybenclamide. Conclusions: hCG may contribute to the reduction in arterial tone seen early in human pregnancy. Its vascular effects are in part mediated by the activation of adenosine 5′-triphosphate-sensitive potassium channels, suggesting a protein kinase A dependent signaling pathway. [Copyright &y& Elsevier]