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PubMed1998

Comparison of effects of ascorbic acid on endothelium-dependent vasodilation in patients with chronic congestive heart failure secondary to idiopathic dilated cardiomyopathy versus patients with effort angina pectoris secondary to coronary artery disease.

Impaired endothelium-dependent vasodilation has been reported to play an important role in the pathogenesis of cardiovascular diseases such as coronary artery disease (CAD) and congestive heart failure (CHF). However, the precise mechanism of endothelial dysfunction has not been elucidated in these conditions. To evaluate the role of oxidative stress in endothelial dysfunction, the effect of antioxidant ascorbic acid on brachial flow-mediated, endothelium-dependent vasodilation during reactive hyperemia and nitroglycerin-induced endothelium-independent vasodilation was examined with high resolution ultrasound in 12 patients with CHF caused by idiopathic dilated cardiomyopathy without established coronary atherosclerosis and in 10 patients with CAD. Flow-mediated vasodilation in CHF (4.4+/-0.5%) and CAD (4.0 - 0.8%) was significantly (p <0.05) attenuated compared with that in 10 control subjects (9.6+/-0.9%). However, nitroglycerin-induced vasodilation was similar in 3 groups (13.7+/-1.3% in control, 13.9+/-1.1% in CHF, 12.7+/-1.4% in CAD). Ascorbic acid could significantly improve flow-mediated vasodilation only in patients with CAD (9.1+/-0.9%) but not with CHF (5.6+/-0.6%), and had no influence on nitroglycerin-induced vasodilation (13.6+/-1.1% in CHF, 14.0+/-1.3% in CAD). These results suggest that, in brachial circulation, augmented oxidative stress mainly leads to endothelial dysfunction in CAD but not in CHF caused by idiopathic dilated cardiomyopathy.

Adult↗
PubMed2001

Adrenergic nerves mediate acetylcholine-induced endothelium-independent vasodilation in the rat mesenteric resistance artery.

Mechanisms underlying acetylcholine-induced endothelium-independent vasodilation were studied in the rat mesenteric vascular bed isolated from Wistar rats. In preparations without endothelium, and contracted by perfusion with Krebs solution containing methoxamine (2-7 microM), perfusion of acetylcholine (1-100 microM) for 1 min produced a concentration-dependent vasodilation. Denervation of denuded preparations by cold storage (4 degrees C for 72 h) abolished the acetylcholine-induced vasodilation; 10 and 100 nM atropine abolished 1 and 10 microM acetylcholine-induced vasodilation, but it inhibited only 20% of vasodilation by 100 microM acetylcholine. The acetylcholine-induced atropine-resistant vasodilation was inhibited by 10 and 100 microM hexamethonium, 5 microM guanethidine, 50 microM bretylium, in vitro 6-hydroxydopamine (2 mM for 20 min, twice), 1 microM capsaicin and 0.5 microM calcitonin gene-related peptide (CGRP)-(8-37) (CGRP receptor antagonist). These findings suggest that the acetylcholine-induced endothelium-independent nicotinic vasodilation requires the presence of intact adrenergic nerves, and is mediated by endogenous CGRP released from CGRP-containing nerves.

Acetylcholine↗
PubMed1997

Lipoprotein(a) selectively impairs receptor-mediated endothelial vasodilator function of the human coronary circulation.

OBJECTIVES: We investigated the influence of lipoprotein(a) [Lp(a)] serum levels on different endothelium-dependent vasodilator stimuli representing different mechanisms of endothelium-dependent vasodilation. BACKGROUND: Lp(a) is an independent predictor for the development and progression of coronary artery disease. Impairment of endothelium-dependent vasodilation of epicardial arteries has been shown in patients with high levels of Lp(a). METHODS: In 108 patients with angiographically normal or minimally diseased coronary vessels, vasomotor responses to acetylcholine, cold pressor testing, increased blood flow and nitroglycerin were assessed. RESULTS: Lp(a) levels > or = 30 mg/dl were associated with significant dose-dependent enhancement of the vasoconstrictor response to acetylcholine [receptor-mediated vasodilation, p = 0.002; acetylcholine 10(-6) mol/liter, -29 +/- 21% vasoconstriction with Lp(a) levels > or = 30 mg/dl vs, -5.6 +/- 25% with Lp(a) levels < 30 mg/dl]. In addition, vasoconstrictor response to cold pressor test (receptor- and flow-mediated vasodilation) was significantly enhanced in patients with Lp(a) levels > or = 30 mg/dl (-13 +/- 12% vs. 1.2 +/- 16%, p = 0.005). In contrast, strictly endothelium-dependent, but non-receptor-mediated, flow-dependent dilation and endothelium-independent dilation with nitroglycerin were not compromised. Linear regression analysis revealed an inverse relation between Lp(a) and both acetylcholine-induced (r = -0.34, p = 0.0007) and cold pressor test-induced (r = -0.44, p = 0.0001) vasodilation. By multivariate analysis, Lp(a) was a strong and independent predictor of paradoxic vasoconstriction only in response to acetylcholine and cold pressor testing. Impairment of coronary blood flow increase in patients with Lp(a) levels > or = 30 mg/dl did not reach statistical significance. CONCLUSIONS: High Lp(a) levels are associated with a selective impairment of vasodilator capacity of receptor-mediated endothelial stimuli. Impaired dilator capacity of the coronary circulation associated with elevated Lp(a) levels may contribute to the pathogenesis of myocardial ischemia in response to trigger mechanisms involving receptor-mediated stimulation such as sympathetic activation.

Acetylcholine↗
PubMed2001

Impaired vasodilator response to organic nitrates in isolated basilar arteries.

1. The differential responsiveness of various sections and regions in the vascular system to the vasodilator activity of organic nitrates is important for the beneficial antiischaemic effects of these drugs. In this study we examined the vasodilator activity of organic nitrates in cerebral arteries, where vasodilation causes substantial nitrate induced headache. 2. Isolated porcine basilar and coronary arteries were subjected to increasing concentrations of glyceryl trinitrate (GTN), isosorbide-5-nitrate (ISMN) and pentaerythritol tetranitrate (PETN). S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and endothelium-dependent vasodilation was investigated for comparison purpose. 3. The vasodilator potency (halfmaximal effective concentration in -logM) of GTN (4.33+/-0.1, n=8), ISMN (1.61+/-0.07, n=7) and PETN (>10 microM, n=7) in basilar arteries was more than 100 fold lower than that of GTN (6.52+/-0.06, n=12), ISMN (3.66+/-0.08, n=10) and PETN (6.3+/-0.13, n=8) observed in coronary arteries. 4. In striking contrast, the vasodilator potency of SNAP (halfmaximal effective concentration in -logM) was almost similar in basilar (7.76+/-0.05, n=7) and coronary arteries (7.59+/-0.05, n=9). Likewise, no difference in endothelium dependent relaxation was observed. 5. Denudation of the endothelium resulted in a small increase of the vasodilator potency (halfmaximal effective concentration in -logM) of GTN (4.84+/-0.09, n=7, P<0.03) in basilar arteries and similar results were obtained in the presence of the NO-synthase inhibitor N(omega)-nitro-L-arginine (4.59+/-0.05, n=9, P<0.03). 6. These results suggest that cerebral conductance blood vessels such as porcine basilar arteries seems to have a reduced expression and/or activity of certain cellular enzymatic electron transport systems such as cytochrome P450 enzymes, which are necessary to bioconvert organic nitrates to NO.

Animals↗
PubMed2004

Vanilloid receptors mediate adrenergic nerve- and CGRP-containing nerve-dependent vasodilation induced by nicotine in rat mesenteric resistance arteries.

Previous studies showed that nicotine induces adrenergic nerve-dependent vasodilation that is mediated by endogenous calcitonin gene-related peptide (CGRP) released from CGRP-containing (CGRPergic) nerves. The mechanisms underlying the nicotine-induced vasodilation were further studied. Rat mesenteric vascular beds without endothelium were contracted by perfusion with Krebs solution containing methoxamine, and the perfusion pressure was measured with a pressure transducer. Perfusion of nicotine (1-100 microm) for 1 min caused concentration-dependent vasodilation. Capsazepine (vanilloid receptor-1 antagonist; 1-10 microm) and ruthenium red (inhibitor of vanilloid response; 1-30 microm) concentration-dependently inhibited the nicotine-induced vasodilation without affecting the vasodilator response to exogenous CGRP. Nicotine-induced vasodilation was not inhibited by treatment with 3,4-dihydroxyphenylalanine (DOPA) receptor antagonist (l-DOPA cyclohexyl ester; 0.001-10 microm), dopamine D1 receptor-selective antagonist (SCH23390; 1-10 microm), dopamine D2 receptor antagonist (haloperidol; 0.1-0.5 microm), ATP P2x receptor-desensitizing agonist (alpha,beta-methylene ATP; 1-10 microm), adenosine A2 receptor antagonist (8(p-sulfophenyl)theophylline; 10-50 microm) or neuropeptide Y (NPY)-Y1 receptor antagonist (BIBP3226; 0.1-0.5 microm). Immunohistochemical staining of the mesenteric artery showed dense innervation of CGRP- and vanilloid receptor-1-positive nerves, with both immunostainings appearing in the same neuron. The mesenteric artery was also densely innervated by NPY-positive nerves. Double immunostainings showed that both NPY and CGRP immunoreactivities appeared in the same neuron of the artery. These results suggest that nicotine acts on presynaptic nicotinic receptors to release adrenergic neurotransmitter(s) or related substance(s), which then stimulate vanilloid receptor-1 on CGRPergic nerves, resulting in CGRP release and vasodilation.

Adrenergic Fibers↗
PubMed2004

Insulin increases glycolysis without further vasodilation in porcine coronary arteries exposed to hypoxia.

In acute ischaemia, glucose-insulin-potassium administration reduces mortality and beta-adrenoceptor antagonists have favourable effects on the outcome of ischaemic heart disease. The present study was designed to investigate whether insulin (1.4x10(-7) M) and the beta-adrenoceptor antagonist, propranolol (10(-5) M), increase hypoxic vasodilation in correspondence with changes in glycolysis. Porcine coronary arteries, precontracted with 10(-5) M prostaglandin F(2alpha), were mounted in a pressure myograph and a microdialysis catheter was inserted in the tunica media. Hypoxic vasodilation, interstitial lactate/pyruvate ratio and interstitial glucose were measured at low (2 mM) and high (20 mM) glucose concentrations. Hypoxia (60 min) caused vasodilation and doubled the lactate/pyruvate ratio. Treatment with insulin quadrupled the lactate/pyruvate ratio during hypoxia, but did not change hypoxic vasodilation. Propranolol blocked isoprenaline-evoked vasodilation, but hypoxic increases in lactate/pyruvate ratio and vasodilation did not change. The combination of insulin and propranolol did not cause further changes compared with each drug added alone, although the combination increased vasoconstriction during reoxygenation. Interstitial glucose fell during hypoxia at an organ bath glucose concentration of 2 mM, and rose at a glucose concentration of 20 mM. Addition of insulin and propranolol alone or in combination had no effect on interstitial glucose concentration. Accordingly, arteries were found to contain only minute amounts of the glucose transporter isoform GLUT4. Our findings suggest that insulin increases arterial glycolysis, but treatment with insulin, propranolol, or both, is not associated with enhanced coronary vasodilation during hypoxia.

Adrenergic beta-Antagonists↗
PubMed2000

Evaluation of endothelium-dependent vasodilation in the human peripheral circulation.

Flow-mediated vasodilation (FMD) in the brachial artery measured by ultrasound, and the increase in forearm blood flow (FBF) induced by local infusion of a muscarinic-receptor agonist have both frequently been used to evaluate endothelium-dependent vasodilation (EDV) in the human forearm. The present study intended to evaluate the relationship between these techniques and to investigate if vasodilation induced by the muscarinic receptor-agonist methacholine (MCh) was owing to production of nitric oxide (NO). FMD during hyperaemia was assessed by ultrasound and FBF was measured by venous occlusion plethysmography during local infusion of MCh or L-arginine in the human forearm. Both these methods were applied in 26 individuals. In another 12 individuals forearm arterial and venous plasma concentrations of nitrate/nitrite (NOx) were measured together with FBF before and during local MCh infusion. While the change in brachial artery diameter induced by sublingually given nitroglycerine and the vasodilatory response to sodium nitroprusside (SNP) given locally in the forearm were significantly correlated (r = 0.70, P < 0.01), FMD showed no relationship with the vasodilation evoked by MCh (r = -0.03) or L-arginine (r = 0.04). The five-fold increase in FBF during MCh infusion was associated with a significant increase in venous plasma NOx concentrations (P < 0.05) and a more than 11-fold increase in forearm NOx-release (P < 0.01). Thus, a significant relationship between the two methods regarding the evaluation of endothelium-independent vasodilation evoked by NO-donors was found, but no relationship was found between the two methods regarding the evaluation of endothelium-dependent vasodilation. Furthermore, vasodilation induced by MCh in the forearm seems to be induced by NO-release.

Adult↗
PubMed2002

Relation of vasodilator response of the brachial artery to inflammatory markers in patients with coronary artery disease.

Endothelial dysfunction of the coronary artery is closely related to elevated levels of systemic inflammatory markers and cardiovascular events in patients with coronary artery disease (CAD). We hypothesized that patients with CAD may have a higher risk of endothelial dysfunction of the peripheral artery than patients without evidence of CAD, and that endothelial dysfunction of the peripheral artery also may be related to elevated levels of inflammatory markers. Using high resolution ultrasound, we assessed the brachial vasodilator response to reactive hyperemia (endothelium-dependent) and sublingual nitroglycerin (endothelium-independent). As inflammatory markers, serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) levels, and lipid profiles were measured in patients with CAD (n = 30, 16 male and 14 female) and normal subjects without evidence of CAD (n = 45, 23 male and 22 female). Patients with CAD (Group II) showed a significantly reduced endothelium-dependent vasodilation as compared with normal subjects (Group I) (4.4 +/- 3.6 vs 7.4 +/- 6.1%, P < 0.05). However, endothelium-independent vasodilation was not significantly different between the two groups (7.7 +/- 7.1 vs 9.7 +/- 8.0%, P > 0.05). In Group II, CRP level was inversely related to endothelium-dependent vasodilation (r = -0.398, P = 0.029). In contrast, ESR level was not significantly associated to endothelium-dependent vasodilation (r = -0.113, P = 0.552). On multivariate analysis, CRP and low density lipoprotein cholesterol levels were significant independent predictors of a blunted endothelium-dependent vasodilation in Group II. Our study showed that elevated CRP level was associated with blunted endothelium-dependent vasodilation of the brachial artery in patients with CAD. Thus, identification of elevated CRP levels combined with demonstration of endothelial dysfunction of the brachial artery may have a possible clinical application for the detection of high risk CAD patients.

Adult↗
PubMed1999

Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors.

Cannabinoids, including the endogenous ligand arachidonyl ethanolamide (anandamide), elicit not only neurobehavioral but also cardiovascular effects. Two cannabinoid receptors, CB1 and CB2, have been cloned, and studies with the selective CB1 receptor antagonist SR141716A have implicated peripherally located CB1 receptors in the hypotensive action of cannabinoids. In rat mesenteric arteries, anandamide-induced vasodilation is inhibited by SR141716A, but other potent CB1 receptor agonists, such as HU-210, do not cause vasodilation, which implicates an as-yet-unidentified receptor in this effect. Here we show that "abnormal cannabidiol" (Abn-cbd) is a neurobehaviorally inactive cannabinoid that does not bind to CB1 receptors, yet causes SR141716A-sensitive hypotension and mesenteric vasodilation in wild-type mice and in mice lacking CB1 receptors or both CB1 and CB2 receptors. Hypotension by Abn-cbd is also inhibited by cannabidiol (20 microgram/g), which does not influence anandamide- or HU-210-induced hypotension. In the rat mesenteric arterial bed, Abn-cbd-induced vasodilation is unaffected by blockade of endothelial NO synthase, cyclooxygenase, or capsaicin receptors, but it is abolished by endothelial denudation. Mesenteric vasodilation by Abn-cbd, but not by acetylcholine, sodium nitroprusside, or capsaicine, is blocked by SR141716A (1 microM) or by cannabidiol (10 microM). Abn-cbd-induced vasodilation is also blocked in the presence of charybdotoxin (100 nM) plus apamin (100 nM), a combination of K(+)-channel toxins reported to block the release of an endothelium-derived hyperpolarizing factor (EDHF). These findings suggest that Abn-cbd and cannabidiol are a selective agonist and antagonist, respectively, of an as-yet-unidentified endothelial receptor for anandamide, activation of which elicits NO-independent mesenteric vasodilation, possibly by means of the release of EDHF.

Animals↗
PubMed2003

Cerebrovascular vasodilation to extraluminal acidosis occurs via combined activation of ATP-sensitive and Ca2+-activated potassium channels.

Albeit controversial, it has been suggested by several authors that nitric oxide (NO) serves as a permissive factor in the cerebral blood flow response to systemic hypercapnia. Potassium channels are important regulators of cerebrovascular tone and may be modulated by a basal perivascular NO level. To elucidate the functional targets of the proposed NO modulation during hypercapnia-induced vasodilation, the authors performed experiments in isolated, cannulated, and pressurized rat middle cerebral arteries (MCA). Extracellular pH was reduced from 7.4 to 7.0 in the extraluminal bath to induce NO dependent vasodilation. Acidosis increased vessel diameter by 35 +/- 10%. In separate experiments, ATP-sensitive potassium channels (KATP) were blocked by extraluminal application of glibenclamide (Glib), Ca2+-activated potassium channels (KCa) by tetraethylammonium (TEA), voltage-gated potassium channels (Kv) by 4-aminopyridine, and inward rectifier potassium channels (KIR) by BaCl2. Na+-K+-ATP-ase was inhibited by ouabain. Application of TEA slightly constricted the arteries at pH 7.4 and slightly but significantly attenuated the vasodilation to acidosis. Inhibition of the other potassium channels or Na+-K+-ATP-ase had no effect. Combined blockade of KATP and KCa channels further reduced resting diameter, and abolished acidosis induced vasodilation. The authors conclude that mainly KCa channels are active under resting conditions. KATP and KCa channels are responsible for vasodilation to acidosis. Activity of one of these potassium channel families is sufficient for vasodilation to acidosis, and only combined inhibition completely abolishes vasodilation. During NO synthase inhibition, dilation to the KATP channel opener pinacidil or the KCa channel opener NS1619 was attenuated or abolished, respectively. The authors suggest that a basal perivascular NO level is necessary for physiologic KATP and KCa channel function in rat MCA. Future studies have to elucidate whether this NO dependent effect on KATP and KCa channel function is a principle mechanism of NO induced modulation of cerebrovascular reactivity and whether the variability of findings in the literature concerning a modulatory role of NO can be explained by different levels of vascular NO/cGMP concentrations within the cerebrovascular tree.

Acidosis↗
PubMed1995

Vasodilator effects of desflurane and isoflurane in the feline small intestine.

The influence of desflurane (DES) and isoflurane (ISO) on the intestinal vasculature was investigated in normoventilated cats (n = 10) during basal chloralose anesthesia (control). We measured heart rate, mean arterial pressure (MAP), and intestinal blood flow (optical drop flowmetry). Intestinal vascular resistance (IVR) was derived. To avoid changes in local vascular tone related to alterations in transmural pressure gradients, intestinal arterial pressure was controlled and kept constant by a variable aortic clamp. Measurements were performed during control and during the administration of DES (3.5% and 7.0% end-tidal) or ISO (0.8% and 1.6% end-tidal). Each animal was exposed to both agents, prior to and after intestinal postganglionic denervation. In the innervated intestine, both DES and ISO dose-dependently decreased IVR. At the high dose, DES (50 +/- 10% decrease in IVR) was a significantly more powerful vasodilator than ISO (37 +/- 12% decrease in IVR). In the denervated intestine, less pronounced vasodilations were produced by both DES and ISO, as compared to the innervated state, and there were, in this situation, no significant differences between agents concerning the magnitude of the vasodilation. As indicated by comparisons between the innervated versus the denervated state, both neurogenic and non-neurogenic mechanisms contributed to the vasodilator responses. The vascular relaxation at the high dose was for ISO associated with a significantly more powerful non-neurogenic vasodilation, and for DES associated with a significantly more powerful neurogenic vasodilation. This suggests that withdrawal of sympathetic neurogenic vasoconstrictor tone is more important for the vasodilation produced by DES than it is for ISO.

Anesthetics, Inhalation↗
PubMed1996

Contribution of calcium-activated potassium channels to the vasodilator effect of bradykinin in the isolated, perfused kidney of the rat.

1. NO- and prostaglandin-independent, endothelium-dependent vasodilator responses to bradykinin are attributed to release of a hyperpolarizing factor. Therefore, the contribution of K+ channels to the renal vasodilator effect of bradykinin was examined in rat perfused kidneys that were preconstricted with phenylephrine and treated with NG-nitro-L-arginine (L-NOARG) and indomethacin to inhibit NO and prostaglandin synthesis. 2. The non-specific K+ channel inhibitors, TEA and TBA reduced vasodilator responses to bradykinin and cromakalim but not those to nitroprusside. 3. Glibenclamide, an inhibitor of ATP-sensitive K+ channels, blocked the vasodilator response to cromakalim without affecting responses to bradykinin. 4. Charybdotoxin, a selective inhibitor of Ca(2+)-activated K+ channels, greatly attenuated vasodilator responses to bradykinin without affecting those to cromakalim or nitroprusside. 5. Iberiotoxin and leiurotoxin, inhibitors of large and small conductance Ca(2+)-activated K+ channels, respectively, were without effect on vasodilator responses to bradykinin, cromakalim or nitroprusside. 6. These results implicate K+ channels, specifically Ca(2+)-activated K+ channels of intermediate conductance, in the renal vasodilator effect of bradykinin and, thereby, support a role for a hyperpolarizing factor.

Adenosine Triphosphate↗
PubMed2007

Impaired NO-mediated vasodilation with increased superoxide but robust EDHF function in right ventricular arterial microvessels of pulmonary hypertensive rats.

Pulmonary hypertension (PH) causes right ventricular (RV) hypertrophy and, according to the extent of pressure overload, eventual heart failure. We tested the hypothesis that the mechanical stress in PH-RV impairs the vasoreactivity of the RV coronary microvessels of different sizes with increased superoxide levels. Five-week-old male Sprague-Dawley rats were injected with monocrotaline (n=126) to induce PH or with saline as controls (n=114). After 3 wk, coronary arterioles (diameter = 30-100 microm) and small arteries (diameter = 100-200 microm) in the RV were visualized using intravital videomicroscopy. We evaluated ACh-induced vasodilation alone, in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME), in the presence of tetraethylammonium (TEA) or catalase with or without L-NAME, and in the presence of SOD. The degree of suppression in vasodilation by L-NAME and TEA was used as indexes of the contributions of endothelial nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF), respectively. In PH rats, ACh-induced vasodilation was significantly attenuated in both arterioles and small arteries, especially in arterioles. This decreased vasodilation was largely attributable to reduced NO-mediated vasoreactivity, whereas the EDHF-mediated vasodilation was relatively robust. The suppressive effect on arteriolar vasodilation by catalase was similar to TEA in both groups. Superoxide, as measured by lucigenin chemiluminescence, was significantly elevated in the RV tissues in PH. SOD significantly ameliorated the impairment of ACh-induced vasodilation in PH. Robust EDHF function will play a protective role in preserving coronary microvascular homeostasis in the event of NO dysfunction with increased superoxide levels.

Acetylcholine↗
PubMed1995

Endothelium-dependent vasodilation of proximal coronary arteries from exercise-trained pigs.

We recently reported that alpha-adrenergic vasoconstriction is blunted and adenosine-induced vasodilation is enhanced in proximal coronary arteries of exercise-trained miniature swine [C. L. Oltman, J. L. Parker, H. R. Adams, and M. H. Laughlin. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H372-H382, 1992]. The purpose of the present study was to determine whether this model of exercise training also alters endothelium-dependent vasodilator responses of proximal coronary arteries. Female Yucatan miniature swine were exercise trained (ET) on a motor-driven treadmill or were cage confined (Sed) for 13-20 wk. Exercise tolerance, heart weight-to-body weight ratios, and skeletal muscle oxidative capacity were all significantly greater in ET than in Sed animals. Vasodilator responses were evaluated in vitro by determining concentration-response curves by using vascular rings (3.5-4 mm in axial length) isolated from right and left coronary arteries. Vasorelaxation responses were determined, after tone had been produced with either 30 microM prostaglandin F2 alpha, 30 mM KCl, or 30 nM endothelin. Concentration-response curves were obtained to endothelium-dependent vasodilators including bradykinin (10(-9)-10(-6) M), substance P (10(-12)-10(-6) M), clonidine (10(-9)-10(-6) M), serotonin (10(-10)-10(-5) M), and the Ca2+ ionophore A-23187 (10(-10)-10(-6) M). Endothelium-independent vasodilator responses to sodium nitroprusside (10(-9)-10(-4) M) were not different between arteries from Sed and ET. Bradykinin, substance P, and A-23187 were potent vasodilators in arteries from both groups, whereas serotonin and clonidine did not consistently produce vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Mechanisms of vasoactive intestinal peptide-mediated vasodilation in human skin.

Vasoactive intestinal peptide (VIP) is known to induce histamine release in human skin and to include a nitric oxide (NO)-dependent dilation in several other vascular beds. However, the relative contribution of histamine and NO to VIP-mediated vasodilation in human skin is unknown. Forty-three subjects volunteered to participate in two studies designed to examine the mechanism of VIP-mediated vasodilation in human skin. Study 1 examined the contribution of NO in the skin blood flow response to eight doses of VIP ranging from 25 to 800 pmol. In addition, study 1 examined a specific role for NO in VIP-mediated dilation. Study 2 examined the relative contribution of NO and histamine to VIP-mediated dilation via H1 and H2 histamine receptors. Infusions were administered to skin sites via intradermal microdialysis. Red blood cell flux was measured by using laser-Doppler flowmetry (LDF), and cutaneous vascular conductance (CVC; LDF/mean arterial pressure) was calculated and normalized to maximal vasodilation. VIP-mediated vasodilation includes a NO-dependent component at doses above 100 pmol, where NO synthase inhibition significantly attenuates CVC (P < 0.05). Inhibition of H1 receptors attenuates the rise in CVC to exogenous VIP (P < 0.05); however, combined H1-receptor inhibition and NO synthase inhibition further reduced VIP-mediated vasodilation compared with either H1 inhibition or NO synthase inhibition alone (P < 0.05). In contrast to H1-receptor inhibition, H2-receptor inhibition did not affect vasodilation to exogenous VIP. Thus, in human skin, VIP-mediated vasodilation includes a NO-dependent component that could not be explained by H1- and H2-receptor activation.

Administration, Topical↗
PubMed2006

Endothelium-dependent vasodilation of cerebral arteries is altered with simulated microgravity through nitric oxide synthase and EDHF mechanisms.

Cephalic elevations in arterial pressure associated with microgravity and prolonged bed rest alter cerebrovascular autoregulation in humans. Using the head-down tail-suspended (HDT) rat to chronically induce headward fluid shifts and elevate cerebral artery pressure, previous work has likewise shown cerebral perfusion to be diminished. The purpose of this study was to test the hypothesis that 2 wk of HDT reduces cerebral artery vasodilation. To test this hypothesis, dose-response relations for endothelium-dependent (2-methylthioadenosine triphosphate and bradykinin) and endothelium-independent (nitroprusside) vasodilation were determined in vitro in middle cerebral arteries (MCAs) from HDT and control rats. All in vitro measurements were done in the presence and absence of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (10(-5) M) and cyclooxygenase inhibitor indomethacin (10(-5) M). MCA caveolin-1 protein content was measured by immunoblot analysis. Endothelium-dependent vasodilation to 2-methylthioadenosine triphosphate and bradykinin were both lower in MCAs from HDT rats. These lower vasodilator responses were abolished with N(G)-nitro-L-arginine methyl ester but were unaffected by indomethacin. In addition, HDT was associated with lower levels of MCA caveolin-1 protein. Endothelium-independent vasodilation was not altered by HDT. These results indicate that chronic cephalic fluid shifts diminish endothelium-dependent vasodilation through alterations in the endothelial nitric oxide synthase signaling mechanism. Such decrements in endothelium-dependent vasodilation of cerebral arteries could contribute to the elevations in cerebral vascular resistance and reductions in cerebral perfusion that occur after conditions of simulated microgravity in HDT rats.

Adenosine Triphosphate↗
PubMed2002

Vascular and neural mechanisms of ACh-mediated vasodilation in the forearm cutaneous microcirculation.

The relative contribution of endothelial vasodilating factors to acetylcholine (ACh)-mediated vasodilation in the forearm cutaneous microcirculation is unclear. The aims of this study were to investigate the contributions of prostanoids and cutaneous C fibers to basal cutaneous blood flow (CuBF) and ACh-mediated vasodilation. ACh was iontophoresed into the forearm, and cutaneous perfusion was measured by laser-Doppler flowmetry. To inhibit the production of prostanoids, four doses of acetylsalicylic acid (ASA; 81, 648, 972, and 1,944 mg) were administered orally. Cutaneous nerve fibers were blocked with topical anesthesia. Cyclooxygenase inhibition did not change basal CuBF or endothelium-mediated vasodilation to ACh. In contrast, ASA (972 and 1,944 mg) significantly reduced the C-fiber-mediated axon reflex in a dose-dependent fashion. Blockade of C-fiber function significantly reduced axon reflex-mediated vasodilation but did not affect basal CuBF or endothelium-dependent vasodilation. The findings suggest that prostanoids do not contribute significantly to basal CuBF or endothelium-dependent vasodilation in the forearm microcirculation. In contrast, prostanoids are mediators of the ACh-provoked axon reflex.

Acetylcholine↗
PubMed2003

Effect of isoflurane on skin-pressure-induced vasodilation.

Since general anesthesia has been shown to attenuate endothelium-dependent vasodilation, it was of interest to verify whether general anesthesia would modify skin vasodilation in response to local pressure application, which is endothelium dependent. To study the effect of general anesthesia on pressure-induced vasodilation development, we examined the effects of low- and high-dose isoflurane. Skin blood flow was measured by laser Doppler flowmetry during 11.1 Pa s(-1) increases in locally applied pressure in anesthetized rats treated with low or high doses of isoflurane. Following the administration of low doses of isoflurane, skin blood flow increased from baseline, with increasing local pressure application (+37 +/- 10% at 2.0 kPa). The increase in skin blood flow was absent in rats treated with high doses (-20 +/- 5% at 2.0 kPa), even when the anesthesia-induced hypotension was corrected by gelofusine infusion (-20 +/- 10% at 2.0 kPa). Whereas sodium-nitroprusside-induced vasodilation developed following low and high doses of isoflurane, acetylcholine-induced vasodilation was impaired with high doses compared to low doses. These data show that pressure-induced vasodilation is abolished with high doses of anesthetics. It is not the anesthesia-induced hypotension, but the depth of anesthesia, which can lead to the disappearance of pressure-induced vasodilation by an alteration in endothelial function.

Acetylcholine↗