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PubMed2002

Role of nitric oxide in mediating vasodilator responses to opioid peptides in the rat.

1. Endomorphins 1 and 2, endogenous ligands for the mu-opioid receptor, and nociceptin (orphanin FQ; OFQ), an endogenous ligand for the ORL1 receptor, have vasodilator activity in the vascular bed of the hindquarters of the rat. In the present study, the role of nitric oxide (NO), vasodilator prostaglandins and the opening of KATP channels in mediating vasodilator responses to these novel agonists was investigated in the rat. 2. Under constant-flow conditions, injections of endomorphins 1 and 2, PL017 ([N-MePhe3,D-Pro4]-morphiceptin), nociceptin and Tyr-D-Ala-Gly-MePhe-Gly(ol)-enkephalin (DAMGO) produced dose-dependent decreases in hindquarters perfusion pressure. Vasodilator responses to endomorphin 1 and 2, acetylcholine and adrenomedullin, were attenuated by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) at a time when vasodilator responses to nociceptin, adrenomedullin and the NO donor diethylamine/NO were not altered. 3. Vasodilator responses to endomorphins 1 and 2, nociceptin, PL017 and DAMGO were not altered after administration of sodium meclofenamate at a time when vasodilator responses to arachidonic acid were reduced significantly or after administration of U-37883A at a time when vasodilator responses to levcromakalim were reduced significantly. 4. The results of these studies indicate that vasodilator responses to endomorphins 1 and 2, PL017 and DAMGO are mediated, in large part, by the release of NO, whereas vasodilator responses to nociceptin are mediated by an L-NAME-insensitive mechanism. Moreover, these results demonstrate that the vasodilator responses to these peptides are not due to the release of vasodilator prostaglandins or the opening of KATP channels in the hindquarters vascular bed of the rat.

Animals↗

PubMed1994

Blockade of adenosine triphosphate-sensitive potassium channels eliminates isoflurane-induced coronary artery vasodilation.

BACKGROUND: The mechanisms by which volatile anesthetics induce vasodilation are unknown. Recent studies of adenosine triphosphate-sensitive potassium channels (KATP channels) in the vascular smooth muscle of the coronary circulation suggest that these channels play a role in the coronary artery dilation produced by hypoxemia, the coronary blood flow (CBF) reactive hyperemic response, and in CBF auto regulation. We therefore conducted this study to determine the role of KATP channels in isoflurane-induced coronary vasodilation. METHODS: Studies were conducted in six open-chest, anesthetized swine. The left anterior descending coronary artery was cannulated and perfused by blood passed through a membrane oxygenator. This preparation allowed us to administer drugs and volatile anesthetics regionally to the perfused myocardium, minimizing systemic effects. Regional CBF response to 1.5% and 3.0% isoflurane administered via the membrane oxygenator was measured before and after blockade of KATP channels, and was compared to the vasodilation produced by regional administration of several doses of sodium nitroprusside and adenosine. Blockade of KATP channels was achieved by regional intracoronary administration of glibenclamide (1-22 micrograms.kg-1.min-1), a specific blocker of these channels. RESULTS: Administration of 1.5 and 3.0 percent isoflurane increased regional CBF by 29 +/- 29% and by 62 +/- 28%, respectively. Under control conditions, blockade of KATP channels decreased mean CBF by 18%, but did not cause ischemia. KATP channel blockade totally eliminated the vasodilator response to both doses of isoflurane. During KATP channel blockade the response to 3% isoflurane was converted to net vasoconstriction: mean delta CBF = -5% +/- 6%, P = < 0.05 versus control. Negative inotropic effects of isoflurane were not eliminated by glibenclamide. Because KATP channel blockade was so effective in eliminating isoflurane-induced coronary vasodilation, the dose of glibenclamide was decreased in sequential experiments, but total blockade of isoflurane vasodilation was achieved even at the smallest dose of glibenclamide studied (1 microgram.kg-1.min-1). The vasodilator response to nitroprusside was not affected, and the vasodilator response to adenosine was partially inhibited (consistent with their known mechanisms of action). CONCLUSIONS: Blockade of KATP channels by glibenclamide completely inhibits isoflurane-induced coronary vasodilation in the regionally perfused swine myocardium. The response to sodium nitroprusside, a drug that induces vasodilation via a different mechanism, was unaffected. The response to adenosine, a drug whose vasodilation is partially mediated via KATP channels, was partially inhibited. These results suggest that in vivo isoflurane-induced coronary artery vasodilation is predominantly mediated by KATP channels.

Adenosine↗

PubMed1995

Contribution of nitric oxide to metabolic coronary vasodilation in the human heart.

BACKGROUND: The vascular endothelium contributes to smooth muscle relaxation by tonic release of nitric oxide. To investigate the contribution of nitric oxide to human coronary epicardial and microvascular dilation during conditions of increasing myocardial oxygen requirements, we studied the effect of inhibiting nitric oxide synthesis with NG-monomethyl-L-arginine (L-NMMA) on the coronary vasodilation during cardiac pacing in patients with angiographically normal coronary arteries with and without multiple risk factors for coronary atherosclerosis. METHODS AND RESULTS: In 26 patients with angiographically normal or near-normal epicardial coronary arteries, metabolic vasodilation was assessed as a change in coronary vascular resistance and diameter during cardiac pacing (mean heart rate, 141 beats per minute). Endothelium-dependent vasodilation was estimated with intracoronary acetylcholine and endothelium-independent dilation with intracoronary sodium nitroprusside and adenosine. These measurements were repeated after 64 mumol/min intracoronary L-NMMA. At rest, L-NMMA produced a 16 +/- 25% (mean +/- SD) increase in coronary vascular resistance (P < .05) and an 11% reduction in distal epicardial coronary artery diameter (P < .01), indicating tonic basal release of nitric oxide from human coronary epicardial vessels and microvessels. Significant inhibition of pacing-induced metabolic coronary vascular dilation occurred with L-NMMA, coronary vascular resistance was 38 +/- 56% higher (P < .03), and epicardial coronary dilation during control pacing (9 +/- 13%) was converted to constriction after L-NMMA and pacing (-6 +/- 9%, P < .04). L-NMMA specifically inhibited endothelium-dependent vasodilation with acetylcholine (coronary vascular resistance was 72% higher [P < .01]) but did not alter endothelium-independent dilation with sodium nitroprusside and adenosine. Nine patients had no major risk factors for atherosclerosis, defined as serum cholesterol > 240 mg/dL, hypertension, or diabetes. The remaining 17 patients with one or more of these risk factors had depressed microvascular vasodilation during cardiac pacing (coronary vascular resistance decreased by 13% versus 36% in those without risk factors, P < .05). The inhibitory effect of L-NMMA on pacing-induced coronary epicardial and microvascular vasodilation was observed only in patients without risk factors, whereas those with risk factors had an insignificant change, indicating that nitric oxide contributes significantly to pacing-induced coronary vasodilation in patients free of risk factors and without endothelial dysfunction. Patients with risk factors also had reduced vasodilation with acetylcholine (40 +/- 28% versus 68 +/- 8% decrease in coronary vascular resistance, P < .01), but the responses to sodium nitroprusside were similar in both groups. CONCLUSIONS: During metabolic stimulation of the human heart, nitric oxide release contributes significantly to microvascular vasodilation and is almost entirely responsible for the epicardial vasodilation. This contribution of nitric oxide is reduced in patients exposed to risk factors for coronary atherosclerosis and leads to a net reduction in vasodilation during stress. An important implication of these findings is that reduced nitric oxide bioavailability during stress in patients with atherosclerosis or risk factors for atherosclerosis may contribute to myocardial ischemia by limiting epicardial and microvascular coronary vasodilation.

Acetylcholine↗

PubMed1990

Age-related decrease of calcitonin gene-related peptide-containing vasodilator innervation in the mesenteric resistance vessel of the spontaneously hypertensive rat.

We previously demonstrated that the mesenteric resistance blood vessels have nonadrenergic, noncholinergic vasodilator innervation in which calcitonin gene-related peptide (CGRP) is a possible neurotransmitter. The role of CGRP-containing vasodilator nerves in hypertension was investigated in perfused mesenteric vascular beds isolated from spontaneously hypertensive rats (SHR). The adrenergic vasoconstrictor responses to perivascular nerve stimulation in both SHR (8-, 15-, and 30-week-old) and age-matched Wistar-Kyoto (WKY) rat preparations increased with aging, but the response was greater in SHR than in WKY rats at all ages. The preparation isolated from SHR and WKY rats was precontracted by continuous perfusion of Krebs' solution containing 7 x 10(-6) M methoxamine plus 5 x 10(-6) M guanethidine. In both SHR and WKY rats, perivascular nerve stimulation (1-8 Hz) produced frequency-dependent vasodilation, which was blocked by 1 x 10(-7) M tetrodotoxin, pretreatment with 5 x 10(-7) M capsaicin, and denervation by cold storage (4 degrees C for 72 hours). The vasodilation induced by perivascular nerve stimulation in SHR greatly decreased with age, whereas a slight decrease in the response with age was found in WKY rats. The neurogenic vasodilation in the young SHR preparation was similar in magnitude to the vasodilation in age-matched WKY rats, whereas the vasodilation in 15- and 30-week-old SHR was significantly smaller than that in age-matched WKY rats. In both SHR and WKY rats, perfusion of rat CGRP (1 x 10(-10) to 3 x 10(-8) M) produced marked vasodilation in a concentration-dependent manner. The CGRP-induced vasodilation in SHR increased with age, whereas an age-related decrease in vasodilation was found in WKY rats. Perivascular nerve stimulation (4 and 8 Hz) of the perfused mesenteric vascular bed evoked an increased release of CGRP-like immunoreactive substance in the perfusate, which was significantly less in 15-week-old SHR than in age-matched WKY rats. Immunohistochemical studies showed an age-related decrease in CGRP-like immunoreactive fibers in SHR but not in WKY rats. These results suggest that CGRP-containing vasodilator innervation is greatly decreased when SHR develop and maintain hypertension. It is also suggested that the decreased vasodilator mechanism by CGRP-containing nerves contributes to the development and maintenance of hypertension.

Aging↗

PubMed1981

Hypoxia impairs vasodilation in the lung.

Alveolar hypoxia causes pulmonary vasoconstriction; we investigated whether hypoxia could also impair pulmonary vasodilation. We found in the isolated perfused rat lung a delay in vasodilation following agonist-induced vasoconstriction. The delay was not due to erythrocyte or plasma factors, or to alterations in base-line lung perfusion pressure. Pretreating lungs with arachidonic acid abolished hypoxic vasoconstriction, but did not influence the hypoxia-induced impairment of vasodilation after angiotensin II, bradykinin, or serotonin pressor responses. Progressive slowing of vasodilation followed angiotensin II-induced constriction as the lung oxygen tension fell progressively below 60 Torr. KCl, which is not metabolized by the lung, caused vasoconstriction; the subsequent vasodilation time was delayed during hypoxia. However, catecholamine depletion in the lungs abolished this hypoxic vasodilation delay after KCl-induced vasoconstriction. In lungs from high altitude rats, the hypoxia-induced vasodilation impairment after an angiotensin II pressor response was markedly less than it was in lungs from low altitude rats. We conclude from these studies that (a) hypoxia impairs vasodilation of rat lung vessels following constriction induced by angiotensin II, serotonin, bradykinin, or KCl, (b) hypoxia slows vasodilation following KCl-induced vasoconstriction probably by altering lung handling of norepinephrine, (c) the effect of hypoxia on vasodilation is not dependent on its constricting effect on lung vessels, (d) high altitude acclimation moderates the effect of acute hypoxia on vasodilation, and (e) the hypoxic impairment of vasodilation is possibly the result of an altered rate of dissociation of agonists from their membrane receptors on the vascular smooth muscle.

Angiotensin II↗

PubMed1989

The vasodilating effect of atrial natriuretic peptide in normotensive and hypertensive humans.

Atrial natriuretic peptide (ANP) infused intra-arterially into the forearm results in a dose-dependent vasodilator response of rapid onset. The maximal forearm vasodilator response to ANP amounts to about 60% of the maximal forearm vasodilator response to sodium nitroprusside and combined infusion of ANP and sodium nitroprusside has an additive vasodilator effect. ANP-induced vasodilation is greater than that of postjunctional alpha 1- or alpha 2-adrenoceptor blockade or of beta 2-adrenoceptor stimulation but is smaller than due to calcium entry blockade. ANP-induced vasodilation can easily be overcome by norepinephrine and to a lesser extent by angiotension II (Ang II). The similarity of the dose-response relationships for vasodilation and for natriuresis suggests that ANP may be equally effective on its renal and vascular targets. In patients with essential hypertension, intra-arterial infusion of ANP produced a greater vasodilator response than in normotensives and this was inversely related to plasma renin activity, suggesting greater vasodilator responsiveness to ANP in low-renin hypertension. ANP caused vasodilation in humans but this may become less apparent when ANP is infused into the systemic circulation because of cardiovascular sympathetic reflex mechanisms blunting ANP vasodilation. Although the role of ANP in circulatory disease states is unclear, it appears that it could serve a physiological function as an endogenous vasodilator (and natriuretic) principle for volume homeostasis in humans.

Atrial Natriuretic Factor↗

PubMed1985

Mixed venous blood temperature response to exercise in heart failure patients treated with short-term vasodilators.

Deep-body or core temperature decreases during exercise in patients with heart failure, primarily due to the circulatory inadequacies associated with the pathophysiology of this condition. Vasodilators are commonly used to treat patients suffering from heart failure because these drugs improve total cardiac output and blood-flow to the regional circulations. In heart failure patients, the core temperature response to exercise should also be affected if the circulation is improved by vasodilators. Patients with severe heart failure were studied at rest and during upright bicycle exercise before, and after, short-term treatment with vasodilators (2-minoxidil, 3-hydralazine, 5-captopril). Their heart rate increased significantly (P less than 0.05) from rest to exercise before (87 +/- 15 109 +/- 14 beats/min), and after 89 +/- 13- 112 +/- 15 beats/min) vasodilators, but there was no drug-related affect on these changes. Mean arterial and pulmonary capillary wedge pressures were significantly (P less than 0.05) decreased at rest and after the administration of vasodilators (mean arterial pressure 88 +/- 7 mmHg before; 77 +/- 8 mmHg after; pulmonary capillary wedge pressure 25 +/- 8 mmHg before, 19 +/- 9 mmHg after). During exercise, the increases in mean arterial and pulmonary capillary wedge pressures were not significantly different from the before vasodilator values (mean arterial pressure 92 +/- 14 mmHg before, 87 +/- 14 mmHg after; pulmonary capillary wedge pressure 31 +/- 11 mmHg before, 29 +/- 11 mmHg after). Vasodilators increased cardiac output significantly (P less than 0.05) at rest (3.1 +/- 0.6 litre/min to 4.1 +/- 1.1 litre/m) and during exercise (4.8 +/- .2 litre/min-5.6 +/- 1.7 litre/min). The core temperature (mixed venous blood temperature) decreased significantly (P less than 0.05) during exercise from 37.04 +/- 0.62 degrees C to 36.65 +/- 0.65 degrees C, before treatment with vasodilators. After administration of vasodilators, resting core temperature was not significantly different (36.95 +/- 0.54 degrees C) and still decreased significantly (P less than 0.05) during exercise to 36.73 +/- 0.53 degrees C. This decrease was significantly (P less than 0.05) different from the core temperature response before the administration of vasodilators. We conclude that heart failure patients, treated with short-term vasodilators, have an attenuation of the core temperature response that typically occurs during exercise. This change in the core temperature response is the result of the vasodilator-induced improvement in circulation.

Adult↗

PubMed1996

Arginine, lysine and ornithine as vasodilators in the forearm of man.

Nitric oxide is an endogenous vasodilator produced from L-arginine and oxygen by stereospecific enzymes. L-arginine itself can act as a vasodilator when administered at high doses to humans. This effect has been attributed by some to provision of extra substrate for production of nitric oxide. This work compares L-arginine-induced vasodilation with that caused by D-arginine, hyperosmolar sodium chloride and by other cationic amino acids in the resting forearm vasculature of normal subjects. By these means we identify whether L-arginine-induced vasodilation has a component related to stereospecific provision of substrate for nitric oxide production, or whether it can be accounted for by other phenomena. Effects of hyperosmolar sodium chloride and both L and D isomers of arginine, lysine and ornithine on forearm blood flow in eight normal male subjects were compared by bilateral forearm venous occlusion plethysmography. Vasodilator responses to saline and each amino acid were compared as the area under dose-response curves with single-factor analysis of variance (ANOVA). The magnitude of vasodilation obtained with the D isomers of each amino acid was compared with the L counterpart by application of single-factor ANOVA to the appropriate areas under dose-response curves. All three cationic amino acids increased forearm blood flow. Part of the increase could be related to the high osmolality of infusates-comparison with equiosmolar sodium chloride solutions shows that ornithine does not differ significantly as a vasodilator (P > 0.4), but that arginine and lysine have greater vasodilator effects than can be accounted for by osmolality alone (P < 0.001). The D isomers of arginine and lysine were more potent dilators than their L counterparts (arginine P < 0.03, lysine P < 0.02). The vasodilator effects of arginine in the forearm vascular bed at rest are not stereospecific, they are common to other cationic amino acids, greater for D isomers and occur only when normal plasma concentrations are raised far above the physiological range. These features suggest that the vasodilator effect of arginine is in part physical and related to the presence of the molecule in the vessel lumen. They do not suggest that increased provision of substrate, with a consequence of increased nitric oxide production, is the principal basis of L-arginine-induced vasodilation in normal humans.

Adolescent↗

PubMed2000

In vivo mechanisms of acetylcholine-induced vasodilation in rat sciatic nerve.

We examined the importance of nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), and neurogenic activity in agonist-induced vasodilation and baseline blood flow [i.e., nerve microvascular conductance (NMVC)] in rat sciatic nerve using laser Doppler flowmetry. Agonists were acetylcholine (ACh) and 3-morpholinosydnonimine (SIN-1). Vasodilation occurring despite NO synthase (NOS) and cyclooxygenase inhibition and showing dependence on K(+) channel activity was taken as being mediated by EDHF. NOS and cyclooxygenase inhibition with N(omega)-nitro-L-arginine (L-NNA) + indomethacin (Indo) revealed two phases of ACh-induced vasodilation: an initial, transient L-NNA + Indo-resistant vasodilation, peaking at 23 +/- 6 s and lasting 145 +/- 69 s, followed by sustained L-NNA + Indo-sensitive vasodilation. L-NNA alone did not affect sustained ACh-induced vasodilation but decreased baseline NMVC by 55%. In the presence of L-NNA + Indo, the K(+) channel blocker tetraethylammonium (TEA) inhibited transient ACh-induced vasodilation by 58% and reduced baseline NMVC by 25%. SIN-1-induced vasodilation increased fourfold in the presence of L-NNA, whereas the specific guanylyl cyclase inhibitor 1H-(1, 2, 4)oxadiazolo(4,3-alpha)quinoxalin-1-one abolished it. However, in homogenates of rat sciatic nerve, SIN-1-stimulated soluble guanylyl cyclase (sGC) activity was unaffected by L-NNA. TTX affected neither SIN-1- nor ACh-induced vasodilation. In conclusion, ACh-induced vasodilation consisted of two components, the first partially mediated by EDHF and the second by a vasodilatory prostanoid + NO. Baseline NMVC was dependent on NO and EDHF. Although L-NNA enhanced SIN-1-induced vasodilation, it had no effect on sGC-activity.

Acetylcholine↗

PubMed2001

Adrenomedullin inhibits neurotransmission of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves in rat mesenteric resistance arteries.

We have reported that the rat mesenteric resistance artery has innervation of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves (CGRPergic nerves). We also demonstrated that adrenomedullin (AM) causes mesenteric vasodilation through activation of CGRP receptors. The present study was designed to examine the effect of AM on neurotransmission of CGRPergic nerves in rat mesenteric arteries. In preconstricted preparations without endothelium, periarterial nerve stimulation (PNS, 1 and 2 Hz) induced a frequency-dependent vasodilation. A bolus injection of CGRP (10 pmol) into the perfusate also caused a vasodilation. AM (0.1 to 10 nM) concentration-dependently caused 40% to 60% inhibition of the PNS-induced vasodilation, but AM did not attenuate vasodilation induced by exogenous CGRP injection. The inhibitory effect of AM (10 nM) on PNS-induced vasodilation was further potentiated by CGRP [8-37] (CGRP receptor antagonist, 50 nM), which attenuated the vasodilator response to the CGRP injection. Combined perfusion of AM [22-52] (AM receptor antagonist, 10 to 100 nM) resulted in further inhibition of PNS-induced neurogenic vasodilation without affecting the vasodilator response to the CGRP injection. CGRP [8-37] but not AM [22-52] antagonized vasodilation induced by AM perfusion. These findings suggest that AM presynaptically inhibits neurotransmission of CGRPergic nerves, probably decreasing CGRP release, via receptors different from CGRP receptors.

Adrenomedullin↗

PubMed2004

The role of bradykinin, AT2 and angiotensin 1-7 receptors in the EDRF-dependent vasodilator effect of angiotensin II on the isolated mesenteric vascular bed of the rat.

1. The mechanisms involved in the vasodilator actions of angiotensin II (Ang II) have not yet been completely elucidated. We investigated the potential mechanisms that seem to be involved in the Ang II vasodilator effect using rat isolated mesenteric vascular bed (MVB). 2. Under basal conditions, Ang II does not affect the perfusion pressure of MVB. However, in vessels precontracted with norepinephrine, Ang II induces vasodilation followed by vasoconstriction. Vasoconstrictor, but not the vasodilation of Ang II, is inhibited by AT(1) antagonist (losartan). The vasodilator effect of Ang II was not inhibited by AT(2), angiotensin IV and angiotensin 1-7 receptor antagonists alone (PD 123319, divalinal, A 779, respectively). 3. The vasodilator effect of Ang II is significantly reduced by endothelial removal (deoxycholic acid), but not by indomethacin. Inhibition of NO-synthase by N(G)-nitro-l-arginine methyl ester (l-NAME) and guanylyl cyclase by 1H-[1,2,3] oxadiazolo [4,4-a] quinoxalin-1-one (ODQ) reduces the vasodilator effect of Ang II. This effect is also reduced by tetraethylammonium (TEA) or l-NAME, and a combination of l-NAME plus TEA increases the inhibitory effect of the antagonists alone. However, indomethacin does not change the residual vasodilator effect observed in vessels pretreated with l-NAME plus TEA. 4. In vessels precontracted with norepinephrine and depolarized with KCl 25 mm or treated with Ca(2+)-dependent K(+) channel blockers (charybdotoxin plus apamin), the effect of Ang II was significantly reduced. However, this effect is not affected by ATP and voltage-dependent K(+) channel blockers (glybenclamide and 4-aminopyridine). 5. Inhibition of kininase II with captopril significantly potentiates the vasodilator effect of bradykinin (BK) and Ang II in the rat MVB. The inhibitory effect of the B(2) receptor antagonist HOE 140 on the vasodilator effect of Ang II is further enhanced by PD 123319 and/or A 779. 6. The present findings suggest that BK plays an important role in the endothelium-dependent vasodilator effect of Ang II. Probably, the link between Ang II and BK release is modulated by receptors that bind PD 123319 and A 779.

Angiotensin I↗

PubMed2006

Location and function of VPAC1, VPAC2 and NPR-C receptors in VIP-induced vasodilation of porcine basilar arteries.

Vasoactive intestinal peptide (VIP) is a vasodilator peptide present in cerebrovascular nerves. Vasoactive intestinal peptide can activate VPAC1, VPAC2 and the NPR-C receptor. This study sought to determine the receptors involved in VIP-induced vasodilation of porcine basilar arteries. Porcine basilar arteries contained the messenger ribonucleic acid of all three receptors. Immunocytochemical analysis of porcine basilar arteries revealed that the VPAC1 receptor is expressed on the endothelium, VPAC2 on the outer layers of the media and the NPR-C receptor throughout the artery, including nerves. Vasodilator responses to all receptor agonists showed that the receptors are functional. The vasodilator response to the VPAC1 receptor agonist was inhibited by L-NAME and abolished by endothelial denudation. Vasodilation induced by Ro-25-1553, the VPAC2 agonist, was unaffected by NOS inhibition or removal of the endothelium. Activation of the NPR-C receptor produced a vasodilation, which was susceptible to NOS inhibition and independent of endothelium. The vasodilator response to electrical stimulation at 20 Hz was attenuated by PG-99-465, the VPAC2 antagonist. This study shows that all known VIP receptors are involved in VIP-mediated vasodilation of porcine basilar arteries. The VPAC1 receptor is located on the endothelium and elicits vasodilation by generating nitric oxide (NO). The VPAC2 receptor is mainly expressed in the outer layers of the smooth muscle and induces vasodilation independently of NO in response to VIP released from intramural nerves. The NPR-C receptor produces NO-dependent vasodilation independently of the endothelium by stimulation of nNOS in intramural nerves.

Animals↗

PubMed2005

Antihypertensive and endothelium-dependent vasodilator effects of Alpinia zerumbet, a medicinal plant.

Alpinia zerumbet (K. Schum), a medicinal plant originated from West Asia, is used in the northeast and southeast of Brazil as infusions or decoctions as a diuretic, antihypertensive, and antiulcerogenic. Experiments were undertaken to determine whether a hydroalcoholic extract obtained from leaves of Alpinia zerumbet (AZE) induces vasodilation in the mesenteric vascular bed (MVB), and an antihypertensive effect was also assessed in rats with DOCA-salt hypertension. In MVB precontracted with norepinephrine, AZE induces a long-lasting endothelium-dependent vasodilation that is not reduced by indomethacin. Inhibition of NO synthase by NG-nitro-L-arginine methyl ester (L-NAME) and guanylyl cyclase by 1H-[1,2,3]oxadiazolo [4,4-a]quinoxalin-1-one (ODQ) reduces the vasodilator effect of AZE. In vessels precontracted with norepinephrine, the vasodilator effect of AZE was not changed by 4-aminopyridine, glibenclamide, or by charybdotoxin plus apamin. Concentrations of atropine, pyrilamine, and yohimbine that significantly reduced the vasodilator effect of acetylcholine, histamine, and clonidine, respectively, did not change the vasodilator effect of AZE. HOE 140, which significantly reduced the vasodilator effect of bradykinin, induced a slight but significant reduction on the vasodilator effect of AZE. Chronic oral administration of AZE induced a significant reduction in systolic, mean, and diastolic arterial pressure in rats with DOCA-salt hypertension. Probably the vasodilator effect of AZE is dependent on the activation of the NO-cGMP pathway and independent of activation of ATP-dependent, voltage-dependent, and calcium-dependent K+ channels. Bradykinin receptors may also participate in the vasodilator effect of AZE. Finally, the vasodilator and antihypertensive effects of AZE demonstrated in the present study provide experimental support for the indication of Alpinia zerumbet as an antihypertensive medicinal plant.

Acetylcholine↗

PubMed1992

Nitric oxide and sensory nerves are involved in the vasodilator response to acetylcholine but not calcitonin gene-related peptide in rat skin microvasculature.

1. The contributions of sensory nerves and nitric oxide (NO) to vasodilator responses to acetylcholine (ACh) and calcitonin gene-related peptide (CGRP) were examined in rat skin microvasculature with a laser Doppler flowmeter to monitor relative blood flow. 2. Perfusion of ACh (100 microM; for 30 min) over a blister base on the rat hind footpad elicited microvascular vasodilatation and this response was not sustained. CGRP (1 microM; 10 min perfusion) also elicited vasodilatation and this response was maintained even when CGRP was no longer in contact with the blister base. 3. The vasodilator response to ACh was significantly smaller in rats pretreated as neonates with capsaicin to destroy primary sensory afferents than it was in age-matched controls. The vasodilator response to CGRP was unaffected by capsaicin pretreatment. 4. Selective inhibitors of NO synthase, NG-nitro-L-arginine (L-NOARG) and NG-monomethyl-L-arginine (L-NMMA) (both at 100 microM) attenuated the vasodilator response to ACh in control rats, but had no effect on the vasodilator response to CGRP. There was a significant L-NOARG-resistant component in control rats while in capsaicin-treated rats the vasodilator response to ACh was virtually abolished by L-NOARG. The inactive stereoisomer NG-monomethyl-D-arginine (100 microM) did not affect the vasodilator response to ACh. 5. The efficacy of L-NOARG and L-NMMA as inhibitors of endothelium-dependent responses was confirmed by use of an endothelium-dependent vasodilator, the calcium ionophore A23187 (100 microM; 10 min perfusion). Vasodilatation to A23187 was strongly attenuated by both L-NOARG and L-NMMA.6. These results suggest that sensory nerves and NO are both involved in the dilatation produced by ACh in rat skin microvasculature. A component of the vasodilator response elicited by ACh involves a direct action on the microvascular endothelium with subsequent generation of NO, while an additional component is elicited via activation of sensory nerves. The vasodilator mediator(s) released by ACh from sensory nerves acts largely independently of NO.7. The vasodilator response to CGRP is independent of a prejunctional action on sensory nerves and of NO.

Acetylcholine↗

PubMed1994

Characterization of ATP-induced vasodilation in the human forearm vascular bed.

BACKGROUND: Animal data indicate that ATP derived from aggregating thrombocytes or endothelium induces an endothelium-dependent vasodilator response that is mediated by P2y-purinergic receptors and is reduced when high dosages are administered. This reduced vasodilator response to high ATP doses has been associated with the concomitant release of endothelium-derived contracting factors. In contrast to the endothelium-dependent vasodilator response, ATP as released from sympathetic nerve endings induces a P2x-purinergic receptor-mediated vasoconstrictor response that may contribute to the attenuated vasodilator response to high dosages of luminally applied ATP. The dual action of ATP might be important in the pathophysiology of disease states characterized by an impaired endothelial function and increased thrombocyte aggregation. This study was performed to characterize the vascular response to ATP in humans. METHODS AND RESULTS: The brachial artery was cannulated in 50 healthy male volunteers (age, 18 to 44 years) for drug infusion and measurement of mean arterial pressure. Forearm blood flow was recorded by venous occlusion strain-gauge plethysmography. ATP induced a dose-dependent vasodilator response that was significantly higher than the effect of equimolar adenosine infusion and that was not reduced by concomitant infusion of the P1-purinergic receptor antagonist theophylline. The infusion of the NO synthase antagonist NG-monomethyl-L-arginine (L-NMMA) reduced the average fall in forearm vascular resistance (FVR) to acetylcholine (-59 +/- 6% [mean +/- SEM] versus -42 +/- 8%; P < .05; N = 10) but did not affect the vasodilator response to ATP (-68 +/- 3% versus -64 +/- 6%; P > .1; N = 10) or sodium nitroprusside (SNP; -53 +/- 3% versus -49 +/- 4%; P > .01; N = 6). The L-NMMA-induced increase in FVR appeared to be related to the type of vasodilator pretreatment, being 94.7 +/- 16.7%, 44.9 +/- 8.7%, and 40.8 +/- 7.3% for acetylcholine, ATP, and SNP pretreatment, respectively (P < .01 for acetylcholine versus ATP and SNP; P > .1 for ATP versus SNP). In contrast to animal data, high dosages of intra-arterially infused ATP (up to 1000 micrograms.100 mL forearm-1.min-1) did not reveal a reduction in the forearm vasodilator response but appeared to be similar to the maximal forearm vasodilation as observed during postocclusive reactive hyperemia. CONCLUSIONS: These observations indicate that ATP induces a potent dose-dependent vasodilator response that is not mediated by P1-purinergic receptor stimulation or by the release of nitric oxide. Moreover, in healthy volunteers, the vasodilator response to high intra-arterial dosages of ATP is not reduced by the release of endothelium-derived contracting factors or by the stimulation of P2x-purinergic receptors on the smooth muscle cells.

Adenosine Triphosphate↗

PubMed2000

Bradykinin-induced vasodilation of human forearm resistance vessels is primarily mediated by endothelium-dependent hyperpolarization.

Bradykinin (BK) stimulates endothelial cells to release a number of relaxing factors, such as NO, prostanoids (PGs), and an endothelium-derived hyperpolarizing factor (EDHF). However, the contributions of NO, PG, and EDHF in the vascular relaxation to BK vary with species and anatomic origin of blood vessels used. Therefore, the present study was designed to investigate the contributions of NO, PG, and EDHF in vasodilation caused by BK in human forearm resistance vessels. Forearm blood flow (FBF) was recorded with venous occlusion plethysmography in healthy nonsmoking subjects. At first, studies were performed to validate the NO clamp technique for its ability to inhibit endogenous NO generation. Brachial artery infusion of serotonin (0.6, 1.8, and 6 ng. 100 mL forearm volume [FAV](-1). min(-1)) caused significant forearm vasodilation (2.6 to 4.6 mL. 100 mL FAV(-1). min(-1)), which is known to be NO mediated. Indeed, during the NO clamp, cumulative doses of serotonin caused no vasodilation (2.4 to 2.6 mL. 100 mL FAV(-1). min(-1)), indicating that the generation of endogenous NO was completely blocked. Thereafter, the vasodilative actions of BK were investigated. Brachial artery infusion of BK (50, 100, and 200 ng. 100 mL FAV(-1). min(-1)) caused significant forearm vasodilation in all studies (from 3.1 to 20.4 mL. 100 mL FAV(-1). min(-1)). After the inhibition of cyclooxygenase and NO synthase activity through the use of aspirin and the NO-clamp technique, BK increased FBF in a similar manner (3.9 to 18.9 mL. 100 mL FAV(-1). min(-1)), indicating that the vasodilative actions of BK are independent of NO and PG generation. However, vasodilation caused by the 2 lower doses of BK were significantly attenuated after K(Ca) channel activity was blocked with tetraethylammonium chloride (0.1 mg. 100 mL FAV(-1). min(-1)), suggesting that in the lower dose range, BK mediates vasodilation through the opening of vascular potassium channels. In conclusion, BK is a potent vasodilator peptide in human forearm resistance vessels, causing vasodilation through hyperpolarization of the vascular wall independent of NO and PG production. In addition, the NO-clamp technique is a valid instrument to investigate the contribution of NO in the vasodilative response to different agents.

Adolescent↗

PubMed1995

Calcitonin gene-related peptide mediates acetylcholine-induced endothelium-independent vasodilation in mesenteric resistance blood vessels of the rat.

The role of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves in acetylcholine chloride (ACh)-induced vasodilation was studied in the perfused mesenteric vascular bed isolated from the rat. Bolus infusions of ACh at smaller doses (0.1 and 1 nmol) produced rapid and short-lived vasodilation. However, larger doses (10 and 100 nmol) of ACh caused a rapid and subsequent long-lasting vasodilator response in which the duration of vasodilation was prolonged in a concentration-dependent manner. Pretreatment with capsaicin (1 mumol/L for 20 minutes) significantly shortened the duration of vasodilator response to ACh but did not affect the initial rapid phase of ACh-induced vasodilation. Chemical removal of the vascular endothelium by perfusion with sodium deoxycholate (1.75 to 1.80 mg/mL) for 30 seconds and subsequent treatment with N omega-nitro-L-arginine (100 mumol/L) to inhibit nitric oxide synthesis abolished the initial rapid vasodilator action of ACh at any given concentration. However, in the same preparation, increasing concentrations (from 1 to 1000 nmol) of ACh produced only the long-lasting vasodilator responses in a concentration-dependent manner. This long-lasting vasodilator response to ACh infusion was abolished by capsaicin pretreatment (1 mumol/L), human CGRP[8-37] (CGRP receptor antagonist, 1 mumol/L), and atropine (muscarinic ACh receptor antagonist, 1, 10, and 100 nmol/L) but not by hexamethonium (nicotinic ACh receptor antagonist, 1 and 10 mumol/L). In the preparations without endothelium, the bolus infusion of ACh (300 nmol for 30 seconds) evoked a long-lasting vasodilation and release of CGRP-like immunoreactivities into the perfusate.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1986

The role of vasodilator therapy in the treatment of severe chronic heart failure.

The rationale for the use of vasodilating agents in the treatment of congestive heart failure is to reverse the systemic vasoconstriction that characterises patients with this disorder, and which may further limit cardiac performance. Nitrates were the first vasodilators used, followed by arterial vasodilators (hydralazine, minoxidil), alpha-adrenergic blockers (prazosin, trimazosin) and, more recently, calcium antagonists, ACE inhibitors, beta-agonists and phosphodiesterase inhibitors. The choice of vasodilator should be based on consideration of overall benefit-risk profiles. Consideration of pharmacological action together with classification of patients into haemodynamic subsets has been used as a basis from which to initiate vasodilator therapy. However, such a classification may not lead to a logical choice of drug and there is no evidence to suggest that patients so selected do better when given long term treatment with peripherally specific drugs than with agents that are not tailored to pretreatment haemodynamic variables. Moreover, changes in central haemodynamics after administration of specific vasodilator drugs may differ from those expected on the basis of their presumed actions on the peripheral vasculature. Dosage requirements are difficult to predict with many vasodilator drugs. Traditionally, such requirements have been established by titrating vasodilating drugs to achieve an arbitrarily defined haemodynamic response. However, there is little correlation between haemodynamic end-points and clinical efficacy in patients with heart failure, and short and long term haemodynamic responses to vasodilator drugs are not necessarily related. Drug-specific haemodynamic and clinical tolerance occurs during the course of treatment with all vasodilator drugs; the extent and frequency with which it develops differs between agents. Tolerance is thought to arise from a reduction in drug receptor affinity and/or density or activation of counter-regulatory forces (mainly neurohormonal) that limit the magnitude of vasodilatation that can be achieved. Development of tolerance to a single agent does not usually preclude efficacy of other agents. ACE inhibitors have been associated with a relatively low incidence of tolerance. This may relate to their natriuretic effect and ability to decrease the degree of neurohormonal activation, actions not shared by other vasodilators. Tolerance is the principal reason for failure of prazosin and nitrates as therapeutic agents in severe chronic heart failure.(ABSTRACT TRUNCATED AT 400 WORDS)

Chronic Disease↗