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PubMed2006

Attenuation of nitric oxide- and prostaglandin-independent vasodilation of retinal arterioles induced by acetylcholine in streptozotocin-treated rats.

Diabetes alters retinal hemodynamics, but little is known about the impact of diabetes on the role of endothelium-derived hyperpolarizing factor (EDHF) in the regulation of retinal circulation. Therefore, we examined how diabetes affects the nitric oxide- and prostaglandin-independent vasodilation of retinal arterioles induced by acetylcholine. Male Wistar rats were treated with streptozotocin (80 mg/kg, i.p.) and experiments were performed 6-8 weeks later. Under artificial ventilation, rats were treated with tetrodotoxin (100 microg/kg, i.v.) to eliminate any nerve activity and prevent movement of the eye. Methoxamine was used to maintain adequate systemic circulation. Fundus images were captured by a digital camera that was equipped with a special objective lens. The vasodilator responses of retinal arterioles were assessed by measuring changes in diameters of the vessels. In streptozotocin-induced diabetic rats and the age-matched controls, acetylcholine increased diameters of retinal arterioles in a dose-dependent manner. The vasodilator responses to acetylcholine in diabetic rats were smaller than those in control rats. The nitric oxide- and prostaglandin-independent vasodilation of retinal arterioles observed under treatment with combination of N(G)-nitro-l-arginine methyl ester (30 mg/kg, i.v.) and indomethacin (5 mg/kg, i.v.) were also attenuated by diabetes. Diabetes did not alter the dilator responses of retinal arterioles to sodium nitroprusside and forskolin. These results suggest that diabetes impairs EDHF-mediated vasodilation of retinal arterioles induced by acetylcholine. The impaired EDHF-mediated vasodilation may contribute to alteration of retinal hemodynamics in diabetes.

Acetylcholine↗

PubMed2001

Impaired endothelium-dependent vasodilation in type 2 diabetes mellitus and the lack of effect of simvastatin.

OBJECTIVE: Although type 2 diabetes is recognized as an independent risk factor for cardiovascular disease and cardiovascular disease is associated with endothelial dysfunction, the influence of type 2 diabetes per se on the endothelial function is controversial. HMG-CoA-reductase inhibitors have been shown to have short-term beneficial effects on endothelial dysfunction among patients with dyslipidemia or cardiovascular disease. The effect of HMG-CoA reductase inhibitors on the endothelial function in diabetes is largely unknown. METHODS: Seventeen patients with type 2 diabetes, free of cardiovascular disease and no other cardiovascular risk factors, except for dyslipidemia, were studied together with ten healthy volunteers. The effect of 5-hydroxytryptamine, as an endothelium-dependent vasodilator, and sodium nitroprusside, as an endothelium-independent vasodilator, on the forearm blood flow was measured using venous occlusion plethysmography. RESULTS: 5-Hydroxytryptamine and sodium nitroprusside, infused in the brachial artery, caused a dose-dependent vasodilation. The vasodilator response to 5-hydroxytryptamine was significantly lower among the diabetic patients, 42 and 56%, than among the controls, 73 and 103%, at a dose of 0.3 and 0.9 ng/kg/min, respectively (P<0.05 and P<0.001). Vasodilator responses to sodium nitroprusside were comparable among the diabetic patients and controls. A 6-week treatment with simvastatin 40 mg once daily did not change the vasodilator responses to 5-hydroxytryptamine or sodium nitroprusside among the patients with diabetes. CONCLUSIONS: The results of this study indicate that the endothelial function is impaired in type 2 diabetes and is not restored after a 6-week treatment period with simvastatin 40 mg.

Case-Control Studies↗

PubMed2003

Calcitonin gene-related peptide: exploring its vasodilating mechanism of action in humans.

OBJECTIVE: In vitro studies suggest that the vasodilator mechanism of action of calcitonin gene-related peptide (CGRP) involves various endothelium-dependent and endothelium-independent mechanisms. An in vivo analysis of the contribution of nitric oxide, prostaglandins, calcium-sensitive potassium channels (K(+)(Ca) channels), and adenosine triphosphate (ATP)-sensitive potassium channels (K(+)(ATP) channels) to CGRP-induced vasodilation in humans was performed. METHODS: CGRP (3, 10, and 30 ng x min(-1) x dL(-1) forearm) was infused into the brachial artery of 40 healthy subjects. Forearm vascular responses were measured by venous occlusion plethysmography. First, dose-response curves were constructed during coinfusion of CGRP with placebo (sodium chloride, 0.9%). After washout, in 5 subgroups (n = 8 each), the infusions of CGRP were repeated with placebo (time-control experiments), N(G)-monomethyl-L-arginine (L-NMMA, a nitric oxide-synthase inhibitor), indomethacin (a cyclooxygenase inhibitor), tetraethylammonium chloride (TEAC) (a K(+)(Ca)-channel blocker), and glyburide (INN, glibenclamide) (a K(+)(ATP)-channel blocker), respectively. RESULTS: CGRP induced a dose-dependent and reproducible decrease in forearm vascular resistance (P < .001). Compared with placebo, L-NMMA reduced the decrease in forearm vascular resistance induced by CGRP (P < .001) (3 and 10 ng x min(-1) x dL(-1) forearm). The absence of an inhibitory effect of L-NMMA on CGRP-induced vasodilation at the highest dose of CGRP suggests that still other mechanisms are involved. The vasodilator response to CGRP was not affected by coinfusion of indomethacin, tetraethylammonium chloride, or glyburide. CONCLUSIONS: The intrabrachial infusion of CGRP results in a dose-dependent and reproducible forearm vasodilator response. CGRP-induced vasodilation is dependent at least in part on the release of nitric oxide and does not involve the release of prostaglandins or the activation of K(+)(Ca) channels or K(+)(ATP) channels in humans.

Adult↗

PubMed1997

Vasodilator effects of C-type natriuretic peptide on cerebral arterioles in rats.

The vasodilator effects of C-type natriuretic peptide (CNP) were investigated in isolated rat cerebral arterioles. CNP caused dose-dependent vasodilation, maximally by 10.0 +/- 2.2% at 10(-6) M. The median effective concentration (EC50) was 5.2 x 10(-10) M. In contrast, atrial natriuretic peptide and B-type natriuretic peptide, other members of the natriuretic peptide family, produced little or no vasodilation. Pretreatment with methylene blue (10(-4) M) abolished CNP-induced vasodilation, whereas pretreatment with NG-monomethyl-L-arginine or indomethacin did not inhibit vasodilation. Thus, CNP is suggested to cause significant vasodilation in cerebral arterioles via a cyclic guanosine monophosphate-dependent mechanism.

Animals↗

PubMed1999

The role of beta 2-adrenergic vascular receptors in the peripheral vasodilation caused by 17 beta-estradiol in anesthetized pigs.

It has been previously shown in anesthetized pigs that intravenous infusion of 2 microg/h of 17beta-estradiol primarily dilated renal, iliac and coronary circulations, while higher doses of the hormone were required to cause vasodilation also in the mesenteric vascular bed. In the same experimental model, a tonic beta2-adrenoceptor mediated vasodilation, which could be argued to attenuate the vasodilator effect of 17beta-estradiol, has been described. The present study was planned to investigate the role of beta2-adrenergic receptors in the hemodynamic responses of renal and mesenteric vascular beds to 17beta-estradiol. Changes in flow caused by intravenous infusion of 2 microg/h of the hormone at constant heart rate and aortic blood pressure in the left renal and superior mesenteric arteries were assessed using electromagnetic flowmeters. In six pigs, infusion of 17beta-estradiol caused an increase in renal blood flow, which averaged 12.1% of the control values, without affecting mesenteric blood flow. In the same pigs, after hemodynamic variables had returned to the baseline values, blockade of beta2-adrenergic receptors with butoxamine caused an increase in aortic blood pressure and an increase in renal and mesenteric resistance. The subsequent infusion of 17beta-estradiol elicited increases in renal and mesenteric blood flow which respectively averaged 19.6% and 12.8%. Therefore, the present study in anesthetized pigs have shown that the vasodilator responses of the renal and mesenteric circulations to 17beta-estradiol were attenuated and even masked by a tonic beta2-adrenoceptor mediated vasodilation. This indicates that some vasodilator effects elicited by normally used replacement doses of the hormone may not be apparent.

Adrenergic beta-Antagonists↗

PubMed1984

Vasodilator therapy for primary pulmonary hypertension.

Primary pulmonary hypertension is an uncommon but serious disease that often results in debilitating symptoms and early death. One approach to treatment has been to attempt reduction of pulmonary arterial pressure and right ventricular afterload by using vasodilator agents to decrease pulmonary arteriolar resistance. Use of a variety of vasodilators has yielded only limited and infrequent success. Although an occasional patient may respond to vasodilator therapy with improved pulmonary hemodynamics and symptomatic status, most patients do not. Reasons for lack of success include the presence of predominantly fixed vascular obstructive disease rather than active vasoconstriction, inexorable progression of disease, and adverse nonpulmonary vascular effects of vasodilators, such as systemic hypotension. Because of occasional beneficial responses, a trial of vasodilators is warranted in patients with primary pulmonary hypertension. Initiation of drug therapy should be undertaken during hemodynamic monitoring in order to allow assessment of response, identification of adverse effects, and comparison of different agents. No vasodilator is clearly superior in primary pulmonary hypertension.

Adrenergic alpha-Antagonists↗

PubMedDate not supplied

Differential effects of 5-HT1B/1D receptor agonists on neurogenic dural plasma extravasation and vasodilation in anaesthetized rats.

These studies compared the effects of the 5-HT1B/1D receptor agonists sumatriptan, CP-122 288 ((R)-N-methyl-[3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl] methanesulphonamide succinate) and CP-93 129 (3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one dihydrochloride) on neurogenic dural extra-vasation and vasodilation in anaesthetized rats. Dural extravasation, evoked by high intensity (1.2 mA) stimulation of the trigeminal ganglion, was measured using the radioactive plasma marker 125I-labelled bovine serum albumin. Dural vasodilation produced by lower intensity (50-300 microA) stimulation of trigeminal fibres, was measured through a closed cranial window using intravital microscopy. All compounds inhibited dural extravasation (rank order of potency: CP-122 288 > > sumatriptan > CP-93 129) and dural vasodilation (rank order of potency: CP-93 129 > > sumatriptan = CP-122 288). Comparison of the potency of these compounds with their potencies in an in vitro functional model, agonist-induced [35S]GTP gamma S binding, suggests that blockade of dural extravasation was consistent with an action at rat 5-HT1D receptors, but activity at another, unknown, "extravasation receptor" could also be involved. In contrast, inhibition of dural vasodilation was consistent with an action at rat 5-HT1B receptors. We suggest that in our preparations, production of dural vasodilation involves activation of trigeminal A delta-fibres whereas production of dural extravasation involves activation of trigeminal C-fibres. The differential effects of compounds on dural extravasation and vasodilation may therefore be due to the different receptor subtypes involved and to the selective localization of these subtypes on different populations of trigeminal sensory fibre.

Anesthesia, General↗

PubMed2000

Medial prefrontal cortex acetylcholine injection-induced hypotension: the role of hindlimb vasodilation.

The injection of acetylcholine (ACh) into the cingulate region of the medial prefrontal cortex (MPFC) causes a marked fall in arterial blood pressure which is not accompanied by changes in heart rate. The purpose of the present study was to investigate the hemodynamic basis for this stimulus-induced hypotension in Sprague-Dawley rats. The study was designed to determine whether a change in the vascular resistance of hindlimb, renal or mesenteric vascular beds contributes to the fall in arterial pressure in response to ACh injection into the cingulate cortex. Miniature pulsed-Doppler flow probes were used to measure changes in regional blood flow and vascular resistance. The results indicated that the hypotensive response was largely due to a consistent and marked vasodilation in the hindlimb vascular bed. On this basis, an additional experiment was then undertaken to determine the mechanisms that contribute to hindlimb vasodilation. The effect of interrupting the autonomic innervation of one leg on the hindlimb vasodilator response was tested. Unilateral transection of the lumbar sympathetic chain attenuated the cingulate ACh-induced vasodilation in the ipsilateral, but not in the contralateral hindlimb. These results suggest that the hypotensive response to cingulate cortex-ACh injection is caused by skeletal muscle vasodilation mediated by a sympathetic chain-related vasodilator system.

Acetylcholine↗

PubMed1981

The influence of indomethacin on vasodilator responses to bradykinin and nitroglycerin in the cat.

The effects of indomethacin, a cyclooxygenase inhibitor, on vasodilator responses to bradykinin and nitroglycerin were investigated in the peripheral vascular bed of the anesthetized cat. Intra-arterial injections of bradykinin and nitroglycerin elicited dose-related decreases in mesenteric and hindquarters vascular resistance. Mesenteric vasodilator responses to nitroglycerin in absolute units were unchanged 30 min after administration of indomethacin whereas responses to bradykinin expressed as an absolute mm Hg decrease in perfusion pressure were increased. Indomethacin was also without effect on vasodilator responses to lower doses of nitroglycerin whereas responses to higher doses of nitroglycerin and bradykinin in absolute units were enhanced in the hindquarters vascular bed. Indomethacin increased vascular resistance in the mesenteric and hindquarters vascular beds and decreased systemic vasodepressor responses to the prostaglandin precursor, arachidonic acid. When the increase in (initial value) vascular resistance was taken into account by expressing vasodilator responses on a percent decrease basis, indomethacin only enhanced the vasodilator response to the highest does of bradykinin studies. Result of the present study suggest that products in the cyclooxygenase pathway may serve to maintain the peripheral vascular bed of the cat in a dilated state but that these metabolites do not mediate vasodilator responses to bradykinin. The present data further suggest that products in the cyclooxygenase pathway may play a minor role in modulating the dilator effects of bradykinin in the mesenteric and hindquarters vascular beds of the cat.

Animals↗

PubMed2000

Effects of age on cholinergic vasodilation of cortical cerebral blood vessels in rats.

The present study examined the age-related changes in the cholinergic vasodilative system originating in the nucleus basalis of Meynert (NBM) and projecting to the cerebral cortex using Wistar rats of three different ages; young adult (4-7 months), old (24-25 months), and very old (32-42 months) rats. The vasodilative responses in frontal and parietal cortices, measured by laser Doppler flowmetry, induced by electrical stimulation of NBM without blood pressure response were well maintained in old rats, but declined significantly in very old rats. Extracellular acethylcholine (ACh) release in both cortices collected by a microdialysis technique showed both basal levels and response to NBM stimulation to be well maintained in both old and very old rats. The vasodilative cerebral blood flow response elicited by stimulation of the muscarinic ACh receptors, using their agonist, arecoline, was also well maintained in old and very old rats. Considering the present data and our previous finding that the cerebral cortical vasodilative response to activation of the nicotinic ACh receptors using their agonist, nicotine, was markedly reduced in very old rats (Neurosci. Lett., 228 (1997) 203), it was concluded that the age-related decline of nicotinic ACh receptor activity was a cause of the decline of the vasodilative responses elicited by NBM stimulation in very old rats. This result suggests that a reduction of the cholinergic vasodilative system in very old rats due to decreased activity of the nicotinic ACh receptor may cause insufficient blood flow in the cortex when the cortical neurons require.

Acetylcholine↗

PubMed2001

Radiation therapy impairs endothelium-dependent vasodilation in humans.

OBJECTIVES: The objective of this study was to test the hypothesis that external-beam radiation induces a chronic impairment of endothelium-dependent vasodilation. BACKGROUND: Radiation therapy is used commonly in the treatment of cancer and is associated with an increased incidence of adverse vascular events related to the field of radiation, including stroke and myocardial infarction. As endothelial injury is central to the pathogenesis of vascular diseases, we hypothesized that radiotherapy induces arterial endothelial dysfunction. METHODS: Sixteen women with unilateral breast cancer who underwent standard external-beam radiation therapy to the breast and axilla >3 years before enrollment and ten healthy women were studied. Vascular ultrasonography was used to image both the artery exposed to radiation and the contralateral artery. Flow-mediated, endothelium-dependent vasodilation and endothelium-independent vasodilation to nitroglycerin of both axillary arteries were measured. RESULTS: Endothelium-dependent vasodilation was significantly impaired in the irradiated axillary arteries compared with the contralateral, nonirradiated arteries (-0.4 +/- 0.4% vs. 3.2 +/- 0.8% p < 0.001) and also compared with control subjects' arteries (-0.4 +/- 0.4% vs. 2.5 +/- 0.6%, p < 0.001). In contrast, endothelium-independent vasodilation was greater in the arteries that received radiation compared with the contralateral arteries (3.8 +/- 0.5% vs. 2.0 +/- 0.4%, p < 0.05) and also compared with control arteries (3.8 +/- 0.5% vs. 2.5 +/- 0.4%, p < 0.05). CONCLUSIONS: External beam radiation therapy impairs endothelium-dependent vasodilation of conduit arteries, implicating a decrease in the bioavailability of nitric oxide. These abnormalities may contribute to the development of arterial occlusive disease and associated clinical events.

Aged↗

PubMed2001

Gender differences in wall shear-mediated brachial artery vasoconstriction and vasodilation.

OBJECTIVES: We sought to investigate wall shear rate (WSR) and brachial artery diameter (BAD) changes simultaneously and to determine whether any gender differences exist in arterial reactivity. BACKGROUND: Wall shear rate/stress and arterial reactivity are rarely assessed at the same time. Furthermore, flow-mediated vasoconstriction has received less attention than flow-mediated vasodilation in humans. METHODS: A new noninvasive evaluation of WSR in the brachial artery, using multigated, pulsed Doppler velocimeter and a double-transducer probe moved and fixed by a robotic system, was developed. RESULTS: The validity of the system was tested in vitro with calibrated tubes and showed a high correlation (r = 0.98, p < 0.001). In 10 men and 10 women of similar age, induction of low and high shear rates by forearm occlusion produced significant vasoconstriction and vasodilation, respectively. The time lag for maximal BAD changes was 3 min for vasoconstriction and 1 min for vasodilation. A greater half-time for vasodilation (96 +/- 6 for men and 86 +/- 12 s for women) than for shear rate (31 +/- 5 s for men and 34 +/- 4 s for women) was observed after discontinuation of occlusion. Relative BAD was correlated with WSR changes, showing a significantly higher slope in women than in men (p < 0.01). Moreover, a larger normalized arterial diameter per shear rate was observed for vasoconstriction (p < 0.01) and vasodilation (p < 0.01) in women than in men. CONCLUSIONS: Shear-mediated arterial vasodilation and vasoconstriction were more pronounced in women than in men, suggesting different gender-related sensitivity in the regulation of large-artery vascular tone.

Adult↗

PubMed2002

Influence of propranolol, enalaprilat, verapamil, and caffeine on adenosine A(2A)-receptor-mediated coronary vasodilation.

OBJECTIVES: The study was done to determine the effects of propranolol, enalaprilat, verapamil, and caffeine on the vasodilatory properties of the adenosine A(2A)-receptor agonist ATL-146e (ATL). BACKGROUND: ATL is a new adenosine A(2A)-receptor agonist proposed as a vasodilator for myocardial stress perfusion imaging. Beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium blockers are commonly used for the treatment of coronary artery disease (CAD), and their effect on ATL-mediated vasodilation is unknown. Dietary intake of caffeine is also common. METHODS: In 19 anesthetized, open-chest dogs, hemodynamic responses to bolus injections of ATL (1.0 microg/kg) and adenosine (60 microg/kg) were recorded before and after administration of propranolol (1.0 mg/kg, ATL only), enalaprilat (0.3 mg/kg, ATL only), caffeine (5.0 mg/kg, ATL only), and verapamil (0.2 mg/kg bolus, ATL and adenosine). RESULTS: Neither propranolol nor enalaprilat attenuated the ATL-mediated vasodilation (225 +/- 86% and 237 +/- 67% increase, respectively, p = NS vs. control). Caffeine had an inhibitory effect (97 +/- 28% increase, p < 0.05 vs. control). Verapamil blunted both ATL- and adenosine-induced vasodilation (63 +/- 20% and 35 +/- 7%, respectively, p < 0.05 vs. baseline), and also inhibited the vasodilation induced by the adenosine triphosphate-sensitive potassium (K(ATP)) channel activator pinacidil. CONCLUSIONS: Beta-blockers and ACE inhibitors do not reduce the maximal coronary flow response to adenosine A(2A)-agonists, whereas verapamil attenuated this vasodilation through inhibition of K(ATP) channels. The inhibitory effect of verapamil and K(ATP) channel inhibitors like glybenclamide on pharmacologic stress using adenosine or adenosine A(2A)-receptor agonists should be evaluated in the clinical setting to determine their potential for reducing the sensitivity of CAD detection with perfusion imaging.

Adrenergic beta-Antagonists↗

PubMed1993

Effects of norepinephrine on endothelium-dependent vasodilation of forearm resistance vessels.

BACKGROUND: Endothelium-dependent dilatation of forearm resistance vessels is attenuated in patients with heart failure. Activation of the sympathetic nervous system could cause this abnormality by way of vasoconstriction and chemical inactivation of nitric oxide. METHODS AND RESULTS: The effects of concurrent intra-arterial norepinephrine infusions (25, 50 and 100 ng/min) on forearm blood flow responses to equipotent doses of an endothelium-dependent vasodilator, methacholine (0.3 and 1.5 micrograms/min), and an endothelium-independent vasodilator, nitroprusside (1 and 5 micrograms/min), were studied in 12 normal subjects. Norepinephrine infusions increased the mean plasma norepinephrine from 255 pg/ml at baseline to 460, 629, and 1089 pg/ml, respectively. Basal forearm blood flow was reduced from 2.9 to 1.6 ml/min/100 ml of forearm volume at the highest dose (p < 0.01). The average response to the lowest dose of methacholine (4.5 ml/min/100 ml) was not significantly reduced by concurrent infusion of norepinephrine (4.4, 4.2, and 4.3 ml/min/100 ml, respectively), whereas the response to the higher dose of methacholine (8.9 ml/min/100 ml) tended to be lower (7.2, 6.7, and 7.4 ml/min/100 ml, respectively) but did not attain statistical significance. Methacholine induced vasodilation was not more sensitive to norepinephrine than nitroprusside responses. Lower body negative pressure (-20 mm Hg) also significantly reduced baseline forearm flow and increased plasma norepinephrine but did not effect either methacholine or nitroprusside induced vasodilation. CONCLUSION: Sympathetic stimulation induced by infusion of norepinephrine or lower body negative pressure is not a potent antagonist to endothelium-dependent vasodilation of the forearm vasculature. These data suggest that sympathetic activation does not completely explain the abnormal endothelium-dependent vasodilation seen in patients with heart failure.

Adult↗

PubMed2000

Role of A(2A)-adenosine receptor activation for ATP-mediated coronary vasodilation in guinea-pig isolated heart.

1. Adenosine-5'-triphosphate (ATP) and adenosine are potent coronary vasodilators. ATP is rapidly converted to adenosine by ectonucleotidases. We examined whether coronary vasodilation caused by exogenous ATP is mediated by P(2) receptor activation or by A(2A)-adenosine receptor activation. 2. Effects of interventions on coronary conductance were determined by measuring coronary perfusion pressure in guinea-pig isolated hearts perfused at a constant flow of 10 ml min(-1). 3. ATP and adenosine both caused sustained, concentration-dependent increases of coronary conductance. Maximal responses to both agonists were equivalent. The values of pD(2) (+/-s.e.mean) for ATP and adenosine were 6.68+/-0.04 and 7.06+/-0.05, respectively. Adenosine was significantly more potent than ATP (P<0. 0001, n=10). 4. The values of pIC(50) for the selective A(2A)-adenosine receptor antagonist SCH58261 to antagonize equivalent responses to ATP and adenosine were 8.28+/-0.08 and 8.28+/-0.06 (P=0.99, n=6), respectively. 5. The non-selective adenosine receptor antagonists xanthine amine congener (XAC) and CGS15943 antagonized similarly the equivalent vasodilations caused by ATP (pIC(50) values 7.48+/-0.04 and 7.45+/-0.06, respectively) and adenosine (pIC(50) values 7. 37+/-0.13 and 7.56+/-0.11). 6. In contrast to ATP and adenosine, the two P(2) agonists 2-methylthio-ATP and uridine-5'-triphosphate failed to cause stable increases of coronary conductance, caused desensitization of vasodilator responses, and were not antagonized by SCH 58261, 8-parasulphophenyltheophylline, or XAC. 7. Glibenclamide attenuated coronary vasodilations caused by ATP and adenosine by 88 and 89%, respectively, but failed to attenuate those caused by 2-methylthio-ATP. 8. These results strongly suggest that sustained, submaximal coronary vasodilation caused by exogenous ATP is entirely mediated by adenosine acting upon A(2A)-adenosine receptors.

Adenosine↗

PubMed2001

The anti-migraine 5-HT(1B/1D) agonist rizatriptan inhibits neurogenic dural vasodilation in anaesthetized guinea-pigs.

These studies investigated the pharmacology of neurogenic dural vasodilation in anaesthetized guinea-pigs. Following introduction of a closed cranial window the meningeal (dural) blood vessels were visualized using intravital microscopy and the diameter constantly measured using a video dimension analyser. Dural blood vessels were constricted with endothelin-1 (3 microg kg(-1), i.v.) prior to dilation of the dural blood vessels with calcitonin gene-related peptide (CGRP; 1 microg kg(-1), i.v.) or local electrical stimulation (up to 300 microA) of the dura mater. In guinea-pigs pre-treated with the CGRP receptor antagonist CGRP((8-37)) (0.3 mg kg(-1), i.v.) the dilator response to electrical stimulation was inhibited by 85% indicating an important role of CGRP in neurogenic dural vasodilation in this species. Neurogenic dural vasodilation was also blocked by the 5-HT(1B/1D) agonist rizatriptan (100 microg kg(-1)) with estimated plasma levels commensurate with concentrations required for anti-migraine efficacy in patients. Rizatriptan did not reverse the dural dilation evoked by CGRP indicating an action on presynaptic receptors located on trigeminal sensory fibres innervating dural blood vessels. In addition, neurogenic dural vasodilation was also blocked by the selective 5-HT(1D) agonist PNU-142633 (100 microg kg(-1)) but not by the 5-HT(1F) agonist LY334370 (3 mg kg(-1)) suggesting that rizatriptan blocks neurogenic vasodilation via an action on 5-HT(1D) receptors located on perivascular trigeminal nerves to inhibit CGRP release. This mechanism may underlie one of the anti-migraine actions of the triptan class exemplified by rizatriptan and suggests that the guinea-pig is an appropriate species in which to investigate the pharmacology of neurogenic dural vasodilation.

Anesthesia↗

PubMed2002

Contribution of cytochrome P450 metabolites to bradykinin-induced vasodilation in endothelial NO synthase deficient mouse hearts.

We have characterized the contribution of endothelial nitric oxide synthase (eNOS), cyclo-oxygenase (COX) and cytochrome P450 (CYP450) to the bradykinin (BK)- induced vasodilation in isolated hearts from wildtype (WT) and eNOS deficient mice (eNOS-/-). The endothelium-dependent vasodilation by bradykinin (BK, 1 microM) was significantly lower in eNOS-/- hearts than that in WT hearts (+247% and +325% of basal flow, respectively), while there was no difference in the endothelium-independent vasodilation by adenosine. In WT hearts, the BK-induced vasodilation was markedly attenuated following inhibition of NOS with ETU (10 microM) but not after COX inhibition with diclofenac (3 microM) (P<0.01). In line with this finding, Bk did not increase the cardiac prostacyclin release as measured by ELISA for 6-keto-PGF1alpha in the coronary venous effluent. In eNOS-/- hearts, the flow response to BK was insensitive to both NOS and COX inhibition. The NOS/COX-independent vasodilatory factor which remained under L-NMMA+DF application was almost completely eliminated by either clotrimazole (3 microM), miconazole (0.5 microM) or 17-ODYA (1 microM), suggesting that it was a metabolite of CPY450 enzymes. Sulfaphenazole (10 microM), a CYP450 2C inhibitor, exerted only a minimal inhibitory effect. In eNOS-/- hearts the effect of CYP450 inhibitors on the BK response was significantly more pronounced than in WT hearts, indicating an enhanced contribution of CYP450 enzymes. These findings suggest that in isolated mouse hearts the BK-induced vasodilation is mediated by NO and CYP450 metabolites but not by prostaglandins. The CYP450 dependent vasodilator was was functionally up-regulated in eNOS-/- hearts and thus likely to compensate for the loss of eNOS in the coronary circulation.

Animals↗

PubMed2004

Novel role for P2X receptor activation in endothelium-dependent vasodilation.

1 ATP is an important vasoactive mediator, which acts via two receptor classes: P2X and P2Y. Activation of P2X receptors has traditionally been associated with the well-characterised vasoconstrictor properties of ATP. 2 In the current study, we have shown that the P2X(1 & 3) receptor ligand, alpha, beta methylene ATP, induces vasodilation of rat isolated mesenteric arteries and that P2X1 receptors are abundantly expressed in the endothelium of these vessels. 3 Second-order rat mesenteric arteries were mounted in myographs and vasomotor responses recorded. Both ATP and alpha, beta methylene ATP induced a constriction followed by a vasodilation. The dilator effects of either ATP or alpha, beta methylene ATP were slower in onset than those induced by acetylcholine. By contrast, the traditional vasodilator P2Y ligand, ADP, induced vasodilation without contraction. 4 Vasodilation induced by alpha, beta methylene ATP was endothelial dependent, but was not affected by treatment of the vessels with L-NAME plus indomethacin alone. Dilation was, however, partially inhibited by the combination of apamin plus charybdotoxin and blocked by treating vessels with all four drugs. 5 Using confocal microscopy, P2X1 receptor immunoreactivity was localised to the endothelial, smooth muscle and adventitial layers of mesenteric vessels. P2X1 protein migrated as a primary band at around 50-60 kDa in vascular tissue. 6 These results show for the first time that P2X1 receptors are expressed on the endothelium and that a selective ligand of this receptor results in vasoconstriction followed by vasodilation. These observations have important implications for our understanding of the role of purines in biological responses.

Adenosine Triphosphate↗