Biomedical subjects

C G Sobey

Publications and source records attributed to C G Sobey.

At least 37 records · Page 2Linked to original sources

PubMed1997

Effect of nitric oxide and potassium channel agonists and inhibitors on basilar artery diameter.

The first goal of this study was to examine the hypothesis that dilatation of the basilar artery in response to activation of ATP-sensitive K+ channels is mediated by nitric oxide (NO). Diameter of the basilar artery (209 +/- 5 microns, mean +/- SE) was measured using a cranial window in anesthetized rats. Aprikalim (a direct activator of ATP-sensitive K+ channels) dilated the basilar artery under control conditions. Inhibition of endogenous NO production with NG-nitro-L-arginine (L-NNA, 10(-4) M) did not alter responses to aprikalim. The second goal was to determine whether vasodilatation in response to NO is dependent on activation of calcium-activated K+ channels. Tetraethylammonium (TEA, 10(-3) M), an inhibitor of calcium-activated K+ channels, did not affect dilator responses to sodium nitroprusside (an NO donor) under control conditions. Responses to nitroprusside (10(-8) and 10(-7) M) were augmented more than twofold during application of L-NNA. In the presence of L-NNA, the augmented portion of the response to nitroprusside was inhibited by TEA and iberiotoxin (5 x 10(-8) M, a highly selective inhibitor of calcium-activated K+ channels), but it was not inhibited by glibenclamide (10(-6) M), an inhibitor of ATP-sensitive K+ channels. These findings suggest that dilator responses of the basilar artery to an activator of ATP-sensitive potassium channels are not mediated by NO. Calcium-activated K+ channels may not normally contribute to dilator responses of the basilar artery to nitroprusside. The effects of TEA and iberiotoxin suggest that when endogenous production of NO is inhibited, sodium nitroprusside causes the opening of calcium-activated K+ channels, contributing to an augmented vasodilator response.

Animals↗

PubMed1997

Mechanisms of bradykinin-induced cerebral vasodilatation in rats. Evidence that reactive oxygen species activate K+ channels.

BACKGROUND AND PURPOSE: Relatively little is know regarding mechanisms by which reactive oxygen species produce dilatation of cerebral arterioles. The goal of this study was to test the hypothesis that vasodilator responses of cerebral arterioles to bradykinin, which produces endogenous generation of reactive oxygen species, involve activation of calcium-dependent potassium channels. METHODS: We used a cranial window in anesthetized rats to examine effects of catalase (which degrades hydrogen peroxide) on responses to bradykinin. In addition, we examined effects of tetraethylammonium (TEA) and iberiotoxin, inhibitors of calcium-dependent potassium channels, on responses of cerebral arterioles to hydrogen peroxide, bradykinin, and papaverine. RESULTS: In cerebral arterioles (baseline diameter = 40 +/- 1 microns) (mean +/- SE), hydrogen peroxide (10 and 100 mumol/L) produced concentration-dependent dilatation. TEA (1 mmol/L), an inhibitor of calcium-dependent potassium channels, produced marked inhibition of vasodilatation in response to hydrogen peroxide. For example, 100 mumol/L hydrogen peroxide dilated arterioles by 13 +/- 2% in the absence and 4 +/- 1% (P < .05 versus control) in the presence of TEA. Bradykinin (10 nmol/L to 1 mumol/L) also produced concentration-dependent dilatation of cerebral arterioles that was inhibited completely by catalase (100 U/mL). TEA or iberiotoxin markedly inhibited vasodilatation in response to bradykinin. For example, 100 nmol/L bradykinin dilated arterioles by 21 +/- 3% in the absence and 2 +/- 2% (P < .05 vs control) in the presence of iberiotoxin (50 nmol/L). CONCLUSIONS: These findings suggest that dilatation of cerebral arterioles in the rat in response to hydrogen peroxide, or hydrogen peroxide produced endogenously in response to bradykinin, is mediated by activation of calcium-dependent potassium channels. Thus, activation of potassium channels may be a major mechanism of dilatation in response to reactive oxygen species in the cerebral microcirculation.

Animals↗

PubMed1997

Effect of subarachnoid hemorrhage on cerebral vasodilatation in response to activation of ATP-sensitive K+ channels in chronically hypertensive rats.

BACKGROUND AND PURPOSE: Cerebral vasodilatation in response to aprikalim, an opener of ATP-sensitive K+ channels, is selectively augmented after subarachnoid hemorrhage (SAH). Vasodilatation in response to activation of ATP-sensitive K+ channels, however, is impaired during chronic hypertension. Hypertension may contribute to a worse outcome after SAH, but the nature of the relationship between hypertension and SAH is uncertain. In the present study we examined responses of the basilar artery to aprikalim after SAH in normotensive Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). METHODS: In anesthetized WKY and SHRSP, we measured changes in diameter of the basilar artery in response to aprikalim and papaverine using a cranial window 2 days after injection of 0.3 mL saline or autologous blood into the cistema magna. RESULTS: Under control conditions, aprikalim (0.1 to 1 mumol/L) and papaverine (10 to 100 mumol/L) produced dilatation of the basilar artery. After SAH, responses to aprikalim were not significantly altered in WKY and were markedly increased in SHRSP compared with saline-injected control rats. In contrast, vasodilator responses to papaverine were not changed by SAH in either WKY or SHRSP, suggesting that augmented vasodilatation in response to aprikalim after SAH was selective. CONCLUSIONS: Responses of the basilar artery to aprikalim were greatly augmented in SHRSP after SAH. Because vasodilator responses to many stimuli are impaired after SAH and cerebral vasodilator responses to several stimuli are impaired by chronic hypertension, augmented responses to activation of K+ channels despite the presence of hypertension are unusual.

ATP-Binding Cassette Transporters↗

PubMed1997

Effects of a novel inhibitor of guanylyl cyclase on dilator responses of mouse cerebral arterioles.

BACKGROUND AND PURPOSE: Nitric oxide-induced vasodilatation is mediated by both cGMP-dependent and -independent mechanisms. Previous studies that examined the role of soluble guanylyl cyclase in cerebral vessels have used methylene blue and LY-83583, compounds that generate superoxide anion and are not specific for inhibition of soluble guanylyl cyclase. We examined the effects of ODQ (1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one), a novel and highly selective inhibitor of soluble guanylyl cyclase, on responses of cerebral arterioles. METHODS: The effects of ODQ on responses of cerebral arterioles to acetylcholine, nitroprusside, 8-bromo-cGMP, and adenosine were examined in anesthetized mice by means of a cranial window. The effects of two concentrations of ODQ were examined in the absence and presence of superoxide dismutase. The effects of NG-nitro-L-arginine, an inhibitor of nitric oxide synthase, were also tested. RESULTS: ODQ (3 and 10 mumol/L) produced concentration-dependent inhibition of dilatation of cerebral arterioles (control diameter = 29 +/- 1 microns) (mean +/- SE) in response to acetylcholine and nitroprusside. For example, 10 mumol/L acetylcholine and 1 mumol/L nitroprusside dilated cerebral arterioles by 28 +/- 3% and 44 +/- 2% in the absence and 6 +/- 2% and 7 +/- 1%, respectively, in the presence of 10 mumol/L ODQ (P < .05 versus control). The inhibitory effects of ODQ were not altered by superoxide dismutase. Vasodilatation in response to 8-bromo-cGMP and adenosine was not inhibited by ODQ. NG-Nitro-L-arginine (100 mumol/L), an inhibitor of nitric oxide synthase, inhibited responses to acetylcholine by approximately 80% but tended to enhance responses to nitroprusside. CONCLUSIONS: Thus, nitric oxide-mediated dilatation of mouse cerebral arterioles is profoundly inhibited by ODQ, an inhibitor of activity of soluble guanylyl cyclase. Cerebral vasodilator responses to adenosine and 8-bromo-cGMP were preserved in the presence of ODQ, indicating that inhibition by ODQ was selective. In contrast to previously used inhibitors of soluble guanylyl cyclase (methylene blue and LY-83583), the effects of ODQ are not mediated by generation of superoxide anion.

Acetylcholine↗

PubMed1996

Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia.

Elevated plasma homocyst(e)ine may predispose to complications of vascular disease. Homocysteine alters vasomotor regulatory and anticoagulant properties of cultured vascular endothelial cells, but little is known about effects of hyperhomocyst(e)inemia on vascular function in vivo. We tested the hypothesis that diet-induced moderate hyperhomocyst(e)inemia is associated with vascular dysfunction in cynomolgus monkeys. Plasma homocyst(e)ine increased from 4.O +/- O.2 microM when monkeys were fed normal diet to 10.6 +/- 2.6 microM when they were fed modified diet (mean +/- SE; P = 0.02). Vasomotor responses were assessed in vivo by quantitative angiography and Doppler measurement of blood flow velocity. In response to activation of platelets by intraarterial infusion of collagen, blood flow to the leg decreased by 42 +/- 9% in monkeys fed modified diet, compared with 14 +/- 11% in monkeys fed normal diet (P = 0.008), Responses of resistance vessels to the endothelium-dependent vasodilators acetylcholine and ADP were markedly impaired in hyperhomocyst(e)inemic monkeys, which suggests that increased vasoconstriction in response to collagen may be caused by decreased vasodilator responsiveness to platelet-generated ADP. Relaxation to acetylcholine and, to a lesser extent, nitroprusside, was impaired ex vivo in carotid arteries from monkeys fed modified diet. Thrombomodulin anticoagulant activity in aorta decreased by 34 +/- 15% in hyperhomocyst(e)inemic monkeys (P = 0.03). We conclude that diet-induced moderate hyperhomocyst(e)inemia is associated with altered vascular function.

Animals↗

PubMed1996

Potassium channels and the cerebral circulation.

1. Hyperpolarization of vascular muscle in response to activation of potassium channels is a major mechanism of vasodilatation. 2. In cerebral blood vessels, two potassium channels have received considerable study recently: ATP-sensitive and calcium-dependent potassium channels. Activation of these potassium channels appears to play a major role in the relaxation of cerebral arteries and arterioles in response to diverse stimuli, including receptor-mediated agonists, intracellular second messengers, reactive oxygen species and hypoxia. 3. The functional influence of ATP-sensitive and calcium-dependent potassium channels may be altered in disease states, including hypertension, diabetes and subarachnoid haemorrhage.

Animals↗

PubMed1996

Effect of subarachnoid hemorrhage on dilatation of rat basilar artery in vivo.

Cerebral vasodilator responses are often impaired following subarachnoid hemorrhage (SAH). Because depolarization of vascular muscle may occur after SAH, we tested in vivo the hypothesis that SAH may augment dilatation in response to hyperpolarization due to activation of K+ channels. Anesthetized rats were studied two days after injection of saline or autologous blood into the cisterna magna. Diameter of the basilar artery in vivo was 224 +/- 5 microns (mean +/- SE) in saline-treated rats and 201 +/- 6 microns in SAH rats (P < 0.05). In control rats, acetylcholine (ACh), sodium nitroprusside (SNP), aprikalim and calcitonin gene-related peptide (CGRP; both activators of ATP-sensitive K+ channels), papaverine, 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP), and brain natriuretic peptide (BNP; an activator of particulate guanylate cyclase) produced concentration-dependent dilatation. In SAH rats, vasodilatation was impaired in response to ACh and SNP. In contrast, vasodilator responses to aprikalim and CGRP were augmented in SAH, rats (by two- to fourfold). Vasodilator responses to 8-BrcGMP, papaverine, and BNP were similar in both groups. Thus responses mediated by activation of soluble guanylate cyclase are selectively impaired by SAH, but responses to guanosine 3',5'-cyclic monophosphate are normal. Vasodilator responses to activation of ATP-sensitive K+ channels are augmented by SAH.

Adenosine Triphosphate↗

PubMed1996

Effect of short-term regression of atherosclerosis on reactivity of carotid and retinal arteries.

BACKGROUND AND PURPOSE: This study tested the hypothesis that functional abnormalities of carotid and ocular arteries may improve after short-term regression of atherosclerosis, before regression of structural abnormalities. METHODS: We examined effects of short-term dietary treatment of atherosclerosis on carotid and ocular vascular responses to serotonin and to platelet activation by collagen in vivo. Three groups of monkeys were studied: normal cynomolgus monkeys, monkeys fed an atherogenic diet for 34 months, and atherosclerotic monkeys that were fed a regression diet for 8.6 +/- 1.1 months (mean +/- SE). We measured changes in carotid blood flow (using a Doppler probe), retinal blood flow (using microspheres), and diameter of the internal carotid artery (using quantitative angiography). Endothelium-dependent relaxation to acetylcholine was studied in rings of internal carotid artery in vitro. RESULTS: Carotid blood flow increased in response to both serotonin and collagen in normal monkeys, decreased in response to both agents in atherosclerotic monkeys, and was restored toward normal after regression. Serotonin had little effect on retinal blood flow in normal monkeys and produced a marked decrease in retinal blood flow in atherosclerotic monkeys; the vasoconstrictor response to serotonin was reduced after regression. Activation of platelets by collagen increased blood flow in normal monkeys, decreased blood flow in atherosclerotic monkeys, and had little effect after regression. Alterations in responses of the internal carotid artery were consistent with changes in carotid and ocular blood flow. Endothelium-dependent relaxation in vitro was impaired by atherosclerosis and was restored toward normal by regression. There was no reduction in intimal area of the atherosclerotic lesion in common carotid and ophthalmic arteries from regression monkeys, despite a marked reduction in cholesteryl ester. CONCLUSIONS: Within a few months of regression of atherosclerosis, endothelial function and hyperresponsiveness of carotid and ocular arteries to serotonin and platelet activation return toward normal. Functional improvement is associated with resorption of lipid from atherosclerotic lesions, but with little reduction in size of intimal lesions.

Acetylcholine↗

PubMed1995

Cholesterol feeding enhances vasoconstrictor effects of products from rabbit polymorphonuclear leukocytes.

We have studied the vasoactive properties of products released from rabbit polymorphonuclear leukocytes (PMNs) before and after short-term (4 and 8 wk) dietary supplementation with 1% cholesterol. Plasma cholesterol levels were similar after 4 and 8 wk of cholesterol diet, whereas gross atherosclerotic lesions were present at 4 wk but significantly more extensive after 8 wk. PMN products from all rabbits caused endothelium-dependent contraction of isolated, control (nonatherosclerotic) rabbit aorta submaximally contracted with phenylephrine. However, both 4 and 8 wk of cholesterol feeding resulted in equivalent contractions by PMN products, which were significantly greater than contractions by control PMNs. Endothelium-dependent contraction (by PMN products) and relaxation (by acetylcholine) were attenuated by 8 wk of cholesterol feeding. PMN products attenuated acetylcholine-induced relaxation of aorta from cholesterol-fed rabbits and of control aorta treated with phenoxybenzamine to reduce muscarinic receptor reserve. We conclude that elevation of plasma cholesterol results in increased release of a PMN product(s) that causes endothelium-dependent constriction.

Acetylcholine↗

PubMed1995

Evidence that expression of inducible nitric oxide synthase in response to endotoxin is augmented in atherosclerotic rabbits.

Atherosclerotic lesions contain monocytes/macrophages and vascular smooth muscle cells and thus may have an increased capacity for generation of nitric oxide by inducible nitric oxide synthase (NOS). We used three approaches (contractile responses, generation of L-citrulline from L-arginine, and staining with NADPH-diaphorase) to test the hypothesis that after administration of lipopolysaccharide (LPS) in vivo, generation of nitric oxide by inducible NOS is augmented in atherosclerotic arteries. New Zealand White (normal, n = 18) and Watanabe heritable hyperlipidemic (atherosclerotic, n = 21) rabbits were anesthetized and injected intravenously with vehicle or LPS. Contractile responsiveness of aortic segments was examined in vitro 4 hours after injection of LPS in vivo. There was a substantial (approximately fivefold) decrease in contractile sensitivity of aortas from LPS-treated atherosclerotic rabbits and a small (approximately twofold) decrease in normal rabbits. Incubation of aortic segments with aminoguanidine, which inhibits inducible NOS, restored contractile responsiveness after LPS treatment. In vitro assay of conversion of [14C]L-arginine to [14C]L-citrulline by aortic segments demonstrated marked (approximately fivefold) increase in calcium-independent conversion of [14C]L-arginine by LPS-treated atherosclerotic, but not normal, aortas. NADPH-diaphorase staining demonstrated positive cells only in the endothelium of normal rabbits and in the lesions and media of the atherosclerotic aortas in both vehicle- and LPS-treated rabbits. The general distribution of these NADPH-diaphorase-positive cells resembled that of smooth muscle cells and not macrophages. Thus, impairment of contractile responses, generation of L-citrulline, and staining with NADPH-diaphorase suggest that atherosclerotic arteries have increased capacity for generation of nitric oxide by inducible NOS.

Amino Acid Oxidoreductases↗

PubMed1994

Cholinergic neurogenic vasodilatation is mediated by nitric oxide in the dog hindlimb.

OBJECTIVE: The aim was to investigate the role of nitric oxide (NO) in cholinergic neurogenic vasodilatation in the dog hindlimb using the NO synthase inhibitor, N-nitro-L-arginine (NOLA), and the NO precursor, L-arginine. METHODS: 20 dogs were anaesthetised with thiopentone and alpha chloralose and experiments were performed in the presence of noradrenergic neurone blockade with guanethidine (15 mg.kg-1 subcutaneously). Using stereotaxic procedures, specific sites in the hypothalamus were electrically stimulated (HS) to produce depressor and hindlimb vasodilator responses. In each experiment, responses to intra-arterial (ia) injections of acetylcholine and glyceryl trinitrate produced increases in femoral blood flow similar to those caused by HS. RESULTS: Vasodilator responses to HS and acetylcholine but not glyceryl trinitrate were reduced by the muscarinic receptor antagonists tropicamide (3-12 mg ia) or atropine (0.5 mg.kg-1 intravenously, i.v.). Administration of NOLA (5-15 mg.kg-1 ia) significantly attenuated the HS induced decrease in arterial pressure [delta AP: control = -21 (SEM 3) mm Hg v NOLA treated = -9(3) mm Hg, p < 0.005] and the increase in femoral blood flow [delta FBF: control = 43(7) ml.min-1 v NOLA treated = 17(4) ml.min-1, p < 0.005]. NOLA also significantly inhibited femoral vasodilator responses to acetylcholine [delta FBF: control = 47(6) ml.min-1 v NOLA treated = 35(6) ml.min-1, p < 0.05] whereas responses to glyceryl trinitrate were enhanced [delta FBF: control = 54(9) ml.min-1 v NOLA treated = 69(9) ml.min-1, p < 0.005]. In addition L-arginine (150-300 mg.kg-1 i.v.), but not D-arginine (150 mg.kg-1 i.v.), reversed the inhibitory effect of NOLA on HS induced dilator responses [delta FBF: NOLA treated = 14(4) ml.min-1 v L-arginine treated = 35(8) ml.min-1, n = 8; greater than NOLA treated, p < 0.05]. CONCLUSIONS: Vasodilatation in the dog hindlimb evoked by activation of cholinergic nerves involves the synthesis of NO; however the source of this NO remains to be determined.

Acetylcholine↗

PubMed1994

Ischaemia/reperfusion enhances phenylephrine-induced contraction of rabbit aorta due to impairment of neuronal uptake.

We studied the effect of ischaemia and reperfusion on vasoconstrictor and vasodilator mechanisms. Anaesthetized rabbits were subjected to 4-h abdominal aortic occlusion and 1-h reperfusion in vivo. Segments of the abdominal (ischaemic-reperfused) and thoracic (control) aorta were then removed for in vitro studies. Ischaemia/reperfusion had no significant effect on relaxant responses to either acetylcholine (ACh:endothelium-dependent) or sodium nitroprusside (SNP:endothelium-independent). The sensitivity of the aorta to contraction by phenylephrine was significantly increased in aortic rings with or without endothelium (by 2.2- and 3.7-fold, respectively), but was not different after 4-h ischaemia without reperfusion. In contrast, responses to methoxamine, serotonin, and U46619 were not affected by ischaemia/reperfusion. Moreover, the relative increase in aortic sensitivity to phenylephrine was prevented by treatment of control and ischaemic-reperfused aortic rings with the neuronal uptake inhibitor cocaine (10(-5) M). These results suggest that after 4-h ischaemia, reperfusion damages sympathetic neuronal uptake mechanisms in rabbit aorta. As a result, phenylephrine, an agonist normally susceptible to neuronal uptake, may exert more potent contractile effects. Endothelium-dependent and endothelium-independent relaxant mechanisms in the aorta appear to be resistant to acute ischaemia and reperfusion.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1994

Vasoconstrictor responses to polymorphonuclear leucocytes from atherosclerotic rabbits.

1. The vascular contractile effects of polymorphonuclear leucocytes (PMN) isolated from control rabbits and from rabbits made atherosclerotic by 1% cholesterol feeding for 8 weeks were examined. 2. Rings of control rabbit thoracic aorta with or without endothelium were mounted at 2 g tension in 10 mL organ baths and were submaximally contracted by phenylephrine (0.1 mumol/L). After 30 min incubation at 37 degrees C, the supernatant of PMN (5 x 10(7)/mL, in Tyrode solution containing 0.25% bovine serum albumin) was obtained by centrifugation for addition to the vascular preparation. 3. Control PMN supernatant (443 microL) caused contraction (0.58 +/- 0.15 g, n = 11) of phenylephrine-contracted aortic rings, which was prevented by removal of the endothelium (0.11 +/- 0.07 g, n = 5, P < 0.05). However, the control PMN supernatant had no contractile effect on aortic rings at resting tension (0.00 +/- 0.00 g, n = 8). 4. By comparison, atherosclerotic PMN supernatant (443 microL) caused a significantly greater contraction of the aortic rings (1.41 +/- 0.13 g, n = 9, P < 0.05 vs control PMN supernatant) that was only partly inhibited by removal of the endothelium (0.45 +/- 0.20 g, n = 9, P < 0.05). Moreover, PMN supernatants from four of seven atherosclerotic rabbits contracted aortic rings at resting tension (3.5 +/- 1.4 g, n = 7). 5. These results suggest that the release of a stable vasoconstrictor substance(s) by PMN is enhanced under conditions of atherosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1994

Requirement for endothelium-derived nitric oxide in vasodilation produced by stimulation of cholinergic nerves in rat hindquarters.

1. We aimed to determine whether nitric oxide (NO) and/or the endothelium is involved in cholinergic neurogenic vasodilatation in the rat isolated hindquarters. 2. The abdominal aorta was cannulated for perfusion of the rat hindquarters with Krebs bicarbonate solution containing phenylephrine, to induce basal constrictor tone. In the presence of noradrenergic neurone blockade with guanethidine (200 mg kg-1, i.p.) electrical stimulation of peri-aortic nerves induced frequency-dependent decreases in hindquarters perfusion pressure, indicating vasodilatation. Both the endothelium-dependent vasodilator, acetylcholine (ACh) and the endothelium-independent vasodilator, sodium nitroprusside (SNP) induced dose-dependent decreases in perfusion pressure. In each experiment, responses to either nerve stimulation, ACh or SNP were recorded before and after treatment with saline vehicle, atropine (1 microM), NG-nitro-L-arginine (L-NOARG, 100 microM), L-arginine (1 mM), L-arginine plus L-NOARG, or 3-3 cholamidopropyl dimethylammonio 1-propanesulphonate (CHAPS, 30 mg). Hindquarters dilatation after each treatment was expressed as a percentage of the control response. 3. Following treatment with saline, responses to nerve stimulation and ACh were 99 +/- 9% and 107 +/- 10% of control, respectively demonstrating the reproducibility of these responses. Nerve stimulation-induced dilation was abolished by atropine (0 +/- 0% of control, P < 0.05) or reduced to 14 +/- 10% of control by NO synthase inhibition with L-NOARG (P < 0.05). Dilator responses to ACh were also abolished by atropine (0 +/- 0% of control, P < 0.05) or inhibited by L-NOARG (59 +/- 10% of control, P < 0.05), indicating that the neurogenic dilatation is cholinergic and is mediated by NO. The administration of the NO precursor, L-arginine, prevented the inhibitory effect of L-NOARG on dilator responses to nerve stimulation and ACh (L-arginine plus L-NOARG: 89 +/- 13% and 122 +/- 24% of control, respectively). In addition CHAPS, which removes endothelial cells, inhibited responses to both nerve stimulation (0 +/- 0% of control, P <0.05) and ACh (33 +/- 8% of control, P <0.05). In contrast,no treatment significantly reduced the vasodilator responses to SNP.4. These observations suggest that cholinergic neurogenic vasodilatation in the rat isolated hindquarters requires the synthesis and release of NO from the endothelium.

Acetylcholine↗

PubMed1993

Myocardial ischaemia: what happens to the coronary arteries?

Study of the effects of myocardial ischaemia and reperfusion has largely been confined to the impairment of cardiac contractility. However, emerging recognition of the importance of endothelium-derived vasoactive factors in blood flow regulation has stimulated interest in the effect of pathological states such as ischaemia on coronary vascular function and is discussed in this review by Christopher Sobey and Owen Woodman. Neutrophils may play a key role in impaired reperfusion and endothelial damage, and pharmacological intervention to preserve endothelial function could significantly improve coronary blood flow and cardiac function after an ischaemic attack.

Animals↗

PubMed1993

Allopurinol and amlodipine improve coronary vasodilatation after myocardial ischaemia and reperfusion in anaesthetized dogs.

1. We have assessed the effect of allopurinol, amlodipine and propranolol pretreatment on both endothelium-dependent and endothelium-independent coronary vasodilatation in vivo, by comparing pre-ischaemic responses with those measured after 60 min of coronary artery occlusion and 30 min of reperfusion in anaesthetized dogs. 2. In 15 untreated dogs ischaemia and reperfusion attenuated the increases in coronary blood flow produced by either acetylcholine (0.01-0.05 micrograms kg-1, i.a.) or glyceryl trinitrate (0.05-0.2 micrograms kg-1, i.a.), to an average of 39 +/- 4% and 42 +/- 5% of the pre-ischaemic control response, respectively (both P < 0.05). 3. In 5 dogs treated with allopurinol (25 mg kg-1, orally, 24 h previously, plus 50 mg kg-1, i.v., 5 min before occlusion), the increases in coronary blood flow after ischaemia and reperfusion (acetylcholine: 78 +/- 12%, glyceryl trinitrate: 60 +/- 3% of pre-ischaemic response) were significantly larger than post-ischaemic responses in untreated dogs (both P < 0.05). 4. Similarly, amlodipine treatment (3 micrograms kg-1 min-1, i.v., starting 90 min before occlusion) in 5 dogs improved post-ischaemic increases in blood flow (acetylcholine: 58.5%, glyceryl trinitrate: 66 +/- 6% of pre-ischaemic response, significantly greater than post-ischaemic responses in untreated dogs, P < 0.05). 5. In contrast, in a further 6 dogs pretreated with propranolol (1 mg kg-1, i.v., 30 min before occlusion,plus 0.5 mg kg-1 h-1, i.v.), blood flow responses after ischaemia and reperfusion were not different from post-ischaemic responses in untreated dogs (acetylcholine: 46 +/- 6%, glyceryl trinitrate: 46 +/-6% of pre-ischaemic response).6. These results suggest that allopurinol and amlodipine protect against the post-ischaemic impairment of endothelium-dependent and endothelium-independent coronary vasodilatation in vivo by mechanisms additional to endothelial protection.

Allopurinol↗

PubMed1992

Impaired endothelium-dependent relaxation of dog coronary arteries after myocardial ischaemia and reperfusion: prevention by amlodipine, propranolol and allopurinol.

1. Anaesthetized, open-chest dogs were subjected to 60 min of left circumflex coronary artery occlusion followed by 90 min of reperfusion. Endothelium-dependent and -independent relaxant responses of the isolated coronary arterial rings were then investigated. 2. The endothelium-dependent, acetylcholine-induced relaxation of ischaemic/reperfused arterial rings was significantly attenuated in comparison to control rings (1.9 fold rightward shift, ischaemic/reperfused maximum relaxation = 57 +/- 13% of control maximum relaxation; P less than 0.05). In contrast, glyceryl trinitrate produced similar relaxant responses in control and ischaemic rings. 3. Pretreatment of dogs with either amlodipine (3 micrograms kg-1 min-1, i.v.) or propranolol (1 mg kg-1, i.v.) completely prevented the postischaemic impairment of endothelium-dependent relaxant responses (100 +/- 3% and 90 +/- 5% of control maximum relaxation, respectively). 4. Allopurinol pretreatment (25 mg kg-1, p.o. 24 h previously, plus 50 mg kg-1 i.v. 5 min before arterial occlusion) partially protected against endothelial dysfunction by preventing the ischaemia-induced rightward shift of the acetylcholine relaxation curve and increasing the maximum relaxation response (83 +/- 7% of control rings). 5. These results confirm that endothelium-dependent coronary vascular relaxation is impaired by ischaemia and reperfusion, and that the ischaemia-induced impairment is reduced by pretreatment with amlodipine, propranolol or allopurinol.

Acetylcholine↗

PubMed1992

Tumour necrosis factor alpha augments the release of an endothelium-dependent vasoconstrictor from human polymorphonuclear leukocytes.

We have studied the effect of cytokine priming by recombinant human tumour necrosis factor alpha (rhTNF alpha) on the release of vasoactive mediators from human polymorphonuclear leukocytes (PMNs). Supernatants of human PMNs (100 microliters, 5 x 10(7) ml, from 12 donors) relaxed precontracted rabbit aortic rings. The relaxations were preceded by a transient contraction in four experiments. In contrast, supernatants of PMNs incubated with rhTNF alpha (0.3 nM, 30 min, 37 degrees C) elicited variable vascular responses that consisted of either a sustained contraction (n = 4), a transient contraction followed by a sustained relaxation (n = 2), or a sustained relaxation only (n = 6). The vascular tone produced by the rhTNF alpha-treated PMN supernatant was significantly greater over 30 min than that produced by the control supernatant (p < 0.01). Endothelium removal prevented the PMN-induced contractions and significantly decreased the vascular tone produced by all rhTNF alpha-treated PMN supernatants (p < 0.05). The PMN supernatants had no vasoactive effect on aortic rings at resting tension. Molecular size analysis indicated that the PMN-derived contractile mediator is > 30,000 Da. These results suggest that human PMNs, primed by rhTNF alpha, release a stable endothelium-dependent vasoconstrictor that opposes the action of a stable, spontaneously released direct vasodilator.

Acetylcholine↗