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G J Dusting

Publications and source records attributed to G J Dusting.

123 records · Page 7Linked to original sources
PubMedDate not supplied

Pericardial release of prostacyclin induced by bradykinin and angiotensin II: effects on coronary blood flow in the dog.

Angiotensin II and bradykinin are potent releasers of prostanoids, and it has been suggested that these prostanoids may modulate vascular tone in a number of organs. We previously showed that the pericardium is an important site of prostacyclin biosynthesis, and in this study we have investigated whether or not prostacyclin released into the pericardial fluid influences coronary blood flow. Angiotensin II and bradykinin were infused intra-aortically into anaesthetized dogs, and coronary blood flow in the circumflex artery was measured with electromagnetic probes. Krebs solution irrigating the pericardial surfaces was monitored for prostanoid release using a cascade of bioassay tissues as previously described. Angiotensin II infusions (25 ng/kg/min) increased arterial blood pressure, decreased coronary blood flow, and increased the release of a prostacyclin-like substance into the pericardial irrigating fluid. Inclusion of indomethacin (1 microgram/ml) in the pericardial irrigating fluid abolished angiotensin II-induced release of the prostacyclin-like substance from the heart, did not affect resting coronary flow, but potentiated the coronary vasoconstrictor response to intra-arterial angiotensin II. Bradykinin infusions (0.2 microgram/kg/min) also released the prostacyclin-like substance into the pericardial fluid, and caused a transient decrease in arterial pressure and increase in coronary blood flow. Inclusion of captopril (1 microgram/ml) in the irrigating fluid increased slightly the release of the prostacyclin-like substance, but did not alter the increase in coronary blood flow produced by bradykinin. Moreover, when prostacyclin release was abolished by pericardial indomethacin, the coronary vasodilator response to bradykinin was not altered. A large intravenous dose of indomethacin (5 mg/kg) increased the coronary vasoconstrictor response to angiotensin II, but, again, did not alter the vasodilator response to bradykinin.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
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Prevention and reversal of tolerance to nitroglycerine with N-acetylcysteine.

A recent study demonstrated that the sulfhydryl donor N-acetylcysteine (NAC) potentiated hemodynamic responsiveness to nitroglycerine (NTG) in patients with ischaemic heart disease. The interaction between NTG and NAC in rings of bovine coronary artery was examined. Vasodilator responses to NTG were determined after elevation of tone with the thromboxane mimetic U46619 [(15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano) prosta-5Z, 13E-dienoic acid]. NAC (1 microM-3 mM) induced no changes in tone of the preparation, but 10 microM NAC significantly potentiated responses to NTG (EC50 reduced from 0.69 +/- 0.19 microM to 0.22 +/- 0.06 microM; p less than 0.01). Increasing degrees of tolerance to NTG were produced at pH 7.4 by preincubating coronary rings with NTG in concentrations of 4.4 and 44 microM, and 0.22 mM. With 0.22 mM NTG, EC50 for subsequently administered NTG was increased to 11.0 +/- 1.8 microM (p less than 0.001 vs. control vessels). The degree of tolerance produced with this concentration of NTG was markedly attenuated by simultaneous (EC50 = 0.50 +/- 0.30 microM; p less than 0.001 vs. tolerant vessels) or subsequent (EC50 = 1.17 +/- 0.59 microM, p less than 0.001 vs. control vessels) incubation with 10 microM NAC. These data confirm that responses to NTG are modulated by sulfhydryl (or specifically cysteine) availability and suggest that in vitro tolerance to NTG is related to sulfhydryl (or cysteine) depletion. It is therefore possible that in vivo potentiation of NTG responses by NAC will be of clinical benefit in preventing or reversing loss of hemodynamic responsiveness to NTG.

Acetylcysteine↗
PubMedDate not supplied

Sympathetic cardiovascular reflex initiated by bradykinin-induced stimulation of cardiac pain receptors in the dog.

1. Bradykinin (0.02-5 microgram) applied to the epicardium of the left ventricle in the open-chest, anaesthetized dog, elicits dose-related reflex pressor effects and acceleration of the heart rate. 2. Bradykinin-induced reflex tachycardia was suppressed after the blockade of beta-adrenoceptors with propranolol, whereas reflex pressor responses were prevented by blocking the alpha-adrenoceptor sites with phenoxybenzamine. 3. Vagotomy and atropine treatment did not affect reflex hypertension and tachycardia to epicardial bradykinin. 4. After spinal section at C1, the pressor responses to epicardial bradykinin were significantly reduced, but still present in all but one experiment. A small acceleration of the heart occurred in two out of five spinal dogs with intact vagi and was absent in three vagotomized spinal dogs. 5. The results indicate the reflex activation of the sympathetic outflow to the heart and blood vessels, mediated mainly at a supraspinal level as a predominant mechanism for the cardiovascular response initiated by bradykinin-induced stimulation of cardiac pain receptors.

Animals↗
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Stimultion by angiotensin of prostacyclin biosynthesis in rats and dogs.

1. Stimulation of prostanoid release by angiotensins (AI and AII) in rat isolated mesenteric vasculature and in the circulation of anaesthetized dogs has been investigated by bioassay. 2. AI and AII released a PGI2-like substance into rat mesenteric effluent and arterial blood of dogs; PGE2, PGF2 alpha, or TXA2 were not detected. 3. AI stimulated PGI2 release in both systems largely as a result of its conversion to AII, since PGI2 release was much reduced after treatment with captorpril. 3. AI stimulated PGI2 release in both systems largely as a result of its conversion to AII, since PGI2 release was much reduced after treatment with captopril. 4. Intravenous AII (0.02-1.0 microgram kg-1min-1) in dogs released PGI2 mainly from the lungs since right atrial blood contained much less than arterial blood. 5. Indomethacin (1 microgram/ml) abolished AII-induced PGI2 release from the memestery preparation, but intravenous idomethacin (10 mg/kg), meclofenamate (2 mg/kg) or aspirin (100 mg/kg) did not eliminate the pulmonary source of PGI2 in dogs. These findings highlight the dangers of assuming in vivo treatment with cyclo-oxygenase inhibitors abolished biosynthesis of all prostanoids.

Angiotensins↗
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Increased conversion of arachidonic acid to vasodilator prostanoids in spontaneously hypertensive rats.

1. Vasodepressor responses to intravenous injection of prostacyclin, arachidonic acid, and nitroprusside were examined in anaesthetized, spontaneously hypertensive rats (SHR) of the Okamoto strain, and in their normotensive Wistar-Kyoto (WKY) controls. 2. Depressor responses to prostacyclin and nitroprusside did not differ significantly between the two strains. 3. The vasodepressor effects of arachidonic acid were greater and much more prolonged in SHR than in WKY. In rats treated with indomethacin (2 mg/kg) arachidonic acid induced only transient depressor responses which did not differ significantly between these strains. 4. It is concluded that SHR do not differ from WKY in their sensitivity to prostacyclin but they have enhanced ability to transform exogenous arachidonic acid into vasodilator prostanoids.

Animals↗
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Metabolism of arachidonic acid in the aorta of spontaneously hypertensive rats.

1. The metabolism of [14C]-arachidonic acid has been studied in isolated aortae from age-matched spontaneously hypertensive (SH) rats and their normotensive Wistar Kyoto (WK) controls. 2. High pressure liquid chromatography of extracts of the incubation mixture from both SH and WK rats revealed the presence of 6-oxo-prostaglandin F1 alpha, the hydration product of prostacyclin, and a single, broad peak of unknown metabolites. No thromboxane B2, or prostaglandins E2 of F2 alpha could be detected in aortic incubations. 3. The SH rats produced significantly more 6-oxo-prostaglandin F1 alpha than the WK rats, but there was no difference between the strains in the proportion of label appearing in the unknown peak of the chromatograms. 4. These data confirm that vascular tissue of SH rats has enhanced ability to transform arachidonic acid into prostacyclin. Induction of these enzymes may be an adaptive response to elevated blood pressure, but the mechanism of this effect has yet to be elucidated.

Animals↗
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Differences in arachidonic acid metabolism and effects of aspirin between one- and two-kidney Goldblatt hypertensive rats.

Vasodepressor responses to prostacyclin, nitroprusside and arachidonic acid were compared in two groups of anaesthetized, two-kidney, one-clip Goldblatt rats. The groups were composed of rats which had high blood pressure (greater than 150 mmHg systolic) or normal blood pressure (less than 140 mmHg systolic). The vasodepressor effects of prostacyclin and nitroprusside and arachidonic acid did not differ significantly between hypertensive and normotensive groups when measured as percentages of resting blood pressure. Thus, in contrast to one-kidney Goldblatt hypertensive rats, there is no evidence for increased vascular conversion of arachidonic acid to prostacyclin in the two-kidney hypertensive model. The effect of cyclo-oxygenase inhibition on development of hypertension in one- and two-kidney Goldblatt rats was also studied by treating them daily with aspirin (200 mg/kg orally) from 3 days before until 3 weeks after clipping the renal artery. Aspirin-treated two-kidney rats developed significantly higher blood pressures than vehicle-treated controls, but the blood pressures of aspirin-treated one-kidney rats increased less after clipping than those of vehicle-treated controls. It appears paradoxical that transformation of arachidonic acid to prostacyclin is increased, while aspirin has a blood pressure lowering effect in one-kidney Goldblatt rats. It is suggested that there might be a more fundamental disturbance in arachidonate metabolism in hypertension which might contribute to increased vascular reactivity.

Animals↗
PubMedDate not supplied

Paf antagonists block induction of nitric oxide synthase in cultured macrophages and vascular smooth muscle cells.

1. Nitric oxide (NO) synthase inhibitors and Paf antagonists abrogate hypotension in septic shock. The latter may act by blocking intracellular transduction mechanisms in vascular smooth muscle cells and inflammatory cells. We examined the effect of Paf antagonists on expression of inducible NO synthase. 2. A murine macrophage cell line (J774.2) and rat vascular smooth muscle cells (VSMC) were stimulated with lipopolysaccharide (LPS), either alone or in combination with Paf or Paf antagonists, BN 50739 or E-6123. 3. NO synthase activity in J774.2 was measured by the conversion of [3H]L-arginine to [3H]L-citrulline. Nitrite accumulation was measured in the culture medium of J774.2 and VSM. 4. BN 50739 (10 mumol/L and E-6123 (1 mumol#L) both reduced the expression of calcium-independent NO synthase activity and nitrite accumulation, while Paf alone had no effect. 5. Inhibition of NO synthase induction by Paf antagonists might afford therapeutic benefits in the management of septic shock and possibly other cardiovascular disorders.

Animals↗
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Differential upregulation of Nox homologues of NADPH oxidase by tumor necrosis factor-alpha in human aortic smooth muscle and embryonic kidney cells.

NADPH oxidases are important sources of vascular superoxide, which has been linked to the pathogenesis of atherosclerosis. Previously we demonstrated that the Nox4 subunit of NADPH oxidase is a critical catalytic component for superoxide production in quiescent vascular smooth muscle cells. In this study we sought to determine the role of Nox4 in superoxide production in human aortic smooth muscle cells (AoSMC) and embryonic kidney (HEK293) cells under proinflammatory conditions. Incubation with tumor necrosis factor-alpha (TNF-alpha, 10 ng/ml) for 12 h increased superoxide production in both cell types, whereas angiotensin II, platelet-derived growth factor or interleukin-1beta had little effects. Superoxide production was completely abolished by the NADPH oxidase inhibitors diphenyline iodonium and apocynin, but not by inhibitors of xanthine oxidase, nitric oxide synthase or mitochondrial electron transport. TNF-alpha upregulated the expression of Nox4 in AoSMC at both message and protein levels, while Nox1 and Nox2 were unchanged. In contrast, upregulation of Nox2 appeared to mediate the enhanced superoxide production by TNF-alpha in HEK293 cells. We suggest that Nox4 may be involved in increased superoxide generation in vascular smooth muscle cells under proinflammatory conditions.

Angiotensin II↗
PubMedDate not supplied

A platelet-activating factor antagonist (WEB 2170) preserves endothelium-dependent vasodilatation and prevents development of a neo-intima induced by a periarterial collar in rabbit carotid arteries.

Platelet-activating factor (PAF) may be involved in adhesion of leucocytes and migration of cells during vascular remodelling for it is expressed in leucocytes after cytokine priming and is required for cell adhesion. We studied the effects of WEB 2170, a potent PAF antagonist, on the development of an atheroma-like neo-intima induced by a peri-arterial collar in rabbits. Either WEB 2170 (3 mg/kg/day) or vehicle was given by subcutaneous injection once a day for 4 or 9 days, and on day 3 peri-arterial collars were applied to both carotid arteries in all animals. Two or 7 days after implanting the collars vasodilator responses to the endothelium-dependent vasodilator, acetylcholine and the endothelium-independent vasodilator, sodium nitroprusside were studied in isolated artery rings from both groups of rabbits. Neo-intima formation after 7 days (day 10 of treatment) was measured by light microscopy as the ratio of cross-sectional areas of intima and media, and expression of inducible nitric oxide synthase (iNOS) was studied by immunohistochemistry. PAF-induced platelet aggregation ex vivo was inhibited specifically in WEB 2170-treated rabbits. At day 5, acetylcholine-induced vasorelaxation in collared artery rings was markedly impaired as compared to control sections from both vehicle- and WEB 2170-treated rabbits. At day 10, acetylcholine-induced vasorelaxation in collared artery rings from vehicle rabbits was markedly less than in controls, but in WEB 2170-treated rabbits, the acetylcholine response in collared arteries was similar to control sections. Intimal thickening was much reduced in WEB 2170-treated rabbits, ratios of intima/media areas being vehicle: 0.21 +/- 0.02 (n = 5) and WEB 2170: 0.07 +/- 0.01 (n = 7; p < 0.01). Immunofluorescence showed expression of iNOS only in the neo-intima of vehicle-treated, collared arteries, but not in the residual neo-intima of WEB 2170-treated, collared arteries. These results suggest that WEB 2170 is effective in preserving endothelial function, prevents the development of neo-intima and blocks iNOS expression in the neo-intima in this model.

Animals↗
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Impaired vasodilator function of nitric oxide associated with developing neo-intima in conscious rabbits.

The aim of this study was to use periarterial manipulation to produce an atheroma-like neo-intima in rabbits and study resting blood flow and vascular responsiveness in vivo. One common carotid artery was enclosed in a silastic collar to induce a neo-intima similar to that of human early atherosclerosis, and carotid blood flow was measured periodically over 8 days in 8 conscious rabbits. The vasodilator responses to intravenous infusions of the endothelium-dependent vasodilator, acetylcholine, and glyceryl trinitrate were measured in each artery at 2 and 7 days after surgical placement of the collar, and again following infusion of the nitric oxide synthase inhibitor, N-nitro-L-arginine (NOLA, 15 mg/kg). Histological examination of the arterial segments at completion of the study revealed significant intimal thickening of the regions of artery enclosed in the collar. Resting blood flow was lower in the collared vascular bed as compared with the control, from as early as 2 days after surgery. Acetylcholine- and glyceryl trinitrate-induced decreases in carotid resistance, however, were no different between the arteries after 2 days. At 7 days after surgery, the vasodilator response to acetylcholine was significantly impaired in the collared vascular bed when compared with the control, while the glyceryl trinitrate-induced vasodilatation was similar in the two beds. Following NOLA infusion, mean arterial pressure was significantly increased and blood flow through both arteries was reduced. After NOLA, acetylcholine-induced vasodilatation in the collared vascular bed was no longer different from the vasodilatation in the control bed.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMedDate not supplied

Nitric oxide in cardiovascular disorders.

Nitric oxide derived from the vascular endothelium and other cells of the cardiovascular system has important roles in physiological regulation of blood flow and may have pathophysiological functions in cardiovascular disease. Nitric oxide can be synthesised from L-arginine by any of three isoforms of nitric oxide synthase (NOS), and its interaction with prostacyclin, its proposed mechanisms of action and cytotoxicity are briefly reviewed in the context of cardiovascular function. Although nitric oxide can hyperpolarize vascular smooth muscle, activation of the endothelium can induce hyperpolarization and vasodilatation by other means. Nitric oxide has important roles in the physiological regulation of local blood flow and blood pressure, especially during exercise and in response to shear stresses and other local factors in arterioles. Nitric oxide is also involved in neurogenic control of the microcirculation through autonomic efferent nerves and it contributes to vasodilatation and inflammation associated with activation of sensory nerves. In pathological circumstances, excess nitric oxide produced by inducible NOS compromises circulatory function in septic shock, during transplant rejection, and during myocardial ischaemia and reperfusion injury. Immunosuppressant drugs like cyclosporin A inhibit the expression of NOS through complex intracellular intermediates. Disturbances in the activity of constitutive and inducible NOS in the artery wall accompany the development of atherosclerosis, vasospasm and thrombosis, and may contribute to some forms of hypertension and diabetic vascular disease. Reversing the nitric oxide defect with therapeutic agents including angiotensin-converting enzyme inhibitors offers promise in protecting against some manifestations of vascular disease.

Animals↗
PubMedDate not supplied

Interaction of epoprostenol (PGI2) with vasoconstrictors on diameter of large coronary arteries of the dog.

The platelet release products thromboxane A2 (TxA2) and serotonin (5-HT) might contribute to coronary vasoconstriction in humans. We have examined the effects of a TxA2-like analogue (U46619), 5-HT, and epoprostenol (PGI2) on the left anterior descending coronary artery of the dog. Changes in diameter were measured by sonomicrometry during perfusion of the vessel with blood from a support dog, at constant flow and distal resistance. Intra-arterial infusions of 5-HT (0.01-1 mumol/L) and U46619 (0.003-0.1 mumol/L) reduced external diameter of the artery (about 2.0 mm) by 0.12 mm and 0.16 mm, respectively. Intra-arterial PGI2 (0.01-0.1 mumol/L) increased the diameter of the artery (by 0.08 mm) and reduced blood pressure of the support dog (by 23 mm Hg), but did not significantly (p greater than 0.05) reduce the vasoconstrictor effects of either 5-HT (0.3 mumol/L) or U46619 (0.1 mumol/L) infused simultaneously. Indomethacin (5 mg/kg i.v.) doubled the direct dilator effect of PGI2, and increased the sensitivity of the artery to 5-HT (by 11.5-fold) and to U46619 (by 2.8-fold). After indomethacin infusion, intra-arterial PGI2 (0.1 mumol/L) reduced the constriction induced by continuous infusion of 5-HT or U46619. These data suggest that PGI2 may be of limited usefulness in preventing constriction of large coronary vessels because it causes hypotension. However, endogenous PGI2 produced by the coronary vessels or pericardium may modulate the influence of coronary vasoconstrictors, and these tissues are therefore potential targets for PGI2-releasing drugs.

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