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Biomedical subjects

G J Dusting

Publications and source records attributed to G J Dusting.

At least 73 records · Page 4Linked to original sources
PubMed1988

Acetylcholine induces vasodilatation in the rabbit isolated heart through the release of nitric oxide, the endogenous nitrovasodilator.

1. Acetylcholine (ACh, 0.03-3.0 microM) induced a dose-dependent vasodilatation in the isolated Langendorff-perfused heart of the rabbit. The vasodilatation was mimicked by exogenous nitric oxide (NO, 0.045-4.5 nmol). 2. There was no detectable vascular relaxing activity in the cardiac effluent when these concentrations of ACh or NO were injected through the heart, even in the presence of an infusion of superoxide dismutase (SOD). 3. Acetylcholine (0.03-3.0 microM), however, induced the release into the cardiac effluent of a material which produced a chemiluminescent signal when reacted with ozone, a response which could be mimicked with exogenous NO (0.045-4.5 nmol) injected through the heart. 4. The effects of ACh, but not those of NO, were antagonized by atropine (2 microM). Prostacyclin (1 microM) injected through the heart induced vasodilatation without the release of a biologically active or chemiluminescent material. 5. During passage through the heart, greater than 99% of the biological activity of exogenous NO disappeared, whereas there was approximately 50% reduction of its chemiluminescent response. This indicates complete transformation into a mixture containing approximately 50% NO2- and 50% of other non-chemiluminescent material(s), presumably NO3-. 6. This study suggests that ACh induces endothelium-dependent vasodilatation in the coronary circulation through the release of the endogenous nitrovasodilator, NO, which is rapidly converted to NO2- and NO3-.

Acetylcholine↗
PubMed1988

Increased vascular reactivity induced by essential fatty acid deficiency in rat autoperfused hindquarters.

The effects of essential fatty acid deficiency (EFAD) on vascular reactivity to vasoconstrictor stimuli were studied in rat autoperfused hindquarters. Weanling male Sprague-Dawley rats (aged 21 days) were fed diets containing 8% (weight/weight) of stearax plus 2% safflower oil (control diet) or 10% stearax (EFAD diet) for 8 weeks. There was no difference in systemic blood pressure or body weight between the two groups. Basal production of immunoreactive 6-keto-PGF1 alpha by aortic segments was much less in EFAD aortae than in control aortae. In contrast, immunoreactive 6-keto-PGF1 alpha produced by incubating aortic segments with exogenous arachidonic acid (12 mumol/l) was much greater in EFAD aortae than in control aortae. Moreover, conversion of [14C]-arachidonate to [14C]-6-keto-PGF1 alpha was more pronounced in EFAD aortae than in control aortae. Vasoconstrictor responses to noradrenaline (0.01-1.0 mumol/l) and angiotensin II (0.001-1.0 mumol/l) infused into the blood perfused hindquarters were then examined. The rats on the EFAD diet were more sensitive to both noradrenaline and angiotensin II than rats on the control diet (P less than 0.05, two-way ANOVA). Thus, a deficiency of essential fatty acids can lead to increased vascular sensitivity to vasoconstrictor stimuli. Deficiency of arachidonic acid in phospholipid stores is also accompanied by augmented cyclo-oxygenase activity in the vessel wall, similar to that observed previously in spontaneously hypertensive rats (SHR) and rats with one kidney renovascular hypertension.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Effects of arachidonate deficiency on endothelium-dependent vascular reactions.

1. The release of endothelium-derived relaxing factor (EDRF), which appears to be impaired in vessels chronically exposed to hypertension, may involve mobilization of arachidonate from phospholipids. In this study the effects of arachidonate deficiency on endothelium-dependent responses were examined in rat isolated aorta. 2. Weanling rats were fed an essential fatty acid-deficient (EFAD) diet for 8 weeks which reduced plasma and aortic phospholipid arachidonate content from 17 to 1.8% and from 21 to 8%, respectively. After this time the rats were killed and the reactivity of aortic rings was studied in organ baths. 3. In aortic rings from control rats the concentration-response curves for the contractile action of phenylephrine were shifted to the left 3.5-fold by removal of the endothelium, and the maximum was not altered. 4. In contrast, in EFAD rings with endothelium, the maximal vasoconstriction to phenylephrine was less than in control rings, and removal of the endothelium increased the maximum (from 1.9 +/- 0.2 to 3.2 +/- 0.1 g, P less than 0.05) and reduced the EC50 7-fold. 5. In EFAD rings precontracted with phenylephrine (0.3 mumol/l) the relaxations produced by the endothelium-dependent dilator acetylcholine were not significantly different from those produced in control rings. The dilator actions of sodium nitroprusside were also similar in EFAD and control rings. 6. Thus, endothelium-dependent dilatation in the aorta is not impaired by partial depletion of phospholipid arachidonate. However, contractile responses to alpha-adrenoceptor agonists are depressed by spontaneously released EDRF in rat aorta, so that the results suggest that depletion of phospholipid arachidonate either augments spontaneous release of EDRF, or impairs EDRF inactivating mechanisms.

Animals↗
PubMed1987

Beta-adrenoceptors on endothelial cells do not influence release of relaxing factor in dog coronary arteries.

1. The aim of this study was to determine if stimulation of a beta-adrenoceptor on endothelial cells could release an endothelium-derived relaxing factor (EDRF) similar to that released by acetylcholine. 2. In dog coronary rings preconstricted with PGF2 alpha or serotonin, removal of the endothelium did not alter the relaxant responses to isoprenaline. However, in rings preconstricted with the thromboxane-mimetic U46619, removal of the endothelium enhanced the response to isoprenaline. 3. The vasorelaxant responses to isoprenaline in endothelium-denuded rings were inhibited in a concentration-dependent manner by the specific beta 1-adrenoceptor antagonist CGP-20712A (3-100 nmol/l), but were not altered by the beta 2-adrenoceptor antagonist ICI-118551 (30 nmol/l). 4. The vasorelaxant responses to isoprenaline in the presence of CGP-20712A (30 nmol/l) or ICI-118551 (30 nmol/l) were not impaired by removal of the endothelium. 5. Endothelium-dependent vasorelaxant responses to acetylcholine and bradykinin were not altered by isoprenaline (0.1 mumol/l) in the presence of CGP-20712A (30 nmol/l). 6. Therefore, the beta-adrenoceptors on dog coronary artery smooth muscle which produce relaxation are predominantly of the beta 1-subtype. Stimulation of any beta 2-adrenoceptors on the endothelium in dog coronary artery does not release EDRF, and does not modulate endothelium-dependent vasodilatation induced by other agents.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1987

Endothelium and the vasodilator action of rat calcitonin gene-related peptide (CGRP).

1 Acetylcholine and rat calcitonin gene-related peptide (CGRP) produced a relaxation in rat isolated aortic rings which was entirely dependent on the presence of the endothelium. 2 In the absence of any exogenous vasodilator agent, the cyclic guanosine monophosphate (cyclic GMP) content was higher in rings with endothelium than in those without. 3 The vasorelaxation produced by acetylcholine and sodium nitroprusside was accompanied by increases in cyclic GMP in the smooth muscle, whereas that produced by CGRP was not accompanied by cyclic GMP accumulation. 4 Therefore, it appears unlikely that CGRP releases an endothelium-derived relaxing factor similar to that released by acetylcholine.

Acetylcholine↗
PubMed1986

Endothelium-dependent vasodilatation in bovine coronary arteries: calcium dependence and inhibition by proadifen.

Vasodilator responses were examined in bovine coronary artery rings preconstricted with the thromboxane-mimetic, U46619. A23187 produced endothelium-dependent vasodilatation that was abolished in calcium-free solution. In contrast, endothelium-dependent vasodilatation produced by arachidonic acid was not altered in calcium-free solution. In calcium-free solution, indomethacin (10 mumol/l) did not affect arachidonate-induced relaxations whereas BW755C (100 mumol/l) reduced relaxations to low concentrations of arachidonate, and proadifen (SKF-525A, 1 mmol/l) abolished them at all concentrations. Endothelium-independent relaxations produced by glyceryl trinitrate were not affected by proadifen (1 mmol/l). It is clear that arachidonic acid bypasses a calcium-dependent step in the release of endothelium-derived relaxing factor, perhaps acting as an intermediate precursor. The data support the hypothesis that a cytochrome P-450 mono-oxygenase may also be involved.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1986

Catecholamine release and potentiation of thromboxane A2 production by nicotine in the greyhound.

Thromboxane A2 was generated by infusing arachidonic acid (2.5 micrograms ml-1) into an extra-corporeal circuit of blood withdrawn from anaesthetized dogs, and assayed on a blood-bathed bioassay cascade of porcine and bovine coronary artery strips, chick rectum and rat stomach strip. All tissues except chick rectum were treated with phentolamine and propranolol to abolish direct effects of catecholamines. The arachidonate-induced contractions of artery strips were abolished by a thromboxane synthetase inhibitor UK-38485 (3 mg kg-1, i.v.), but were not altered by the 5-hydroxytryptamine antagonist ketanserin (10 microM) administered over the tissues. Intravenous infusion of adrenaline (0.2 and 0.4 micrograms kg-1 min-1) reversibly potentiated the coronary contractions produced by arachidonate, but did not alter contractions when applied directly over the bioassay tissues. Intra-aortic infusion of nicotine (5 or 10 micrograms kg-1 min-1) also increased the arachidonate-induced contractions of the bioassay tissues but only on those experiments where nicotine caused appreciable adrenaline release, as indicated by relaxation of chick rectum. Phenoxybenzamine (2 mg kg-1, i.v.) blocked the potentiation effect of adrenaline and nicotine on coronary contractions. The specific alpha 2-adrenoceptor antagonist, idazoxan (1 mg kg-1, i.v.), also blocked nicotine-induced potentiation of the contractions. These findings suggest that the ability of nicotine to potentiate thromboxane release from circulating platelets and blood cells is dependent upon the release of adrenaline, and probably involves an action on alpha-adrenoceptors of the circulating blood elements.

Animals↗
PubMed1986

Physiological concentrations of epinephrine potentiate thromboxane A2 release from platelets in the isolated rat heart.

The isolated rat heart perfused with washed platelets was used as a model to examine platelet-vessel wall interactions. Release of prostacyclin and thromboxane A2 was measured, using a cascade of smooth muscle bioassay tissues or radioimmunoassays of the stable hydration products. In hearts perfused with rabbit or human platelets, injection of sodium arachidonate caused release of both prostacyclin and thromboxane A2. In hearts perfused with aspirin-pretreated platelets, arachidonate released only prostacyclin indicating that thromboxane A2 originates largely in the platelets. Infusion of epinephrine (0.6-6 nmol/liter) through the heart potentiated arachidonate-induced release of thromboxane A2. Similar potentiation of thromboxane A2 release was observed in rat hearts perfused with either rabbit or human platelets, and in rabbit hearts perfused with rabbit platelets. In contrast, when rabbit platelets were infused through an incubation coil of tubing in place of the heart, epinephrine did not alter thromboxane A2 release. There was no significant loss of rabbit platelets on perfusion through rat hearts, and no aggregates were observed in the effluent either before or immediately after arachidonate injections, even in the presence of epinephrine. Thus, potentiation of thromboxane A2 production could not be explained by aggregation. However, it is clear from these studies that physiological concentrations of epinephrine can potentiate thromboxane A2 release from platelets when they are stimulated by arachidonic acid within the heart. This could result from a redirection of arachidonate metabolism to a local potentiating factor in the vessel wall. Potentiation of thromboxane A2 release might contribute to myocardial ischemia associated with platelet activation.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Calcitonin gene-related peptide stimulates cyclic AMP formation in rat aortic smooth muscle cells.

In rat aortic smooth muscle cells in culture, calcitonin gene-related peptide stimulated cAMP formation in a dose-dependent manner, half-maximally effective at 0.5 to 1 nM. There was no effect on formation of cGMP, which was increased 300-fold in the same experiments by atriopeptin or sodium nitroprusside. The vasodilator effect of CGRP in rat aorta requires an intact endothelium, indicating that increase in vascular smooth muscle cAMP is not in itself sufficient to bring about relaxation. cAMP is probably a mediator of CGRP action in vascular smooth muscle.

Animals↗
PubMed1985

Inhibition of vasoconstrictor mechanisms by dazoxiben in the rat mesenteric vasculature.

Sympathetic neurotransmission can be modulated by prostaglandins in a number of tissues, but it is not known whether thromboxane A2 also influences neurotransmission. In this study, vasoconstrictor responses to electrical stimulation of the sympathetic nerves and to injection of noradrenaline were examined in the blood perfused mesentery of the rat in situ. The thromboxane synthetase inhibitor dazoxiben, infused into the perfusion circuit at 10-100 mumol/l, significantly inhibited constrictor responses to nerve stimulation and to injected noradrenaline and vasopressin. The cyclo-oxygenase inhibitor indomethacin (28 mumol/kg intravenously) had no effect on responses to nerve stimulation or noradrenaline, but pretreatment with indomethacin abolished the inhibitory effect of dazoxiben on vasoconstrictor responses. The thromboxane-mimetic (U46619, 10 nmol/l) slightly reduced responses to nerve stimulation (but not to noradrenaline), whereas prostacyclin (3-10 nmol/l) and PGE2 (3 nmol/l) markedly reduced responses both to nerve stimulation and to injections of noradrenaline. These prostanoids did not alter perfusion pressure at these concentrations. The data suggest that the inhibitory effect of dazoxiben on sympathetic neurotransmission is unlikely to be due directly to inhibition of thromboxane synthesis. Inhibition might result from diversion of endoperoxide metabolism to endogenous prostanoids that, in turn, inhibit activation of vasoconstrictor mechanisms.

Animals↗
PubMed1985

Prostanoids and adrenaline release: a study of [3H]adrenaline efflux from the rabbit isolated, perfused, adrenal gland.

[3H]Adrenaline was incorporated in an isolated perfused preparation of the rabbit adrenal gland and the effects of indomethacin, PGE2 and PGI2 on its release were investigated. Efflux of [3H]adrenaline was elicited by electrical stimulation of the splanchnic nerve (60 s at 5 Hz). Indomethacin (3 and 30 microM) had no effect on stimulation-induced efflux. PGE2 (30, 90 and 300 nM) reduced the efflux; with 90 nM PGE2 the inhibition amounted to approximately 30%. PGI2, in concentrations from 90 to 600 nM, was without effect. These findings indicate that release of [3H]adrenaline from the rabbit adrenal gland is not subject to modulation by endogenous adrenal prostaglandins; however, PGE2 may play a role in some pathological situations.

Adrenal Glands↗
PubMed1984

Vascular prostacyclin and Goldblatt hypertensive rats.

Vascular prostacyclin production in Goldblatt hypertension was examined in one-kidney, one clip (1K, 1C) and two-kidney, one clip (2K, 1C) rat models. Vasodepressor responses to prostacyclin and nitroprusside correlated well with resting blood pressure in both groups of rats, but when measured as a percentage of resting blood pressure the responses did not differ significantly between hypertensive rats and the normotensive controls within each group. In contrast, the vasodepressor effects of arachidonic acid (1-3 mg/kg, i.v.) were much greater in the 1K, 1C rats than in their normotensive controls, but did not differ significantly between hypertensive 2K, 1C rats and sham-operated controls. The effects of arachidonic acid were virtually abolished by indomethacin (10 mg/kg, i.v.). The metabolism of [14C]-arachidonic acid was also studied in isolated aortae of both one- and two-kidney rats by high pressure liquid chromatography of extracts of the incubation mixture. [14C]-6-oxo-PGF1 alpha was the only prostanoid conversion product recovered from the incubations and significantly more of this metabolite was produced by aortic tissue from 1K, 1C rats than from normotensive controls. There was no difference in [14C]-6-oxo-PGF1 alpha production between 2K, 1C rats and controls. These results demonstrate an enhanced ability of vascular tissue from 1K, 1C hypertensive rats to convert exogenous arachidonate to vasodilator prostacyclin, but this is not evident in the two-kidney model. Although enhanced biosynthetic capacity for prostacyclin in the one-kidney model and spontaneously hypertensive rats does not lessen peripheral vascular resistance, it might reflect a fundamental disturbance in phospholipid metabolism which contributes to increased vascular resistance.

Animals↗
PubMed1983

Prostanoids in platelet-vascular interactions.

Prostacyclin, the labile prostanoid product of arachidonic acid metabolism in vascular endothelium, is the most potent known inhibitor of platelet aggregation and is highly effective in relaxing vascular smooth muscle. Its production is probably critically important in the maintenance of an intact vasculature. Although there is some evidence that prostacyclin circulates as a hormone, it is probably most important as a locally active agent in preventing thrombosis and maintaining patent vessels. Several factors can influence prostacyclin production, the most important of which probably act locally at sites of vessel wall injury. The most promising therapeutic approaches toward using prostacyclin's beneficial effects in vascular disease may lie in the use of drugs aimed at increasing prostacyclin production. Among these are thromboxane synthesis inhibitors, which act by diverting prostaglandin endoperoxides through the prostacyclin synthetase pathway, and lipoxygenase inhibitors, which might act chiefly by preventing formation of metabolites capable of inhibiting prostacyclin synthetase.

Blood Platelets↗
PubMed1983

Prostacyclin produced by the pericardium and its influence on coronary vascular tone.

To determine the influence of pericardial fluid prostacyclin on coronary blood flow, the latter was measured in the circumflex artery of anesthetized dogs. Intraaortic infusions of angiotensin II (25 ng . kg-1 . min-1) reduced blood flow and released prostacyclin into pericardial fluid. Epicardial and pericardial superfusion with indomethacin (1 micrograms/ml) abolished prostacyclin release and significantly increased the coronary vasoconstrictor effect of angiotensin II; this treatment did not appear to affect vascular synthesis of prostacyclin. Pericardial prostacyclin may modulate the coronary vasoconstrictor effect of angiotensin, but its general role as a regulator of coronary vascular resistance is probably limited. A more important effect of pericardial prostacyclin may be exerted on the large coronary vessels in the epicardial surface. Release of prostacyclin into pericardial fluid represents a potential mechanism for opposing coronary vasospasm, especially if platelet activation is found to be a contributory factor in vasotonic angina pectoris.

Angiotensin II↗
PubMed1982

Coronary vasoconstriction induced by leukotrienes in the anaesthetized dog.

In the anaesthetized dog LTC4, LTD4 (0.3-10 micrograms, injected into the coronary artery) and the thromboxane-mimetic U46619 (5-10 micrograms) decreased coronary blood flow. LTE4 (1-10 micrograms), however, did not affect coronary blood flow. The vasoconstrictor responses to LTC4, LTD4 or U46619 were not altered by the cyclo-oxygenase inhibitor indomethacin (5 mg/kg i.v.). LTC4 and LTD4 did not stimulate the release of any prostaglandin-like substance into the pericardial fluid. It is concluded that LTC4 and LTD4 are able to produce coronary vasoconstriction in vivo independent of the production of any cyclo-oxygenase metabolites of arachidonic acid.

Anesthesia↗