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Biomedical subjects

G J Dusting

Publications and source records attributed to G J Dusting.

At least 109 records · Page 6Linked to original sources
PubMed1978

Prostacyclin (PGI2) induces coronary vasodilatation in anaesthetised dogs.

Prostacyclin (PGI2), the predominant metabolite of arachidonic acid in isolated hearts, relaxes strips of bovine coronary artery and is a potent vasodilator in isolated perfused hearts. We have examined the actions of prostacyclin on coronary blood flow in open chest dogs anaesthetised with chloralose. An electromagnetic flow probe was fitted to the left circumflex artery and phasic coronary flow, mean coronary flow (a measure of coronary volume flow over 4 s intervals), and coronary vascular resistance were recorded together with aortic pressure and heart rate. Intravenous infusion of prostacyclin (0.05 to 1.0 microgram.kg.1.min.1), reduced coronary vascular resistance and aortic pressure according to dose, but had only small effects on phasic coronary flow or mean coronary flow. Both tachycardia and bradycardia occurred during infusion of prostacyclin, but 6-oxo-prostaglandin F1alpha (infused at 10 micrograms.kg-1.min-1), the stable degradation produce of prostacyclin, had no cardiovascular effects. The coronary vasodilator effects of prostacyclin were clear when it was injected into the left circumflex artery via a fine catheter distal to the flow probe. Prostacyclin (0.05 to 0.5 microgram) increased phasic coronary flow and mean coronary flow up to 3 fold and reduced coronary vascular resistance without affecting aortic pressure or heart rate, although higher doses had systemic effects. Prostaglandin E1 (0.1 to 0.5 microgram), which also dilated the coronary vessels, had a longer lasting effect and was 1 to 4 times more potent than prostacyclin. Prostaglandin E2, (0.5 to 4 microgram) was less potent than prostacyclin. In four dogs prostacyclin (20 to 500 micrograms) applied epicardially to the left ventricle caused marked and prolonged coronary vasodilatation. Epicardial application of prostacyclin (10 to 25 micrograms) to the right ventricle increased coronary sinus oxygen content with minimal changes in blood pressure. The endoperoxide prostaglandin H2 was a coronary vasodilator of similar potency to prostacyclin, but its analogue U46619 is a vasoconstrictor. Inhibition of cyclo-oxygenase with indomethacin (5 mg.kg-1 i.v.) or sodium meclofenamate (2 mg.kg-1 i.v.) potentiated the coronary dilator effects of prostacyclin given intravenously or into the coronary artery. Cyclo-oxygenase inhibition did not alter the hypotensive effects and increased the coronary vasodilator potency of prostacyclin relative to prostaglandin E2. Thus the sensitivity of the coronary vascular bed to prostacyclin is enhanced when endogenous biosynthesis of prostaglandin-like substances is inhibited. Although the importance of arachidonic acid metabolites in the coronary circulation still requires validation in vivo, it is clear that prostacyclin, and not prostaglandin E2, is the prostaglandin most likely to be involved.

Animals↗
PubMed1977

Prostacyclin (PGI2) is a weak contractor of coronary arteries of the pig.

The actions of prostacyclin (PGI2), prostaglandin E2 (PGE2), prostaglandin H2 (PGH2) and arachidonic acid have been examined on isolated coronary arteries from pigs. Arachidonate metabolites contracted this tissue, the order of potency being PGH2 greater than PGE2 greater than PGI2 suggesting that the coronary vasoconstrictor effects of PGH2 are limited by metabolism to PGI2. Sodium arachidonate and linoleate weakly relaxed porcine coronary arteries, but the former induced a secondary prolonged contraction: only the contraction was abolished by indomethacin. Thus the relaxation induced by fatty acids does not depend on metabolism to prostaglandin-like substances.

Animals↗
PubMed1977

Prostacyclin (PGX) is the endogenous metabolite responsible for relaxation of coronary arteries induced by arachindonic acid.

The actions of prostacyclin (PGX) and several other derivatives of arachidonic acid were examined on spiral-strips of bovine coronary artery. The strips were contracted by PGE2 and thromboxane A2. Although PGH2 usually cause a transient contraction followed by a relaxation, a few strips were only contracted whilst others were only relaxed. Prostacyclin invariably relaxed coronary artery strips. Sodium arachidonate usually relaxed the strips but occasionally had no effect. Indomethacin increased the resting tone and abolished or substantially reduced the relaxation induced by sodium arachidonate. 15-hydroperoxy arachidonic acid (15-HPAA), a specific inhibitor of prostacyclin synthetase, also increased the resting tone, abolished the effects of sodium arachidonate and the relaxation component of the PGH2 response, but did not greatly modify the relaxation induced by exogenous prostacyclin. These results strongly suggest that prostacyclin mediates the relaxation induced by arachidonic acid in bovine coronary artery strips. As PGH2 is avidly converted into prostacyclin by the vascular tissue of several species including man, prostacyclin is probably involved in the local regulation of the coronary vascular bed.

Animals↗
PubMed1976

Humoral response and blood pressure regulation during hypercapnia and haemorrhage in dogs.

1. The blood-bathed organ technique was used to study the release of catecholamines, angiotensin II and prostaglandin-like (PL) substances into the circulation during hypercapnia and after haemorrhage in anaesthetized dogs. 2. Elevated blood concentrations of noradrenaline, angiotensin II and prostaglandin-like substances have been detected during both experimental conditions. 3. The rise of arterial blood pressure during hypercapnia and after haemorrhage was associated with elevated concentrations of angiotensin II in the blood and could be abolished by inhibition of the angiotensin I-converting enzyme with SQ 20881. 4. The compensation of arterial pressure during both stresses was significantly impaired by release of prostaglandin-like substances; it could be restored by inhibition of prostaglandin biosynthesis with indomethacin. 5. The results indicate that activation of the renin-angiotensin system represents the major humoral mechanism for the maintenance of arterial pressure during hypercapnic acidosis and after haemorrhage.

Angiotensin II↗
PubMed1973

Acidaemia produced by spinal stimulation in the pithed rat.

1. Electrical stimulation of the thoraco-lumbar spinal nervous outflow in the pithed rat preparation produces a fall in arterial blood pH.2. A component of the acidaemic response results from stimulation of skeletal muscle, since the acidaemic response is reduced when contractions of muscle are blocked with gallamine.3. The residual acidaemic response in gallamine-treated rats is reduced by adrenalectomy, suggesting that catecholamines liberated from the adrenal medulla may mediate part of the effect.4. Guanethidine reduces the acidaemic response remaining in adrenalectomized, gallamine-treated rats, suggesting that the effect of noradrenaline released from sympathetic nerve endings contributes to the fall in pH.5. Neither phenoxybenzamine nor propanolol alone significantly reduces the acidaemic response in gallamine-treated rats, but a combination of the two antagonists almost abolishes the effect. Hence the acidaemia is mediated through effects of catecholamines on both alpha- and beta-adreno-receptors.6. Since acidaemia affects responses to sympathetic nerve stimulation and sympathomimetic amines, the significance of these observations is discussed with reference to the use of the pithed rat preparation for assessment of drugs affecting adrenergic mechanisms.

1-Propanol↗
PubMed1972

Depressor responses to spinal stimulation in the pithed rat.

1. Electrical stimulation of the spinal nerves in the pithed rat preparation produces a pressor response due to sympathetic vasoconstriction.2. When the vasoconstrictor effect of sympathetic stimulation is abolished by guanethidine or hexamethonium and the blood pressure is raised by noradrenaline infusion, spinal stimulation produces depressor responses or complex responses containing depressor components.3. Contractions of skeletal muscle caused by stimulation of motor nerves result in complex changes in blood pressure consisting of a pressor component due to clamping of muscle blood vessels and a secondary depressor phase due to functional hyperaemia.4. The depressor response is partly due to stimulation of cholinergic postganglionic fibres. The acetylcholine released, which causes vasodilatation, may be the overflow from neuromuscular junctions or ganglionic synapses.5. Stimulation of the nerves to the adrenal medulla causes release of adrenaline which has a vasodilator effect during noradrenaline infusion.

Adrenalectomy↗
PubMedDate not supplied

Effect of prostacyclin infusion during low-flow ischaemia in the isolated perfused rat heart.

Although prostacyclin (PGI2) has been shown to exert a protective effect on ischaemic hearts its precise mode of action remains obscure. Possible explanations include protection of the high energy phosphate stores (ATP and CP), maintenance of homeostasis with respect to Ca2+, and an antiaggregatory effect. The following experiments were undertaken to investigate these possibilities, using isolated, spontaneously beating rat hearts perfused with Krebs-Henseleit solution. Ischaemia was induced at 37 degrees C for 30 min by reducing the flow rate from 10.0 to 0.1 ml/min, and was followed by reperfusion. PGI2 was given as a constant infusion (20 ng/ml). The hearts were frozen and assayed for ATP and CP, or digested in HNO3 and assayed for Ca2+. Peak developed tension was recorded throughout. The results show that PGI2 slowed the rate of decline of developed tension during low flow perfusion, and hastened the recovery of contractions on reperfusion. These effects could not be accounted for in terms of an improved supply of ATP or CP, or an altered tissue Ca2+. The protective effect of PGI2 on isolated, buffer-perfused hearts may be a reflection of a generalized, but undefined, mechanism of cell preservation which has also been observed in other systems.

Adenosine Triphosphate↗
PubMedDate not supplied

Prostaglandins, their intermediates and precursors: cardiovascular actions and regulatory roles in normal and abnormal circulatory systems.

The characterization of newly found unstable metabolites of arachidonic acid has provided new perspectives for cardiovascular regulatory mechanisms and new insights into disorders of the circulatory system. Since these intermediates are often more potent on and more specific for cardiovascular structures than the classical prostaglandins, they are more likely candidates as physiologic mediators of circulatory events. Their instability in vitro need not preclude these roles; on the contrary, the limited pharmacology described to date suggests that they function purely as local hormones. As such, changes in the rate of generation of these unstable but potent compounds would provide an excellent control system. The stable prostaglandins may represent only overflow of degradation products of the active mediators associated with pathologic events. For example, the dicovery of prostacyclin and the realization that this prostaglandin and not PGE2 is the primary metabolite of arachidonic acid in blood vessels emphasizes the need to reinterpret many of the previously held hypotheses that proposed that prostaglandins of the E series contributed to the regulation of vessel tone and blood pressure, Moreover, the contribution made by abnormal prostaglandin mechanisms to hypertensive disease should now take into account that a deficiency of prostacyclin and not PGE2 could be a major factor causing the elevated tension developed in vascular smooth muscle and the augmented vessel responsiveness to stimuli associated with hypertension.

Animals↗
PubMedDate not supplied

Dexamethasone inhibits endotoxin-induced changes in calcium and contractility in rat isolated papillary muscle.

This study investigates whether endotoxin-induced contractile dysfunction is associated with a defect in the modulation of calcium homeostasis and the potential mechanisms involved. Treatment of rats in vivo with endotoxin significantly decreased the magnitude of contractile transients in electrically stimulated left ventricular papillary muscle isolated after an equilibration period of 6 hours. Although no significant difference was found in the peak intracellular calcium concentration ([Ca2+]i) between the endotoxin-treated and control groups, resting [Ca2+]i) was significantly elevated in the endotoxin-treated group, producing a smaller Ca2+ transient (basal-peak difference) in this group. Pretreatment of rats with dexamethasone prevented the endotoxin-induced decrease in peak tension and inhibited the elevation in resting [Ca2+]i, with a resultant maintenance of Ca2+ transient magnitude. Similar observations were made during stimulation of the muscles by the beta-adrenoceptor agonist, isoprenaline. These results show that endotoxin-induced reduction of cardiac contractile performance is mediated, at least in part, by elevating resting [Ca2+]i, and a glucocorticoid protected from these negative effects. While endotoxin reduces the magnitude of the Ca2+ transient it does not alter peak [Ca2+]i availability. Further investigation is required to determine whether endotoxin decreases contractile performance by reducing the sensitivity of cardiac myofilaments to calcium.

Adrenergic beta-Agonists↗
PubMedDate not supplied

Angiotensin-induced release of a prostacyclin-like substance from the lungs.

Intravenous infusions of angiotensins I and II into anesthetized dogs caused release of a prostacyclin-like substance into arterial blood: prostacyclin (PGI2) was detected by direct bioassay on bovine coronary artery, rat stomach strip, and rat colon, all of which were treated with phenoxybenzamine, propranolol, and Sar1-Ile8-angiotensin II. This effect of angiotensin I, but not of angiotensin II, was abolished by captopril (1 mg/kg, i.v.), and the effect of angiotensin II was abolished by Sar1-Ala8-angiotensin II (0.5 micrograms/kg/min, i.v.). The PGI2-like substance disappeared during incubation of arterial blood for 6 min, and much less appeared in mixed venous blood withdrawn from the right atrium of pulmonary artery, indicating that it originates from the lungs. Neither arterial nor mixed venous blood contained measurable amounts of prostaglandin E2; infusions of noradrenaline did not release the PGI2-like substance. Release of the PGI2-like substance by angiotensin II was reduced after intravenous administration of indomethacin (2, 5, or 10 mg/kg), aspirin (100 mg/kg), aspirin (100 mg/kg), and meclofenamic acid (2 mg/kg), but was not completely eliminated by any of the above inhibitors. In indomethacin-treated dogs the residual relaxation of the bovine coronary artery induced by intravenous angiotensin II was not further reduced by treating the tissues with hyoscine, mepyramine, cimetidine, and methysergide. Either the pulmonary site of PGI2 biosynthesis, which is stimulated by angiotensin, is partly resistant to inhibition by nonsteroidal anti-inflammatory drugs, or the PGI2-like substance is an unknown substance with similar biological properties.

Angiotensin II↗