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Biomedical subjects

G J Dusting

Publications and source records attributed to G J Dusting.

At least 91 records · Page 5Linked to original sources
PubMed1982

The pericardium as a source of prostacyclin in the dog, ox and rat.

Cyclo-oxygenase products of arachidonic acid metabolism formed by the pericardium and epicardial surface of dog heart were identified and quantitated by radioimmunoassay after separation by high-pressure liquid chromatography. Pieces of parietal pericardium, of dog, ox and rat, when incubated in vitro produced mainly 6-keto-PGF1 alpha, with lesser amounts of PGE2, PGF2 alpha and thromboxane B2. Biosynthesis of all prostanoids increased during incubation of the parietal pericardium of each species with arachidonic acid, but 6-keto-PGF1 alpha was still the major metabolite. When slices of dog heart were incubated with arachidonic acid (1 microgram/ml) the rates of 6-keto-PGF1 alpha formation by the parietal pericardium was much greater than that of the myocardium and endocardium. Epicardial slices appeared to be intermediate in 6-keto-PGF1 alpha formation. The hearts of anesthetized dogs were also irrigated in situ with Krebs' solution, and during the first 5 min of epicardial irrigation the pericardial fluid leaving the heart again contained high levels of 6-keto-PGF1 alpha, with lesser amounts of the other prostanoids. Addition of arachidonic acid (3 micrograms/ml) to the irrigating fluid caused an increase in all measured prostanoid levels, although 6-keto-PGF1 alpha remained the predominant metabolite. In contrast, intravenous infusion of isoproterenol selectively increased the release of 6-keto-PGF1 alpha from the irrigated heart. It is concluded that the pericardium and epicardium continuously release prostacyclin into the pericardial fluid, and that the increased release of this substance observed when cardiac workload increases derives mainly from these membranous sources. This raises the interesting possibility that pericardial prostacyclin might influence coronary vascular tone and chemoreflexes which arise from the epicardium during myocardial ischemia.

6-Ketoprostaglandin F1 alpha↗
PubMed1981

Prostacyclin (PGI2) release accompanying angiotensin conversion in rat mesenteric vasculature.

The relationship between angiotensin conversion and release of prostaglandins (PGs) were studied in isolated, perfused, mesenteric vasculature of rats. PGs in the mesenteric effluent were detected by bovine coronary artery and rat stomach strip, and by radioimmunoassay of 6-oxo-PGF1 alpha and PGE2. Angiotensin II (AII) was assayed simultaneously using rabbit aorta. Both angiotensin I (AI) and AII released a prostacyclin (PGI2)-like substance, but little PGE2 from the mesentery, AII being 5 times more potent. Indomethacin (2.8 micrometers) abolished angiotensin-induced release of PGI2. Of the AI (0.2--1.5 nmol) injected into the perfusion medium, 3--8% was converted to AII in passage through the mesentery. Captopril (4 micrometers), infused through the mesentery, inhibited AI-induced PGI2 release, but did not affect release induced by AII. Release of the PGI2-like substance by higher doses of AI (2--20 nmol) in the presence of captopril was always accompanied by concomitant contraction of rabbit aorta, indicating residual conversion of AI. Infusion of (Sar1, Ala8)AII (3--30 nM) through the mesentery abolished PGI2 release by both peptides. By choosing doses of AI and AII which produce equivalent amounts of AII in the mesenteric effluent, it appeared that AII generated locally in the mesenteric vasculature was a more effective stimulus for PGI2 generation than AII in the perfusion fluid. There is no evidence for intrinsic activity of AI, and release of the PGI2-like substance appears to be mediated through an AII receptor.

Angiotensin I↗
PubMed1981

Effects of prostacyclin on cardiovascular reflexes from the ventricular epicardium of the dog: comparison with the effects of prostaglandin E2.

Application of bradykinin to the exposed ventricular surface of the dog's heart produced reflex pressor effects and tachycardia, whereas application of nicotine evoked reflex hypotension and bradycardia. Prostacyclin (PGI2) or prostaglandin E2 (PGE2), when applied epicardially, had no effects by themselves but potentiated the reflex pressor changes to bradykinin; the depressor responses to nicotine were not changed. The potentiating effect of PGI2 was prompt but short-lived, whereas that of PGE2 was slow in onset but prolonged. The results suggest that PGI2, which is present in the pericardial fluid, may contribute to signalling of pain and reflex circulatory changes when kinin formation occurs during myocardial ischaemia or pericardial inflammation.

Animals↗
PubMed1981

Hypoventilation and elevation of end-expiratory pressure release a substance which relaxes isolated arteries and disaggregates platelets in the presence of cyclooxygenase inhibitors.

A prostacyclin-like substance was detected by bioassay in the blood of dogs and cats during hypoventilation and increased end-expiratory pressure. This biologically active material, most likely originating from lungs, relaxed isolated vascular strips and disaggregated platelets. Its release was not prevented by indomethacin or aspirin. Biological activity was not abolished by 10 min incubation of blood at 38 degrees C. Although the identity of the substance has not been established the release of a biologically active prostacyclin-like material might play a role in circulatory adaptation to disturbed ventilatory function.

Animals↗
PubMed1981

Vasodepressor effects of arachidonic acid and prostacyclin (PGI2) in hypertensive rats.

1. Vasodepressor responses to prostacyclin and nitroprusside were compared in anaesthetized, spontaneously hypertensive rats of the Okamoto strain and Wistar--Kyoto controls, and also in one-kidney, one-clip hypertensive rats and unilaterally nephrectomized controls of the Sprague--Dawley strain. The responses, measured as a percentage of resting blood pressure, did not differ significantly between the hypertensive rats and the normotensive controls within each strain. 2. The effects of intravenous injections of arachidonic acid were also studied in each strain. 3. The vasodepressor effects of high doses of arachidonic acid (1 or 3 mg/kg) were much greater and more prolonged in both groups of hypertensive rats. These differences were abolished by indomethacin (2 mg/kg). 4. Comparisons between the strains showed that whereas Okamoto rats have significantly greater depressor responsiveness to nitroprusside and prostacyclin than Sprague--Dawley rats, the depressor effects of high doses of arachidonic acid (1 and 3 mg/kg) were smaller in the normotensive Wistar--Kyoto than in the Sprague--Dawley rats. 5. It is concluded that hypertensive rats have enhanced ability to transform exogenous arachidonic acid into vasodilator prostanoids. This occurs both in spontaneous hypertension and in experimental renal hypertension. However, rats of the Okamoto strain appear to have reduced ability to form prostacyclin when compared with Sprague--Dawley rats.

Animals↗
PubMed1981

Failure of aspirin to modify the hypotensive action of captopril in spontaneously hypertensive rats.

1. Oral administration of the angiotensin converting enzyme inhibitor, captopril (30 mg/kg per day) to spontaneously hypertensive rats of the Okamoto strain progressively reduced arterial blood pressure by 60 mmHg over 4-5 days. 2. Oral treatment of spontaneously hypertensive rats with aspirin (200 mg/kg per day) for one week did not alter blood pressure, but it greatly reduced the vasodepressor effects of intravenous injections of arachidonic acid (3 mg/kg). 3. The fall in blood pressure of spontaneously hypertensive rats treated concurrently with both aspirin (200 mg/kg per day) and captopril (30 mg/kg per day) was not different to the fall observed in rats treated with captopril alone. 4. The hypotensive action of captopril in spontaneously hypertensive rats does not appear to be due to stimulation of vasodilator prostanoid biosynthesis.

Animals↗
PubMed1981

Stimulation of prostacyclin release from the epicardium of anaesthetized dogs.

1 The generation of prostanoids in the hearts of anaesthetized dogs was studied by irrigating in situ the epicardial surface with Krebs solution. Prostanoids were measured by direct bioassay on smooth muscles and by radioimmunoassay of 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) and prostaglandin E2 (PGE2) in the epicardial irrigation fluid. 2 The epicardial irrigation fluid contained a prostacyclin-like substance, as indicated by the bioassay tissues, and immunoreactive 6-oxo-PGF1 alpha; PGE2-like materials were also detected. By both methods the output of the prostacyclin-like substance, which decreased with time of epicardial irrigation, was increased by manipulating the heart and by adding arachidonic acid (3 microgram/ml), and decreased by adding indomethacin (1 microgram/ml) to the irrigation fluid. 3 Bioassayed prostacyclin and immunoreactive 6-oxo-PGF1 alpha in the epicardial irrigation fluid increased by about 3-5 ng/ml during and after infusion of isoprenaline (0.1 microgram kg-1 min-1). The substance was not released by isoprenaline when indomethacin was added to the irrigation fluid, or when propranolol (0.5 mg/kg) was given intravenously. 4 Aortic constriction, bilateral carotid artery occlusion and intravenous angiotensin infusion all increased output of the prostacyclin-like substance into the epicardial irrigation fluid. The output was abolished by treating the heart with indomethacin (10 mg/kg intravenously or 1 microgram/ml epicardially). 5 The prostacyclin-like substance was also released by all of the above stimuli after the parietal pericardium had been removed and replaced by a plastic sheet. 6 It is concluded that prostacyclin is continually released from tissues close to the epicardial surface and from the pericardium, and that prostacyclin generation increases when cardiac workload increases. Prostacyclin of epicardial or pericardial origin might therefore contribute to metabolic regulation of coronary blood flow.

Angiotensins↗
PubMed1980

Some direct and reflex cardiovascular actions of prostacyclin (PGI2) and prostaglandin E2 in anaesthetized dogs.

1 The aim of the study was to determine the mechanism of the hypotension and bradycardia produced by prostacyclin (PGI2). 2 Haemodynamic studies were carried out in nineteen open-chest beagle dogs anaesthetized with chloralose. PGI2 was infused intravenously or into the left atrium. 3 Infusions of PGI2 either intravenously or into the left atrium equally reduced arterial pressure and total peripheral resistance but bradycardia was greater after infusion into the left atrium. 4 Comparison of effects of PGI2 with those of prostaglandin E2 (PGE2) showed that although left atrial infusions both reduced aortic pressure and total peripheral resistance, PGE2 always increased heart rate, cardiac output and maximum acceleration. 5 Similar effects were observed with sodium nitroprusside except that it always caused tachycardia and reduced stroke volume. 6 Atropine (0.05 or 1 mg/kg i.v.) reduced or reversed the bradycardia induced by PGI2 but its hypotensive effects were reduced only after 1 mg/kg atropine. After vagotomy changes in cardiac output, stroke volume and maximum acceleration were increased, the hypotensive effects of PGI2 were reduced and the bradycardia was reversed; effects induced by PGE2 were not significantly altered. 7 The hypotension induced by prostacyclin is due to two components, a direct relaxation of vascular smooth muscle and a reflex, non-cholinergic vasodilatation. The bradycardia is reflex in nature and is partially mediated by the vagus pathway.

Anesthesia↗
PubMed1979

Biotransformation and cardiovascular effects of arachidonic acid in the dog.

The biotransformation and cardiovascular effects of arachidonic acid (AA) were studied in the circulation of anaesthetized dogs. Arterial blood was continuously bioassayed for arachidonate metabolites using the blood-bathed organ technique of Vane. AA (5-10 microgram/ml) infused into an incubation coil of flowing blood was converted into a labile substance which contracted the vascular tissues (rabbit aorta, RbA; rabbit coeliac and mesenteric arteries, RbCA and RbMA; bovine coronary artery, BCA) and the gastrointestinal smooth muscle strips (rat stomach strip, RSS; rat colon, RC). These effects could be mimicked by exogenously generated thromboxane A2 (TXA2). Conversion of AA was inhibited by indomethacin and the selective thromboxane synthetase inhibitor, imidazole (100 microgram/ml). The half-life of TXA2 in blood was 30-47 sec, a similar value to that found in aqueous solutions at 37 degrees C. PGH2 was also converted in blood to other product(s) which contracted RSS and RC, relaxed RbCA and RbMA but had little effect on RbA. Intravenous infusion of AA (50-800 microgram kg-1 min-1) caused effects on the bioassay tissues which could be mimicked by prostacyclin. The AA infusion also induced falls in pulmonary and systemic arterial pressures and bradycardia. All effects were abolished by indomethacin (5 mg/kg) or aspirin (200 mg/kg). Radioimmunoassay confirmed that the major product of intravenously infused AA was 6-oxo-PGF1alpha, the chemical degradation product of prostacyclin. Thus, although AA is transformed to the vasoconstrictor TXA2 when incubated for sufficient time with blood alone, on rapid pulmonary transit it is transformed into a prostacyclin-like substance.

Animals↗
PubMed1979

Elimination of prostacyclin (PGI2) and 6-oxo-PGF1 alpha in anaesthetized dogs.

The plasma concentration of 6-oxo-PGF1 alpha was measured by radioimmunoassay after constant rate infusion of 6-oxo-PGF1 alpha or prostacyclin (PGI2) into anaesthetized dogs. A steady-state plasma concentration was rapidly attained with both compounds. After termination of the infusions, the concentration of 6-oxo-PGF1 alpha declined according to a bi-exponential process. The steady-state plasma concentrations of 6-oxo-PGF1 alpha obtained after infusion of 6-oxo-PGF1 alpha and PGI2 were approximately 10 times higher than the corresponding steady-state level of PGF2 alpha measured after infusion of PGF2 alph into the same dogs. The data presented suggest that PGI2 and 6-oxo-PGF1 alpha are eliminated more slowly than PGF2 alpha, probably because they are not taken up and metabolized in the lungs as rapidly as PGF2 alpha.

Animals↗
PubMed1978

Vascular actions of arachidonic acid and its metabolites in perfused mesenteric and femoral beds of the dog.

The effects of arachidonate and its major metabolites were examined in vascular beds perfused via the femoral and mesenteric arteries of chloralose-anaesthetised dogs. Close intra-arterial injection of prostacyclin (PGI2, 0.02--2 microgram), PGE2 (0.05--1 microgram) and their precursors, the endoperoxide PGH2 (0.5--2 microgram) and sodium arachidonate (100--550 microgram), all induced vasodilatation. Sodium linoleate (500 microgram) was inactive. Prostacyclin was equally active in both vascular beds, but PGE2 was more potent in the femoral and less so in the mesenteric bed. PGH2 was of similar potency to prostacyclin in both beds, but 6-oxo-PGF 1 alpha (10--100 microgram) was inactive. Thromboxane A2 (TXA2, 1--2 microgram) was a potent vasoconstrictor of the mesenteric bed, but not the femoral bed, although the endoperoxide analogue U46619 was vasocontrictor in both vasculatures. Fatty acid hydroperoxides did not specifically modify the vasodilator effects of PGH2 or arachidonate, presumably because these inhibitors are rapidly reduced in vivo. Indomethacin and meclofenamate potentiated vasodilatation induced by prostacyclin or endoperoxide, but reduced or abolished that caused by arachidonate. The rise in perfusion pressure induced by TXA2 was potentiated and prolonged by indomethacin. Inhibition of synthesis of endogenous prostacyclin, by exacerbating the vasoconstrictor action of TXA2, may have contributed to this effect.

Animals↗
PubMed1978

Implications of prostacyclin generation for modulation of vascular tone.

1. The biotransformation of arachidonic acid and prostacyclin in the circulation was studied in anaesthetized dogs, using the blood-bathed organ technique. 2. In passage through the lungs, arachidonate (50-800 microgram kg-1 min-1) was transformed into prostacyclin. No thromboxane A2 or prostaglandin E2 could be detected in arterial blood. 3. In dogs treated with indomethacin (5 mg/kg), intravenous infusions of arachidonate had no cardiovascular effects and no prostacyclin was produced. Therefore, the vasodilator effects of arachidonate in vivo may be attributable to prostacyclin formation. 4. Prostacyclin, unlike prostaglandin E2, is not inactivated by passage across the lungs, and only about 50% disappears in one passage through peripheral vascular beds. 5. Thus prostacyclin released from the lungs could function as a circulating vasodilator and contribute to the regulation of blood vessel tone and blood pressure.

Animals↗
PubMed1978

Recirculation of prostacyclin (PGI2) in the dog.

1 The inactivation of prostacyclin (PGI2) in the circulation of anaesthetized dogs has been studied by the blood-bathed organ bioassay technique. 2 Spiral strips of bovine coronary and rabbit coeliac or mesenteric artery detected concentrations of PGI2 of 2 to 5 ng/ml. These tissues were insensitive to concentrations at least 200 fold higher of 15-oxo-PGI2 and 6-oxo-PGF1alpha. 3 PGI2 assayed on bovine coronary artery, rabbit coeliac artery or rat stomach strip, had a half life in blood of 3.0 +/- 0.3 min, indicating non-enzymatic degradation. 4 No disappearance could be detected by bovine coronary artery when PGI2 was infused across the lungs (0.1 to 0.5 microgram kg-1 min-1). However, PGI2 was partially inactivated in passage through vascular beds of hindquarters and liver. 5 Of PGI2 infused into the aorta 35 to 65% escaped inactivation in one complete circulation. Therefore, endogenous PGI2 released from the lungs may function as a circulating hormone.

Animals↗