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Biomedical subjects

K M Mullane

Publications and source records attributed to K M Mullane.

69 records · Page 4Linked to original sources
PubMed1982

Prostacyclin can either increase or decrease heart rate depending on the basal state.

1 The influence of the basal heart rate on the change in rate induced by prostacyclin (PGI2) was investigated in beagles anaesthetized with chloralose. 2 In male dogs with a low basal heart rate (less than 100 beats/min) PGI2, in doses up to 0.5 microgram/kg intravenously, induced hypotension and tachycardia. 3 In contrast, PGI2-induced hypotension was accompanied by bradycardia when either the basal heart rate was increased (greater than 130 beats/min) with isoprenaline or nitroprusside, or the dose of PGI2 was increased. 4 Female beagles were less sensitive than males to the stimulation of a reflex bradycardia by PGI2. 5 The influence of prostaglandin E2 (PGE2) and bradykinin on heart rate was also found to depend upon the basal state in some dogs. 6 Bilateral vagotomy reversed the bradycardia provoked by PGI2, PGE2 and bradykinin. 7 Thus, PGI2-induced bradycardia in dependent on both the dose and the basal heart rate. Similarly the effects of PGE2 and bradykinin on heart rate also depend upon the basal state in some dogs. Moreover, there is a correlation between the ability of all three agonists to induce bradycardia, suggesting a common mechanism of action.

Animals↗
PubMed1980

Prostacyclin mediates the potentiated hypotensive effect of bradykinin following captopril treatment.

The effect of angiotensin-converting enzyme inhibition by captopril on the release of a prostacyclin-like substance by bradykinin, angiotensin I and angiotensin II was studied by means of the blood-bathed bioassay technique of Vane. Administration of captopril abolished the release of prostacyclin-like substance induced by angiotensin I, potentiated the release provoked by bradykinin and did not alter that due to angiotensin II. Potentiation of the bradykinin-induced renal vasodilatation with captopril could be completely reversed by indomethacin, which also abolished the kinin-induced release of prostacyclin-like substance. Potentiation of the bradykinin-induced hypotension was markedly attenuated but not completely reversed by cyclo-oxygenase inhibition. It is suggested that following converting inhibition increased production of prostacyclin by elevated kinin levels may contribute to the antihypertensive action of angiotensin-converting enzyme inhibitors.

Angiotensin I↗
PubMed1980

Prostacyclin release and the modulation of some vasoactive hormones.

Prostaglandin release into the circulation of the dog was studied by means of the blood-bathed bioassay system of Vane. Bradykinin, angiotensin II and angiotensin I selectively released a prostacyclin-like substance into the circulation, whereas no release was detected with adrenaline, noradrenaline, 5-hydroxytryptamine or acetylcholine. Release induced by bradykinin was mainly of renal origin, whereas that induced by the angiotensins was of more widespread origin, including the lungs and kidneys. No thromboxane A2 or prostaglandin-like substance could be detected from blood by any of these stimuli. Prostacyclin released by bradykinin contributed to the vascular actions of the kinin as indicated by treatment with cyclo-oxygenase inhibitors. Prostacyclin release also contributed to a reduced pressor effect of angiotensin II. This study indicates that prostacyclin release induced by the vasoactive peptides modulates some of their vascular actions.

Angiotensin I↗
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

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↗
PubMed1976

Genetic hypertension in rats is accompanied by a defect in renal prostaglandin catabolism.

Noradrenaline releases prostaglandins in the kidney, and in rats these augment rather than reduce vasoconstriction produced by the amine. Homogenates of kidneys of New Zealand rats inbred for hypertension exhibit lower prostaglandin inactivation by 15-hydroxydehydrogenase than controls. At the same time, augmentation of noradrenaline vasoconstriction by the released prostaglandin is exaggerated. This biochemical defect could be the inherited abnormality primarily responsible for the development of hypertension in these animals.

Animals↗
PubMed1976

Contribution of prostaglandins to the renal vascular supersensitivity to vasoconstrictor agents exhibited by New Zealand genetic hypertensive rats.

1. Studies were made of the effects on responses to vasoconstrictor agents of prostaglandins released from Krebs perfused isolated kidneys of genetic hypertensive and normotensive rats. 2. Prostaglandin E-like activity, detected by bioassay, was released from kidneys of both groups of rats during the vasoconstriction produced by noradrenaline, angiotensin or prostaglandin F2alpha. 3. In preparations obtained from hypertensive rats, responses to higher doses of noradrenaline or angiotensin were initially greater than those from normotensive rats and these were then reduced to a greater extent by infusion of indomethacin, which abolished release of prostaglandin E-like activity. Thereafter, in kidneys of either group, vasoconstriction to noradrenaline was potentiated by infusion of prostaglandin E2. 4. We conclude that, in rats, renal prostaglandins released in response to vasoconstrictor agents could augment the effect of such agents and in genetic hypertensive rats release of renal prostaglandins could contribute to the disease.

Animals↗
PubMedDate not supplied

Platelet depletion and infarct size in an occlusion-reperfusion model of myocardial ischemia in anesthetized dogs.

The formation of platelet aggregates and release of platelet-derived vasoactive mediators have been suggested to aggravate ischemic myocardium. The contribution of platelets to myocardial damage induced by 90-min occlusion and 5-h reperfusion in chloralose-anesthetized dogs was assessed after depletion of platelets with specific antidog platelet antiserum. Dogs treated with antiplatelet antiserum showed greater than 90% reduction in circulating platelets and serum TxB2 levels, but showed no reduction in infarct size (58 +/- 3 vs. 51 +/- 3% of risk area for control and thrombocytopenic dogs, respectively). Platelet depletion had no hemodynamic effect during the occlusion or reperfusion phases, nor reduced the incidence of arrhythmias. These results indicate that platelet aggregates or platelet-derived mediators do not contribute directly to the extent of damage in this occlusion-reperfusion model of myocardial ischemia.

Anesthesia↗
PubMedDate not supplied

Neutrophil depletion suppresses 111In-labeled platelet accumulation in infarcted myocardium.

Platelets and neutrophils accumulate rapidly in infarcted myocardium. Although antineutrophil agents reduce the size of the infarcted area, this is not observed with antiplatelet drugs. The possibility that myocardial ischemia-induced platelet deposition was secondary to a neutrophil-mediated event was assessed by injecting prostacyclin-washed autologous 111In-labeled platelets and measuring the amount of radioactivity in different regions of the heart following 90-min occlusion of the left anterior descending coronary artery followed by reperfusion for periods up to 5 h. Platelet deposition during the reperfusion phase was linear with time and similar to the time course of neutrophil accumulation. There was a transmural distribution of radioactivity across the myocardium where the "zone" between infarcted and risk regions, called the "interface," greater than infarct greater than risk greater than normal. Neutropenia (21 +/- 2% control levels), induced with specific sheep anti-dog neutrophil antiserum, had minimal effects on platelet aggregation ex vivo, but significantly reduced platelet accumulation in the ischemic myocardium following 5-h reperfusion and abolished the transmural platelet distribution. These results suggest that myocardial platelet deposition is secondary to a neutrophil-mediated event in this occlusion-reperfusion model of myocardial injury. Interactions between platelets and neutrophils at the site of tissue damage may influence the process of myocardial ischemic injury.

Animals↗
PubMedDate not supplied

Presence of cytochrome P-450-dependent monooxygenase in intimal cells of the hog aorta.

Cytochrome P-450-dependent mixed function oxidase activity is present in vascular tissue; however, as far as we could determine, the distribution of monooxygenase activity across the blood vessel wall has not previously been assessed. The aryl-hydrocarbon hydroxylase activity was examined by metabolism of benzo[a]pyrene in microsomes prepared from intimal and smooth muscle cell scrapings of the hog thoracic aorta. Microsomes of intimal cells comprising 95% endothelial cells showed an approximately 2.5-fold increase in aryl-hydrocarbon hydroxylase activity compared with that in microsomes prepared from medial smooth muscle cells. Michaelis-Mentin kinetics for the intimal enzyme yielded an apparent Km value of 11.11 microM and an apparent Vmax of 3-OH benzo[a]pyrene of 40 pmol/mg protein/10 min. Aryl-hydrocarbon hydroxylase activity was dependent on nicotinamide adenine dinucleotide phosphate and was inhibited by 7,8 benzoflavone, SKF 525A, and carbon monoxide. The localization of cytochrome P-450-dependent mixed function oxidase primarily to the intimal surface of the aorta may indicate a role for this enzyme system in vasoregulation and the pathogenesis of atherosclerosis.

Animals↗