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Biomedical subjects

N S Dhalla

Publications and source records attributed to N S Dhalla.

At least 253 records · Page 14Linked to original sources
PubMed1981

Lack of effect of prostaglandins on rat heart myofibrillar ATPase activity.

Although various prostaglandins have been shown to elicit an inotropic response in the rat heart, the subcellular basis responsible for this effect is unknown. The purpose of this study was to examine the influence of three prostaglandins with varying inotropic potencies on myofibrillar ATPase activity in the rat heart. PGF2 alpha, PGI2 and PGE2 were found to have no influence on basal or Ca2+-stimulated myofibrillar ATPase activity. In addition, no influence was observed on the sensitivity of myofibrillar ATPase activity to Ca2+. Alternative mechanisms to explain the inotropic effect are discussed.

Adenosine Triphosphatases↗
PubMed1981

Protective effect of sulfinpyrazone against catecholamine metabolite adrenochrome-induced arrhythmias.

Single intravenous injection of adrenochrome (10 to 50 mg/kg body weight), an oxidation product of catecholamines, has been shown to induce arrhythmias and cause death in anesthetized rats in a dose-dependent manner. Sulfinpyrazone, which is an inhibitor of platelet aggregation, was found to protect animals from these adrenochrome effects. It is suggested that sudden death due to arrhythmias in patients following the first attack of myocardial infarction of during other stressful situations may be linked to the formation of adrenochrome from abnormally high catecholamine levels in blood. Furthermore, results presented here also suggest that the reduction in the mortality rate of patients on sulfinpyrazone therapy may involve an antiarrhythmic property of the drug.

Adrenochrome↗
PubMed1981

Ventricular dysfunction and necrosis produced by adrenochrome metabolite of epinephrine: relation to pathogenesis of catecholamine cardiomyopathy.

We have examined the effects of adrenochrome and other metabolites of epinephrine on the ultrastructure and contractile activity of isolated rat hearts perfused under conditions in which the heart rate and coronary flow were controlled. Perfusion of hearts with epinephrine or metanephrine significantly increased contractile force; vanillylmandelic acid and dihydroxymandelic acid did not alter contractile force development, whereas adrenochrome (50 mg/L) declined contractile force with epinephrine (50 mg/L) was associated with increased resting tension and maximum rates of force development and relaxation, and decreased time for peak tension development and 1/2 relaxation. On the other hand, hearts perfused with adrenochrome showed early decline followed by steady increase in resting tension; maximum rates of force development and relaxation were reduced and times for peak tension development and 1/2 relaxation were increased. Hearts perfused or 10 minutes or more with adrenochrome (50 mg/L), but not epinephrine, metanephrine, dihydroxymandelic acid or vanillylmandelic aicd, showed ultrastructural damage. Adrenochrome concentrations of 10 or 25 mg/L altered the appearance of mitochondria after 30 minutes of perfusion. Infusion of epinephrine (1 mg/L) during perfusion with adrenochrome partially maintained contractile force during the first 15 minutes of perfusion but did not alter the severity of ultrastructural changes due to adrenochrome. These results are consistent with the concept that oxidation products of catecholamines such as adrenochrome are partly responsible for inducing myocardial necrosis and failure following massive catecholamine injections in intact animals.

Adrenochrome↗
PubMed1981

Insulin-induced enhancement of uptake of noradrenaline in atrial strips.

1 Addition of insulin to the organ bath increased the force of contraction of guinea-pig left atrial strips driven electrically at 1 Hz. 2 The positive inotropic response to insulin remained unaltered in atria depleted of catecholamine or when beta-adrenoceptors were blocked by addition of propranolol to the organ bath. 3 The response os isolated atria to noradrenaline was significantly reduced in the presence of insulin. 4 Insulin affected neither the calcium accumulating abilities of the heart sarcolemma, mitochondria or microsomes, nor the cyclic adenosine 3',5'-monophosphate (cyclic-AMP)-protein kinase-induced stimulation of microsomal calcium uptake. 5 Addition of insulin to the organ bath enhanced significantly the ability of the cardiac tissue to take up [3H]-noradrenaline as well as [3H]-metaraminol. The activities of monoamine oxidase and catechol-O-methyl transferase were not changed after addition of insulin to homogenates of the heart. 6 The ability of insulin to facilitate uptake of noradrenaline would be expected to cause a decrease in the amount of the amine reaching the receptors, thus leading to a diminished response to this amine. This may explain, at least in part, insulin-induced subsensitivity to noradrenaline. 7 This view is supported by the observation that after blockade of amine uptake by destruction of nerve terminals, insulin failed to reduce the positive inotropic response to noradrenaline.

Animals↗
PubMed1981

Effect of prostaglandins on rat heart sarcolemmal ATPases.

The ability of prostaglandins (PG) D2, E1, E2, F2 alpha and I2 (2.8 X 10(-11) to (2.8 X 10(-7) M) to modify Ca2+, Mg2+ and (Na+ + K+)-ATPase activities of rat heart sarcolemmal membrane fractions was examined. Administration of PGE2, PGF2 alpha, and PGI2 reduced basal (Na + + K+)-ATPase activity by up to 30, 80, and 80%, respectively. PGE1 and PGD2 were ineffective at any concentration. Neither Mg2+ -ATPase nor Ca2+ -ATPase was affected by PG treatment. Kinetic analysis revealed that the (Na+ + K+)-ATPase activity reducing ability of PGE2, PGF2 alpha and PGI2 was of a complex nature involving a reduction in Vmax and an elevation of the respective K values for either substrate or activator. These results demonstrate that some PG's are potent inhibitors of rat heart (Na+ + K+)-ATPase. These PG's produced varied inotropic influences on isolated heart preparations and it is uncertain whether their myocardial actions are dependent on enzyme inhibition.

Adenosine Triphosphatases↗
PubMed1981

Role of changes in microsomal calcium uptake in the effects of reperfusion of Ca2+-deprived rat hearts.

This study was designed to investigate changes in contractile force, resting tension, and microsomal Ca2+ uptake in isolated rat hearts perfused under conditions associated with reversible and irreversible stages of the calcium paradox phenomenon. Five minutes of reperfusion with normal medium containing 1.25 mM calcium after 5 minutes of Ca2+-free perfusion produced a marked rise in resting tension, no recovery of contractile force, and a 63% depression in microsomal Ca2+ uptake. When reperfusion was carried out after 5 minutes of perfusion with 0.025 mM or greater concentrations of Ca2+, after less than 5 minutes of Ca2+-free exposure or after 5 minutes of varying degrees of hypothermic Ca2+-free perfusion, the increase in resting tension and decrease in contractile force development as well as microsomal Ca2+ accumulation were either absent or reduced. Furthermore, reperfusion-induced increases in resting tension and decreases in microsomal Ca2+ uptake also were found to be dependent on the duration of reperfusion as well as on the calcium concentration of the reperfusion medium. Microsomes isolated from control, Ca2+-free perfused or reperfused hearts were found to have similar phospholipid composition, protein profiles (SDS-polyacrylamide gel electrophoresis), and electron microscopic appearance. Whereas Ca2+-free perfusion alone had no effect on any of the parameters studied, reperfusion also depressed microsomal Ca2+-binding, Mg2+-ATPase, and Ca2+-stimulated ATPase activities. Changes in microsomal Ca2+ uptake exhibited sigmoidal relationships with the ability of Ca2+-depleted hearts to recover their contractile force or increase their resting tension upon reperfusion. Our findings suggest that reperfusion-induced contracture and intracellular calcium overload may be associated in part with a defect in the ability of sarcoplasmic reticulum to regulate calcium.

Animals↗
PubMed1981

Effect of cyclic AMP phosphodiesterase inhibitors on cardiac sarcolemmal 5'-nucleotidase.

Two different membrane preparations (fraction HL and fraction S) were used to study the effect of caffeine, theophylline, dipyridamole and papaverine on cardiac sarcolemmal 5'-nucleotidase. Caffeine and theophylline inhibited the 5'-nucleotidase in both fractions, but theophylline appeared to be a more potent agent. The inhibitory effect of caffeine seemed to be the same in both membrane preparations, but the enzyme in fraction S appeared to be more sensitive to theophylline than that present in fraction HL. The inhibition was of the competitive type in both preparations. The inhibitory effect of caffeine and theophylline on 5'-nucleotidase may not be related to their actions on phosphodiesterase since dipyridamole and papaverine, which are also known to inhibit phosphodiesterase, did not affect the 5'-nucleotidase activity. It is suggested that by inhibiting 5'-nucleotidase, caffeine and theophylline may influence the production of adenosine in the myocardium and thereby may interfere with an important mechanism for the regulation of coronary blood flow.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1981

Adrenochrome-induced coronary artery constriction in the rat heart.

Adrenochrome, an oxidation product of epinephrine, has been demonstrated to produce cardiotoxic effects. In this study, we have investigated whether this agent can alter coronary resistance in isolated rat hearts. Concentrations of adrenochrome from 1 to 1000 ng/ml increased coronary pressure in a dose- and time-dependent manner. The highest concentration produced a 3-fold elevation in pressure after a 1-hr perfusion. Myocardial contractile force decreased only with either 100 or 1000 ng/ml of adrenochrome and this effect was evident after substantial elevations in coronary pressure. The elevation in coronary pressure was significantly reduced by two calcium antagonists, verapamil and D-600. Furthermore, the degree of constriction by adrenochrome was dependent on the CaCl2 concentration in the perfusion medium. High concentrations of indomethacin or propranolol attenuated the degree of coronary pressure elevation, whereas acetylsalicylic acid and phenoxybenzamine were without effect. Sulfinpyrazone, which has been shown to reduce the arrhythmogenic action of adrenochrome in vivo, significantly reduced the coronary pressure increases. These results suggest that adrenochrome is a potent coronary constricting agent in the rat heart and its action is seemingly dependent on external Ca++ availability.

Adrenochrome↗
PubMed1981

Influence of reducing agents on adrenochrome-induced changes in the heart.

To elucidate the role of oxidation products of catecholamines play in myocardial necrosis, we examined the effects that adrenochrome in the presence of some reducing agents and that autoxidized solution of adrenochrome have on the ultrastructure and force of contraction in the isolated rat heart. Addition of ascorbic acid (1 mM) or cysteine (0.5 mM) into a perfusion medium containing 25 mg/L of adrenochrome produced ultrastructural damage greater than that seen with adrenochrome alone, whereas addition of dithiothreitol (0.5 mM) did not. The rate of failure of the heart due to adrenochrome was accelerated by use of ascorbic acid and dithiothreitol. Reduction of adrenochrome into other oxidation products of catecholamines by these reducing agents was indicated by the results of spectral analysis studies. Myocardial damage or contractile failure did not occur if the adrenochrome solution was allowed to autoxidize for 24 hours before perfusion. These data indicate that oxidation products of epinephrine other than adrenochrome are involved in the genesis of catecholamine-induced cardiotoxicity. This effect may occur through the formation of cardiotoxic free radicals, as well as through interaction of these oxidation products with sulfhydryl groups.

Adrenochrome↗
PubMed1980

A selective concentration-dependent dysrhythmogenic and antidysrhythmic action of prostaglandins E2, F2 alpha and I2 (prostacyclin) on isolated rat hearts.

Prostaglandins (PGs) E2, F2 alpha and I2 were examined for their effects on the electrical and mechanical activities of isolated rat, rabbit and guinea-pig hearts. All PGs produced dysrhythmias in rat hearts at low concentrations only, while higher concentrations were antiarrhythmic. Guinea-pig hearts were less responsive while rabbit hearts were completely resistant.

Animals↗