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Biomedical subjects

M Karmazyn

Publications and source records attributed to M Karmazyn.

At least 109 records · Page 6Linked to original sources
PubMed1985

Prostaglandins and heart disease.

The role of prostaglandins (PGs) in cardiac pathophysiology has been reviewed with special emphasis on clinically applied aspects. Several PGs are synthesized and released by the heart and coronary vessels. Their synthesis is altered by various factors such as physical manipulation of tissue, pharmacological treatments and pathological conditions such as myocardial over-reactivity and ischemia. The involvement of PGs in cardiac dysfunction remains controversial, although it has been proposed that various PGs such as PGI2 or PGB2 may play a role in disaggregating platelets, inhibiting thrombus progression and coronary vasodilatation. The balance between thromboxane A2 (TXA2), a proaggregatory agent released from platelets and PGI2 may have a role in the genesis and management of angina and myocardial infarction. The use of non-steroidal anti-inflammatory agents in these conditions remains controversial; their possible beneficial effects are believed to be due to inhibition of TXA2 synthesis whereas their failure to be effective may be a consequence of concomitant inhibition of PGI2 production. Modulation of endogenous PG synthesis and administration of exogenous PGs or their analogues appear to be two therapeutic approaches in the management of certain cardiac diseases. Accordingly, there is a great need for synthesizing stable and potent PG analogues as well as specific inhibitors of PG synthesis in addition to studying their pharmacology and therapeutics. In this review we have emphasized the involvement of PGs in the pathogenesis of some forms of cardiac disease and have highlighted some therapeutic implications of these substances for the treatment of heart disease.

Angina Pectoris↗
PubMed1984

Involvement of calcium in coronary vasoconstriction due to prolonged hypoxia.

In this study we employed a hypoxic rat heart model for investigating the mechanisms of coronary spasm. Perfusion of the isolated heart with hypoxic medium resulted in initial coronary dilatation followed by sustained constriction. Pretreatment of rats with 5 mg/kg reserpine did not alter the rate of the magnitude of constriction during 60 minutes of hypoxic perfusion. The hypoxia-induced vasoconstriction was not affected by the inclusion of either 1 or 10 micrograms/ml phentolamine in the perfusion buffer, but phenoxybenzamine (0.1 and 1 microgram/ml) significantly attenuated the degree of constriction. Since phenoxybenzamine and phentolamine were equally effective in preventing the phenylephrine-induced coronary constriction, it is unlikely that the effect of phenoxybenzamine was due to an alpha-receptor blocking property but instead may be accounted for by its calcium channel blocking action. Two calcium channel blockers, verapamil and D-600 (0.1 and 1 microgram/ml), were also effective. The rate of rise in coronary pressure was substantially reduced by decreasing the concentration of calcium and was increased by elevating the concentration of calcium in the perfusion medium, but the magnitude of hypoxia-induced constriction was not affected. These results are consistent with the suggestion that the coronary constriction seen during hypoxia does not involve adrenergic mechanisms but is dependent upon the availability of calcium.

Adrenergic alpha-Antagonists↗
PubMed1984

Calcium-ionophore stimulated release of leukotriene C4-like immunoreactive material from cardiac tissue.

Administration of leukotrienes to cardiac tissue produces contractile depression and coronary artery constriction [5,8], thus making it possible that these substances mediate cardiac dysfunction under pathologic conditions. Up to now no studies have been performed to determine whether cardiac tissue has the inherent ability to produce leukotrienes. The present study was therefore carried out to ascertain whether isolated hearts perfused with saline buffer devoid of any blood constituents can produce leukotrienes under a variety of pharmacologic and pathologic situations. No leukotriene (LT) C4 was detected under control conditions or from hearts subjected to global ischemia and reperfusion or hypoxia and reoxygenation. A23187, a Ca2+ ionophore markedly stimulated LTC4 release. This effect was prevented by nordihydroguaiaretic acid, a selective lipoxygenase inhibitor. The addition of arachidonate as substrate had no effect on LTC4 release. In an attempt to divert arachidonate to LTC4 production, indomethacin, a cyclo-oxygenase inhibitor was added before arachidonate. No LTC4-like immunoreactivity was found in these experiments. These studies suggest that a lipoxygenase pathway for leukotriene production is present either in the coronary vasculature or myocardium. It was stimulated only by Ca2+ ionophore, probably indicating a requirement for high amounts of intracellular Ca2+.

Animals↗
PubMed1984

A direct protective effect of sulphinpyrazone on ischaemic and reperfused rat hearts.

Initiation of 60 min ischaemia to rat isolated hearts produced a depression in developed tension and heart rate. Subsequent reperfusion caused a greatly exacerbated creatine phosphokinase (CPK) efflux and limited functional recovery. Sulphinpyrazone (100 ng ml-1 and 1 microgram ml-1) significantly reduced CPK release, particularly after reperfusion, the lower concentration being more effective. A reduction in the mechanical depression during ischaemia and enhanced recovery after reperfusion were seen only with 100 ng ml-1 sulphinpyrazone. Heart rate and coronary perfusion pressure were unaffected by drug treatment. The reduction in reperfusion-induced CPK efflux by 100 ng ml-1 sulphinpyrazone was maximal when the drug was present throughout the perfusion period although some protection was evident when sulphinpyrazone was present either during ischaemia or reperfusion only. An enhanced recovery in contractility was seen only when the drug was present throughout all phases of perfusion. It is suggested that sulphinpyrazone exerts a direct protective effect on the heart particularly during reperfusion. The degree of protection is critically dependent on the concentration of sulphinpyrazone.

Animals↗
PubMed1984

Mechanical trauma to bladder epithelium liberates prostanoids which modulate neurotransmission in rabbit detrusor muscle.

Transitional epithelium of the rabbit urinary bladder has been implicated as a major site of prostanoid production and various studies have indicated that prostanoids have significant influences in muscle activity and neurotransmission in the bladder. We have examined the possibility that mechanical irritation of the epithelium could release diffusable substances which could influence neuromuscular function in the bladder. Epithelium was dissected from muscle strips of rabbit urinary bladder and the two components were incubated in separate chambers. Krebs' solution bathing epithelium was transferred to the bath in which the muscle was being field stimulated. Increases in the basal tension and spontaneous activity of the muscle as well as in the electrically evoked responses were observed after transfer and were related to the intensity of the irritation given the epithelium sample. The effects were mimicked by prostaglandins E1 E2, F2 alpha and I2 and the transfer effect was reduced significantly by pretreatment of the epithelium, but not the muscle, with indomethacin (10 microM) or ibuprofen (100 microM). Transfer of solution bathing-irritated epithelium also raised basal tension but not the maximum response to bethanechol. Finally, radioimmunoassay was used to demonstrate that irritation of epithelium samples caused the appearance of prostaglandin and 6-oxo-prostaglandin F1 alpha in the bathing medium and that this appearance was profoundly depressed by indomethacin (10 microM). It is plausible, therefore, that mechanical irritation of the bladder epithelium could result in changes in neuromuscular function in the underlying muscle layers and that these changes would be consistent with the symptoms associated with mechanical trauma of urothelium.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Comparative effects of calcium channel blocking agents and varying extracellular calcium concentration on hypoxia/reoxygenation and ischemia/reperfusion-induced cardiac injury.

OUr study was designed to evaluate and compare the effects of three structurally different calcium channel blocking drugs, verapamil (10 and 100 ng/ml), diltiazem (1 and 10 micrograms/ml) and nifedipine (10 and 100 ng/ml), and altering calcium concentration on two models of heart damage, hypoxia/reoxygenation and ischemia/reperfusion (60 min/15 min) of isolated rat hearts. The increase in creatine phosphokinase release by hypoxia and reoxygenation was significantly decreased by treatment with all three drugs. Reoxygenation-induced enzyme efflux was enhanced by a 3-fold elevation in external CaCl2 and depressed by a two-thirds calcium reduction. In contrast, elevation of calcium concentration had no significant effect on postischemia reperfusion-induced creatine phosphokinase efflux whereas "low calcium" decreased release during reperfusion. Two drugs which effectively reduced reperfusion- (nifedipine) or reoxygenation- (diltiazem) induced enzyme release as well as reducing calcium concentration were evaluated to determine during which phase of perfusion these treatments exerted their beneficial effect. The reduction of creatine phosphokinase release during reoxygenation by diltiazem was dependent on the drug's presence during the hypoxia phase of perfusion whereas low calcium (either reoxygenation or reperfusion) or nifedipine treatment (reperfusion) was protective irrespective of whether the treatment was present during hypoxia/ischemia or reoxygenation/reperfusion. The reduction in enzyme release was associated with an enhanced mechanical recovery and a reduction in arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Reduction of enzyme release from reperfused ischemic hearts by steroidal and non-steroidal prostaglandin synthesis inhibitors.

Exacerbation of heart tissue damage by reperfusion of the ischemic myocardium is a well documented phenomenon. The present study was undertaken to evaluate prostaglandin (PG) involvement in reperfusion-induced damage of isolated globally ischemic rat hearts. Reperfusion produced significant increases in creatinephosphokinase (CPK) and lactic dehydrogenase (LDH) efflux which was accompanied by enhanced PG release. Three non-steroidal antiinflammatory drugs; indomethacin, mefenamic acid and ASA, and the steroidal agents; dexamethasone, hydrocortisone and methylprednisolone significantly reduced both the release of CPK and PGs upon reperfusion whereas only indomethacin and mefenamic acid decreased LDH release. There was a significant correlation between the inhibition of PG synthesis and the attenuation of CPK leakage by both non-steroidal (P less than 0.001) and steroidal (P = 0.02) antiinflammatory agents. In spite of beneficial effects on enzyme release, drug treatment did not enhance recovery of mechanical function after reperfusion. The results suggest that inhibition of PG biosynthesis may be beneficial in preserving membrane, particularly mitochondrial integrity of the reperfused myocardium.

Animals↗
PubMed1983

Physiological and pathophysiological aspects of cardiac prostaglandins.

It has now been demonstrated that prostaglandins produce a wide variety of actions on cardiac tissue. These effects are quite complex and are dependent on such factors as type of prostaglandin, animal species, experimental format, as well as the amount of prostaglandin employed. The last factor is of particular concern since the administration of large amounts of prostaglandins may not truly reflect the actual actions of the endogenously synthesized prostaglandins which are likely to be at a very low concentration. In this review we have attempted to analyze the pharmacological properties of prostaglandins on cardiac tissue including coronary arteries and myocardium as well as the subcellular basis for their actions. The possible reasons for the diverse effects of prostaglandins under different experimental conditions have been pointed out. An effort has also been made to synthesize the existing information concerning the actions of prostaglandins on heart in terms of current concepts. A discussion is presented concerning the role of endogenously synthesized prostaglandins in physiological and pathological aspects of cardiac performance and the potential use of prostaglandins and prostaglandin synthesis inhibitors in the treatment of heart disease.

Animals↗
PubMed1982

Effect of adenosine in the cardiac actions of prostaglandins E2, I2, and F2 alpha.

Previous reports have demonstrated an antagonistic influence of adenosine in the biological effects of prostaglandins (PGs). We examined such a possible relationship on the isolated rat heart perfused at constant pressure and maintained at a constant heart rate. PGE2 and PGF2 alpha (2.8 X 10(-11) to 2.8 X 10(-7) M) exerted a positive inotropic influence on the heart with PGF2 alpha demonstrating the greater maximum effect. PGI2 had a negative inotropic effect only at high concentrations (2.8 X 10(-9) to 2.8 X 10(-7) M). The coronary flow was decreased by both PGE2 and PGF2 alpha. The concentrations of PGI2 employed had minimal vasoactive properties (20% increase in flow at 2.9 X 10(-7) M). Adenosine at concentrations which increased coronary flow by 24 to 63% (0.1 to 10 microM) had no influence on either the alteration in contractile force produced by PGE2 PGF2 alpha, or PGI2 or on the coronary effects of PGE2 or PGI2. Adenosine did, however, attenuate the degree of coronary flow reduction produced by PGF2 alpha administration. These results are suggestive of a selective inhibiting influence of adenosine on the coronary constricting effects of PGF2 alpha, in the isolated rat heart.

Adenosine↗
PubMed1982

Effect of cholesterol feeding and gender on the response of the isolated rat heart to hypoxia.

The effect of hypoxic perfusion on isolated hearts from male and female rats fed either a control or 2% cholesterol supplemented diet was studied. Initiation of hypoxia produced a rapid decline in rate of hearts from either male or female animals irrespective of diet regimen. However, hearts from male rats fed a control diet exhibited a significantly higher (P less than 0.01) resting rate during normoxic perfusion when compared with hearts from cholesterol-fed animals. Hypoxia also produced a rapid loss of myocardial contractile force and this effect was influenced by neither diet treatment nor animal gender. Similarly, there was little change in time to peak height of developed tension due to diet. Contracture development during hypoxic perfusion was significantly higher in hearts from female rats fed a cholesterol-supplemented diet compared with hearts from control diet fed female animals, whereas no changes were observed due to diet in hearts from male animals. Coronary resistance was increased as a result of hypoxic perfusion. In hearts from cholesterol-fed male rats this effect was substantially attenuated. Conversely, cholesterol supplementation resulted in a higher (P less than 0.05) coronary resistance in hearts from female animals either during normoxic or the early period of hypoxic perfusion. Prostacyclin synthesis as measured by immunoreactive 6-keto-PGF1 alpha efflux did not differ between hearts from either male or female rats during normoxic perfusion. Hypoxia significantly reduced 6-keto-PGF1 alpha efflux from hearts of cholesterol-fed male rats whereas it produced no effect in any other treatment category. Our results demonstrate a substantial contribution of dietary cholesterol and animal gender in the response of the isolated rat heart to hypoxic perfusion.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

A possible mechanism of inotropic action of prolactin on rat heart.

Prolactin possesses positive inotropic actions in isolated heart preparations although the mechanism of this influence is not understood. Our study was designed to investigate the mechanism of this effect on the rat heart. Prolactin (50 ng/ml) produced a time-dependent increase (60%) in contractile force that reached maximum after 30 min and remained steady for a further 30 min. A similar time-dependent phenomenon was seen with 200 ng/ml prolactin although the maximum inotropic effect was reduced. Indomethacin (30 micrograms/ml) significantly reduced the inotropic effect of both prolactin concentrations although the effect of the hormone was not related to the release of 6-keto-PGF1 alpha, the prostacyclin metabolite. Propranolol (1-20 micrograms/ml) significantly reduced the positive inotropic effect of prolactin. Prolactin however had no influence on myocardial adenylate cyclase activity. Hearts that were removed from animals pretreated with 1.25 or 2.50 mg/kg reserpine did not respond to prolactin administration. It is suggested that the inotropic influence of prolactin is mediated by endogenous catecholamine liberation.

6-Ketoprostaglandin F1 alpha↗
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

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

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

Effect of nonsteroidal anti-inflammatory drugs on the hypoxic rat heart.

The influence of the nonsteroidal anti-inflammatory drugs indomethacin (10 microgram/ml), mefenamic acid (10 ng/ml) and acetylsalicylic acid (50 microgram/ml) were investigated for their effects on hypoxically perfused rat hearts. Hypoxia-induced mechanical cardiodepression was attenuated to varying degrees by most drugs, although only mefenamic acid reduced the degree of bradycardia. All the agents reduced in some measure the rise in resting tension produced by hypoxic perfusion and enhanced the functional activity of the myocardium upon reoxygenation of hearts made hypoxic for 10 min only. The degree of contracture after reoxygenation was substantially attenuated by all three drugs. Although coronary flow decreased dramatically during prolonged hypoxia, this phenomenon was significantly prevented by the nonsteroidal anti-inflammatory drugs. Cellular Na content of hypoxic hearts treated with mefenamic acid was elevated, whereas no other significant electrolyte changes were observed. The presence of mefenamic acid results in a reduced extracellular space size, whereas cellular water content was increased by both mefenamic acid and acetylsalicylic acid. Calcium transport of isolated mitochondria from hypoxically or normoxically perfused hearts was not modified by any treatment. Indomethacin, acetylsalicylic acid and mefenamic acid all significantly inhibited prostaglandin release from the heart. These results suggest that various nonsteroidal anti-inflammatory drugs may offer some protective influence on hypoxic rat hearts particularly with respect to coronary artery patency during hypoxic perfusion.

Animals↗
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↗