Biomedical subjects

N S Dhalla

Publications and source records attributed to N S Dhalla.

At least 109 records · Page 6Linked to original sources

PubMed1994

Alterations in G-proteins in congestive heart failure in cardiomyopathic (UM-X7.1) hamsters.

In order to explain the attenuated sympathetic support during the development of heart failure, the status of beta-adrenergic mechanisms in the failing myocardium was assessed by employing cardiomyopathic hamsters (155-170 days old) at moderate degree of congestive heart failure. The norepinephrine turnover rate was increased but the norepinephrine content was decreased in cardiomyopathic hearts. The number and the affinity of beta receptors in the sarcolemmal preparations were not changed in these hearts at moderate stage of congestive heart failure. While the basal adenylyl cyclase activity was not altered in sarcolemma, the stimulation of enzyme activity by NaF, forskolin, Gpp(NH)p or epinephrine was depressed in hearts from these cardiomyopathic hamsters. Since G-proteins are involved in modifying the adenylyl cyclase activity, the functional and bioactivities as well as contents of both Gs and Gi proteins were determined in the cardiomyopathic heart sarcolemma. The functional stimulation of adenylyl cyclase by cholera toxin, which activates Gs proteins, was markedly depressed whereas that by Pertussis toxin, which inhibits Gi proteins, was markedly augmented in cardiomyopathic hearts. The cholera toxin and pertussis toxin catalyzed ADP-ribosylation was increased by 37 and 126%, respectively; this indicated increased bioactivities of both Gs and Gi proteins in experimental preparations. The immunoblot analysis suggested 74 and 124% increase in Gs and Gi contents in failing hearts, respectively. These results suggest that depressed adenylyl cyclase activation in cardiomyopathic hamsters may not only be due to increased content and bioactivity of Gi proteins but the functional uncoupling of Gs proteins from the adenylyl cyclase enzyme may also be involved at this stage of heart failure.

Adenosine Diphosphate Ribose↗

PubMed1994

Cardiac sarcoplasmic reticulum Ca(2+)-ATPase expression in streptozotocin-induced diabetic rat heart.

Chronic diabetes due to streptozotocin administration has been shown to induce heart dysfunction characterized by prolonged relaxation time as well as decreased Ca2+ transport and Ca(2+)-ATPase (SERCA2) activities of the cardiac sarcoplasmic reticulum (SR). Rats made diabetic with 65 mg/kg of streptozotocin for 3 and 5 weeks exhibited decreased SR Ca(2+)-pump activities; these were normalized upon treatment with insulin. Northern blot and slot blot analyses did not show statistically significant reduction in the relative level of SERCA2 mRNA expression in diabetic or insulin treated rats. Quantitation of SERCA2 protein by Western blot did not reveal any change in diabetic and insulin treated animals. These results suggest that the defect in SR Ca(2+)-pump may not be due to changes at the transcriptional or translational levels in the diabetic heart.

Animals↗

PubMed1994

Modification of myosin isozymes and SR Ca(2+)-pump ATPase of the diabetic rat heart by lipid-lowering interventions.

To define metabolic influences on cardiac myosin expression and sarcoplasmic reticulum (SR) Ca(2+)-stimulated ATPase streptozotocin-diabetic rats were treated for 9-10 wk with etomoxir, an inhibitor of carnitine palmitoyl transferase I (CPT-1) and fatty acid synthesis, or an antilipolytic drug, acipimox. Etomoxir reduced myosin V3 of diabetic rats but did not normalize it. However, the high serum triglyceride, free-fatty acid and cholesterol concentrations in diabetic animals were greatly reduced. After bypassing the CPT-1 inhibition with a medium-chain fatty acid (miglyol) diet, the V3 contents and serum lipids were still reduced in the etomoxir-treated diabetic rats; V3 was also reduced in diabetic rats fed miglyol or treated with acipimox. Since low serum insulin or triiodothyronine concentrations in diabetic rats were not improved by these interventions but changes in V3 were correlated with those in triglyceride, free-fatty acid and cholesterol concentrations, it is likely that myosin may be influenced by some metabolic factors. To assess the role of adrenergic influences, diabetic rats (7-8 wk) were treated with an antisympathotonic drug, moxonidine, a beta-adrenoceptor blocking drug, propranolol, and a bradycardic drug, tedisamil. Myosin V3 was not reduced significantly in moxonidine-treated or propranolol-treated rats in comparison to untreated diabetic rats. Serum thyroid hormones and insulin were not altered, whereas triglycerides were reduced but not significantly by these antiadrenergic agents. Lowering serum lipids in diabetic rats by treatment with etomoxir, miglyol and acipimox increased the depressed SR Ca(2+)-stimulated ATPase activity. On the other hand, in diabetic rats treated with moxonidine, propranolol or tedisamil, the ATPase activity was not increased significantly. These results suggest that normalization of blood lipids is important for improving subcellular organelle function in diabetic hearts with impaired glucose utilization.

Animals↗

PubMed1994

Oxidative stress modifies the activity of cardiac sarcolemmal phospholipase C.

We have examined the direct effects of oxidant metabolites on cardiac sarcolemmal phosphoinositide phospholipase C which transduces signals from various receptors for the modulation of intracellular Ca2+ levels. The enzyme activity in rat cardiac sarcolemmal membranes that had been preincubated (10 min; 37 degrees C) with xanthine-xanthine oxidase, a superoxide anion generating system, was not significantly affected. The addition to this system of superoxide dismutase, which converts superoxide anion to hydrogen peroxide (H2O2), resulted in a significant decrease of the enzyme activity in comparison with control values. Such decrease was fully prevented by catalase. Preincubation of sarcolemma with hypochlorous acid also gave a significant inhibition of phospholipase C, which was counteracted by the synthetic thiol reducer dithiothreitol. H2O2-pretreatment induced a concentration-dependent inhibition of the enzyme which was prevented by catalase but not by the iron chelator deferoxamine. Dithiothreitol was able to protect against, as well as to recover the enzyme activity from the H2O2 effects. These data suggest that superoxide anions and hydroxyl radicals did not interfere with phospholipase C activity, and that the nonradical oxidants, H2O2 and hypochlorous acid, may have acted through oxidation of thiol (SH) groups. The existence of reactive SH groups associated with the enzyme was confirmed by the inhibitory effects of SH modifiers (p-chloromercuriphenylsulfonic acid, 5'5'-dithio-bis(2-nitrobenzoic acid), N-ethylmaleimide and methyl methanethiosulfonate), which were prevented and in some cases also reversed by dithiothreitol. The biological reducer glutathione (GSH) was not able to recover the H2O2-induced inhibition of phospholipase C, whereas its oxidized form (GSSG) decreased the enzyme activity both in control and H2O2-pretreated membranes. The enzyme was active in a wide range of GSH/GSSG redox states, but H2O2 pretreatment narrowed this range. The results showed that oxidative stress changed the redox state of sarcolemmal phospholipase C, and this deactivated the enzyme. The oxidants' concentrations that significantly impaired phospholipase C in this study were compatible with those occurring in vivo during ischemia-reperfusion [Am. J. Med. 91(Suppl. 3C):235, 1991]. This supports the possibility that alteration of the receptor-associated phospholipase C may be a factor in the oxidant-related dysfunction of the ischemic-reperfused heart.

Animals↗

PubMed1994

Mechanisms of cardiac cell damage due to catecholamines: significance of drugs regulating central sympathetic outflow.

A chronically increased rate of catecholamine release has various deleterious actions. Isoproterenol injections (80 mg/kg body weight) resulted in depressed Ca2+ transport in the sarcolemma (ATP-dependent Ca2+ uptake, Na(+)-dependent Ca2+ uptake) and sarcoplasmic reticulum (Ca2+ uptake) of rat heart. The formation of malondialdehyde owing to lipid peroxidation was increased. Pretreatment with vitamin E (10-25 mg/kg/day) strongly inhibited the membrane damage. The toxic effects of catecholamines arise most probably from their oxidation, and it is therefore important either to reduce the central sympathetic outflow or to prevent the oxidation. An inappropriately high sympathetic outflow is a typical feature of Western affluent societies, and is linked to psychosocial stress and hypercaloric nutrition. However, established pharmacologic interventions to reduce sympathetic outflow have proven not practicable because of marked side effects. Using radiotelemetry for monitoring cardiovascular parameters of spontaneously hypertensive rats treated with clonidine or moxonidine, we showed that clonidine, unlike moxonidine, resulted in rebound hypertension after drug withdrawal. Because the rebound blood pressure and the typical side effects of clonidine associated with low patient compliance are mainly mediated by alpha-adrenoceptors, it can be inferred that the I1-imidazoline agonist moxonidine does not exhibit the side effects commonly seen with clonidine and therefore represents a promising approach for reducing an inappropriately high central sympathetic outflow.

Analysis of Variance↗

PubMed1993

Role of extracellular matrix proteins in heart function.

The cardiac interstitium is populated by nonmyocyte cell types including transcriptionally active cardiac fibroblasts and endothelial cells. Since these cells are the source of many components of the cardiac extracellular matrix, and because changes in cardiac extracellular matrix are suspected of contributing to the genesis of cardiovascular complications in disease states such as diabetes, hypertension, cardiac hypertrophy and congestive heart failure, interest in the mechanisms of activation of fibroblasts and endothelial cells has led to progress in understanding these processes. Recent work provides evidence for the role of the renin-angiotensin-aldosterone system in the pathogenesis of abnormal deposition of extracellular matrix in the cardiac interstitium during the development of inappropriate cardiac hypertrophy and failure. The cardiac extracellular matrix is also known to change in response to altered cardiac performance associated with post-natal aging, and in response to environmental stimuli including intermittent hypoxia and abnormal nutrition. It is becoming clear that the extracellular matrix mainly consists of molecules of collagen types I and III; they form fibrils and provide most of the connective material for typing together myocytes and other structures in the myocardium and thus is involved in the transmission of developed mechanical force. The data available in the literature support the view that the extracellular matrix is a dynamic entity and alterations in this structure result in the development of heart dysfunction.

Cardiomegaly↗

PubMed1993

Alteration of collagenous protein profile in congestive heart failure secondary to myocardial infarction.

The rat model of myocardial infarction is characterized by progressive cardiac hypertrophy and failure. Rats with infarcts greater than 30% of the left ventricle exhibited early and moderate stages of heart failure 4 and 8 weeks after the occlusion of the left coronary artery, respectively. As heart failure is usually associated with remodeling of the extracellular matrix, a histological and biochemical study of cardiac collagenous proteins was carried out using failing hearts. Total collagen content in the right ventricle increased at 2, 4, and 8 weeks following occlusion of the left coronary artery whereas such a change in viable left ventricle was seen after 4 and 8 weeks. Total cardiac hydroxyproline concentration was increased in both right and left ventricular samples from the infarcted animals when compared to those of control; this increase was due to elevation of pepsin-insoluble collagen fraction. The myocardial noncollagenous/collagenous protein ratio was decreased in experimental right and left ventricular samples when compared to control samples. These findings suggest that an increase in cross-linking of cardiac collagen as well as disparate synthesis of collagenous and noncollagenous proteins occurs in this model of congestive heart failure.

Animals↗

PubMed1993

Regulation of cardiac sarcolemmal Ca2+ channels and Ca2+ transporters by thyroid hormone.

In order to examine the regulatory role of thyroid hormone on sarcolemmal Ca(2+)-channels, Na(+)-Ca2+ exchange and Ca(2+)-pump as well as heart function, the effects of hypothyroidism and hyperthyroidism on rat heart performance and sarcolemmal Ca(2+)-handling were studied. Hyperthyroid rats showed higher values for heart rate (HR), maximal rates of ventricular pressure development +(dP/dt)max and pressure fall -(dP/dt)max, but shorter time to peak ventricular pressure (TPVP) and contraction time (CT) when compared with euthyroid rats. The left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVEDP), as well as aortic systolic and diastolic pressures (ASP and ADP, respectively) were not significantly altered. Hypothyroid rats exhibited decreased values of LVSP, HR, ASP, ADP, +(dP/dt)max and -(dP/dt)max but higher CT when compared with euthyroid rats; the values of LVEDP and TPVP were not changed. Studies with isolated-perfused hearts showed that while hypothyroidism did not modulate the inotropic response to extracellular Ca2+ and Ca2+ channel blocker verapamil, hyperthyroidism increased sensitivity to Ca2+ and decreased sensitivity to verapamil in comparison to euthyroid hearts. Studies of [3H]-nitrendipine binding with purified cardiac sarcolemmal membrane revealed decreased number of high affinity binding sites (Bmax) without any change in the dissociation constant for receptor-ligand complex (Kd) in the hyperthyroid group when compared with euthyroid sarcolemma; hypothyroidism had no effect on these parameters. The activities of sarcolemmal Ca(2+)-stimulated ATPase, ATP-dependent Ca2+ uptake and ouabain-sensitive Na(+)-K+ ATPase were decreased whereas the Mg(2+)-ATPase activity was increased in hypothyroid hearts. On the other hand, sarcolemmal membranes from hyperthyroid samples exhibited increased ouabain-sensitive Na(+)-K+ ATPase activity, whereas Ca(2+)-stimulated ATPase, ATP-dependent Ca2+ uptake, and Mg(2+)-ATPase activities were unchanged. The Vmax and Ka for Ca2+ of cardiac sarcolemmal Na(+)-Ca2+ exchange were not altered in both hyperthyroid and hypothyroid states. These results indicate that the status of sarcolemmal Ca(2+)-transport processes is regulated by thyroid hormones and the modification of Ca(2+)-fluxes across the sarcolemmal membrane may play a crucial role in the development of thyroid state-dependent contractile changes in the heart.

Animals↗

PubMed1993

Possible role of phospholipase C in the induction of Ca(2+)-paradox in rat heart.

In order to investigate the involvement of phosphoinositide-specific phospholipase C (PLC), an enzyme associated with phosphoinositide signal transduction pathway, for the occurrence of Ca(2+)-paradox (loss of contractile activity associated with contracture), rat hearts perfused with Ca(2+)-free medium (1 to 5 min) were reperfused (5 to 10 min) with medium containing 1.25 mM Ca2+. Crude membranes isolated from hearts perfused with Ca(2+)-free medium exhibited a significantly increased activity of PLC, whereas normal activity was detected in hearts reperfused with Ca(2+)-containing medium. A significant rise in PLC activity was observed at 1 min of Ca(2+)-free perfusion; maximal increase was seen at 4 min of Ca(2+)-free perfusion. Minimal concentration of Ca2+ in the perfusion medium required for showing an increase in PLC activity was 10 microM, whereas that required for the occurrence of Ca(2+)-paradoxic changes in heart function upon reperfusion was 50 microM. Perfusion of the hearts with Ca(2+)-free medium in the presence of low Na+ or at low temperature, which prevents the occurrence of Ca(2+)-paradox upon reperfusion, did not prevent the increase in PLC activity. An increase during Ca(2+)-free perfusion similar to that seen for PLC was also observed for two other enzymes, namely the phosphatidylinositol (PI) 4-kinase and the PI-4-monophosphate (PIP) 5-kinase, which synthesize the PLC substrate, phosphatidylinositol 4,5-bisphosphate (PIP2). No alteration of the alpha-adrenoreceptors was observed after 5 min of Ca(2+)-free perfusion. On the other hand, the observed changes in PLC activity during Ca(2+)-free perfusion appear to be due to some redistribution of the enzyme in the myocardium. These results suggest a possible role of the phosphoinositide/PLC pathway in the induction of Ca(2+)-paradox via mechanisms which do not appear to be associated with changes in the characteristics of alpha-adrenergic receptors.

Animals↗

PubMed1993

Characterization of adenylyl cyclase in heart sarcolemma in the absence or presence of alamethicin.

Alamethicin is commonly used as an agent for unmasking the latent enzyme activities in vesicular membrane preparations; however, relatively little is known about the effect of this agent on the characteristics of adenylyl cyclase in heart sarcolemma. By employing rat heart sarcolemmal preparation, we observed 5 to 6 fold increase in adenylyl cyclase activity upon treatment with alamethicin. Kinetic experiments using various concentrations of MgATP revealed that the increase in adenylyl cyclase activity in alamethicin treated membranes was associated with an increase in Vmax as well as affinity of the substrate for the enzyme. Dose-responses of the control and alamethicin-treated preparations to various activators of adenylyl cyclase revealed that the sensitivity of the enzyme to forskolin, NaF and GppNHp, was markedly increased upon treating sarcolemma with alamethicin. The activation of adenylyl cyclase by forskolin was also enhanced by increasing the concentration of alamethicin in the incubation medium. Furthermore, there was a greater increase in adenylyl cyclase activity with different concentrations of Mn2+ in the presence of alamethicin. These results suggest that alamethicin treatment alters the characteristics of adenylyl cyclase in addition to unmasking the enzyme activity in the purified sarcolemmal vesicular preparation.

Adenosine Triphosphate↗

PubMed1993

Characteristics and mechanisms of tachyphylaxis of cardiac contractile response to insulin.

Although insulin is known to cause internalization of its own receptors, the physiological significance of this phenomenon is not clear. In the isolated rat heart we observed that the positive inotropic effect of 25 munits/ml insulin was completely abolished if the heart was preperfused with insulin for 10 min. This tachyphylactic response to insulin began to appear 3-4 min after starting preperfusion with insulin and was partially reversible after 30 min of washing. Preperfusion with insulin did not affect the action of vanadate, which has insulin-like effect on glucose transport, or the actions of the other positive inotropic agents, isoproterenol and ouabain. The presence of propranolol in the perfusion medium, unlike atenolol, phenoxybenzamine, guanethidine, verapamil or quinidine, modified the inotropic as well as tachyphylactic responses to insulin. The positive inotropic and tachyphylactic responses to insulin were not altered in hearts from reserpine-treated animals. Perfusion of heart with glucose-free solution abolished the tachyphylaxis due to insulin. Likewise, no tachyphylactic response to insulin was evident when iodoacetate, but not sodium fluoride, was added in medium containing glucose. These results suggest that ATP formed during glycolysis may play an important role in insulin-induced tachyphylaxis with respect to cardiac contractile activity.

Adenosine Triphosphate↗

PubMed1993

Role of endothelin in heart function in health and disease.

A comprehensive review of the literature has revealed that endothelins belong to a family of vasoactive peptides which are formed and released from the endothelium. By producing constriction of the coronary arteries and peripheral blood vessels, endothelins are known both to reduce coronary bloodflow and increase blood pressure and thus can be seen to affect heart function adversely. On the other hand, endothelins are capable of producing positive inotropic and chronotropic effects by directly affecting both the myocardium and nodal tissues. Prolonged actions of high concentrations of endothelins can be seen to induce relative hypoxia in the myocardium which will eventually result in heart dysfunction. The mechanisms of actions of endothelin on smooth muscle cells and cardiomyocytes include interaction with endothelin receptors on the cell surface, activation of phospholipase C through G-proteins, and increase in the intracellular concentration of Ca2+ through the increase in phosphoinositol turnover. Endothelins were found to exert no effects on sarcolemmal Na+,K(+)-ATPase, Na(+)-Ca2+ exchange and Ca2+ pump systems nor on the sarcoplasmic reticular Ca2+ pump system and myofibrillar ATPase activities in the rat heart. Marked elevation in the levels of plasma endothelins and down-regulation of endothelin receptors in ischemia-reperfusion injury, hypertension and chronic diabetes indicate a significant role of endothelins in the genesis of heart dysfunction under different pathological conditions.

Animals↗

PubMed1993

Pathophysiology of cardiac dysfunction in congestive heart failure.

Although various factors, such as myocardial infarction, pressure overload and volume overload, result in the development of congestive heart failure (CHF), the pathogenesis of contractile dysfunction in this situation is poorly understood. Loss of cardiac muscle due to myocardial infarction appears to activate several humoral and hormonal pathways, including the renin-angiotensin and sympathetic systems which serve as adaptive mechanisms to maintain cardiovascular performance at early stages of failure. However, under chronic conditions, an altered hormonal profile produces deleterious effects and permits transition from the compensated heart to the failing heart. Since several risk factors--such as hypertension, hypercholesteremia, stress, diabetes, smoking, ageing, obesity and lack of exercise--precipitate ischemic heart disease, it is possible that development of CHF due to myocardial infarction may vary according to the nature of these pathogenetic entities. While a great deal of research work remains in this area of investigation, it is becoming evident that cardiac dysfunction is intimately associated with calcium handling abnormalities of cardiac cells. In view of the role of sarcolemma, sarcoplasmic reticulum and mitochondria in regulating the intracellular concentration of Ca2+ and the importance of myofibrillar interaction with Ca2+, it appears that Ca2+ handling and Ca2+ interaction abnormalities in the failing heart are due to remodelling of different subcellular organelles. Such a remodelling of the subcellular organelles may be due to changes in gene expression for different protein components or the interactions of proteins with phospholipids. Accordingly, it is proposed that new interventions, which could prevent the remodelling of subcellular organelles, be developed for improving the therapy of CHF.

Aged↗

PubMed1992

Paradoxical role of lipid metabolism in heart function and dysfunction.

The heart utilizes fatty acids as a substrate in preference to glucose for the production of energy. The rate of fatty acid uptake and oxidation by heart muscle is controlled by the availability of exogenous fatty acids, the rate of acyl translocation across the mitochondrial membrane and the rate of acetyl-CoA oxidation by the citric acid cycle. Carnitine acyl-CoA transferase appears to have an important function in coupling the fatty acid activation and acyl transfer to the oxidative phosphorylation. Activated fatty acids are also utilized for the synthesis of triglycerides and membrane phospholipids in the myocardium. The inhibition of long chain acyl-carnitine transferase I reduces the oxidation of fatty acids and promotes the synthesis of lipids in the myocardium. Accumulation of fatty acids and their metabolites such as long chain acyl-CoA and long chain acyl-carnitine has been associated with cardiac dysfunction and cell damage in both ischemic and diabetic hearts. Alterations in the composition of membrane phospholipids are also considered to change the activities of various membrane bound enzymes and subsequently heart function under different pathophysiological conditions. Chronic diabetes was found to be associated with increased plasma lipids, subcellular defects and cardiac dysfunction. Lowering the plasma lipids or reducing the oxidation of fatty acids by agents such as etomoxir, an inhibitor of palmitoylcarnitine transferase I was found to promote glucose utilization and remodel the subcellular membranous organelles in the heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗

PubMed1992

Changes in adrenergic receptors during the development of heart failure.

Moderate and severe stages of congestive heart failure due to the loss of myocardium upon coronary occlusion in rats was associated with an increase in alpha-adrenergic receptors and a decrease in beta-adrenergic receptors in the viable left ventricle. However, at early stages of heart failure the number of beta-adrenergic receptors was decreased without any changes in the number of alpha-adrenergic receptors. The affinities of these receptors to alpha receptor antagonist (3H-prazosin) and beta receptor antagonist (3H-dihydroalprenolol) were not altered in the failing hearts. On the other hand, the pattern of changes in both alpha- and beta-adrenergic receptors in heart membranes treated with oxygen free radical generating system was different from that seen in the failing hearts. In particular, the affinities for these receptors were decreased whereas the number of beta-receptors was increased and the number of alpha-receptors was decreased or unchanged. These results indicate that alterations in the adrenergic receptors in heart failure are not due to the formation of oxygen free radicals.

Animals↗

PubMed1992

Ca(2+)-channels and adrenoceptors in diabetic skeletal muscle.

The status of Ca(2+)-channels and adrenoceptors in the hind leg skeletal muscle was examined in rats 8 weeks after inducing diabetes by an intravenous injection of streptozotocin (65 mg/kg). Scatchard plot analysis of the data on specific binding of 3H-nitrendipine with crude membranes from diabetic muscle revealed an increase in the density of Ca(2+)-channels without any significant change in their affinity for the ligand. An increase in the density of beta-adrenoceptors without any alteration in their affinity, as measured by 3H-dihydroalprenolol binding, was also evident in the diabetic muscle. The observed increase in the number of Ca2+ channels or beta-adrenoceptors seems specific since no change in the alpha-adrenoceptor density or affinity, as measured by 3H-prazosin binding, was seen in the diabetic membranes. These results support the view that higher activities of Ca2+ transport systems or regulatory mechanisms may be associated with hyperfunction of the diabetic skeletal muscle.

Animals↗

PubMed1992

Alterations in Ca(2+)-channels during the development of diabetic cardiomyopathy.

In order to examine the status of Ca2+ channels in heart sarcolemma during the development of diabetes, rats were injected intravenously with 65 mg/kg streptozotocin and hearts were removed 1, 3 and 8 weeks later. Crude membranes from the ventricular muscle were prepared and the specific binding of 3H-nitrendipine was studied by employing different concentrations of this Ca(2+)-antagonist. A significant decrease in both dissociation constant and maximal number of 3H-nitrendipine binding was observed in 3 and 8 weeks diabetic preparations. No such alterations were evident in diabetic brain membranes. Treatment of diabetic animals with insulin prevented the occurrence of these changes in the myocardium. The altered 3H-nitrendipine binding characteristics in diabetic heart membranes may not be due to the high levels of circulating catecholamines in this experimental model because no such changes were seen upon injecting a high dose (40 mg/kg) of isoproterenol in rats for 24 hr. The reduced number of 3H-nitrendipine binding sites may decrease Ca(2+)-influx through voltage sensitive Ca2+ channels and partly explain the depressed cardiac contractile force development in chronic diabetes whereas the increased affinity of Ca2+ channels may partly explain the increased sensitivity of diabetic heart to Ca2+.

Animals↗

PubMed1992

Modification of subcellular organelles in pressure-overloaded heart by etomoxir, a carnitine palmitoyltransferase I inhibitor.

To examine the signals regulating cardiac growth and molecular structure of subcellular organelles, cardiac hypertrophy was induced in rats by constriction of the abdominal aorta for 12-13 wk or by treatment with a carnitine palmitoyltransferase I inhibitor, etomoxir (12-15 mg/kg body wt) for 12-13 wk. In contrast to pressure overload, etomoxir redistributed the myosin isozyme population from V3 to V1 and increased the sarcoplasmic reticulum (SR) Ca(2+)-stimulated ATPase activity. When rats with pressure-overloaded hearts were treated with etomoxir, the cardiac hypertrophy was increased whereas the shift in myosin isozymes from V1 to V3 was prevented and the depression in SR Ca(2+)-stimulated ATPase activity was reversed. Plasma thyroid hormone and insulin concentrations were not altered but triglyceride concentrations were reduced in etomoxir-treated rats with pressure overload. The data demonstrate a dissociation between cardiac muscle growth and changes in subcellular organelles and indicate that a shift in myocardial substrate utilization may represent an important signal for molecular remodeling of the heart.

Animals↗