Nasir Afzal

Decreased expression of cardiac sarcoplasmic reticulum Ca2+-pump ATPase in congestive heart failure due to myocardial infarction

Myocardial infarction in rats induced by occluding the left coronary artery for 4, 8 and 16 weeks has been shown to result in congestive heart failure (CHF) characterized by hypertrophy of the viable ventricular myocardial tissue. We have previously demonstrated a decreased calcium transport activity in the sarcoplasmic reticulum (SR) of post-myocardial infarction failing rat hearts. In this study we have measured the steady state levels of the cardiac SR Ca2+-pump ATPase (SERCA2) mRNA using Northern blot and slot blot analyses. The relative amounts of SERCA2 mRNA were decreased with respect to GAPDH mRNA and 28 S rRNA in experimental failing hearts at 4 and 8 weeks post myocardial infarction by about 20% whereas those at 16 weeks declined by about 35% of control values. The results obtained by Western blot analysis, revealed that the immunodetectable levels of SERCA2 protein in 8 and 16 weeks postinfarcted animals were decreased by about 20% and 30%, respectively. The left ventricular SR Ca2+-pump ATPase specific activity was depressed in the SR preparations of failing hearts as early as 4 weeks post myocardial infarction and declined by about 65% at 16 weeks compared to control. These results indicate that the depressed SR Ca2+-pump ATPase activity in CHF may partly be due to decreased steady state amounts of SERCA2 mRNA and SERCA2 protein in the failing myocardium.

Beneficial Effects of Verapamil in Diabetic Cardiomyopathy

It has been suggested that the occurrence of an intracellular Ca2+ overload may result in the development of diabetic cardiomyopathy, which is associated with depletion of high-energy phosphate stores and a derangement of ultrastructure and cardiac dysfunction. Accordingly, the effects of verapamil, a Ca2+ antagonist, on cardiac function, ultrastructure, and high-energy phosphate stores in the myocardium were evaluated in rats made diabetic by an intravenous injection of streptozocin (65 mg/kg). Four weeks after the induction of diabetes, the animals were treated with three doses (2, 4, or 8 mg kg−1 day−1) of verapamil for 4 wk until they were used for the measurement of different parameters. Untreated diabetic animals had slower heart rates, depressed rate of contraction and rate of relaxation, lower peak left ventricular systolic pressure, and elevated left ventricular diastolic pressure. All of these changes were significantly improved in diabetic rats receiving verapamil treatment. The beneficial effects of verapamil were more evident with higher doses (8 mg · kg−1 · day−1) than with the lower doses (2 mg · kg−1 · day−1). The diabetic animals also showed alterations in myocardial high-energy phosphate stores and exhibited evidence of ultrastructural damage; these abnormalities were improved by verapamil treatment without affecting their hyperglycemic status. Our results demonstrate that verapamil is capable of preventing diabetes-induced myocardial changes and support the involvement of Ca2+ in the cardiac pathology during diabetes.

Cardiac Sarcolemmal Na+/H+ Exchange after a Myocardial Infarction in the Rat

A growing number of studies have implicated the Na+/H+ exchanger in ischemic/reperfusion damage to the heart [1–7]. Other studies have now demonstrated accelerated ion flow through this exchanger in hypoxic/ reoxygenation insult to the heart as well [8–10]. While these are important pathological events, they are largely immediate reactions of Na+/H+ exchange activity in response to changes in the intracellular ionic environment in the heart. These reactions occur so quickly that they likely do not involve structural changes in the protein or alterations in protein synthesis. However, during low-flow ischemia of a relatively long duration, there are indications that these pathways are beginning to be activated. Changes in the Na+/H+ exchange mRNA message have been detected in hearts after three hours of low-flow ischemia [11]. These changes do not occur in global ischemia experiments, which employ considerably shorter ischemic periods (≤1 hour) [11,12]. Chronic alterations in the exchanger would be more likely to occur during conditions where an adaptive stimulus is placed upon the heart for a much longer period of time and/or where the tissue is allowed sufficient time to induce its adaptive mechanisms. A stimulus that frequently induces an adaptive response in the heart is myocardial disease.