Verapamil Accelerates the Transition to Heart Failure in Obese, Hypertensive, Female SHHF/Mcc-facp Rats

Abstract

We sought to characterize the effects of the nonselective Ca2+ channel antagonist, verapamil, and the vascular-selective Ca2+ channel antagonist, felodipine, on obese, hypertensive, heart failure-prone, female SHHF/Mcc-fa(cp) rats. Rats were treated for < or = 2 months with verapamil (57 mg/kg/day) or felodipine (24 mg/kg/day). Blood pressures were determined at monthly intervals by the tail-cuff method. Heart weights and myosin isoforms were measured at the end of treatment. Direct cardiac effects of verapamil and felodipine were examined in electrically field stimulated, fura-2/AM-loaded cardiomyocytes. Both Ca2+ channel antagonists reduced systolic blood pressures. Verapamil, but not felodipine, increased heart weights and decreased expression of the myosin V1 isoform. In older animals, 75% of those treated with verapamil developed end-stage congestive heart failure. Age-matched control and felodipine-treated rats remained healthy. In isolated cardiomyocytes, 10(-9) M verapamil significantly reduced Ca2+ transient amplitudes but 10(-9) M felodipine did not. Both Ca2+ channel antagonists reduced blood pressures in obese, hypertensive, female SHHF rats. Verapamil, but not felodipine, produced heart failure in a large number of these animals. Differences between the in vivo effects of the two Ca2+ channel antagonists may be related to the differing effects on sarcolemmal Ca2+ influx.

Comparison of Verapamil and Felodipine Treatment on Lipid and Glucose Metabolism in Obese Female SHHF/Mcc-facp Rats

“…Verapamil also caused weight loss in this study and under most circumstances, the loss of body weight in obesity would be considered a beneficial effect. However, since weight loss with verapamil was also associated with an impairment of glycemic control and with earlier development of CHF (22), this would negate any potential positive effect of weight loss on metabolism. Our study would seem to indicate that obese patients with a positive family history of CHF could exhibit similar problems with verapamil.…”

“…Abdominal obesity (android type) has been \hewn to confer greater risk for development of diabetes and cardiovascular disease compared to lower body obesity (gynoid distribution) (32)(33)(34)(35). The loss of more subcutaneous fat compared to abdominal fat may be associated with the progression of cardiovascular disease in the verapamil rats (22). In contrast, felodipine-treated rats had relatively less abdominal fat and improved glucose metabolism, which may have contributed to the slower progression of cardiovascular disease in this group (22).…”

“…The loss of more subcutaneous fat compared to abdominal fat may be associated with the progression of cardiovascular disease in the verapamil rats (22). In contrast, felodipine-treated rats had relatively less abdominal fat and improved glucose metabolism, which may have contributed to the slower progression of cardiovascular disease in this group (22). Glucose Metabolism.…”

“…Details on the effect of verapamil on the development of CHF are discussed in Park et al (22). In the 6-month age group, rats were fed 0.25% verapamil (n = S), 0.1% felodipine (n = 5 ) , or control chow (n = 4) for 8 weeks.…”

Merits of Non-Invasive Rat Models of Left Ventricular Heart Failure

“…The overt signs of decompensated HF found in the SHHF often include subcutaneous edema, tachypnea and shallow rapid breathing, cold tails, cyanosis, lethargy, piloerection, pulmonary edema, pleural effusion, ascites, cardiomegaly, left and right atrial dilatation, and hepatomegaly [85]. Death typically occurs at 18 months in obese females [103] and 19 months in lean males [86,96] as HF severity increases with decompensation. Although HF onset is more rapid in obese SHHFs, lean males compare well to the hypertrophic qualities of obese SHHFs and also compare closely to human HF pathogenesis [81].…”