Differential response to vesnarinone by cardiac fibroblasts isolated from normal and aortic regurgitant hearts

Vesnarinone, a quinoline derivative with modest positive inotropic action, has been shown in several studies to benefit patients with clinical congestive heart failure. The cellular basis of its clinical benefit is not known, although the drug has several pharmacologic effects demonstrated both in isolated cardiac myocytes and in other noncardiac cell types. To investigate the possibility that the clinical benefit of vesnarinone is based, at least in part, on the inhibition of pathologic myocardial fibrosis, we examined its effects on cultured cardiac fibroblasts isolated from both normal and aortic regurgitant New Zealand White rabbit hearts. As in people, rabbits with moderate-to-severe aortic regurgitation often develop congestive heart failure that, at necropsy, is characterized by exuberant myocardial fibrosis. A dose-response curve was constructed with vesnarinone concentrations ranging from 10(-4 ) to 10(-9 ) mol/L. Cellular survival was decreased by exposure to nanomolar concentrations of drug but not at the higher doses tested. Fibroblasts isolated from normal hearts responded maximally at 10(-7 ) mol/L vesnarinone, whereas fibroblasts from aortic regurgitant hearts responded maximally at 10(-8 ) mol/L. These concentrations of drug are more than an order of magnitude lower than those believed to be associated with clinical benefit from earlier studies. Our results indicate that vesnarinone can suppress cardiac fibroblast proliferation and suggest that this action may be useful in therapies designed to prevent congestive heart failure in aortic regurgitation.