Analysis of Responses to a Selective Phosphodiesterase III Inhibitor, SK&F 94120, on Isolated Myocardium, Including Human Ventricular Myocardium from “End-Stage” Failure Patients

Abstract

The actions of SK&F 94120, a selective phosphodiesterase (PDE III) inhibitor, have been characterised on human ventricular myocardium obtained from heart failure patients. Some actions have been compared directly with those of the drug on guinea pig and cat ventricular myocardium. SK&F 94120 caused positive inotropic responses in preparations from all three species. In the human preparations, there was no evidence of differential activity in ventricles obtained from patients with heart failure associated with ischaemic heart disease, congestive cardiomyopathy, or mitral valve disease. The mechanism of positive inotropic activity of SK&F 94120 demonstrated characteristics of PDE III inhibition--e.g., potentiation of isoprenaline responses and reversal by carbachol. In addition, in human tissue a highly significant correlation between positive inotropic activity and increases in intracellular cAMP was demonstrated. Electrophysiological studies in human and guinea pig myocardium demonstrated that SK&F 94120 enhanced the second inward Ca2+ current over the same concentration range as that needed for positive inotropic activity. This was demonstrated in preparations incubated in Krebs bicarbonate solution and, more clearly, in solutions with raised K+ concentration. The data described in this report establish that inhibition of PDE III is an effective positive inotropic mechanism in human ventricular myocardium. Comparison of the responses in human, guinea pig, and cat myocardium shows clear similarities of responses with only small quantitative differences.