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.