Forskolin, cyclic nucleotides and positive inotropism in isolated papillary muscles of the rabbit

The effects of forskolin, isoprenaline, sodium nitroprusside and the frequency of stimulation were examined on cyclic nucleotide levels and tension responses in rabbit isolated right ventricular papillary muscles. Increasing the frequency of stimulation from 0.01 Hz to 1.6 Hz induced positive inotropic responses that were not obviously related to alterations in the level of either cyclic AMP or cyclic GMP. Isoprenaline induced rapid, concentration-related positive inotropic responses that were associated with increases in the levels of both cyclic AMP and cyclic GMP. There existed good correlations between the increases in tension and the concentrations of both cyclic nucleotides measured in the tissues. Forskolin induced concentration-related positive inotropic responses that were slow to develop. These responses were accompanied by concentration-related increases in the levels of cyclic AMP but not cyclic GMP. The tension responses correlated well with the levels of cyclic AMP measured. The cyclic AMP levels produced by forskolin were some 8 fold higher than those induced by isoprenaline for similar increases in tension. Sodium nitroprusside was without inotropic effect either positive or negative; it nevertheless elevated cyclic GMP levels whilst slightly reducing cyclic AMP levels. These data show that the ratio of cyclic AMP to cyclic GMP does not correlate well with changes in mammalian cardiac contractility. The data further suggest that whilst the intracellular concentration of cyclic AMP in rabbit ventricular myocardium may be an important determinant of positive inotropism, the relationship between the two parameters is more complex than simple proportionality between the tension generated and the amount of cyclic AMP measured within the cells.