Reduced contractile responses to forskolin and a cyclic AMP analogue in myocytes from failing human ventricle

Abstract

Myocytes were isolated from the right or left ventricles of failing and non-failing human hearts. Contractile responses to increasing concentrations of Ca 2+, isoprenaline, forskolin and dibutyryl cyclic AMP (a lipophilic analogue of cyclic AMP) were determined. Responses were correlated with the age of the patient, and the severity of failure as defined by New York Heart Association class of symptoms (NYHA), left ventricular ejection fraction (LVEF), left ventricular end diastolic pressure (LVEDP) and dose of diuretics prescribed (diuretic class). The maximum contraction amplitude in high Ca 2+ did not change with either age or severity of failure (n = 31–40 patients). Responses to isoprenalinc (relative to Ca 2+ in the same cell, isoprenaline/calcium ratio) decreased with increasing age (P < 0.001, n = 38), and increasing severity of disease (NYHA, P < 0.001, n = 38; LVEF, P < 0.001, n = 34; LVEDP, P < 0.001, n = 30; diuretic class, P < 0.01, n = 36). The decrease in forskolin/calcium ratio also correlated with age (n = 17, P < 0.005) and increasing severity (NYHA, P < 0.002, n = 17; LVEF, P < 0.05, n = 15; LVEDP, P < 0.02, n = 14; diuretic class, P < 0.05, n = 15). Multiple regression indicated that the contribution of age was greater than that of disease severity for both isoprenaline and forskolin responses. The dibutyryl cyclic AMP/calcium ratio did not change significantly with the age of the patient (P > 0.1, n = 13), or severity as defined by LVEDP (P = 0.05–0.1, n = 12) but did decrease with increasing NYHA class (P < 0.01, n = 13) or diuretics (P < 0.02. n = 12) or with low LVEF (P < 0.002, n = 12). Overall, neither forskolin nor dibutyryl cyclic AMP produced maximum responses greater than isoprenaline in myocytes from failing hearts. Where the response to isoprenaline was not limited by the appearance of arrhythmias, forskolin or dibutyryl cyclic AMP could give a significant (but small) increase in contraction over that with isoprenaline alone. These results provide evidence for a post-receptor defect in addition to β-adrenoceptor desensitisation in myocytes from failing human heart.