Incomplete reversal of β‐adrenoceptor desensitization in human and guinea‐pig cardiomyocytes by cyclic nucleotide phosphodiesterase inhibitors

Abstract

The decreased response to β‐adrenoceptor stimulation seen in heart failure may be related to a defect in cyclic AMP production. The inotropic effects of the selective phosphodiesterase (PDE) III inhibitors, SKa&F 94120 and SK&F 94836, and the non‐selective PDE inhibitor, 3‐isobutyl‐1‐methylxanthine (IBMX), alone and when combined synergistically with isoprenaline, were studied in control and β‐adrenoceptor‐desensitized ventricular myocytes. Myocytes isolated from noradrenaline‐treated guinea‐pigs had a reduced maximum response to isoprenaline compared with control animals (60.0 ± 2.5%, n = 42 vs 79.5 ± 1.7% maximum calcium: n = 46, P < 0.001). Together with an approximately 20 fold increase in the isoprenaline EC50, this is indicative of β‐adrenoceptor desensitization as a result with chronic infusion with noradrenaline. The maximum inotropic response of IBMX was depressed following noradrenaline treatment, from 74.9 ± 4.6% (n = 7) in control, to 61.7 ± 2.70% (n = 6), as a percentage of maximum calcium in noradrenaline‐treated guinea‐pig ventricular myocytes (P < 0.02). The pD2 value for IBMX was also reduced (P < 0.02). No significant differences in the inotropic effects of SK&F 94120 and SK&F 94836 were seen between control and β‐adrenoceptor desensitized myocytes. Threshold inotropic concentrations of SK&F 94120 and SK&F 94836 caused a five fold decrease in the EC50 of control myocytes for isoprenaline, and an 11 fold decrease in the noradrenaline‐treated guinea‐pig ventricular myocytes. The maximum response to isoprenaline in myocytes isolated from normal guinea‐pigs was unaffected by PDE inhibition; either at threshold or maximum inotropic concentrations, or by CPT cyclic AMP, an analogue of cyclic AMP. A significant potentiation of the maximum isoprenaline response by threshold inotropic concentrations was observed with SK&F 94120 (P < 0.05), but not with IBMX or SK&F 94836, in myocytes isolated from noradrenaline‐treated guinea‐pig hearts. This potentiation, however, did not completely restore the response to levels seen in control myocytes. The extent of potentiation of the maximum isoprenaline response by maximum inotropic concentrations of either IBMX or CPT cyclic AMP, was no greater than that by threshold concentrations of IBMX, in myocytes isolated from noradrenaline‐treated guinea‐pig hearts. In cardiac myocytes isolated from the explanted hearts of 16 patients with heart failure, threshold concentrations of IBMX and SK&F 94120 decreased the isoprenaline EC50 by a factor of four and six, respectively, but potentiation of the maximum isoprenaline response occurred only with SK&F 94120. The attenuated isoprenaline response was increased from 60.3 ± 4.5% to 74.3 ± 4.2% as a % maximum calcium (P < 0.05, n = 6), but remained substantially lower than the 116 ± 7% (P <0.001, n = 6) seen in myocytes isolated from non‐failing hearts. We conclude that the reduced maximum contraction amplitude with isoprenaline in cardiac myocytes from either patients in end‐stage failure, or noradrenaline‐treated guinea‐pigs, is partly but not solely due to insufficient cyclic AMP levels, since inhibition of cyclic AMP degradation does not result in complete reversal of the β‐adrenoceptor desensitization. 1993 British Pharmacological Society