Opposite effects of cyclic GMP and cyclic AMP on Ca²⁺ current in single heart cells

Abstract

The slow inward Ca²⁺ current, I_Ca, is fundamental in the initiation of cardiac contraction and neurohormonal regulation of cardiac function¹. It is increased by β-adrenergic agonists, which stimulate synthesis of cyclic AMP (cAMP) and cAMP-dependent phosphorylation^2–4. The neurotransmitter acetylcholine reduces I_Ca^5–7 by an unknown mechanism^8,9. There is strong evidence that acetylcholine reduces I_Ca by decreasing adenylate cyclase activity⁷, but cGMP has also been implicated as ACh stimulates cGMP accumulation and activates cGMP-dependent protein kinase^10–13. Application of cGMP decreases contractile force¹⁴, decreases ⁴⁵Ca flux¹⁵, shortens the duration of action potentials¹⁶ and inhibits Ca-dependent action potentials¹⁷. Other studies, however, have concluded that cGMP levels do not correlate with contractile force^10,11,18,19 and that cGMP has no effect on I_Ca²⁰. We have therefore examined the effects of intracellular perfusion of cGMP on I_Ca using isolated, voltage-clamped cells from frog ventricle. We find that cGMP has negligible effects on basal I_Ca, but greatly decreases the I_Ca that had been elevated by β-adrenergic agonists or by intracellular perfusion with cAMP. The decrease of I_Ca is mediated by cAMP hydrolysis via a cGMP-stimulated cyclic nucleotide phosphodiesterase.