The intracellular mechanisms of cGMP, a major intracellular mediator of nitric oxide that regulates the contractility of cardiac muscle, are still to some extent unknown. To investigate these mechanisms, we observed the effects of 8-bromo-cyclic GMP (8br-cGMP) on myofibrillar Ca2+ sensitivity and Ca2+ handling of the sarcoplasmic reticulum (SR) using beta-escin-skinned preparations from Wistar rat hearts. Both low (1 microM) and high doses (100 microM) of 8br-cGMP significantly decreased the myofibrillar Ca2+ sensitivity obtained from pCa-tension relationships to a similar extent (pCa50; from 6.04 to 5.95 by 1 microM 8br-cGMP and 6.00 to 5.89 by 100 microM 8br-cGMP, respectively, n = 9 each). Whereas this Ca2+ desensitization induced by 100 microM 8br-cGMP was blocked by 1 microM KT5823, a specific inhibitor of cGMP-dependent protein kinase (PKG), not induced by 1 microM 8br-cGMP was not effected by KT5823. When the amount of Ca2+ released from the SR was estimated by the peak amplitude of 25 mM caffeine-induced contractions after constant Ca2+-loading by pCa 6, both doses of 8br-cGMP significantly augmented the caffeine-induced peak force to a similar extent (125 +/- 5.8% by 1 microM 8br-cGMP and 116 +/- 5.1% by 100 microM 8br-cGMP, respectively, n = 6 each). The two observed effects of cGMP (a decrease in myofibrillar Ca2+ sensitivity and an increase in Ca2+ uptake by the SR) may participate in regulating myocardial contraction via nitric oxide. Low and high doses of cGMP seem to work mainly via PKG-independent and PKG-dependent pathways, respectively.
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