Intracellular mechanisms of cGMP-mediated regulation of myocardial contraction.
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.
Satoh
S
S
Department of Bioclimatology and Medicine, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan. satoshin@tsurumi.beppu.kyushu-u.ac.jp
Makino
N
N
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D007211:Indoles; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D019210:Troponin I / Q000378:metabolism
D000470:Alkaloids; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D019210:Troponin I; C073601:KT 5823; C016276:8-bromocyclic GMP; D006152:Cyclic GMP; D002118:Calcium