Effects of kappa-opioid receptor activation on myocardium.
Kappa-opioid receptor stimulation of the heart transiently increases twitch amplitude and decreases Ca2+-dependent actomyosin Mg2+-ATPase activity through an undetermined mechanism. One purpose of the present study was to determine if the increase in twitch amplitude is due to changes in myofilament Ca2+ sensitivity. We also wanted to determine if kappa-opioid receptor activation alters maximum actin-myosin ATPase activity and Ca2+ sensitivity of tension in a way consistent with protein kinase A or protein kinase C (PKC) action. Rat hearts were treated with U50,488H (a kappa-opioid receptor agonist), phenylephrine plus propranolol (alpha-adrenergic receptor stimulation), isoproterenol (a beta-adrenergic receptor agonist), or phorbol 12-myristate 13-acetate (PMA, receptor independent activator of PKC) or were untreated (control), and myofibrils were isolated. U50,488H, phenylephrine plus propranolol, and PMA all decreased maximum Ca2+-dependent actomyosin Mg2+-ATPase activity, whereas isoproterenol treatment increased maximum Ca2+-dependent actomyosin Mg2+- ATPase activity. Untreated myofibrils exposed to exogenous PKC-epsilon, but not PKC-delta, decreased maximum actomyosin Mg2+-ATPase activity. Langendorff-perfused hearts treated with U50,488H, phenylephrine plus propranolol, or isoproterenol had significantly higher ventricular ATP levels compared with control hearts. PKC inhibitors abolished the effects of U50,488H on Ca2+-dependent actomyosin Mg2+-ATPase activity and myocardial ATP levels. U50,488H and PMA treatment of isolated ventricular myocytes increased Ca2+ sensitivity of isometric tension compared with control myocytes at pH 7.0. The U50,488H-dependent increase in Ca2+ sensitivity of tension was retained at pH 6.6. Together, these findings are consistent with the hypotheses that 1) the positive inotropy associated with kappa-opioid receptor activation may be due in part to a PKC-mediated increase in myofilament Ca2+-sensitivity of tension and 2) the kappa-opioid receptor-PKC pathway is a modulator of myocardial energy status through reduction of actomyosin ATP consumption.
Pyle
W G
WG
Department of Physiology, University of Tennessee, Memphis, Tennessee 38163, USA.
Lester
J W
JW
Hofmann
P A
PA
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D017301:Ca(2+) Mg(2+)-ATPase / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004734:Energy Metabolism; D006321:Heart / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000502:physiology*; D015398:Signal Transduction
D018712:Analgesics, Non-Narcotic; D017473:Receptors, Opioid, kappa; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D017301:Ca(2+) Mg(2+)-ATPase