kappa-opioid receptor stimulation inhibits cardiac hypertrophy induced by beta1-adrenoceptor stimulation in the rat.
To test the hypothesis that kappa-opioid receptor stimulation inhibits cardiac hypertrophy induced by beta1-adrenoceptor stimulation, we determined the effects of trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methanesulfonate salt (U50,488H), a selective kappa-opioid receptor agonist, on cardiac hypertrophy induced by isoprenaline, a selective beta-adrenoceptor agonist, in neonatal ventricular myocytes upon blockade of beta2-adrenoceptor. Hypertrophy of cardiomyocytes was determined by increases in (i) total protein content; (ii) [3H]leucine incorporation; and iii) cell size. 10 micromol/l isoprenaline increased all three parameters. The effects were abolished by 2 micromol/l propranolol, a beta-adrenergic receptor antagonist, or 300 nmol/l CGP20712A, a beta1-adrenoceptor antagonist, but not by 100 nmol/l ICI118,551, a beta2-adrenoceptor antagonist. The effects were also abolished by Rp-cAMPs 100 micromol/l, a protein kinase A inhibitor and not by pertussis toxin 5 mg/l. The effects of isoprenaline in the presence or absence of ICI118,551 were also abolished by 1 micromol/l U50,488H. The inhibitory effects of U50,488H were abolished by 1 micromol/l nor-binaltorphimine, a selective kappa-opioid receptor antagonist. U50,488H also abolished the increases in the amplitude and frequency of the spontaneous intracellular Ca2+ transient induced by 10 micromol/l isoprenaline in the presence or absence of ICI118,551, an effect also abolished by nor-binaltorphimine. In conclusion the results show that kappa-opioid receptor stimulation abolished both the cardiac hypertrophy and enhanced amplitude and frequency of the spontaneous intracellular Ca2+ transient induced by beta1-adrenoceptor stimulation.
Shan
Dan
D
Key Lab of Molecular Biology and Drug Research, Jinzhou Medical College, Jinzhou, China.
Wang
Hongxin
H
Su
Yuhong
Y
Jing
Yang
Y
Wong
Tak Ming
TM
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D007093:Imidazoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology*; D007930:Leucine / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011412:Propanolamines / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*
D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D007093:Imidazoles; D011412:Propanolamines; D011506:Proteins; D017473:Receptors, Opioid, kappa; C026777:ICI 118551; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C049763:CGP 20712A; D007930:Leucine; D007545:Isoproterenol; D002118:Calcium