Stimulation of kappa-opioid receptor reduces isoprenaline-induced cardiac hypertrophy and fibrosis.

The aim of the present study was to determine whether U50,488H (a selective kappa-opioid receptor agonist) inhibits cardiac hypertrophy and fibrosis induced by beta-adrenoceptor stimulation in a rat model. Cardiac hypertrophy and fibrosis were developed by intraperitoneal administration of isoprenaline (ip. 3.0 mg/kg/day,14 days). In the isoprenaline-treated group, heart weight and heart-to-body ratio increased significantly. Hypertrophic alterations were observed in light micrographs of tissue and transmission electron micrographs of myocardial ultra structures. Increases in heart weight, heart-to-body ratio, diameter of cardiomyocytes, and morphological hypertrophic alterations induced by isoprenaline were significantly attenuated by U50,488H(i.p. 1.25 mg/kg/day). Growth of cardiomyocytes was induced by incubating with isoprenaline (10(-6) mol/l), which resulted in an increase in optical density (OD) values. The increased OD value was attenuated by U50,488H(10(-7) mol/l-10(-5) mol/l) in a dose dependent manner. Animals receiving administration of isoprenaline displayed significant fibrosis. The extent of isoprenaline induced left ventricular fibrosis was dramatically reduced in U50,488H treated animals. Increased cardiac fibroblast proliferation and collagen synthesis induced by isoprenaline, as evidenced by increased OD value, (3)H-thymidine, and (3)H-proline incorporation, were significantly reduced in the U50,488H treated group. The specific extracellular matrix proteins, including type I, type III collagen and fibronectin, which increased after administration of isoproterenol, were also attenuated by U50,488H. The abovementioned effects of U50,488H were completely abolished by nor-BNI (nor-binaltorphimine), a selective kappa-opioid receptor antagonist. The enhanced intracellular Ca(2+) transient and L-type Ca(2+) current elicited by isoprenaline in cardiomyocytes were significantly inhibited by U50,488H. This study provides the first morphological evidence of the inhibitory effect of U50,488H on isoprenaline-induced cardiac hypertrophy and fibrosis via kappa-opioid receptor stimulation.