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

The aim of the present study was to determine whether U50,488H (a selective κ-opioid receptor agonist) inhibits cardiac hypertrophy and fibrosis induced by β-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(ip. 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, 3H-thymidine, and 3H-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 κ-opioid receptor antagonist. The enhanced intracellular Ca2+ transient and L-type Ca2+ 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 κ-opioid receptor stimulation.