Cardiac Effects Of Growth Hormone-releasing Peptide And Anti-fibrosis And Its Mechanism Research

Background and Objectives GHRPs are a class of synthetic peptidyl GHS that have been reported to exert GH-indenpedent cardiac effects via GHS-R and CD₃₆. The underlying mechanisms of the cardiac protective properties of GHRPs are poorly understood. This study was to investigate the effect of GHRPs on cardiac contraction, relaxation and calcium handling, and the ameliorative effects of GHRPs on heart failure and cardiac fibrsis in CHF rats and SHR.Methods (1) Acute effects of GHRPs on the developing forces of isolated rat hearts were observed by a Langendorff perfusion setting. Calcium response of rat myocardiocytes to GHRPs was visualized by confocal imaging system; (2) Pressure-overload CHF rat model was created by abdominal aortic banding. Echocardiography and cardiac catheterization were performed to monitor cardiac function. Fluorometry was used to measure plasma nonepinephrine and RIA was used to measure serum GH and IGF-1, PRA, aldosterone and ET-1. Cardiac mRNA expression of GHS-R was measured by RT-PCR. In order to study the GH-independent effects of GHRP, global cardiac ischemia and reperfusion was created on hypophysectomized rats and the direct protect effect of hexarelin on heart was observed. Cardiac outflow perfusate CK activity was used as an indicator of the cardiac protective effect of GHRP; (3) Picro-sirius red staining, VanGioson staining, MTT assay, ³H-thymidine incorporation, ³H-proline incorporation, hydroxyproline assay, RT-PCR, western blot were used to study the effect of hexarelin on cardiac fibrosis of SHR and on proleferation and collagen synthesis of cardiac fibroblast.Results (1) Four GHRPs facilitated ventricular contraction and dilation in a dose-dependent manner with similar potencies. These GHRPs had no significant influence on heart rate. All GHRPs induced biphasic increase [Ca²⁺]j with a transient phase (phase-1) followed by a plateau phase (phase 2). Phase-1 response was abolished by pretreatment with thapsigargin. Phase-2 response was eliminated by removing Ca²⁺ influx, by verapamil, or by 24h pretreatment with PMA; (2) GHRP treatment significantly decreased stress-related hormone levels (such as plasma NE, PRA, aldosterone and ET-1) and increased the body weight in CHF rats. Furthermore, GHRP treatment significantly mitigated LV dysfunction and cardiac remodeling in CHF rats with increased EF, LVESP and PWTD,...