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The Positive Inotropic and Calcium-Mobilizing Effects of Growth Hormone-Releasing Peptides on Rat Heart

Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College (X.-B.X., J.-M.C., J.-J.P., R.-K.X., M.-C.C.), Beijing 100005, China; Division of Cardiology, Department of Medicine, Peking Union Hospital (C.N., W.-L.Z.), Beijing 100005, China; Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center (K.A.), Los Angeles, California 90048; and Endocrine Cell Biology, Prince Henry’s Institute of Medical Research (C.C.), Melbourne 3168, Australia

Address all correspondence and requests for reprints to: Dr. Chen Chen, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australia. E-mail: chen.chen{at}med.monash edu.au.

GH-releasing peptides (GHRP) are synthetic peptides exerting GH-dependent or GH-independent effects via GH secretagogue receptor on many organs, including the heart. The underlying mechanisms of the cardiotropic properties of GHRP are poorly understood. This study investigates these effects of four GHRP in isolated perfused heart preparations and isolated neonatal and adult ventricular myocytes. The calcium response of cardiocytes to GHRP was visualized using confocal microscopy. All tested GHRP facilitated both ventricular contraction and relaxation in a dose-dependent manner, moderately decreasing coronary flow, but not modifying heart rate. GHRP induced a biphasic increase in intracellular free Ca²⁺ of the cardiocytes, consisting of a transient phase (phase 1), followed by a plateau phase (phase 2). Phase 1 was abolished by pretreatment with thapsigargin, a Ca²⁺-adenosine triphosphatase inhibitor of the sarcoplasmic reticulum. The phase 2 response was eliminated by removing extracellular free Ca²⁺, by verapamil, a voltage-gated Ca²⁺ channel blocker, or by 24-h pretreatment with phorbol 12-myristate 13-acetate, down-regulating protein kinase C. In isolated (denervated) heart, GHRP have a direct cardiotropic, without chronotropic, effect. GHRP elevate myocardial intracellular free Ca²⁺ through activating Ca²⁺ influx via voltage-gated Ca²⁺ channels and triggering Ca²⁺ release from thapsigargin-sensitive intracellular Ca²⁺ stores. Protein kinase C mediates the GHRP-induced Ca²⁺ influx, but not Ca²⁺ release. These finding support a number of roles for GHRP in the cardiovascular system.

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