Gonadotrophin-releasing hormone (GnRH) is a hypothalamic hormone transported by the hypophyseal portal bloodstream to the pituitary gland, where it binds to GnRH receptors. However, GnRH receptors are expressed in multiple extrapituitary tissues, although their physiological relevance is not fully understood. GnRH agonists are employed extensively in steroid deprivation therapy, especially to suppress testosterone in prostate cancer. Because GnRH agonist treatment is associated with increased coronary heart disease and myocardial infarction, we investigated the impact of GnRH on cardiomyocyte contractile function. Cardiomyocytes were isolated from mouse hearts and mechanical and intracellular Ca(2+) properties were evaluated, including peak shortening amplitude (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90) ), maximal velocity of shortening/relengthening (± dLdt), electrically-stimulated rise in Fura-2 fluorescence intensity (ΔFFI) and Ca(2+) decay. GnRH (1 ng/ml) increased PS, ± dL/dt, resting FFI and ΔFFI, and prolonged TPS, TR(90) and Ca(2+) decay time, whereas 1 pg/ml GnRH affected all these cardiomyocyte variables, except TPS, resting FFI and ΔFFI. A concentration of 1 fg/ml GnRH and the GnRH cleavage product, GnRH-[1-5] (300 pg/ml), had no effect on any cardiomyocyte parameter. The 1 pg/ml GnRH-elicited responses were attenuated by the GnRH receptor antagonist cetrorelix (10 μm), the protein kinase A (PKA) inhibitor H89 (1 μm) but not the protein kinase C inhibitor chelerythrine chloride (1 μm). These data revealed that GnRH is capable of regulating cardiac contractile function via a GnRH receptor/PKA-dependent mechanism. If present in the human heart, dysfunction of such a system may play an important role in cardiac pathology observed in men treated with GnRH agonists for prostate cancer.

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