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The Antihypertensive Chromogranin A Peptide Catestatin Acts as a Novel Endocrine/Paracrine Modulator of Cardiac Inotropism and Lusitropism

Departments of Cell Biology (T.A., A.M.Q., B.T., M.C.C.) and Pharmaco-Biology (T.A., M.C.C.), University of Calabria, Arcavacata di Rende 87030, Italy; and Department of Medicine (B.K.B., P.T.L., S.K.M.), University of California and Veterans Affairs San Diego Healthcare System, San Diego, California 92093-0838

Address all correspondence and requests for reprints to: S. K. Mahata, Department of Medicine, University of California and Veterans Affairs San Diego Healthcare System, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0838. E-mail: smahata{at}ucsd.edu; or Bruno Tota, Department of Cell Biology University of Calabria, 87030 Arcavacata di Rende (CS) Italy. E-mail: tota{at}unical.it.

Circulating levels of catestatin (Cts; human chromogranin A_352–372) decrease in the plasma of patients with essential hypertension. Genetic ablation of the chromogranin A (Chga) gene in mice increases blood pressure and pretreatment of Chga-null mice with Cts prevents blood pressure elevation, indicating a direct role of Cts in preventing hypertension. This notable vasoreactivity prompted us to test the direct cardiovascular effects and mechanisms of action of wild-type (WT) Cts and naturally occurring human variants (G364S-Cts and P370L-Cts) on myocardial and coronary functions. The direct cardiovascular actions of WT-Cts and human variants were determined using the Langendorff-perfused rat heart. WT-Cts dose-dependently increased heart rate and coronary pressure and decreased left ventricular pressure, rate pressure product and both positive and negative LVdP/dt. WT-Cts not only inhibited phospholamban phosphorylation, but also the inotropic and lusitropic effects of WT-Cts were abolished by chemical inhibition of β₂-adrenergic receptors, Gi/o protein, nitric oxide or cGMP, indicating involvement of β₂-adrenergic receptors-Gi/o protein-nitric oxide-cGMP signaling mechanisms. In contrast, G364S-Cts did not affect basal cardiac performance but abolished isoproterenol-induced positive inotropism and lusitropism. P370L-Cts decreased rate pressure product and inhibited only isoproterenol-induced positive inotropism and lusitropism by 70%. Cts also inhibited endothelin-1-induced positive inotropism and coronary constriction. Taken together, the cardioinhibitory influence exerted on basal mechanical performance and the counterregulatory action against β-adrenergic and endothelin-1 stimulations point to Cts as a novel cardiac modulator, able to protect the heart against excessive sympathochromaffin overactivation, e.g. hypertensive cardiomyopathy.

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				S. V. Kabadi and A. Ally Negative Cardiotropism by Catestatin and Its Variants Endocrinology, October 1, 2008; 149(10): 4778 - 4779. [Full Text] [PDF]