The antihypertensive chromogranin a peptide catestatin acts as a novel endocrine/paracrine modulator of cardiac inotropism and lusitropism.
Circulating levels of catestatin (Cts; human chromogranin A352-372) 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 beta2-adrenergic receptors, Gi/o protein, nitric oxide or cGMP, indicating involvement of beta2-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 beta-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.
Angelone
Tommaso
T
Department of Cell Biology, University of Calabria, 87030 Arcavacata di Rende, Italy.
Quintieri
Anna Maria
AM
Brar
Bhawanjit K
BK
Limchaiyawat
Pauline T
PT
Tota
Bruno
B
Mahata
Sushil K
SK
Cerra
Maria Carmela
MC
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000188:drug therapy; D002316:Cardiotonic Agents / Q000494:pharmacology*; D053379:Chromogranin A / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D019332:Endothelin-1 / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D019899:Paracrine Communication / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
D000959:Antihypertensive Agents; D002316:Cardiotonic Agents; D053379:Chromogranin A; D019332:Endothelin-1; D010446:Peptide Fragments; C109084:chromogranin A (344-364); D007545:Isoproterenol