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Ghrelin induces vasoconstriction in the rat coronary vasculature without altering cardiac peptide secretion

¹Christchurch Cardioendocrine Research Group, Christchurch School of Medicine, Christchurch 8001, New Zealand; Departments of ²Pharmacology and Toxicology and ³Physiology, Biocenter Oulu, University of Oulu, FIN-90014 Oulu, Finland; ⁴Department of Pathophysiology, Semmelweis University, Budapest 8015; and ⁵Heart Institute, Faculty of Medicine, University of Pécs, 7624 Pécs, Hungary

Submitted 4 March 2004 ; accepted in final form 11 May 2004

We administered ghrelin, a novel growth hormone-releasing hormone, to isolated perfused rat hearts, coronary arterioles, and cultured neonatal cardiomyocytes to determine its effects on coronary vascular tone, contractility, and natriuretic peptide secretion and gene expression. We also determined cardiac levels of ghrelin and whether the heart is a source of the circulating peptide. Ghrelin dose dependently increased coronary perfusion pressure (44 ± 9%, P < 0.01), constricted isolated coronary arterioles (12 ± 2%, P < 0.05), and significantly enhanced the pressure-induced myogenic tone of arterioles. These effects were blocked by diltiazem, an L-type Ca²⁺ channel blocker, and bisindolylmaleimide (Bis), a protein kinase C (PKC) inhibitor. Interestingly, coinfusion of ghrelin with diltiazem completely restored myocardial contractile function that was decreased 30 ± 3% (P < 0.01) by diltiazem alone. In contrast, combination of ghrelin with diltiazem or Bis did not significantly alter atrial natriuretic peptide (ANP) secretion, which was decreased 40% (P < 0.01) and 50% (P < 0.05) by these agents alone, respectively. Administration of ghrelin to cultured cardiomyocytes had no effect on ANP or B-type natriuretic peptide secretion or gene expression. Detectable amounts of low-molecular-weight ghrelin were present in cardiac tissue extracts but not in isolated heart perfusate. Thus we provide the first evidence that ghrelin has a coronary vasoconstrictor action that is dependent on Ca²⁺ and PKC. Furthermore, the data obtained from diltiazem infusion suggest that ghrelin has a role in regulation of contractility when L-type Ca²⁺ channels are blocked. Finally, the observation that immunoreactive ghrelin is found in cardiac tissue suggests the presence of a local cardiac ghrelin system.

calcium channels; protein kinases; natriuretic peptides

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