Ghrelin induces vasoconstriction in the rat coronary vasculature without altering cardiac peptide secretion.
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 Ca(2+) 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 Ca(2+) and PKC. Furthermore, the data obtained from diltiazem infusion suggest that ghrelin has a role in regulation of contractility when L-type Ca(2+) channels are blocked. Finally, the observation that immunoreactive ghrelin is found in cardiac tissue suggests the presence of a local cardiac ghrelin system.
Pemberton
Chris J
CJ
Christchurch Cardioendocrine Research Group, Christchurch School of Medicine, Christchurch 8001, New Zealand.
Tokola
Heikki
H
Bagi
Zsolt
Z
Koller
Akos
A
Pöntinen
Juhani
J
Ola
Antti
A
Vuolteenaho
Olli
O
Szokodi
István
I
Ruskoaho
Heikki
H
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000502:physiology; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D054439:Ghrelin; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D036361:Peptide Hormones / Q000494:pharmacology* / Q000502:physiology*; D010477:Perfusion; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects*
D020746:Calcium Channels, L-Type; D054439:Ghrelin; D036361:Peptide Hormones; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D011493:Protein Kinase C; D002118:Calcium