Positive and negative contractile effects of somatostatin-14 on rat ventricular cardiomyocytes.
Somatostatin-14 elicits negative inotropic and chronotropic actions in atrial myocardium. Less is known about the effects of somatostatin-14 in ventricular myocardium. The direct contractile effects of somatostatin-14 were assessed using ventricular cardiomyocytes isolated from the hearts of adult rats. Cells were stimulated at 0.5 Hz with CaCl2 (2 mM) under basal conditions and in the presence of the beta-adrenoceptor agonist, isoprenaline (1 nM), or the selective inhibitor of the transient outward current (Ito), 4-aminopyridine (500 microM). Somatostatin-14 did not alter basal contractile response but it did inhibit (IC50 = 13 nM) the response to isoprenaline (1 nM). In the presence of 4-aminopyridine (500 microM), somatostatin-14 stimulated a positive contractile response (EC50 = 118 fM) that was attenuated markedly by diltiazem (100 nM). These data indicate that somatostatin-14 exerts dual effects directly in rat ventricular cardiomyocytes: (1) a negative contractile effect, observed in the presence of isoprenaline (1 nM), coupled to activation of Ito; and (2) a previously unreported and very potent positive contractile effect, unmasked by 4-aminopyridine (500 microM), coupled to the influx of calcium ions via L-type calcium channels. The greater potency of somatostatin-14 for producing the positive contractile effect indicates that the peptide may exert a predominantly stimulatory influence on the resting contractility of ventricular myocardium in vivo, whereas the negative contractile effect, observed at much higher concentrations, could indicate that localized elevations in the concentration of the peptide may serve as a negative regulatory influence to limit the detrimental effects of excessive stimulation of cardiomyocyte contractility.
Department of Therapeutics and Pharmacology, The Centre for Cardiovascular and Genetics Research, School of Medicine, The Queen's University of Belfast, Northern Ireland, UK.
F
F
Murray
D
D
Bell
E J
EJ
Kelso
B C
BC
Millar
B J
BJ
McDermott
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003864:Depression, Chemical; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013004:Somatostatin / Q000494:pharmacology*; D013268:Stimulation, Chemical
D020746:Calcium Channels, L-Type; D002316:Cardiotonic Agents; D015221:Potassium Channels; D013004:Somatostatin; D015761:4-Aminopyridine