Staurosporine, a protein kinase C inhibitor, inhibits atrial natriuretic peptide secretion induced by sarafotoxin, endothelin and phorbol ester.
We studied the effects of two peptides of the endothelin/sarafotoxin family, sarafotoxin-b (SRTX-b) and endothelin (ET-1), as well as the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on immunoreactive atrial natriuretic peptide (IR-ANP) release and on haemodynamic parameters (perfusion pressure, heart rate and contractile force) in isolated perfused rat hearts in order to examine the role of intracellular signals in the regulation of ANP secretion. Infusion of SRTX-b at doses of 0.9 and 2.7 nM for 30 min caused a gradual, dose-dependent increase in IR-ANP release and a more rapid coronary vasoconstriction similar to the infusions of ET-1 (2.7 nM) or TPA (46 nM), known to activate protein kinase C in heart cells. A transient inotropic response with a later decrease in contractile force was observed after infusion of each agent. SRTX-b and TPA produced a sustained chronotropic effect, while ET-1 did not significantly affect the heart rate. Infusion of 100 nM of staurosporine, a potent inhibitor of protein kinase C, did not affect basal IR-ANP release into the perfusion fluid but slightly decreased perfusion pressure, heart rate and contractile force. When infused together with SRTX-b, ET-1 or TPA, staurosporine significantly inhibited the ANP secretion, coronary vasoconstriction and changes in cardiac function induced by the peptides or phorbol ester. This study shows that SRTX-b stimulates ANP release with a potency similar to that of ET-1 and that the kinetics of their effects on ANP secretion resemble those of TPA.(ABSTRACT TRUNCATED AT 250 WORDS)
Pitkänen
M
M
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Mäntymaa
P
P
Ruskoaho
H
H
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D016232:Endothelins / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D000470:Alkaloids; D016232:Endothelins; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D009320:Atrial Natriuretic Factor; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate