title: Proarrhythmic effects of pinacidil are partially mediated through enhancement of catecholamine release in isolated perfused guinea-pig hearts.
abstract: The contribution of adrenergic stimulation to the proarrhythmic effects of pinacidil (30 microM), an opener of ATP-sensitive potassium channels (K+ATP), was tested in an isolated guinea-pig heart model of global ischemia (10 min) and reperfusion (10 min). None (0%) of the control hearts (n=10) elicited arrhythmias during ischemia or reperfusion. In the pinacidil-treated group, one heart (5%) experienced episodes of ventricular tachycardia (VT)/fibrillation (VF) during normoxia. During ischemia, 63% (12 out of 19) of pinacidil-treated hearts exhibited episodes of VT or VF. Hearts not in VT or VF (n=7) at the time of reperfusion, exhibited 71% VT and 43% VT/VF upon reperfusion. Proarrhythmic effects of pinacidil during ischemia or reperfusion were completely reversed by glyburide (n=9; 10 microM), a K+ATP antagonist, or nadolol (n=9; 3 microM), a beta-adrenergic antagonist. Isoproterenol (n=10; 50 nM), a beta-adrenergic agonist, induced a 20% incidence of ischemic VT and VF, and a 70% incidence of reperfusion VF, while methoxamine (n=10; 10 microM), an alpha-adrenergic agonist, demonstrated little proarrhythmia (20% VT/VF at reperfusion only). Proarrhythmic effects of isoproterenol were reversed by nadolol, but not glyburide. Pinacidil caused a slight potentiation of tachycardia induced by a bolus injection of tyramine (30 micro g), an indirectly acting sympathomimetic, but bolus injections of pinacidil (100 micro g) had no effect on heart rate. Nisoxetine, a catecholamine uptake 1 inhibitor, had no proarrhythmic effects when given alone. Catecholamine levels were reduced in pinacidil-treated hearts relative to vehicle-treated. In conclusion, it is suggested that the proarrhythmic effects of pinacidil following global ischemia and reperfusion in the isolated perfused guinea-pig heart appears to involve stimulation of beta-adrenoceptors. These proarrhythmic effects of pinacidil do not appear to be mediated solely through direct opening of K+ATP, but rather through an indirect enhancement of catecholamine release.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Cardiovascular Pharmacology, Princeton, NJ 08543-4000, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: D'Alonzo
authors.forename: J L
authors.initials: JL
authors.lastname: Zhu
authors.forename: R B
authors.initials: RB
authors.lastname: Darbenzio
authors.forename: C R
authors.initials: CR
authors.lastname: Dorso
authors.forename: G J
authors.initials: GJ
authors.lastname: Grover
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000322:Adrenergic Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D004837:Epinephrine / Q000378:metabolism*; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000633:toxicity*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008729:Methoxamine / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D009248:Nadolol / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D010477:Perfusion; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D014439:Tyramine / Q000494:pharmacology
chemical_list: D000322:Adrenergic Agonists; D000319:Adrenergic beta-Antagonists; D006146:Guanidines; D015221:Potassium Channels; D005473:Fluoxetine; C011386:nisoxetine; D009248:Nadolol; D020110:Pinacidil; D000255:Adenosine Triphosphate; D008729:Methoxamine; D007545:Isoproterenol; D005905:Glyburide; D009638:Norepinephrine; D014439:Tyramine; D004837:Epinephrine