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: A J D'Alonzo, J L Zhu, R B Darbenzio, C R Dorso, G J Grover
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 30 Issue 2 Pg. 415-23 (Feb 1998) ISSN: 0022-2828 [Print] England
• PMID: 9515018 (Publication Type: Journal Article)
• Copyright: Copyright 1998 Academic Press Limited.

Chemical References

• Adrenergic Agonists
• Adrenergic beta-Antagonists
• Guanidines
• Potassium Channels
• Fluoxetine
• nisoxetine
• Nadolol
• Pinacidil
• Adenosine Triphosphate
• Methoxamine
• Isoproterenol
• Glyburide
• Norepinephrine
• Tyramine
• Epinephrine

Topics

• Adenosine Triphosphate (metabolism)
• Adrenergic Agonists (pharmacology)
• Adrenergic beta-Antagonists (pharmacology)
• Animals
• Arrhythmias, Cardiac (etiology, metabolism, physiopathology)
• Epinephrine (metabolism)
• Fluoxetine (analogs & derivatives, pharmacology)
• Glyburide (pharmacology)
• Guanidines (toxicity)
• Guinea Pigs
• Heart (drug effects, physiology)
• In Vitro Techniques
• Isoproterenol (pharmacology)
• Methoxamine (pharmacology)
• Myocardial Reperfusion Injury (complications, metabolism, physiopathology)
• Myocardium (metabolism)
• Nadolol (pharmacology)
• Norepinephrine (metabolism)
• Perfusion
• Pinacidil
• Potassium Channels (drug effects, metabolism)
• Tyramine (pharmacology)