The Antiarrhythmic Effect and Possible Ionic Mechanisms of Pilocarpine on Animal Models

Abstract

This study was designed to evaluate the effects of pilocarpine and explore the underlying ionic mechanism, using both aconitine-induced rat and ouabain-induced guinea pig arrhythmia models. Confocal microscopy was used to measure intracellular free-calcium concentrations ([Ca²⁺]_i) in isolated myocytes. The current data showed that pilocarpine significantly delayed onset of arrhythmias, decreased the time course of ventricular tachycardia and fibrillation, reduced arrhythmia score, and increased the survival time of arrhythmic rats and guinea pigs. [Ca²⁺]_i overload induced by aconitine or ouabain was reduced in isolated myocytes pretreated with pilocarpine. Moreover, M₃-muscarinic acetylcholine receptor (mAChR) antagonist 4-DAMP (4-diphenylacetoxy-N-methylpiperidine-methiodide) partially abolished the beneficial effects of pilocarpine. These data suggest that pilocarpine produced antiarrhythmic actions on arrhythmic rat and guinea pig models induced by aconitine or ouabain via stimulating the cardiac M₃-mAChR. The mechanism may be related to the improvement of Ca²⁺ handling.

Keywords

animal models arrhythmias Ca2+M3mAChR pilocarpine

References

Gabelt BT , Kaufman PL Inhibition of outflow facility and accommodative and miotic responses to pilocarpine in rhesus monkeys by muscarinic receptor subtype antagonists. J Pharmacol Exp Ther. 1992;263(3):1133-1139.

Maslanskl JA , Powelt R. , Deirmengiant C. , et al. Assessment of the muscarinic receptor subtypes involved in pilocarpine-induced seizures in mice. Neurosci Lett. 1994;168(1-2):225-228.

Wang HZ , Shi H. , Lu Y. , Yang BF , Wang ZG Pilocarpine modulates the cellular electrical properties of mammalian hearts by activating a cardiac M3 receptor and a K+ current. Br J Pharmacol. 1999;126(8):1725-1734.

Ponicke K. , Heinroth-Hoffmann I. , Brodde OE Demonstration of functional M3 muscarinic receptors in ventricular cardiomyocytes of adult rats. Br J Pharmacol. 2003;138(1):156-160.

Shi H. , Wang HZ , Lu Y. , Yang BF , Wang ZG Choline modulates cardiac membrane repolarization by activating an M3 muscarinic receptor and its coupled K+ channel. J Membr Biol. 1999;169(1):55-64.

Yang BF , Lin HX , Xu CQ , Liu Y. , Wang HZ , Han H. Choline produces cytoprotective effects against ischemic myocardial injuries: evidence for the role of cardiac m3 subtype muscarinic acetylcholine receptors . Cell Physiol Biochem. 2005;16(4-6):163-174.

Shu H. , Yi MW , Xu LP , Miao CY , Su DF Increased susceptibility of ventricular arrhythmias to aconitine in anaesthetized rats is attributed to the inhibition of baroreflex. Clin Exp Pharmacol Physiol. 2004;31(4):249-253.

Trzeciakowski JP Protective action of cimetidine against ouabain-induced pressor effects, arrhythmias, and lethality in guinea pigs. J. Cardiovasc Pharmacol. 1985; 7(4):622-629.

Mest HJ , Forster W. The central nervous effect of prostaglandins I2, E2 and F2α on aconitine-induced cardiac arrhythmia in rats. Prostaglandins. 1979;18(2):235-239.

10.

Dong DL , Liu Y. , Zhou YH , Song WH , Wang H. , Yang BF Decreases of voltage dependent K+ currents densities in ventricular myocytes of guinea pigs by chronic oxidant stress. Acta Pharm Sin. 2004;25(6):751-755.

11.

Sun HL , Chu WF , Dong DL , Liu Y. , Bai YL , Wang HX Choline-modulated arsenic trioxide-induced prolongation of cardiac repolarization in Guinea pig. Basic Clin Pharmacol Toxicol. 2006;98(4):381-388.

12.

Li DL , Liu Y. , Wang L. , Yang BF Protective effects of pilocarpine on myocardial ischemia-reperfusion injury . Chin Pharm J. 2007;42(19):1473-1476.

13.

Goldhaber JI , Weiss JN Oxygen free radicals and cardiac reperfusion abnormalities. Hypertension. 1992;20(1): 118-127.

14.

Fu M. , Wu M. , Wang JF , Qiao YJ , Wang Z. Disruption of the intracellular Ca2+ homeostasis in the cardiac excitation-contraction coupling is a crucial mechanism of arrhythmic toxicity in aconitine-induced cardiomyocytes. Biochem Biophys Res Commun. 2007;354(4): 929-936.

15.

Wada K. , Nihira M. , Hayakawa H. , Tomita Y. , Hayashida M. , Ohno Y. Effects of long-term administrations of aconitine on electrocardiogram and tissue concentrations of aconitine and its metabolites in mice. Forensic Sci Int. 2005;148(1):21-29.

16.

Moroz VM , Lipnitskii TN Dysfunction of ionic channels in cardiomyocyte sarcolemma and cardiac arrhythmias . Bull Exp Biol Med. 2006;141(4):397-399.

17.

Gong DM , Shan HL , Zhou YH , Dong DL , Yang BF The ion targets of arrhythmias induced by ouabain and aconitine in guinea pig and rat ventricular myocytes. Yao Xue Xue Bao. 2004;39(5):328-332.