Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1992 Mar;105(3):715–719. doi: 10.1111/j.1476-5381.1992.tb09044.x

Effects of pinacidil on guinea-pig isolated perfused heart with particular reference to the proarrhythmic effect.

R Padrini 1, S Bova 1, G Cargnelli 1, D Piovan 1, M Ferrari 1
PMCID: PMC1908469  PMID: 1628158

Abstract

1. The effects of pinacidil (10, 30, 50 microM) on contractility (+dP/dtmax), coronary perfusion pressure (cP), and ECG intervals (PR, QRS, QT) have been studied on constant-flow perfused guinea-pig hearts, driven at four frequencies (2.5, 3, 3.5, 4 Hz). 2. Pinacidil decreased +dP/dtmax, cP and the QT interval in a dose-dependent manner, whereas the PR interval was increased. QRS duration was not modified. All these effects were independent of driving frequency. Pinacidil decreased the interval from Q-wave to T-wave peak (QTpeak) to a greater extent than the QT interval, thus decreasing the QTpeak/QT ratio. This effect, unlike that on QT interval, was more evident at the highest frequency of stimulation. 3. In 4 out of 20 hearts treated with pinacidil sustained ventricular fibrillation (VF) occurred following a short run of premature ventricular beats (R on T phenomenon). 4. In separate experiments, an attempt to induce VF electrically was made at drug concentrations ranging from 10 microM to 100 microM (8 experiments for each concentration). In control conditions and at the lowest concentrations of pinacidil tested (10 microM) VF could never be induced; in the presence of 30 microM pinacidil VF was induced in 5 out of 8 experiments. Drug concentrations higher than 50 microM permitted the induction of VF in every case. 5. Although the concentrations of pinacidil producing ventricular fibrillation are 30-40 times higher than those found in patients under long term treatment with this agent, it is suggested that caution should be used in prescribing this drug, at least in patients suffering from myocardial ischaemia.

Full text

PDF
715

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Almotrefi A. A., Baker J. B. The antifibrillatory potency of aprindine, mexiletine, tocainide and lignocaine compared on Langendorff-perfused hearts of rabbits and guinea-pigs. J Pharm Pharmacol. 1980 Nov;32(11):746–750. doi: 10.1111/j.2042-7158.1980.tb13059.x. [DOI] [PubMed] [Google Scholar]
  2. Arena J. P., Kass R. S. Activation of ATP-sensitive K channels in heart cells by pinacidil: dependence on ATP. Am J Physiol. 1989 Dec;257(6 Pt 2):H2092–H2096. doi: 10.1152/ajpheart.1989.257.6.H2092. [DOI] [PubMed] [Google Scholar]
  3. Arena J. P., Kass R. S. Enhancement of potassium-sensitive current in heart cells by pinacidil. Evidence for modulation of the ATP-sensitive potassium channel. Circ Res. 1989 Aug;65(2):436–445. doi: 10.1161/01.res.65.2.436. [DOI] [PubMed] [Google Scholar]
  4. Bova S., Padrini R., Cargnelli G., Piovan D., Ferrari M. The influence of acidosis on the myocardial uptake and electrocardiographic effects of disopyramide. Eur J Pharmacol. 1989 Sep 13;168(2):179–185. doi: 10.1016/0014-2999(89)90563-3. [DOI] [PubMed] [Google Scholar]
  5. Burgess M. J. Relation of ventricular repolarization to electrocardiographic T wave-form and arrhythmia vulnerability. Am J Physiol. 1979 Mar;236(3):H391–H402. doi: 10.1152/ajpheart.1979.236.3.H391. [DOI] [PubMed] [Google Scholar]
  6. Carlsen J. E., Kardel T., Jensen H. A., Tangø M., Trap-Jensen J. Pinacidil, a new vasodilator: pharmacokinetics and pharmacodynamics of a new retarded release tablet in essential hypertension. Eur J Clin Pharmacol. 1983;25(4):557–561. doi: 10.1007/BF00542128. [DOI] [PubMed] [Google Scholar]
  7. Chi L., Uprichard A. C., Lucchesi B. R. Profibrillatory actions of pinacidil in a conscious canine model of sudden coronary death. J Cardiovasc Pharmacol. 1990 Mar;15(3):452–464. doi: 10.1097/00005344-199003000-00016. [DOI] [PubMed] [Google Scholar]
  8. Cook N. S. The pharmacology of potassium channels and their therapeutic potential. Trends Pharmacol Sci. 1988 Jan;9(1):21–28. doi: 10.1016/0165-6147(88)90238-6. [DOI] [PubMed] [Google Scholar]
  9. Fan Z., Nakayama K., Hiraoka M. Pinacidil activates the ATP-sensitive K+ channel in inside-out and cell-attached patch membranes of guinea-pig ventricular myocytes. Pflugers Arch. 1990 Jan;415(4):387–394. doi: 10.1007/BF00373613. [DOI] [PubMed] [Google Scholar]
  10. Goldberg M. R. Clinical pharmacology of pinacidil, a prototype for drugs that affect potassium channels. J Cardiovasc Pharmacol. 1988;12 (Suppl 2):S41–S47. doi: 10.1097/00005344-198812002-00008. [DOI] [PubMed] [Google Scholar]
  11. Hondeghem L. M., Katzung B. G. Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Annu Rev Pharmacol Toxicol. 1984;24:387–423. doi: 10.1146/annurev.pa.24.040184.002131. [DOI] [PubMed] [Google Scholar]
  12. Hondeghem L. M., Snyders D. J. Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation. 1990 Feb;81(2):686–690. doi: 10.1161/01.cir.81.2.686. [DOI] [PubMed] [Google Scholar]
  13. Kakei M., Noma A., Shibasaki T. Properties of adenosine-triphosphate-regulated potassium channels in guinea-pig ventricular cells. J Physiol. 1985 Jun;363:441–462. doi: 10.1113/jphysiol.1985.sp015721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kawashima S., Liang C. S. Systemic and coronary hemodynamic effects of pinacidil, a new antihypertensive agent, in awake dogs: comparison with hydralazine. J Pharmacol Exp Ther. 1985 Feb;232(2):369–375. [PubMed] [Google Scholar]
  15. Kerr M. J., Wilson R., Shanks R. G. Suppression of ventricular arrhythmias after coronary artery ligation by pinacidil, a vasodilator drug. J Cardiovasc Pharmacol. 1985 Sep-Oct;7(5):875–883. doi: 10.1097/00005344-198509000-00010. [DOI] [PubMed] [Google Scholar]
  16. Kuo C. S., Munakata K., Reddy C. P., Surawicz B. Characteristics and possible mechanism of ventricular arrhythmia dependent on the dispersion of action potential durations. Circulation. 1983 Jun;67(6):1356–1367. doi: 10.1161/01.cir.67.6.1356. [DOI] [PubMed] [Google Scholar]
  17. Litovsky S. H., Antzelevitch C. Transient outward current prominent in canine ventricular epicardium but not endocardium. Circ Res. 1988 Jan;62(1):116–126. doi: 10.1161/01.res.62.1.116. [DOI] [PubMed] [Google Scholar]
  18. Longman S. D., Clapham J. C., Wilson C., Hamilton T. C. Cromakalim, a potassium channel activator: a comparison of its cardiovascular haemodynamic profile and tissue specificity with those of pinacidil and nicorandil. J Cardiovasc Pharmacol. 1988;12(5):535–542. [PubMed] [Google Scholar]
  19. Nicholls D. P., Murtagh J. G., Scott M. E., Morton P., Shanks R. G. Acute haemodynamic effects of pinacidil in man. Br J Clin Pharmacol. 1986 Sep;22(3):287–292. doi: 10.1111/j.1365-2125.1986.tb02889.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Nielsen C. B., Mellemkjaer S., Nielsen-Kudsk F. Pinacidil uptake and effects in the isolated rabbit heart. Pharmacol Toxicol. 1989 Jan;64(1):14–19. doi: 10.1111/j.1600-0773.1989.tb00592.x. [DOI] [PubMed] [Google Scholar]
  21. Noma A. ATP-regulated K+ channels in cardiac muscle. Nature. 1983 Sep 8;305(5930):147–148. doi: 10.1038/305147a0. [DOI] [PubMed] [Google Scholar]
  22. Sheu S. S., Lederer W. J. Lidocaine's negative inotropic and antiarrhythmic actions. Dependence on shortening of action potential duration and reduction of intracellular sodium activity. Circ Res. 1985 Oct;57(4):578–590. doi: 10.1161/01.res.57.4.578. [DOI] [PubMed] [Google Scholar]
  23. Smallwood J. K., Steinberg M. I. Cardiac electrophysiological effects of pinacidil and related pyridylcyanoguanidines: relationship to antihypertensive activity. J Cardiovasc Pharmacol. 1988 Jul;12(1):102–109. doi: 10.1097/00005344-198807000-00014. [DOI] [PubMed] [Google Scholar]
  24. Tseng G. N., Hoffman B. F. Actions of pinacidil on membrane currents in canine ventricular myocytes and their modulation by intracellular ATP and cAMP. Pflugers Arch. 1990 Jan;415(4):414–424. doi: 10.1007/BF00373618. [DOI] [PubMed] [Google Scholar]
  25. Wang Z. G., Fermini B., Nattel S. Repolarization differences between guinea pig atrial endocardium and epicardium: evidence for a role of Ito. Am J Physiol. 1991 May;260(5 Pt 2):H1501–H1506. doi: 10.1152/ajpheart.1991.260.5.H1501. [DOI] [PubMed] [Google Scholar]
  26. Weston A. H. Smooth muscle K+ channel openers; their pharmacology and clinical potential. Pflugers Arch. 1989;414 (Suppl 1):S99–105. doi: 10.1007/BF00582256. [DOI] [PubMed] [Google Scholar]
  27. Wolleben C. D., Sanguinetti M. C., Siegl P. K. Influence of ATP-sensitive potassium channel modulators on ischemia-induced fibrillation in isolated rat hearts. J Mol Cell Cardiol. 1989 Aug;21(8):783–788. doi: 10.1016/0022-2828(89)90717-7. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES