Hostname: page-component-78c5997874-v9fdk Total loading time: 0 Render date: 2024-11-10T17:30:49.642Z Has data issue: false hasContentIssue false
  • English
  • Français

Effects of rolipram, pimobendan and zaprinast on ischaemia-induced dysrhythmias and on ventricular cyclic nucleotide content in the anaesthetized rat

Published online by Cambridge University Press:  02 June 2005

M. D. Carceles ,
F. Aleixandre ,
T. Fuente ,
J. López-Vidal  and
M. L. Laorden
M. D. Carceles
Affiliation:
University School of Medicine, Department of Anaesthesiology, CSV Arrixaca Hospital, Murcia, Spain
F. Aleixandre
Affiliation:
University School of Medicine, Department of Anaesthesiology, CSV Arrixaca Hospital, Murcia, Spain
T. Fuente
Affiliation:
University School of Medicine, Department of Nuclear Medicine, CSV Arrixaca Hospital, Murcia, Spain
J. López-Vidal
Affiliation:
University School of Medicine, Department of Anaesthesiology, CSV Arrixaca Hospital, Murcia, Spain
M. L. Laorden
Affiliation:
University School of Medicine, Department of Pharmacology, CSV Arrixaca Hospital, Murcia, Spain
Get access

Extract

Summary

Background and objective: This study was designed to compare the haemodynamic, electrophysiological and pharmacodynamic effects of three selective inhibitors of the different isoenzyme forms of phosphodiesterase (PDE) on ischaemia-induced dysrhythmias in the anaesthetized rat. The drugs used were pimobendan, a selective PDE III inhibitor, rolipram, a selective PDE IV inhibitor, and zaprinast, a selective PDE V inhibitor.

Methods: The coronary artery was occluded 15 min after commencing drug administration, and myocardial ischaemia was maintained for 30 min during which the heart rate and mean arterial pressure were recorded. cAMP and cGMP were determined by radioimmunoassay.

Results: Pretreatment with rolipram decreased the duration of ventricular tachycardia without any change in the incidences of dysrhythmias or the mortality rate. This drug did not modify ventricular content of adenosine 3′,5′-cyclic monophosphate (cAMP) or guanosine 3′,5′-cyclic monophosphate (cGMP). Pimobendan (1 mg kg−1 + 0.1 mg kg−1 min) decreased the duration of ventricular tachycardia. This dose of pimobendan and zaprinast (1 mg kg−1 + 0.1 mg kg−1 min−1) increased the incidence rate of ventricular fibrillation following coronary artery ligation and the mortality rate. Moreover, both drugs increased cGMP in the ventricle.

Conclusions: The results demonstrated that pimobendan and zaprinast increased the incidence of dysrhythmias and the mortality rate, which was accompanied by an increase in the ventricular content of cGMP. Rolipram decreased the duration of ventricular tachycardia without a change in the cyclic nucleotide content or in the mortality rate.

Keywords

ENZYME INHIBITORS, phosphodiesterase inhibitors, pimobendan, rolipram, zaprinastISCHAEMIA, myocardial ischaemiaNUCLEOTIDES, CYCLIC, cAMP, cGMPRAT
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 20 , Issue 3 , March 2003 , pp. 205 - 211
Copyright
© 2003 European Society of Anaesthesiology

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Podzuweit T. Early arrhythmias resulting from acute myocardial ischaemia; possible role of cyclic AMP. In: Parratt JR, ed. Early Arrhythmias Resulting from Myocardial Ischaemia: Mechanisms and Prevention by Drugs. London, UK: Macmillan, 1982: 171–198.
Lubbe WF, Nguyen T, West EJ. Modulation of myocardial cyclic AMP and vulnerability to fibrillation in the rat heart. Fed Proc 1983; 42: 2460–2464.Google Scholar
Yoshida Y, Hirai M, Yamada T, et al. Antiarrhythmic efficacy of dipyridamole in treatment of reperfusion arrhythmias: evidence for cAMP-mediated triggered activity as a mechanism responsible for reperfusion arrhythmias. Circulation 2000; 101: 624–630.Google Scholar
Lubbe WF, Podzuweit T, Daries PS, Opie LH. The role of cyclic adenosine monophosphate in adrenergic effects on ventricular vulnerability to fibrillation in the isolated perfused rat heart. J Clin Invest 1978; 61: 1260–1269.Google Scholar
Podzuweit T, Els DJ, McCarthy J. Cyclic AMP mediated arrhythmias induced in the ischaemic pig heart. Basic Res Cardiol 1981; 76: 443–448.Google Scholar
Kane KA, Morcillo-Sanchez EJ, Parratt JR, Rodger IW, Shahid M. The relationship between coronary artery occlusion-induced arrhythmias and myocardial cyclic nucleotide levels in the anaesthetized rat. Br J Pharmacol 1985; 84: 139–145.Google Scholar
Packer M. Effect of phophodiesterase inhibitors on survival of patients with chronic congestive heart failure. Am J Cardiol 1989; 63: 41A–45A.Google Scholar
Pabla R, Bland-Ward P, Moore PK, Curtis MJ. An endogenous protectant effect of cardiac cyclic GMP against reperfusion-induced ventricular fibrillation in the rat heart. Br J Pharmacol 1995; 116: 2923–2930.Google Scholar
Ellison WG, Ellison KE, Sweeney MO, Epstein LM, Maisel WH. Management of arrhythmias in heart failure. Cardiol Rev 2002; 10: 8–14.Google Scholar
Pamboukian SV, Carere RG, Webb JG, et al. The use of milrinone in pre-transplant assessment of patients with congestive heart failure and pulmonary hypertension. J Heart Transplant 1999; 18: 367–371.Google Scholar
Skrabal MZ, Stading JA, Behmer-Miller KA, Hilleman DE. Advances in the treatment of congestive heart failure: new approaches for an old disease. Pharmacotherapy 2000; 20: 787–792.Google Scholar
Movsesian MA. Therapeutic potential of cyclic nucleotide phosphodiesterase inhibitors in heart failure. Expert Opin Investig Drugs 2000; 9: 963–973.Google Scholar
Carceles MD, Aleixandre F, Fuente T, López-Vidal J, Laorden ML. Combined phosphodiesterase inhibition and B-blockade in the GI104313, decreases ischemia-induced arrhythmias in the rat. Can J Anaesth 2001; 48: 486–492.Google Scholar
Clark C, Foreman MI, Kane KA, McDonald FM, Parrat JR. Coronary artery ligation in anaesthetized rats as a method for the production of experimental dysrrhythmias and for the determination of infarct size. J Pharmacol Meth 1980; 3: 357–358.Google Scholar
Hartree EF. Determination of protein: a modification of the Lowry method that gives a linear photometric response. Anal Biochem 1972; 48: 442–446.Google Scholar
Marshall RJ, Muir AW, Winslow E. Development of a severe model of early coronary artery ligation-induced dysrrhythmias in the anaesthetized rat. Br J Pharmacol 1981; 73: 951–995.Google Scholar
Daugherty A, Frayn KN, Redfern WS, Woodward B. The role of catecholamines in the production of ischaemia-induced ventricular arrhythmias in the rat in vivo and in vitro. Br J Pharmacol 1986; 87: 265–277.Google Scholar
Holdbrook M, Coker SJ. Effects of zaprinast and rolipram on platelet aggregation and arrhythmias following myocardial ischaemia and reperfusion in anaesthetized rabbits. Br J Pharmacol 1991; 103: 1973–1979.Google Scholar
Jones RB, Frodsham G, Kickinson K, Foster GA. Effect of flosequinam on ischaemia-induced arrhythmias and on ventricular cyclic nucleotide content in the anaesthetized rat. Br J Pharmacol 1993; 108: 1111–1116.Google Scholar
Sugiura M, Ogawa K, Yamazaki N. Concentration of myocardial cyclic AMP and ventricular fibrillation induced by aminophyline. Jpn Heart J 1979; 20: 177–182.Google Scholar
Colluci WS, Wright RF, Braunwald E. New positive inotropic agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical developments. N Engl J Med 1986; 314: 349–358.Google Scholar
Lynch JJ, Kitzen JM, Hoff PT, Lucchesi BR. Effects of pimobendan (UD-CG 115 BS) a new positive inotropic molecule on ventricular tachycardia and ischemic ventricular fibrillation in a conscious canine model of recent myocardial infarction. Cardiovasc Pharmacol 1989; 12: 547–554.Google Scholar
Corr PB, Witkowski FX, Sobel BE. Mechanisms contributing to malignant dysrrhythmias induced by ischaemia in the cat. J Clin Invest 1978; 61: 109–119.Google Scholar
Worthington MG, Opie LH. Contrasting effects of cyclic AMP increase caused by β-adrenergic stimulation or by adenylate cyclase activation on ventricular fibrillation threshold of isolated rat heart. J Cardiovasc Pharmacol 1992; 20: 595–600.Google Scholar
Uno T, Kanayama H, Miyazaki Y, Ogawa K, Stake T. Increased cyclic GMP in atrial fibrillation. J Electrocardiol 1986; 19: 51–57.Google Scholar
Klein HH, Boble RM, Pich S, Lindert-Heimberg S, Wollenweber J, Nebendahl K. Time delay of cell death by Na+–H+-exchange inhibition in regionally ischemic reperfused porcine hearts. J Cardiovasc Pharmacol 1997; 30: 235–240.Google Scholar
Hoag JB, Quian Y-Z, Nayeem MA, D'Angelo M, Kukreja RC. ATP-sensitive potassium channel mediates delayed ischemia protection by heat stress in rabbit heart. Am J Physiol 1997; 273: H2458–H2464.Google Scholar