An endogenous protectant effect of cardiac cyclic GMP against reperfusion‐induced ventricular fibrillation in the rat heart

Abstract

1 After a period of myocardial ischaemia, reperfusion of the myocardium can elicit cardiac arrhythmias. Susceptibility to these arrhythmias declines with time, such that a preceding period of more than approximately 40 min ischaemia is associated with few reperfusion-induced arrhythmias. We have tested the hypothesis that this decline in susceptibility occurs, in part, because of protection by endogenous guanosine 3':5'-cyclic monophosphate (cyclic GMP). 2 Rat isolated hearts were subjected to 60 min left regional ischaemia followed by reperfusion (n = 10 per group). Methylene blue (20 gM), a soluble guanylate cyclase inhibitor, raised the incidence of reperfusion-induced ventricular fibrillation (VF) from 10% in control hearts to 80% (P<0.05). This effect of methylene blue was abolished by co-perfusion with zaprinast (100 juM), a phosphodiesterase inhibitor which, in the rat heart, is cyclic GMP-specific (specific for the type-V phosphodiesterase isozyme). 3 Methylene blue reduced cyclic GMP levels in the ischaemic, non-ischaemic and reperfused myocardium (P<0.05) to 50 +10, 52+12 and 70+7 fmolmg-1 tissue wet weight, respectively from control values of 143 + 38, 147 +43 and 156+15 fmol mg-'. Co-perfusion with zaprinast prevented this effect, and cyclic GMP levels were actually elevated (P< 0.05) to 366 + 102, 396 + 130 and 293+22 fmol mg -in ischaemic, non-ischaemic and reperfused myocardium, respectively. Zaprinast by itself also elevated cyclic GMP content. Cyclic AMP levels were not affected by zaprinast or methylene blue. 4 In conclusion, when endogenous cardiac cyclic GMP synthesis is reduced, susceptibility to reperfusion-induced VF after sustained ischaemia is substantially increased. The effect is prevented by inhibiting cyclic GMP degradation. Therefore cyclic GMP appears to be an endogenous intracellular cardioprotectant, and its actions may account for the low susceptibility to VF normally encountered in hearts reperfused after sustained ischaemia.

Antiarrhythmogenic Effect of Reconstituted High-Density Lipoprotein Against Ischemia/Reperfusion in Rats

“…The NO-induced production of cGMP in the myocardium plays an important role in the antiarrhythmic effect of NO (34). The increase in myocardial cGMP inhibits Ca 2ϩ influx through L-type Ca channels and reduces Ca 2ϩ overload during I/R (35).…”

Expression, structure and chromosomal localization of the human cGMP‐binding cGMP‐specific phosphodiesterase PDE5A gene

“…The increase in intracellular cGMP concentrations. These results demonstrated that methylene blue, a soluble guanylate cyclaseinhibitor, raised the incidence of reperfusion-induced ventricular arrhythmias in isolated rat hearts and that M&B22948 abolished this effect of methylene blue through an increase in ventricular cGMP content [39]. In addition, cGMP-mediated inhibition of L-type Ca 2ϩ channel activity in cardiac myocytes has shown that cGMP could play a physiological role in cardiac functions [40].…”

Capsaicin-sensitive local sensory innervation is involved in pacing-induced preconditioning in rat hearts: role of nitric oxide and CGRP?

“…Rapid pacing-induced slight ischaemia and mechanical stress result in a release of several ischaemic metabolites from the myocytes and/or coronary endothelium, which in turn activate the capsaicin-sensitive sensory nerve endings. The concomitant neural release of NO and/or CGRP leads to an activation of K ATP and an increase in cGMP concentration, which may significantly contribute to the cardioprotective effect of preconditioning (Szilvassy et al 1993(Szilvassy et al , 1994aPabla et al 1995;Gross and Auchampach 1992). We conclude that the presence of an intact local sensory innervation is a prerequisite to elicit pacing-induced preconditioning; that a significant portion of basal cardiac NO content may be derived form capsaicin-sensitive neural sources; and that NO and CGRP released from these nerve fibres may be involved in the mechanism of pacing-induced preconditioning in the rat heart.…”