Abstract

Hydrogen peroxide (H₂O₂) produces complex cardiac effects that may involve altered calcium homeostasis. The cardiotoxic effects of H₂O₂ can be attenuated by adenosine A1 receptor agonists. The present study examined the effect of H₂O₂ on L-type Ca⁺⁺current (I_Ca,L) in guinea pig ventricular myocytes under two different recording conditions and the influence of adenosine receptor agonists. H₂O₂ (100 μM), did not have any significant effect on I_Ca,L, under conventional whole cell patch configuration. However, when recorded under nystatin perforated patch configuration, H₂O₂ caused a gradual and significant increase (84 ± 14%) in I_Ca,Lcompared to control values. N⁶-cyclopentyladenosine (CPA), an adenosine A1 receptor agonist, significantly attenuated the effect of H₂O₂. The inhibitory effect of N⁶-cyclopentyladenosine was antagonized by 8cyclopentyl-1,3-dipropylxanthine, an adenosine A1 receptor antagonist. The A2A and A3 receptor agonists, 2-p-(2-Carboxyethyl)phenethylamino-5′- N - ethylcarboxamidoadenosine (CGS-21680) and 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-d-ribofuranuronamide, respectively, did not modulate the enhancement of I_Ca,L by H₂O₂. Moreover the effects of N⁶-cyclopentyladenosine were mimicked by the protein kinase C inhibitor bisindolylmaleimide. Thus, our results demonstrate a potent stimulatory effect of H₂O₂ on I_Ca,Lin guinea pig ventricular myocytes. We further demonstrate that adenosine A1 receptor activation attenuates this effect. Our results suggest a potential basis for altered calcium homeostasis in response to H₂O₂ as well as the salutary effects of A1 receptor activation against H₂O₂-induced cardiotoxicity.