Hydrogen peroxide-induced stimulation of L-type calcium current in guinea pig ventricular myocytes and its inhibition by adenosine A1 receptor activation.
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 (ICa,L) in guinea pig ventricular myocytes under two different recording conditions and the influence of adenosine receptor agonists. H2O2 (100 microM), did not have any significant effect on ICa,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 ICa,L compared 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-be ta-D-ribofuranuronamide, respectively, did not modulate the enhancement of ICa,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 ICa,L in 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.
Thomas
G P
GP
Department of Pharmacology & Toxicology and Physiology, Medical Sciences Building, The University of Western Ontario, London, Ontario, Canada N6A 5C1.
Sims
S M
SM
Cook
M A
MA
Karmazyn
M
M
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects*; D020746:Calcium Channels, L-Type; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008297:Male; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D018047:Receptors, Purinergic P1 / Q000187:drug effects* / Q000502:physiology
D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D018047:Receptors, Purinergic P1; C048599:N(6)-cyclopentyladenosine; D006861:Hydrogen Peroxide; D011493:Protein Kinase C; D000241:Adenosine; D002118:Calcium