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 (ICa,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 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,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 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,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.
Footnotes
-
Send reprint requests to: Dr. M. Karmazyn, Department of Pharmacology and Toxicology, The University of Western Ontario, Medical Sciences Building, London, Ontario N6A 5C1, Canada.
-
↵1 This work was supported by a grant from the Medical Research Council of Canada (MRCC). M.K. is a Career Investigator of the Heart and Stroke Foundation of Ontario and SMS is a recipient of a Scientist Award from the MRCC.
-
↵2 Current address: Experimental Cardiology Group, Masonic Medical Research Laboratory, Utica, NY 13501.
- Abbreviations:
- H2O2
- hydrogen peroxide
- ICa,L
- L-type calcium current
- [Ca++]i
- cytosolic calcium
- PKC
- protein kinase C
- BIS
- bisindolylmaleimide
- EGTA
- ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetra acetic acid
- HEPES
- N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]
- CPA
- N6 cyclopentyladenosine
- Received February 24, 1998.
- Accepted May 13, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|