Contribution of 4-hydroxy-2,3-trans-nonenal to the reduction of beta-adrenoceptor function in the heart by oxidative stress.
Oxidative stress reduces adenylate cyclase activity and also the maximal response to beta-adrenoceptor stimulation in the rat heart, while beta-adrenoceptor density is not affected or increased. Since free sulfhydryl groups are essential to beta-adrenoceptor function and the sulfhydryl reactive substance 4-hydroxy-2,3-trans-nonenal (HNE) is responsible for part of the effects of oxidative stress, the effect of HNE on beta-adrenoceptor function in field stimulated left atria of the rat was determined. To this end field stimulated atria were incubated with 10 microM, 100 microM and 1 mM HNE for 25 min. After removing the excess of HNE, beta-adrenoceptor function was determined by measuring the positive inotropic response to (-)-isoproterenol. It was found that 10 microM HNE had no effect on beta-adrenoceptor function, whereas 100 microM HNE reduced the maximal effect to (-)-isoproterenol without affecting the pD2 (-log EC50). At these concentrations, HNE had no effect on either beta-adrenoceptor density or on c-AMP production. After 1 mM HNE, the atria stopped contracting. Since the effects of the synthetic thiol inactivator N-ethyl maleimide were similar to those of HNE, it was concluded that the reduction of beta-adrenoceptor function by HNE is probably the result of alkylation of free sulfhydryl groups. Our results indicate that the reduction of adenylate cyclase activity by oxidative stress is not mediated by the production of HNE, however oxidative stress and HNE both reduce the maximal response to beta-adrenoceptor stimulation.
Haenen
G R
GR
Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
Plug
H J
HJ
Vermeulen
N P
NP
Timmerman
H
H
Bast
A
A
D000262:Adenylyl Cyclases / Q000378:metabolism; D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D016275:Atrial Function; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology
D000447:Aldehydes; D011943:Receptors, Adrenergic, beta; D000262:Adenylyl Cyclases; C027576:4-hydroxy-2-nonenal; D007545:Isoproterenol