Cardioprotective actions of verapamil on the beta-adrenergic receptor complex in acute canine Chagas' disease.
The effect of verapamil treatment on the myocardial beta-adrenergic adenylyl cyclase complex in acute canine Chagas' disease was investigated. Relative to uninfected animals, 30 days of infection with T. cruzi reduced myocardial adenylyl cyclase activity by over 75%. With continuous verapamil treatment, the infection-associated reduction in adenylyl cyclase activity was less than 50%. The individual components of the beta-adrenergic receptor complex were characterized.


BACKGROUND
(1) increased right ventricular (RV) beta-adrenergic receptor (beta AR) density five-fold; (2) decreased left ventricle beta AR density by 20%; (3) reduced the proportion of high-affinity beta AR receptors to the same extent in both left and right ventricles; (4) reduced alpha s by 50% as determined by Western blot analysis, increased alpha 11-3 but did not change alpha 0; and (5) decreased the magnitude of pertussis-toxin-dependent [32P]ADP ribosylation by 60% as well as the proportion of [32P]ADP-ribose incorporated in alpha 0. Verapamil treatment of infected animals restored RV beta AR receptor density, alpha s and alpha i1-3 to control levels but had no influence on any aspect of pertussis-toxin-dependent [32P]ADP-ribosylation. Verapamil treatment of uninfected animals also: (1) increased beta-adrenergic adenylyl cyclase activity; (2) increased beta AR density in the RV but not the LV; (3) reduced high- to low-affinity beta-adrenergic receptors; and (4) affected only alpha i2 (50% decrease). The results indicate that the major actions of verapamil on the beta-adrenergic adenylyl cyclase complex in acute canine Chagas' disease may help to account for its cardioprotective effects.
Chen
G
G
Department of Medicine, Colombia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Barr
S
S
Walsh
D
D
Rohde
S
S
Brewer
A
A
Bilezikian
J P
JP
Wittner
M
M
Tanowitz
H B
HB
Morris
S A
SA
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D014355:Chagas Disease / Q000378:metabolism*; D004285:Dogs; D006321:Heart / Q000469:parasitology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D011943:Receptors, Adrenergic, beta; D014700:Verapamil; D000262:Adenylyl Cyclases