Increased uncoupling of beta-, beta 1- and beta 2-adrenoceptor to myocardial contraction in failing human myocardium.
Coupling of myocardial beta-, beta 1-, beta 2- and alpha-adrenoceptors (AR) to myocardial contraction was investigated in patients with various degrees of heart failure. With the use of delta Vcfc, a load independent parameter of myocardial contraction, AR mediated contraction was evaluated. beta-AR mediated contraction, delta Vcfc by infusion of a beta-AR agonist, isoproterenol, declined with the advancement of heart failure from 0.41 Circ/sec (NYHA I) to 0.31 (NYHA II), 0.22 (NYHA III) and 0.12 (NYHA IV). Dobutamine, a beta 1-AR full agonist, mediated delta Vcfc was 92-97% of that of isoproterenol. On the other hand, terbutaline sulfate, a full agonist to beta 2-AR, increased delta Vcfc partially in comparison with isoproterenol; 51% in NYHA I, 52% in NYHA II, 36% in NYHA III and 17% in NYHA IV. An alpha 1-AR agonist, methoxamine had little effect on myocardial contractility beta-AR and alpha-AR densities were analyzed by saturation binding isotherms of myocardial membrane fraction with 125I-Iodocyanopindolol (ICYP) and 3H-Bunazosin, respectively. beta-1 and beta 2-ARs were separated by competition binding of 125ICYP with a highly selective beta 1 AR antagonist, CGP20712A. There was a progressive down regulation of beta, beta 1- and beta 2-ARs with the advancement of heart failure. A new index was used to examine coupling of ARs to myocardial contraction; Coupling Index. The index was slightly decreased in NYHA II in beta- and beta 1-ARs. In beta 2-AR, the coupling index declined as heart failure advanced from NYHA I to NYHA IV.(ABSTRACT TRUNCATED AT 250 WORDS)
Takahashi
M
M
First Department of Internal Medicine, Shiga University of Medical Science, Japan.
Shichiri
G
G
Amano
M
M
Kanamori
T
T
Kinoshita
M
M
D000328:Adult; D000368:Aged; D001667:Binding, Competitive; D004280:Dobutamine / Q000494:pharmacology*; D015536:Down-Regulation; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D020120:Iodocyanopindolol; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011799:Quinazolines / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013726:Terbutaline / Q000494:pharmacology*
D011799:Quinazolines; D011943:Receptors, Adrenergic, beta; D004280:Dobutamine; D020120:Iodocyanopindolol; C018176:bunazosin; D010869:Pindolol; D007545:Isoproterenol; D013726:Terbutaline