NEGATIVE INOTROPIC ACTION OF ALPHA-1A ADRENOCEPTOR BLOCKING-AGENTS - ROLE OF ADENOSINE AND ATP-SENSITIVE K+ CHANNELS

1. The effects of alpha(1) adrenoceptor blocking agents doxazosin, ind oramin, 5-methylurapidil, niguldipine, WB-4101 and chloroethylclonidin e (CEC) on the force of contraction (F-c), velocity of contraction (+d F/dt) and relaxation (-dF/dt) of guinea pig papillary muscles were stu died. 2. All examined substances were applied in a wide concentration range (0.01-30.0 mu M) for at least 30 min at each concentration. Only alpha(1a) blockers [i.e., niguldipine (0.01-0.3 mu M), 5-methylurapid il (1-30 mu M) and WB-4101 (1-30 mu M)] showed a concentration-depende nt negative inotropic action. 3. This effect was significantly attenua ted in the presence of glibenclamide (1 mu M) and almost completely ab olished by 1,3-dipropyl-8-p-sulfophenylxanthine (1 mu M), an antagonis t of adenosine receptors with a sight selectivity for the A(1) subtype . 4. Pretreatment with dibenamine, an irreversible blocker of alpha(1) adrenoceptors (0.6 mu M for 40 min), abolished this effect, whereas p retreatment with CEC, an irreversible blocker of alpha(1b) adrenocepto rs (1 mu M for 20 min), and pertussis toxin (10 mu g/kg IP, 4 to 5 day s before experiments) diminished it. 5. The alpha(1b) adrenoceptor blo cking agents in the presence of the unblocked alpha(1b) adrenoceptor t rigger the negative inotropic action, which seems to include adenosine receptor stimulation and activation of ATP-sensitive K+ channels (K-A TP) through an inhibitory G protein. (C) 1998 Elsevier Science Inc.