Negative inotropic action of alpha-1a adrenoceptor blocking agents: role of adenosine and ATP-sensitive K+ channels.

1. The effects of alpha1 adrenoceptor blocking agents doxazosin, indoramin, 5-methylurapidil, niguldipine, WB-4101 and chloroethylclonidine (CEC) on the force of contraction (Fc), velocity of contraction (+dF/dt) and relaxation (-dF/dt) of guinea pig papillary muscles were studied. 2. All examined substances were applied in a wide concentration range (0.01-30.0 microM) for at least 30 min at each concentration. Only alpha1a blockers [i.e., niguldipine (0.01-0.3 microM), 5-methylurapidil (1-30 microM) and WB-4101 (1-30 microM)] showed a concentration-dependent negative inotropic action. 3. This effect was significantly attenuated in the presence of glibenclamide (1 microM) and almost completely abolished by 1,3-dipropyl-8-p-sulfophenylxanthine (1 microM), an antagonist of adenosine receptors with a slight selectivity for the A1 subtype. 4. Pretreatment with dibenamine, an irreversible blocker of alpha1 adrenoceptors (0.6 microM for 40 min), abolished this effect, whereas pretreatment with CEC, an irreversible blocker of alpha1b adrenoceptors (1 microM for 20 min), and pertussis toxin (10 microg/kg IP, 4 to 5 days before experiments) diminished it. 5. The alpha1a adrenoceptor blocking agents in the presence of the unblocked alpha1b adrenoceptor trigger the negative inotropic action, which seems to include adenosine receptor stimulation and activation of ATP-sensitive K+ channels (K[ATP]) through an inhibitory G protein.