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Negative inotropic action of alpha-1a adrenoceptor blocking agents: role of adenosine and ATP-sensitive K+ channels
1Department of Pharmacology, Medical University of Gdańsk, Poland. ikocic@amg.gda.pl
Abstract:
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.
Insights
Alpha1a adrenoceptor blockers cause a negative inotropic effect in guinea pig heart muscle. This action involves adenosine receptors and ATP-sensitive potassium channels, modulated by alpha1b adrenoceptors.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
Background:
- Alpha1 adrenoceptors play a role in regulating cardiac contractility.
- Specific subtypes of alpha1 adrenoceptors may have distinct effects on heart function.
Purpose of the Study:
- To investigate the effects of various alpha1 adrenoceptor blocking agents on guinea pig papillary muscle contractility.
- To elucidate the specific roles of alpha1a and alpha1b adrenoceptor subtypes in mediating these effects.
Main Methods:
- Studied the effects of alpha1 adrenoceptor blockers (doxazosin, indoramin, 5-methylurapidil, niguldipine, WB-4101, chloroethylclonidine) on papillary muscle force and velocity.
- Utilized concentration-response studies and pretreatment with specific antagonists (glibenclamide, adenosine receptor antagonists, dibenamine, CEC) and pertussis toxin.
Main Results:
- Alpha1a blockers (niguldipine, 5-methylurapidil, WB-4101) induced a concentration-dependent negative inotropic effect.
- This effect was attenuated by glibenclamide and abolished by an adenosine A1 receptor antagonist.
- Pretreatment with alpha1 (dibenamine) and alpha1b (CEC) blockers, and pertussis toxin, modulated the negative inotropic response.
Conclusions:
- Alpha1a adrenoceptor blockade triggers a negative inotropic action in the presence of unblocked alpha1b adrenoceptors.
- This mechanism appears to involve adenosine receptor stimulation and activation of ATP-sensitive potassium channels (K[ATP]) via an inhibitory G protein.