Neutral/negative α 1 -AR antagonists and calcium channel blockers at comparison in functional tests on guinea-pig smooth muscle and myocardium.

BACKGROUND: Constitutive (agonist-independent) activity is a prerogative of many G protein-coupled receptors (GPCRs) including α1 -adrenoceptors (α1 -ARs). Inhibition of such an activity at α1 -AR subtypes by antagonists with negative efficacy is difficult to be adequately tested.

METHODS: In the present experimental approach, we compared the activity of three calcium channel blockers (nifedipine, diltiazem and verapamil) and of three potent benzodioxane-based α1 -AR antagonists, differing for subtype selectivity and inverse agonist properties, in producing smooth muscle relaxation and negative inotropy under the same test conditions. We selected, as benzodioxane derivatives, (S)-WB4101, inverse agonist with slight α1A /α1B -α1D AR selectivity, and two previously developed analogues. Both of these are potent antagonists at α1D -AR, that is the α1 - AR subtype suspected of the highest susceptibility to inverse agonists for its high degree of basal activity, but only one is inverse agonist.

RESULTS: We found that all the three benzodioxane-related α1 -AR antagonists have significant intrinsic relaxant activity on non-vascular smooth muscle and moderate negative inotropic effect, while they do not relax aorta. Their potency is always lower than that of three calcium channel blockers.

CONCLUSIONS: Intrinsic myorelaxant and negative inotropic activity of the three benzodioxane-based α1 -AR antagonist is related neither to a particular profile of α1 -AR subtype selectivity nor to whether or not being an inverse agonist, but it parallels the calcium antagonists effects indicating a direct interaction of the three α1 -AR antagonists with L-type Ca2+ channels.