Interaction of ketanserin and its metabolite ketanserinol with 5HT2 receptors in pulmonary and coronary arteries of calf

A comparison of 5-hydroxytryptamine (5HT)-induced contractions was made on cocaine-treated strips of bovine pulmonary arteries and large coronary arteries. The affinities of the 5HT2 antagonist ketanserin, its metabolite ketanserinol, yohimbine and rauwolscine were estimated for both arteries. Ketanserin was a competitive antagonist of the effects of 5HT in both arteries. The KB values (-log mol/l) were 9.5 for large coronary arteries and 9.4 for pulmonary arteries. Ketanserinol was also a competitive antagonist of the effects of 5HT in both arteries. The KB values (-log mol/l) were 6.5 for large coronary arteries and 6.4 for pulmonary arteries. A combination of ketanserin with ketanserinol antagonized the 5HT effects as expected from competition of the 3 drugs for a single class of receptor in both arteries. Yohimbine and rauwolscine were competitive antagonists of the effects of 5HT in pulmonary artery. The KB-values (-log mol/l) were 6.8 for yohimbine and 6.5 for rauwolscine. A combination of ketanserin with either yohimbine or rauwolscine antagonized the 5HT effects as expected from competition of all 4 drugs for a single class of receptors in pulmonary arteries. The evidence is consistent with the assumption that smooth muscle 5HT receptors of both pulmonary artery and large coronary artery are of the 5HT2 class. The reduction of the ketone of ketanserin to alcohol (i.e. ketanserinol) causes an approximately 1000-fold decrease in affinity for arterial 5HT2 receptors. Reported peak plasma levels of ketanserinol are too low (less than or equal to 10(-7) mol/l) in humans to account for a contribution of the metabolite to the blockade of 5HT effects by ketanserin.