The pharmacology of ketanserin, the first selective serotonin S2-antagonist

The quinazolinedione derivative ketanserin was studied in many known and newly introduced tests to obtain its detailed pharmacological profile. Ketanserin was a potent, orally very effective antagonist of endogenous serotonin (5‐HT): 0.15 mg/kg (ED50 s.c. and p.o.) protected rats from the gastric lesions induced by the mast cell activator compound 48/80. Many other in vivo observations, such as antagonism of tryptamine‐induced cyanosis in rats (ED50 s.c., 0.056 mg/kg), inhibition of mescaline‐induced head twitches in rats (ED50 s.c., 0.097 mg/kg), and inhibition of 5‐HT‐induced effects in various species, revealed the potent antagonist activity of ketanserin on vasoconstrictor and bronchoconstrictor actions of serotonin. When compared to other compounds with 5‐HT‐antagonist activity, the pharmacological profile of ketanserin corresponds to that of a potent, peripherally acting serotonin antagonist with weak associated α‐adrenergic blocking and antihistamine activity. In addition, binding experiments and studies on isolated tissues and platelets disclosed the high selectivity of ketanserin's serotonin antagonism. Serotonin S2‐receptors of the rat frontal cortex were labeled by low concentrations of ketanserin (Ki = 0.39 nM), and affinity of drugs for S2‐receptors highly correlated with their activity against serotonin‐induced contractions of blood vessel preparations (e.g., of the rat caudal artery, A2‐value of ketanserin: 0.83 nM) and serotonin‐induced platelet aggregation. In these experiments, ketanserin was devoid of serotonin! ‐binding, of agonist activity on vascular smooth muscle, of inhibition of 5‐HT uptake into platelets, and of 5‐HT antagonism on gastrointestinal smooth muscle. The absence of all these secondary activities is pharmacologically characteristic for ketanserin when compared to known serotonin‐antagonists. On the basis of this profile of pure and selective serotonin S2‐antagonism, ketanserin was studied in experimental hypertension and in many spontaneous and induced circulatory dysfunctions. A prolonged antihypertensive effect can be obtained with ketanserin in the absence of distinct compensatory mechanisms. Vascular dysfunction can start at low, sensitizing concentrations of serotonin and be almost completely corrected by ketanserin, despite the involvement of other mediators. Ketanserin is a very effective antagonist of the mixture of vasoactive substances released by aggregating platelets. In experimental thrombosis, sustained ke