412 T I P S - O c t o b e r 1 9 8 3

The mode of action of ketanserin I would like to press Dr Janssen for a little more evidence in support of his conclusion that it ' . . . is probably correct to assume that when a substance such as ketanserin is clinically effective at low therapeutic dose levels, serotonin is involved and the pathol- ogy is 5-HT2-receptor mediated' 1. The key phrase here is, of course, 'low therapeutic dose levels' since, as clearly documented by Dr Janssen and his colleagues, ketan- serin loses selectivity for 5-HT2-receptors as the dose/concentration is increased. From my own experimental experience with ketanserin, I know that at certain doses and concentrations, selective blockade of 5-HT~-receptors can easily be achieved. I am not yet convinced that the doses of ketanserin used clinically fall into this category.

Ten mg of ketanserin given i.v. is a typi- cal clinical dose following which dilation of peripheral blood vessels, antihypertensive effects and beneficial responses in conges- tive cardiac failure and thrombophlebitis have been obtained 1. As one would expect, 5-HT~-receptor blockade is achieved with this dose; the ketanserin investigational brochure records inhibition of 5-HT- evoked digital venospasm for up to 8 h in healthy volunteers 2. However, the evi- dence that this antagonism is selective, i.e. that no concomitant blockade of al- adrenoceptors is occurring, is less well sup- ported by the facts. Dr Janssen quotes one study a in which no evidence for at- adrenoceptor blockade was obtained in hypertensive patients using phenylephrine as the al-adrenoceptor agonist. On the other hand, a recent study 4, employing a double-blind crossover design, comes to precisely the opposite conclusion using methoxamine as the at-adrenoceptor stimulant.

Other data are available which suggest that al-adrenoceptor blockade occurs in humans with the doses of ketanserin used clinically. Thus, the mean plasma concen- trations following an i.v. dose of 10 mg in healthy volunteers reach 5 x 10 -v M shortly after injection, exceed 10-TM for at least 1 h and are still more than 6 × 10 -8 M 2 h after drug administration 2. These concentrations are more than adequate to displace radioligand binding to al-adrenoceptors 2 and to inhibit vasoconstrictor responses to al-adrenoceptor agonists 2.5. In healthy human volunteers, 5-10 mg of ketanserin given i.v. increases peripheral blood flow

measured by plethysmography and even 5 mg, by the same route, is able to abolish a classic sympathetic vasoconstrictor reflex, the reduction in peripheral blood flow induced by cold 2. It bears emphasis that, although vasoconstrictor responses to 5-HT are abolished for up to 8 h, the vasodilation in healthy volunteers and the cardiovascular changes in hypertensive patients are of much shorter duration 2.

The challenge to Dr Janssen is, there- fore, to refute the suggestion based on the above considerations that al-adrenoceptor blockade occurs after the doses of ketan- serin used clinically, and that this property adequately accounts for the clinical benefit achieved in conditions such as hypertension and congestive cardiac failure. At the very least he should be prepared to specify the 'low therapeutic dose levels' at which selec- tive blockade of 5-HT2-receptors can be

obtained. Without such information, the use of ketanserin as a tool to implicate 5-HT~-receptors in pathology can only be of limited value, and may even be mislead- ing.

JOHN R. FOZARD

Centre de Recherche Merrell International, 16, rue d'Ankara, 67084 Strasbourg Cedex, France.

Reading list 1 Janssen, P. A. J. (1983) Trends Pharmacol. Sci. 4,

198-206 2 Janssen Phatmaceufica (1982) Ketanserin: the

First Pure and Selective 5-HT~-Receptor Block- ing Agent 6th edn unpublished Investigational New Drug Brochure

3 Wenting, G. J., Man. in't Veld, A. J., Woittier, A. J., Boomsma, F. and Sehatekamp, M. A. D. H. (1982) C//n. Sci. 63,435S-438S

4 Reiman, I. W. and Fr6hlich, J. C. (1983)Lancet i, 703-704

5 Van Nueten, J. M., Janssen, P. A. J., Van Berk, J., Xhonneux, R., Verbeuren, T. J. and Vanhoutte, P. M. (1981)J. Pharmacol. Exp. Ther. 218, 217-230

Paul Janssen replies The assumption that al-adrenoceptor block- ade does not occur after doses of ketan- serin used clinically was based on three inde- pendent observations, that i.v. treatment with 10 mg ketanserin fails to shift the doso--response curve to phenylephrine (Kulbertus, H. and Ball, S. G., personal communications, also see Ref. 1). More recent studies show that prolonged treat- ment with ketanserin (10 mg i.v. followed by a 3-h infusion at 4 mg h -1 or 40 mg orally b.i.d, or t.i.d, for 3 days or 3 weeks) antagonizes the pressor effects to high doses of phenylephrine and/or methox- amine but not those to lower doses of these agents (Amery, A. and Ball, S. G., per- sonal communications, also see Ref. 2). The displacement of the dose-response curve by ketanserin does not seem to fulfill the criteria for competitive antagonism. In contrast, prazosin causes a parallel shift to the right of the whole dose-response curve (Ball, S. G., personal communication, also see Ref. 1).

These data suggest that ketanserin at therapeutic doses has weak m- adrenoceptor blocking properties and that they are slow in onset. The al-adrenoceptor blocking properties of ketanserin seem to be different from those of praz.osin.

Ketanserin lowers blood pressme within minutes after i.v. injection, at a time when no a-blocking activity can be~ demon-

strated. It is thus unlikely that al-blockade contributes to the acute blood pressure low- ering effect of the drug. During prolonged treatment, the m-blocking activity of ketanserin is so weak that on its own it can- not explain the antihypertensive effect of the drug either. It is possible that ketanserin lowers blood pressure by S2-serotonergic receptor blockade alone, or by a combina- tion of predominantly S~- and mild al- receptor blockade.

We have recently synthesized several S2-serotonergic receptor blockers (e.g. R 56 413, R 55 667) that do not bind to al- adrenoceptors. These agents do not reduce blood pressure in spontaneously hyperten- sive rats, and thus confirm that not S2- blockade but al-blockade appears to be responsible for the blood pressure lowering effect of ketanserin in the rat. The effects on blood pressure of these new S2-blockers is currently being studied in patients with essential hypertension. Hopefully, these data will indicate whether S2-receptor blockade on its own can reduce blood pressure in man and to what extent.

PAUL JANSSEN

Janssen Pharmaceutica, Turnhoutseweg 30, B-2340 Bearse, Belgium.

References 1 Wanting, G. J., Man in't Veld, A. J., Woittiez,

A. J., Boomsma, F. and Schalekamp, M. A. D. H. C//n. Sci. (in press)

2 Reimann, I. W. and Fr61ich, J. C. (1983) Lancet i, 703-704