Summary
Ketanserin is a new antihypertensive agent with affinity to serotonin (5-HT)2 receptors and at higher concentrations also to α 1-adrenoceptors. The present study was designed to evaluate the relative functional importance of the antagonism of α 1-adrenoreceptors and 5-HT2-receptors in the antihypertensive mechanism of action of ketanserin and analogues after acute administration. In the spontaneously hypertensive rat, ketanserin and the two ketanserin analogues, R56413 and R55667 (which have relatively weaker α-adrenolytic properties) were studied with regard to their ability to reduce the blood pressure after acute administration in the conscious rat and their ability to shift the dose response curves for 5-HT and phenylephrine in the pithed rat. The agents tested reduced the blood pressure only in a dose range where they blocked α 1-adrenoceptors and there was a striking correlation between the degree of hypotension and the degree of inhibition of the phenylephrine induced pressor responses. 5-HT2-receptor blockade alone did not influence basal blood pressure. However, following pretreatment with R55667 in a low dose the blood pressure reduction to prazosin was enhanced.
It is concluded that following acute administration in the rat the major portion of the antihypertensive response to ketanserin is due to an α 1-adrenoceptor blockade but that the 5-HT2-receptor blockade contributes.
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Abbreviations
- 5-HT:
-
5-hydroxytryptamine
- SHR:
-
spontaneously hypertensive rat
- SNS:
-
sympathetic nervous stimulation
References
Antonaccio MJ, Cote D (1976) Centrally mediated antihypertensive and bradycardic effects of methysergide in the spontaneously hypertensive rat. Eur J Pharmacol 36:451–454
Ball SG, Zabludowski JR, Robertson JIS (1983) Mechanism of antihypertensive action of ketanserin in man. Br Med J 287:1065
Collins MG, Vanhoutte PM (1981) Studies on the mechanisms of tachyphylaxis to 5-hydroxytryptamine in perfused kidneys from spontaneously hypertensive and normotensive rats. J Cardiovasc Pharmacol 3:229–235
Docherty JR, McGrath JC (1980) An examination of factors influencing adrenergic transmission in the pithed rat with special reference to noradrenaline uptake mechanisms and post-junctional α-adrenoceptors. Naunyn-Schmiedeberg's Arch Pharmacol 313:101–111
Engel G, Göthert M, Müller-Schweinitzer E, Schlicker E, Sistonen L, Stadler PA (1983) Evidence for common pharmacological properties of [3H]5-hydroxytryptamine binding sites, presynaptic 5-hydroxytryptamine autoreceptors in CNS and inhibitory presynaptic 5-hydroxytryptamine receptors on sympathetic nerves. Naunyn-Schmiedeberg's Arch Pharmacol 324:116–124
Fozard JR (1982) Mechanisms of the hypotensive effect of ketanserin. J Cardiovasc Pharmacol 4:829–838
Fozard JR (1983) The mode of action of ketanserin. TIPS 4:412
Gillespie JS, Muir TC (1967) A method of stimulating the complete sympathetic outflow from the spinal cord to the blood vessels in the pithed rat. Br J Pharmacol 30:78–87
Hedner T, Persson B, Berglund G (1983) Ketanserin, a novel 5-hydroxytryptamine antagonist: monotherapy in essential hypertension. Br J Clin Pharmacol 16:121–125
Hedner T, Persson B, Berglund G (1984) Experience with ketanserin, a serotonin (S2) antagonist, in longterm treatment of essential hypertension. Clin Exp Hypertens 3:743–751
Humphrey PPÅ, Fenuik W, Watts AD (1982) Ketanserin, a novel antihypertensive drug? J Pharm Pharmacol 34:541
Janssen PAJ (1983) Paul Janssen replies. TIPS 4:412
Kalkman HU, Timmermans PBMWM, Van Zwieten PA (1982) Characteristics of the antihypertensive properties of ketanserin (R41468) in rats. J Pharmacol Exp Ther 222:227–231
Leysen JE, Awouters F, Kenis L, Lauderon J, Vandenberk J, Janssen PAJ (1981) Receptor binding profile of R41468, a novel antagonist of 5-HT2 receptors. Life Sci 28:1015–1022
Persson B, Hedner T, Henning M (1982) Cardiovascular effects in the rat of ketanserin, a novel 5-hydroxytryptamin receptor blocking agent. J Pharm Pharmacol 34:442–445
Persson B, Hedner T, Berglund G (1983) Ketanserin in essential hypertension: Effects during rest and exercise. Eur J Clin Pharmacol 25:307–312
Pettersson A, Hedner T, Henning M, Persson B (1984) Antihypertensive effects of chronic 5-hydroxytryptamine (5-HT2) receptor blockade with ketanserin in the spontaneously hypertensive rat. Naunyn-Schmiedeberg's Arch Pharmacol 328:43–47
Shipley RE, Tilden JH (1947) A pithed rat preparation suitable for assaying pressor substances. Proc Soc Exp Biol Med 64:453–455
Vanhoutte PM, Van Neuten JM (1983) Ketanserin, a novel antihypertensive drug. J Pharm Pharmacol 35:339–340
Van Neuten JM, Janssen PAJ, Van Beek J, Xhonneau R, Verbeuren TJ, Vanhoutte PM (1981) Vascular effects of ketanserin (R41468) a novel antagonist of 5-HT2 serotonergic receptors. J Pharmacol Exp Ther 218:217–230
Wenting GJ, Wottiez AJ, Man in't Weld AJ, Schalekamp MADH (1984) 5-HT, alpha-adrenoceptors, and blood pressure. Effects of ketanserin in essential hypertension and autonomic insufficiency. Hypertension 6:100–109
Yamaguchi J, Kopin IJ (1980) Differential inhibition of alpha-1 and alpha-2 adrenoceptormediated pressor responses in pithed rats. J Pharmacol Exp Ther 214:275–281
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Pettersson, A., Gradin, K., Hedner, T. et al. Antihypertensive mechanism of action of ketanserin and some ketanserin analogues in the spontaneously hypertensive rat. Naunyn-Schmiedeberg's Arch. Pharmacol. 329, 394–397 (1985). https://doi.org/10.1007/BF00496374
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DOI: https://doi.org/10.1007/BF00496374