Differences in the chronic hypotensive mechanism of action of ketanserin in spontaneously hypertensive and Wistar-Kyoto rats

Abstract

To investigate the hypotensive effect and mechanism of action of chronic administration of ketanserin in spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto (WKY) rats. SHR and WKY rats were given chronic ketanserin infusions via osmotic minipumps to minimize fluctuations in drug concentrations and receptor responsiveness. In SHR treated with intravenous infusions of 3.0 (n = 9) or 6.0 mg/kg per day (n = 8) ketanserin for 7 days, significant dose-dependent falls in systolic blood pressure (SBP) were observed during the infusion period. Heart rate did not change in either the vehicle- or the ketanserin-treated groups of SHR. In WKY rats intravenously infused with 3.0 (n = 9) or 6.0 mg/kg per day (n = 10) ketanserin, dose-dependent falls in SBP were also observed during the infusion period, with the changes reaching statistical significance at the 6.0 mg/kg per day dose. The changes in heart rate were not different from those in control rats. Pressor responses to the type 2 5-hydroxytryptamine (5HT2)-receptor agonist (+/-)-alpha-methyl-5-hydroxytryptamine (5.0-125.0 micrograms/kg), as assessed on day 7, were reduced dose-dependently in all ketanserin-infused rats. alpha 1-Adrenoceptor responses to 1.0-10.0 micrograms/kg intravenous phenylephrine were attenuated in only the WKY rats infused with 6.0 mg/kg per day ketanserin. In the SHR treated with ketanserin there was no change in the pressor responsiveness to phenylephrine. Baroreflex sensitivity on day 7 was significantly greater in the ketanserin-infused SHR than in their respective controls. Changes in baroreflex sensitivity were not significantly different in WKY rats following ketanserin infusion. These results show that chronic administration of ketanserin lowers blood pressure in both SHR and WKY rats. In SHR the alpha 1-adrenoceptor-blocking effects of ketanserin are compensated for, and the reduction in blood pressure by day 7 is maintained predominantly by, 5HT2-receptor blockade. In WKY rats ketanserin-induced hypotension is associated with concomitant blockade of 5HT2- and alpha 1-receptors. The present study therefore suggests a differential mechanism of action of ketanserin in hypertensive and normotensive rats during chronic treatment.