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  • Title: Differences in the chronic hypotensive mechanism of action of ketanserin in spontaneously hypertensive and Wistar-Kyoto rats.
    Author: Balasubramaniam G, Lee HS, Mah SC.
    Journal: J Hypertens; 1994 Jan; 12(1):7-14. PubMed ID: 8157947.
    Abstract:
    OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
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