Abstract P3048: The 5-ht 7 Receptor is Essential for 5-ht-Induced Hypotension in the Doca Salt Hypertensive Rat

Abstract

Infusions of 5-HT into normotensive rats reduce blood pressure over a one week period. Pharmacological studies show the 5-HT 7 receptor is necessary for at least the initial (first 24 hours) hypotension. However, if serotonergic agonists are to be considered as therapeutic tools for the treatment of hypertension, the receptor mechanisms causing sustained hypotension must be identified and shown to be effective in individuals with chronic hypertension. We hypothesized that the 5-HT 7 receptor would be essential for sustained 5-HT-stimulated hypotension in both normal and deoxycorticosterone acetate (DOCA) salt hypertensive rats. We further investigated whether endogenous activation of the 5-HT 7 receptor contributed to blood pressure regulation in normal or DOCA-salt hypertensive rats. We used a newly created 5-HT 7 receptor KO rat and WT littermates (derived on a Sprague-Dawley background). Both male and female genotyped rats were implanted with a radio-telemeter at approximately 3 months of age, uninephrectomized and implanted with DOCA (200 mg/kg) and given salt (1.0% NaCl + 0.2% KCl) for four weeks. At this point, animals were given an Alzet minipump that infused 5-HT (25 ug/kg/min) for 7 days; pumps were then removed. Prior to DOCA-salt administration, mean arterial blood pressure (MAP; mm Hg) of male and female KO rats did not differ from that of their respective wildtype (WT) littermates. After 4 weeks of DOCA-salt treatment MAPs in KO rats were not different from their WT littermates (Male WT = 158±12 vs KO 173±9.7; Female WT = 155±9.5; KO = 144±8.4). 5-HT infusion reduced MAP (mm Hg) in the WT DOCA salt males from 158±12 to 113±7.7, and in WT DOCA-salt females from 155±9.5 to 123.4±1.9. In marked contrast, 5-HT infusion did not significantly reduce the blood pressure of either male or female KO rats. These findings support two important conclusions. First, the 5-HT 7 receptor does not affect blood pressure regulation in the male or female DOCA-salt hypertensive rats. Second, exogenous 5-HT administration profoundly reduced blood pressure in both male and female DOCA-salt (WT) rats via continued activation of the 5-HT 7 receptor. This study supports the potential of using 5-HT 7 receptor agonists as a novel antihypertensive therapy.