5-Hydroxytryptamine may be a viable treatment option for hypertension resistant to diuretic treatment

Serotonin (5-hydroxytryptamine, 5-HT) causes a sustained reduction in mean arterial pressure (MAP) during chronic (1 wk) infusion in both normo- and hypertensive rats. We hypothesized that the hypotensive effect of 5-HT will remain intact in male Dahl salt-sensitive (Dahl SS) rats that are unresponsive to a diuretic. Male Dahl SS rats on a normal or 4% NaCl diet were instrumented with radiotelemeters for blood pressure measurement. Following the collection of baseline MAP, ALZET mini-pumps containing 5-HT (25 μg/kg/min) were implanted. On the same day as pump implantation, rats were either 1) switched to drinking water containing the diuretic trichlormethiazide (TCM, 250 mg/L) or 2) maintained on regular drinking water. Following a week of infusion, blood samples were collected, and standard blood chemistry panels were run to investigate any potential effects on liver, kidney, or cardiometabolic parameters as well as electrolyte balance. On normal salt after 1 wk of infusion, rats receiving both 5-HT and TCM had a significantly lower MAP (122.0 ± 3.3 mmHg; n = 5) than rats receiving 5-HT alone (P = 0.0030, 131 ± 2.7 mmHg; n = 5). After 1 wk of infusion, high-salt diet rats receiving both 5-HT and TCM had the greatest reduction in MAP (-20.7 ± 1.7 mmHg; n = 4). 5-HT administration did not modify kidney or liver function as assessed by measurements of plasma in rats on a normal salt diet. Collectively, these data suggest 5-HT may be an effective additive to current frontline antihypertensive medications. Furthermore, 5-HT remains effective even when drug resistance develops to at least one of those standard monotherapies (thiazide diuretics).NEW & NOTEWORTHY 5-HT is an effective antihypertensive agent in Dahl SS rats that are nonresponsive to a diuretic when placed on a high-salt (4%) diet. 5-HT may be a viable treatment option for hypertension that is resistant to currently approved therapeutics.