Chronic serotonin (5-hydroxytryptamine, 5-HT) infusion results in a sustained fall in blood pressure in the sham and deoxycorticosterone acetate (DOCA)-salt rat. The exact mechanism(s) underlying a 5-HT-induced fall in blood pressure are not yet known. We hypothesize that 5-HT lowers blood pressure in a nitric oxide (NO)-dependent manner by reducing total peripheral resistance (TPR), either through a reduction in sympathetic nervous system (SNS) tone and/or direct stimulation of vascular 5-HT receptors. 5-HT (25 μg/kg/min; s.c.) or vehicle was infused to male Sprague Dawley or DOCA-salt hypertensive rats. Mean arterial pressure (MAP) was measured via radiotelemetry. Cardiac output (CO) was measured via aortic flow probes. 5-HT produced a significant reduction in MAP, increase in cardiac output (CO) and stroke volume (SV), and a significant reduction in total peripheral resistance (TPR). Additionally, 5-HT produced a sustained (one-month) fall in blood pressure in the DOCA-salt rat, but did not prevent the development of DOCA-salt hypertension. Isometric contractile force was measured in the sham and DOCA-salt superior mesenteric artery (SMA) to determine whether direct 5-HT receptor activtation was capable of relaxing the SMA. BW 723C86 (5-HT2B), CP 93129 (5-HT1B), and LP-44 (5-HT7) did not relax the SMA from sham or DOCA-salt rats vs. vehicle. Electrical field stimulation (EFS) was used to determine whether 5-HT was acting to inhibit neurogenic contraction in the isolated SMA. EFS-induced contraction was not significantly different in 5-HT incuabted vs. vehicle incuabted SMA under several conditions. Finally, several studies implicate the importance of the serotonin transporter (SERT) in mediating the effects of 5-HT. 5-HT produced a significantly greater fall in MAP in the SERT WT rat vs. the SERT KO rats suggesting a potentially important role for SERT in producing a 5-HT-induced fall in blood pressure. This research fills a gap in our understanding of how 5-HT functions in the cardiovascular system and validates our hypothesis that 5-HT lowers blood pressure through a reduction in total peripherl resistance. However, this research suggests that 5-HT is not acting through direct receptor mediated vascular relxation or through inhibition of NE release at the nerve terminal in the superior mesenteric artery to lower blood pressure.
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