Activation of the 5-HT₇ receptor but not nitric oxide synthase is necessary for chronic 5-hydroxytryptamine-induced hypotension

New findings: What is the central question of this study? What mechanisms account for the hypotension observed during chronic elevations in circulating 5-hydroxytryptamine in rats? What is the main finding and its importance? Chronic 5-hydroxytryptamine-induced hypotension requires continued activation of the 5-HT₇ receptor subtype but does not require NO, an outcome that resolves previous conflicting results. Therapeutic interruption of the hypotensive actions of 5-HT under pathophysiological conditions can only be achieved through blockade of the 5-HT₇ receptor.

Abstract: Low dose infusion of 5-hydroxytryptamine (5-HT) to rats causes both an acute and a chronic fall in arterial blood pressure. The 5-HT₇ receptor subtype plays a critical part in the observed hypotension. Acute (minutes to hours) 5-HT infusion shows no depressor role for nitric oxide (NO), but 5-HT depressor responses under chronic conditions suggest that NO production may be critical. We test the hypothesis that NO contributes to the chronic, but not the acute, depressor response to 5-HT. We compared the role of NO and 5-HT₇ receptors in 5-HT-induced hypotension under acute and chronic conditions in the same animal. Mean arterial pressure and heart rate were measured by radiotelemetry in conscious rats during 5 days of saline or 5-HT (25 μg kg^-1 min^-1 ; osmotic pump) infusion and for 2 days after infusion was stopped. To quantify the contributions of NO and the 5-HT₇ receptor to 5-HT-induced hypotension, the nitric oxide synthase (NOS) inhibitor l-NAME or the selective 5-HT₇ receptor antagonist SB-267790 were given at 1, 3 and 5 days of chronic infusion, and 1 day after 5-HT infusion pumps were removed. N^ω -Nitro-l-arginine methyl ester (l-NAME) caused a pressor response of the same magnitude in the absence or presence of 5-HT infusion. Conversely, SB-269970 did not affect mean arterial pressure in the absence of 5-HT infusion and reversed the 5-HT-induced depressor response at each time point. Our findings demonstrate that acute and chronic 5-HT-induced hypotension does not require NOS activation but does require continued activation of the 5-HT₇ receptor.