Activation of 5‐HT7 receptor but not NOS is necessary for chronic 5‐HT‐induced hypotension

Activation of 5‐HT7 receptor but not NOS is necessary for chronic 5‐HT‐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 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 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 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 (MAP) and heart rate (HR) were measured via radiotelemetry in conscious rats during 5 days of saline or 5‐HT (25 μg/kg/min; osmotic pump) infusion and for two 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 SB267790 were given at 1, 3 and 5 days of chronic infusion, and 1 day after 5‐HT infusion pumps were removed. L‐NAME caused a pressor response of the same magnitude in the absence or presence of 5‐HT infusion. Conversely, SB269970 did not affect MAP 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.

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