Abstract P212: Splanchnic and Hepatic Portal Hemodynamics in the Hypotensive Actions of 5-HT

Abstract

Circulating 5-hydroxytryptamine (5-HT) regulates mean arterial pressure (MAP) under some conditions. Infusion of low doses of 5-HT into rats leads to a sustained decrease in MAP which is prevented by the selective 5-HT7 receptor (5-HT7R) antagonist SB269970 or by inhibition of nitric oxide (NO) production. Time-dependent changes in the splanchnic circulation play a critical role in the sustained depressor response to 5-HT. We hypothesized that activation of 5-HT7Rs reduces MAP in part by causing decreased splanchnic vascular resistance and/or increased hepatic portal vascular resistance. Anesthetized male Sprague Dawley rats were instrumented with arterial and venous lines for pressure measurements and 5-HT/SB269970 infusion, and a Transonic probe on the portal vein to measure portal flow. Within 20 minutes of starting an infusion of 5-HT (25 ug/kg/min), MAP was significantly reduced (63±2 vs baseline 82±4 mmHg), whereas splanchnic vascular resistance (4.1±0.6 vs 2.4±0.1 ml/min/mmHg) and portal vascular resistance (0.18±0.08 vs 0.11±0.3) were increased. In a separate group of rats subjected to 24 hours of 5-HT infusion, MAP was reduced compared to control values (70±3 vs 84±2 mmHg), but portal vascular resistance (0.23±0.07 vs 0.17±0.04) and splanchnic vascular resistance (2.6±0.3 vs 2.4±0.1) were near control values. These animals then received an infusion of SB269970 to determine the direct contribution of the 5HT7R to hemodynamics after 24 hours of 5-HT exposure. After 20 minutes of SB269970 infusion, MAP (83±3 mmHg) was completely restored to baseline values while splanchnic vascular resistance (2.1 ±0.1 vs 2.6±0.1) and portal vascular resistance (0.12±0.3 vs 0.23±0.7) were decreased. These data suggest that the ability of 5-HT7R activation to increase splanchnic vascular resistance is effectively opposed over time by an endogenous vasodilator, which we suspect is nitric oxide. The data also indicate that changes in splanchnic vascular resistance are unlikely to participate in the chronic hypotensive effect of 5-HT, whereas increased resistance to flow through the hepatic portal system could play a role.