5-HT does not lower blood pressure in the 5-HT₇ knockout rat

The fall in mean arterial pressure (MAP) after 24 h of 5-HT infusion is associated with a dilation of the portal vein (PV) and abdominal inferior vena cava (Ab IVC); all events were blocked by the selective 5-HT₇ receptor antagonist SB269970. Few studies have investigated the contribution of the 5-HT₇ receptor in long-term cardiovascular control, and this requires an understanding of the chronic activation of the receptor. Using the newly created 5-HT₇ receptor knockout (KO) rat, we presently test the hypothesis that continuous activation of the 5-HT₇ receptor by 5-HT is necessary for the chronic (1 wk) depressor response and splanchnic venodilation. We also address if the 5-HT₇ receptor contributes to endogenous cardiovascular regulation. Conscious MAP (radiotelemeter), splanchnic vessel diameter (ultrasound), and cardiac function (echocardiogram) were measured in ambulatory rats during multiday 5-HT infusion (25 μg·kg^-1·min^-1 via minipump) and after pump removal. 5-HT infusion reduced MAP and caused splanchnic venodilation of wild-type (WT) but not KO rats at any time point. The efficacy of 5-HT-induced contraction was elevated in the isolated abdominal inferior vena cava from the KO compared with WT rats, supporting loss of a relaxant receptor. Similarly, the efficacy of 5-HT causing an acute pressor response to higher doses of 5-HT in vivo was also increased in the KO vs. WT rat. Our work supports a novel mechanism for the cardiovascular effects of 5-HT, activation of 5-HT₇ receptors mediating venodilation in the splanchnic circulation, which could prove useful in the treatment of cardiovascular disease.