5-HT causes splanchnic venodilation

Abstract

Serotonin [5-hydroxytryptamine (5-HT)] causes relaxation of the isolated superior mesenteric vein, a splanchnic blood vessel, through activation of the 5-HT₇ receptor. As part of studies designed to identify the mechanism(s) through which chronic (≥24 h) infusion of 5-HT lowers blood pressure, we tested the hypothesis that 5-HT causes in vitro and in vivo splanchnic venodilation that is 5-HT₇ receptor dependent. In tissue baths for measurement of isometric contraction, the portal vein and abdominal inferior vena cava relaxed to 5-HT and the 5-HT_1/7 receptor agonist 5-carboxamidotryptamine; relaxation was abolished by the 5-HT₇ receptor antagonist SB-269970. Western blot analyses showed that the abdominal inferior vena cava and portal vein express 5-HT₇ receptor protein. In contrast, the thoracic vena cava, outside the splanchnic circulation, did not relax to serotonergic agonists and exhibited minimal expression of the 5-HT₇ receptor. Male Sprague-Dawley rats with chronically implanted radiotelemetry transmitters underwent repeated ultrasound imaging of abdominal vessels. After baseline imaging, minipumps containing vehicle (saline) or 5-HT (25 μg·kg^-1·min^-1) were implanted. Twenty-four hours later, venous diameters were increased in rats with 5-HT-infusion (percent increase from baseline: superior mesenteric vein, 17.5 ± 1.9; portal vein, 17.7 ± 1.8; and abdominal inferior vena cava, 46.9 ± 8.0) while arterial pressure was decreased (~13 mmHg). Measures returned to baseline after infusion termination. In a separate group of animals, treatment with SB-269970 (3 mg/kg iv) prevented the splanchnic venodilation and fall in blood pressure during 24 h of 5-HT infusion. Thus, 5-HT causes 5-HT₇ receptor-dependent splanchnic venous dilation associated with a fall in blood pressure.NEW & NOTEWORTHY This research is noteworthy because it combines and links, through the 5-HT₇ receptor, an in vitro observation (venorelaxation) with in vivo events (venodilation and fall in blood pressure). This supports the idea that splanchnic venodilation plays a role in blood pressure regulation.

Keywords: SB-269970; blood pressure; imaging; pharmacology; serotonin; veins.

Fig. 1.

A: Western analyses of the 5-HT₇ receptor in homogenates of the portal vein (PV), thoracic (above diaphragm) vena cava (TVC), and abdominal inferior vena cava (Ab IVC) from the same set of 9 animals (3 animals/lane, 3 lanes). The blot was reprobed with α-actin. B: densitometry of all nonoutlying values for the 5-HT₇ receptor signal relative to α-actin expression. Bars represent means ± SE for the number of lanes and animals specified on the graph.

Fig. 2.

Relaxation of the endothelin (ET)-1-contracted isolated thoracic VC (above diaphragm; TVC), PV, and Ab IVC to 5-HT (A) and 5-carboxamidotryptamine (5-CT; B). The magnitude of venous contraction to 1 nM ET-1 was PV = 279.1 ± 44.6 mg, Ab IVC = 206.2 ± 54.7 mg, and TVC = 66.1 ± 7.0 mg. Points represent means ± SE for the number of animals in parentheses. Veins were taken from the same animals for intravessel comparison of sensitivity to each agonist.

Fig. 3.

Ability of the 5-HT₇ receptor antagonist SB-269960 to antagonize 5-CT-induced relaxation in the isolated Ab IVC (A) and PV (B). Points represent means ± SE for the number of animals in parentheses. These veins were taken from the same animals for intra-arterial comparison. *Significant difference vs. vehicle-exposed tissues at the maximum agonist concentration tested (P < 0.05).

Fig. 4.

A: diagram of ultrasound wand/transducer placement for image procurement using the Vevo2100. The tan box shows the initial position of the plane imaged by the ultrasound probe. The drawing was done by Chris McKee. B: representative B-mode ultrasound images taken at baseline (left) and 24 h after 5-HT (right) in the same rat. Horizontal lines quantify size.

Fig. 5.

Change in vessel diameter (A) and physiological parameters (B) with infusion of vehicle (open bars) and 5-HT (solid bars). Bars represent means ± SE for the number of animals indicated in parentheses (n). *Statistical differences between 5-HT after 24 h and 5-HT reversal. ∞Significant differences between vehicle and 5-HT after 24 h.

Fig. 6.

Mean arterial blood pressure (A) and magnitude of the fall in blood pressure (percent baseline; B) in rats infused with SB-269970 or vehicle before pump implantation with 5-HT (25 μg·kg⁻¹·min⁻¹). Measures of blood pressure were done 24 h after pump implantation and then again after SB-269970 removal. Points/bars represent means ± SE for the number of animals in parentheses. *Statistical differences between the two bracketed bars.

Fig. 7.

5-HT-induced changes in vessels diameters (A) and cardiovascular parameters (B) in rats infused with SB-269970 or vehicle before pump implantation with 5-HT (25 μg·kg⁻¹·min⁻¹). Measures of blood pressure were done 24 h after pump implantation. Saline + saline animals were used as controls for infusion of vehicles that carried both 5-HT and SB-269970. Points/bars represent means ± SE for the number of animals in parentheses. *Significant from own baseline, ∞significant compared with 5-HT + SB-269970, ±significant compared with saline + saline.