5-Hydroxytryptamine Lowers Blood Pressure in Normotensive and Hypertensive Rats

Abstract

Arterial hyper-responsiveness to 5-hydroxytryptamine (5-HT) is a hallmark of hypertension, and plasma levels of free 5-HT are elevated in hypertension. We hypothesized that chronic administration of 5-HT would cause blood pressure to 1) rise in normotensive rats and 2) rise significantly more in hypertensive rats. The deoxycorticosterone acetate (DOCA)-salt hypertensive and sham normotensive rat were used. Animals were implanted with minipumps that delivered 5-HT (or vehicle) at a rate of 25 g/kg/min for 7 days. Free plasma 5-HT was elevated significantly by this protocol. Within 48 h, mean arterial blood pressure measured telemetrically decreased in sham (106 Ϯ 2 to 83 Ϯ 2 mm Hg) and in DOCA-salt hypertensive (166 Ϯ 9 to 112 Ϯ 3 mm Hg) rats; vehicle did not change blood pressure in either group. Ganglionic blockade (hexamethonium) reduced blood pressure to a greater magnitude in DOCA vehicle-administered rats (peak fall arterial pressure, 91 Ϯ 14 mm Hg) compared with DOCA 5-HT-administered rats (40 Ϯ 6 mm Hg). Maximal acetylcholine-induced (NO-dependent) relaxation in phenylephrine-contracted aortic strips was greater in 5-HTadministered (69.2 Ϯ 9.1% relaxation) versus vehicle-administered (39.7 Ϯ 14.2%) DOCA rats; aortic endothelial cell nitric oxide synthase expression was higher in the 5-HT-versus vehicle-administered DOCA-salt rats. In normotensive and DOCAsalt hypertensive rats, the nitric oxide synthase (NOS) inhibitor N -nitro-L-arginine (0.5 g/l in water) prevented the fall in blood pressure to 5-HT. We conclude that chronic exogenous 5-HT reduces blood pressure in normotensive and hypertensive rats through mechanisms critically dependent on NOS.Serotonin [5-hydroxytryptamine (5-HT)] was discovered and characterized over 60 years ago by the Italian scientist Erspamer (Erspamer and Asero, 1952) and by Irving Page (Rapport et al., 1948; Page and McCubbin, 1953a,b). In the periphery, 5-HT is made primarily in the enterochromaffin cells of the intestine. The circulatory system is exposed to 5-HT through aggregation of platelets (which take up and store a millimolar concentration of 5-HT), release from adrenergic nerves that have taken up 5-HT, and through direct exposure to 5-HT that is free in the blood. In many tissues, 5-HT is taken up and concentrated by the serotonin transporter (SERT) and is rapidly metabolized to an inactive metabolite, 5-hydroxyindole acetic acid (5-HIAA), by intracellular monoamine oxidase.5-HT was originally described as a substance derived from serum (sero) that increased the tone of smooth muscle (tonin). Because of the close association of the platelet with the blood vessel, there has been a long-standing question as to the role of 5-HT in controlling vascular tone and modifying blood pressure under normotensive and hypertensive conditions. Several findings suggest that 5-HT contributes to systemic hypertension. These include the following findings: 1) plasma levels (free) of 5-HT are elevated in experimental and human models of hypertension (Fetkovska et al., 1990;Carr...

Serotonin and Blood Pressure Regulation

“…Contrary to these ideas, we observed that 5-HT caused a decrease in blood pressure in the conscious sham and DOCA-salt hypertensive rats (Diaz et al, 2008). In these studies, 5-HT was given in an Alzet miniosmotic pump (25 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) placed subcutaneously and with an antioxidant.…”

One-Month Serotonin Infusion Results in a Prolonged Fall in Blood Pressure in the Deoxycorticosterone Acetate (DOCA) Salt Hypertensive Rat

“…Blood collection and platelet poor plasma (PPP)/platelet rich plasma (PRP) preparation were conducted according to our previously published methods. 11 Briefly, 5 mL of blood was collected from left cardiac ventricle using a heparin-coated syringe. The blood was transferred into an EDTA anticoagulant vacutainer tube.…”

“…In both the normotensive and DOCAsalt hypertensive rat, the fall in blood pressure was eliminated by administration of the nitric oxide synthase inhibitor NGnitro-L-arginine. 11 The fall in blood pressure is enabled by a fall in total peripheral resistance (TPR), not cardiac output, as flow Special Issue: Celebrating 25 Years of the Serotonin Club …”

“…In both the normotensive and DOCAsalt hypertensive rat, the fall in blood pressure was eliminated by administration of the nitric oxide synthase inhibitor NGnitro-L-arginine. 11 The fall in blood pressure is enabled by a fall in total peripheral resistance (TPR), not cardiac output, as flow probe measurements support, 13 and the functioning of the serotonin transporter (SERT) accounts for ∼50% of the fall in blood pressure stimulated by 5-HT in the male rat. 14 Separate efforts are being made to establish (1) the vascular bed(s) most greatly affected by 5-HT; and (2) the 5-HT receptors or mechanisms by which the fall in blood pressure is established.…”

“…17,18 Finally, the DOCA-salt rat is the original model in which we demonstrated the ability of chronic (one week) administration of 5-HT to reduce blood pressure. 11 In the present study, in addition to telemetric measures of blood pressure, we measured isometric contraction of the isolated artery from all rats. Loss of vascular contraction to agonists of the adrenergic receptor would support a fall in TPR, as would potentiation of endothelial cell dependent relaxation.…”