Pharmacological evidence that 5‐HT_1D activation induces renal vasodilation by NO pathway in rats

Abstract

5-HT is a powerful vasoconstrictor substance in renal vasculature (mainly by 5-HT₂ activation). Nevertheless, 5-HT is notable for its dual cardiovascular effects, producing both vasodilator and vasoconstrictor actions. This study aimed to investigate whether, behind the predominant serotonergic vasoconstrictor action, THE 5-HT system may exert renal vasodilator actions, and, if so, characterize the 5-HT receptors and possible indirect pathways. Renal perfusion pressure (PP), systemic blood pressure (SBP) and heart rate (HR) measurement in in situ autoperfused rat kidney was determined in phenylephrine infused rats. Intra arterial (i.a.) bolus administration of 5-HT (0.00000125-0.1 μg/kg) decreased renal PP in the presence of a phenylephrine continuous infusion (phenylephrine-infusion group), without modifying SBP or HR. These vasodilator responses were potentiated by 5-HT₂ antagonism (ritanserin, 1 mg/kg i.v.), whereas the responses were abolished by 5-HT₁ /₇ antagonist (methiothepin, 100 μg/kg i.v.) or 5-HT1D antagonist (LY310762, 1 mg/kg i.v.). The i.a. administration (0.00000125 to 0.1 μg/kg) of 5-CT or L-694,247 (5-HT1D agonist) mimicked 5-HT vasodilator effect, while other agonists (1-PBG, α-methyl-5-HT, AS-19 (5-HT₇), 8-OH-DPAT (5-HT1A) or CGS-12066B (5-HT1B)) did not alter baseline haemodynamic variables. L-694,247 vasodilation was abolished by i.v. bolus of antagonists LY310762 (5-HT1D, 1 mg/kg) or L-NAME (nitric oxide, 10 mg/kg), but not by i.v. bolus of indomethacin (cyclooxygenase, 2 mg/kg) or glibenclamide (ATP-dependent K(+) channel, 20 mg/kg). These outcomes suggest that 5-HT1D activation produces a vasodilator effect in the in situ autoperfused kidney of phenylephrine-infusion rats mediated by the NO pathway.

5‐HT modulates the rat mesenteric vasopressor outflow by 5‐HT1D sympatholytic receptors

“…While 5‐HT showed a significant dose‐ and frequency‐dependent inhibition of electrically‐induced MPP increases, α‐methyl‐5‐HT did not vary them. These mesenteric vasoconstrictions by 5‐HT 2 receptor activation have previously been demonstrated by us in the in situ autoperfused rat mesentery, and also in other in situ autoperfused territories, such as the kidney and the hindquarter . Although 5‐HT 2 receptors are related to sympathoexcitatory actions, we have established that vasoconstrictor effects by specifically 5‐HT 2B/2C receptors in mesenteric territory are not mediated through adrenergic system .…”

“…Although the study of the indirect mechanism is out of the scope of the present investigation, it is possible that the sympatholytic effect in the mesenteric vascular bed due to 5‐HT 1D activation is associated to nitric oxide (NO), rather than to the release of other vasodilator agents, since (i) we have already demonstrated the interrelation between the sympathoinhibitory/vasodilator action of 5‐HT 1D receptors and the NO pathway in the renal vascular bed, and (ii) the nitrergic nerves stand out within the mesenteric innervation that regulates the vascular functionality, proving that the release of NO in the mesentery controls the noradrenergic activity …”