Hypertension exhibits 5-HT4 receptor as a modulator of sympathetic neurotransmission in the rat mesenteric vasculature

Hypertens Res. 2019 May;42(5):618-627. doi: 10.1038/s41440-019-0217-7. Epub 2019 Jan 29.

Abstract

Sympathetic overdrive is a key player in hypertension, where the mesenteric vasculature plays a relevant role in modulating blood pressure. Although 5-HT inhibits noradrenergic mesenteric neurotransmission in normotensive rats, its effect on the mesenteric sympathetic drive in hypertensive rats has not been studied. We investigated the influence of in vivo 5-HT by characterizing the implicated serotonergic receptors on the mesenteric sympathetic outflow in rats with N-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Hypertension was induced in male Wistar rats by L-NAME administration (30 mg/kg per day; 21 days) in drinking water. The rats were anesthetized (sodium pentobarbital; 60 mg/kg, i.p.), prepared for the in situ autoperfused rat mesentery, and subjected for monitoring their systemic blood pressure (SBP), heart rate (HR), and mesenteric perfusion pressure (MPP). Electrical stimulation of mesenteric sympathetic nerves resulted in frequency-dependent increases in MPP without altering SBP or HR. The 5-HT and cisapride (5-HT4 agonist) i.a. bolus (1-25 µg/kg) inhibited vasopressor responses by electrical stimulation of the mesenteric nerves, unlike an i.a. bolus (25 µg/kg each) of the agonist 5-carboxamidotryptamine (5-HT1/7 agonist), α-methyl-5-HT (5-HT2), or 1-PBG (5-HT3). However, i.a. cisapride (25 µg/kg) did not affect the noradrenaline-induced vasoconstriction in the mesenteric vasculature. Administration of the selective 5-HT4 receptor antagonist GR 125487 (1 mg/kg, i.v.) completely abolished cisapride- and 5-HT-evoked mesenteric sympatholytic effects. Additionally, ELISA analysis demonstrated higher 5-HT4 receptor expression in mesenteric arteries from L-NAME-hypertensive compared with normotensive rats. Our findings suggest that L-NAME-induced hypertension modifies the 5-HT modulation of the rat mesenteric sympathetic drive: prejunctional 5-HT4 receptors are involved in the serotonergic sympathoinhibitory effect.

Keywords: 5-HT4 receptor; L-NAME; hypertensive rat; mesenteric vasculature; sympathetic nervous system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cisapride
  • Disease Models, Animal
  • Hypertension / metabolism*
  • Indoles
  • Male
  • Mesenteric Arteries / metabolism*
  • NG-Nitroarginine Methyl Ester
  • Rats, Wistar
  • Receptors, Serotonin, 5-HT4 / metabolism*
  • Splanchnic Circulation*
  • Sulfonamides
  • Sympathetic Nervous System / metabolism*
  • Synaptic Transmission
  • Vasoconstriction

Substances

  • Indoles
  • Sulfonamides
  • Receptors, Serotonin, 5-HT4
  • Cisapride
  • NG-Nitroarginine Methyl Ester
  • GR 113808