Central Blockade of E-Prostanoid 3 Receptor Ameliorated Hypertension Partially by Attenuating Oxidative Stress and Inflammation in the Hypothalamic Paraventricular Nucleus of Spontaneously Hypertensive Rats

Cardiovasc Toxicol. 2021 Apr;21(4):286-300. doi: 10.1007/s12012-020-09619-w. Epub 2020 Nov 9.

Abstract

Hypertension, as one of the major risk factors for cardiovascular disease, significantly affects human health. Prostaglandin E2 (PGE2) and the E3-class prostanoid (EP3) receptor have previously been demonstrated to modulate blood pressure and hemodynamics in various animal models of hypertension. The PGE2-evoked pressor and biochemical responses can be blocked with the EP3 receptor antagonist, L-798106 (N-[(5-bromo-2methoxyphenyl)sulfonyl]-3-[2-(2-naphthalenylmethyl) phenyl]-2-propenamide). In the hypothalamic paraventricular nucleus (PVN), sympathetic excitation can be introduced by PGE2, which can activate EP3 receptors located in the PVN. In such a case, the central knockdown of EP3 receptor can be considered as a potential therapeutic modality for hypertension management. The present study examined the efficacy of the PVN infusion of L-798106, by performing experiments on spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKYs). The rats were administered with chronic bilateral PVN infusion of L-798106 (10 μg/day) or the vehicle for 28 days. The results indicated that the SHRs had a higher mean arterial pressure (MAP), an increased Fra-like (Fra-LI) activity in the PVN, as well as a higher expression of gp91phox, mitogen-activated protein kinase (MAPK), and proinflammatory cytokines in the PVN compared with the WKYs. Additionally, the expression of Cu/Zn-SOD in the PVN of the SHRs was reduced compared with the WKYs. The bilateral PVN infusion of L-798106 significantly reduced MAP, as well as plasma norepinephrine (NE) levels in the SHRs. It also inhibited Fra-LI activity and reduced the expression of gp91phox, proinflammatory cytokines, and MAPK, whereas it increased the expression of Cu/Zn-SOD in the PVN of SHRs. In addition, L-798106 restored the balance of the neurotransmitters in the PVN. On the whole, the findings of the present study demonstrate that the PVN blockade of EP3 receptor can ameliorate hypertension and cardiac hypertrophy partially by attenuating ROS and proinflammatory cytokines, and modulating neurotransmitters in the PVN.

Keywords: Hypertension; Hypothalamic paraventricular nucleus (PVN); Inflammation; L-798106; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Antihypertensive Agents / pharmacology*
  • Antioxidants / pharmacology
  • Blood Pressure / drug effects*
  • Cardiomegaly / metabolism
  • Cardiomegaly / physiopathology
  • Cardiomegaly / prevention & control
  • Disease Models, Animal
  • Hypertension / metabolism
  • Hypertension / physiopathology
  • Hypertension / prevention & control*
  • Inflammation Mediators / metabolism*
  • Male
  • Oxidative Stress / drug effects*
  • Paraventricular Hypothalamic Nucleus / drug effects*
  • Paraventricular Hypothalamic Nucleus / metabolism
  • Paraventricular Hypothalamic Nucleus / physiopathology
  • Prostaglandin Antagonists / pharmacology*
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Reactive Oxygen Species / metabolism
  • Receptors, Prostaglandin E, EP3 Subtype / antagonists & inhibitors*
  • Receptors, Prostaglandin E, EP3 Subtype / metabolism
  • Signal Transduction
  • Sulfonamides / pharmacology*

Substances

  • 5-bromo-2-methoxy-N-(3-(naphthalen-2-yl-methylphenyl)acryloyl)benzenesulfonamide
  • Anti-Inflammatory Agents
  • Antihypertensive Agents
  • Antioxidants
  • Inflammation Mediators
  • Prostaglandin Antagonists
  • Ptger3 protein, rat
  • Reactive Oxygen Species
  • Receptors, Prostaglandin E, EP3 Subtype
  • Sulfonamides