A novel antihypertension agent, sargachromenol D from marine brown algae, Sargassum siliquastrum, exerts dual action as an L-type Ca2+ channel blocker and endothelin A/B2 receptor antagonist

Bioorg Med Chem. 2017 Sep 1;25(17):4649-4655. doi: 10.1016/j.bmc.2017.07.002. Epub 2017 Jul 6.

Abstract

We isolated the novel vasoactive marine natural products, (5E,10E)-14-hydroxy-2,6,10-trimethylpentadeca-5,10-dien-4-one (4) and sargachromenol D (5), from Sargassum siliquastrum collected from the coast of the East Sea in South Korea by using activity-guided HPLC purification. The compounds effectively dilated depolarization (50mMK+)-induced basilar artery contraction with EC50 values of 3.52±0.42 and 1.62±0.63μM, respectively, but only sargachromenol D (5) showed a vasodilatory effect on endothelin-1 (ET-1)-induced basilar artery contraction (EC50=9.8±0.6μM). These results indicated that sargachromenol D (5) could act as a dual antagonist of l-type Ca2+ channel and endothelin A/B2 receptors. Moreover, sargachromenol D (5) lowered blood pressure in spontaneous hypertensive rats (SHRs) 2h after oral treatment at a dose of 80mg/kg dose and the effect was maintained for 24h. Based on our ex vivo and in vivo experiments, we propose that sargachromenol D (5) is a strong candidate for the treatment of hypertension that is not controlled by conventional drugs, in particular, severe-, type II diabetes-, salt-sensitive, and metabolic disease-induced hypertension.

Keywords: Endothelin A/B(2) receptor antagonist; Endotheline-1; Isolation; L-type Ca(2+) channel blocker; Marine natural product; Severe hypertension; Vasodilation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antihypertensive Agents / chemistry*
  • Antihypertensive Agents / isolation & purification
  • Antihypertensive Agents / pharmacology
  • Basilar Artery / drug effects
  • Basilar Artery / physiology
  • Benzopyrans / chemistry*
  • Benzopyrans / isolation & purification
  • Benzopyrans / pharmacology
  • Blood Pressure / drug effects
  • Calcium Channel Blockers / chemistry*
  • Calcium Channel Blockers / isolation & purification
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, L-Type / chemistry
  • Calcium Channels, L-Type / metabolism
  • Endothelin A Receptor Antagonists / chemistry*
  • Endothelin A Receptor Antagonists / isolation & purification
  • Endothelin A Receptor Antagonists / pharmacology
  • Endothelin B Receptor Antagonists / chemistry*
  • Endothelin B Receptor Antagonists / isolation & purification
  • Endothelin B Receptor Antagonists / pharmacology
  • Male
  • Phaeophyceae / chemistry*
  • Phaeophyceae / metabolism
  • Rabbits
  • Rats
  • Rats, Inbred SHR
  • Receptor, Endothelin A / chemistry
  • Receptor, Endothelin A / metabolism
  • Receptor, Endothelin B / chemistry
  • Receptor, Endothelin B / metabolism

Substances

  • Antihypertensive Agents
  • Benzopyrans
  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Endothelin A Receptor Antagonists
  • Endothelin B Receptor Antagonists
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • sargachromenol