Anti-hypertensive mechanisms of cyclic depsipeptide inhibitor ligands for G q/11 class G proteins

Matthew M. Meleka, Alethia J. Edwards, Jingsheng Xia, Shelby A. Dahlen, Ipsita Mohanty, Matthew Medcalf, Shaili Aggarwal, Kevin D. Moeller, Ole V. Mortensen, Patrick Osei-Owusu

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Augmented vasoconstriction is a hallmark of hypertension and is mediated partly by hyper-stimulation of G protein couple receptors (GPCRs) and downstream signaling components. Although GPCR blockade is a key component of current anti-hypertensive strategies, whether hypertension is better managed by directly targeting G proteins has not been thoroughly investigated. Here, we tested whether inhibiting G q/11 proteins in vivo and ex vivo using natural cyclic depsipeptide, FR900359 (FR) from the ornamental plant, Ardisia crenata, and YM-254890 (YM) from Chromobacterium sp. QS3666, or it's synthetic analog, WU-07047 (WU), was sufficient to reverse hypertension in mice. All three inhibitors blocked G protein-dependent vasoconstriction, but to our surprise YM and WU and not FR inhibited K + -induced Ca 2+ transients and vasoconstriction of intact vessels. However, each inhibitor blocked whole-cell L-type Ca 2+ channel current in vascular smooth muscle cells. Subcutaneous injection of FR or YM (0.3 mg/kg, s.c.) in normotensive and hypertensive mice elicited bradycardia and marked blood pressure decrease, which was more severe and long lasting after the injection of FR relative to YM (FR t1/2 ≅ 12 h vs. YM t1/2 ≅ 4 h). In deoxycorticosterone acetate (DOCA)-salt hypertension mice, chronic injection of FR (0.3 mg/kg, s.c., daily for seven days) reversed hypertension (vehicle SBP: 149 ± 5 vs. FR SBP: 117 ± 7 mmHg), without any effect on heart rate. Our results together support the hypothesis that increased LTCC and G q/11 activity is involved in the pathogenesis of hypertension, and that dual targeting of both proteins can reverse hypertension and associated cardiovascular disorders.

Original languageEnglish
Pages (from-to)264-275
Number of pages12
JournalPharmacological Research
Volume141
DOIs
StatePublished - Mar 2019

Keywords

  • Arginine vasopressin (CID: 644077)
  • Bay K8644 (CID: 2303
  • Blood pressure
  • Calcium signaling
  • Cyclic depsipeptides
  • Endothelin-1 (CID: 16212950)
  • FR900359 (CID: 14101198)
  • G inhibitor ligands
  • G proteins
  • L-type calcium channel
  • Nifedipine (CID: 63011)
  • Phenylephrine (CID: 5284443)
  • U46619 (CID: 5311493)
  • WU-07047 (PMID: 25875152)
  • YM-254890 (CID: 9919454)

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