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Journal article
Anti-hypertensive mechanisms of cyclic depsipeptide inhibitor ligands for G(q/11) class G proteins
Pharmacological research, v 141, pp 264-275
01 Mar 2019
PMID: 30634050
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 Ca2+ 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 (FRt1/2 congruent to 12h vs. YMt1/2 congruent to 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 +/- 7mmHg), 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.
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Details
- Title
- Anti-hypertensive mechanisms of cyclic depsipeptide inhibitor ligands for G(q/11) class G proteins
- Creators
- Matthew M. Meleka - Drexel UniversityAlethia J. Edwards - Departments of Pharmacology & Physiology, United States.Jingsheng Xia - Departments of Pharmacology & Physiology, United States.Shelby A. Dahlen - Departments of Pharmacology & Physiology, United States.Ipsita Mohanty - Departments of Pharmacology & Physiology, United States.Matthew Medcalf - Washington University in St. LouisShaili Aggarwal - Departments of Pharmacology & Physiology, United States.Kevin D. Moeller - Washington University in St. LouisOle V. Mortensen - Departments of Pharmacology & Physiology, United States.Patrick Osei-Owusu - Departments of Pharmacology & Physiology, United States.
- Publication Details
- Pharmacological research, v 141, pp 264-275
- Publisher
- Elsevier
- Number of pages
- 12
- Grant note
- R01MH106912 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) Margaret Q. Landenberger Foundation Brody postdoctoral fellowship from the Philadelphia Foundation R01HL139754 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) R01GM122747 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) Pennsylvania Department of Health (CURE) 16SDG27260276 / American Heart Association HL139754; NIH - MH106912 / NIH - NHLBI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000460997000021
- Scopus ID
- 2-s2.0-85059783341
- Other Identifier
- 991019169542704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Pharmacology & Pharmacy