Long-term blood pressure lowering and cGMP-activating actions of the novel ANP analog MANP

Yang Chen, Jacob J. Schaefer, Seethalakshmi R. Iyer, Gerald E. Harders, Shuchong Pan, S. Jeson Sangaralingham, Horng H. Chen, Margaret M. Redfield, John C. Burnett

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Based on the cardiac hormone atrial natriuretic peptide (ANP) and its seminal role in blood pressure (BP) homeostasis, we investigated the chronic BP lowering actions of a novel ANP analog currently entering clinical trials for hypertension. Previous reports demonstrate that this analog MANP activates the guanylyl cyclase A receptor (GC-A) and results in more potent biological actions compared with ANP; thus, it may represent a new therapeutic drug for hypertension. A major goal of this study was to establish that chronic subcutaneous delivery of MANP is feasible and hypotensive together with cGMP effects. We investigated the BP-lowering and cGMP-activating actions of acute and chronic subcutaneous delivery in normal and hypertensive rats. Furthermore, we explored vascular mechanisms of MANP in human aortic smooth muscle cells (HASMC) and ex vivo in isolated arteries. In normal rats with a single subcutaneous injection, MANP promoted robust dose-dependent BPlowering actions and natriuresis, together with cGMP activation. Most importantly in hypertensive rats, once-a-day subcutaneous injection of MANP for 7 days induced cGMP elevation and long-term BP reduction compared with vehicle. Mechanistically, in HASMC, MANP activated cGMP and attenuated angiotensin II-mediated increases in intracellular Ca2+ levels while directly vasorelaxing arterial rings. Our study demonstrates for the first time the effectiveness of subcutaneous administration of MANP for 7 days and provides innovative, vascular mechanisms of BP regulation supporting its continued development as a novel therapeutic for hypertension.

Original languageEnglish (US)
Pages (from-to)R669-R676
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume318
Issue number4
DOIs
StatePublished - Apr 2020

Keywords

  • 3′,5′-cyclic guanosine monophosphate
  • Atrial natriuretic peptide
  • Guanylyl cyclase A receptor
  • Hypertension
  • MANP
  • Natriuretic peptide
  • Smooth muscle cells
  • Subcutaneous

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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