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EXPERIMENTAL STUDIES

Vascular actions of brain natriuretic peptide: modulation by atherosclerosis and neutral endopeptidase inhibition

^a Cardiorenal Research Laboratory, Divisions of Cardiovascular Diseases and Cardiovascular Surgery, Departments of Internal Medicine, Physiology and Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, Minnesota, USA

Manuscript received September 2, 1998; revised manuscript received September 13, 1999, accepted November 15, 1999.

Reprint requests and correspondence: Dr. John C. Burnett, Jr., Mayo Clinic and Foundation, 200 First Street SW, Guggenheim 9, Rochester, Minnesota 55905
burnett.john{at}mayo.edu

Objectives

We sought to define the vascular actions of the cardiac hormone brain natriuretic peptide (BNP) on cellular proliferation and cyclic guanosine monophosphate (cGMP) in human aortic vascular smooth muscle cells (HAVSMCs). Secondly, we investigated BNP and acetylcholine (ACh) vasorelaxations in aortic rings from normal and atherosclerotic rabbits in the presence and absence of long-term oral inhibition of neutral endopeptidase (NEP).

Background

The vascular actions of BNP are not well defined, despite the presence of its receptor in vascular smooth muscle and the upregulation of NEP, the ectoenzyme that degrades BNP, in the vascular wall in atherosclerosis.

Methods

HAVSMCs stimulated with fetal calf serum (FCS) were pulsed with bromodeoxyuridine (BrdU) with and without BNP. The HAVSMCs were incubated in the presence and absence of BNP to assess cGMP. Vasorelaxations to BNP and ACh were assessed in rings in normal and atherosclerotic rabbits in the presence and absence of long-term oral inhibition of NEP, together with assessment of atheroma formation.

Results

FCS-stimulated BrdU uptake in HAVSMCs was suppressed with BNP. BNP potentiated cGMP in HAVSMCs. BNP resulted in potent vasorelaxation in normal isolated aortic rings, which were impaired in atherosclerotic versus normal rabbits and preserved with NEP inhibition, which also decreased atheroma formation. Relaxations to ACh, which were also impaired in atherosclerosis, were preserved with inhibition of NEP.

Conclusions

We conclude that BNP potently inhibits vascular smooth muscle cell proliferation and potentiates the generation of cGMP. BNP potently relaxes the normal rabbit aorta, and this response is impaired in atherosclerosis but preserved with inhibition of NEP, together with a reduction in atheroma formation and preservation of relaxations to ACh.

Abbreviations and Acronyms   ACh = acetylcholine   BNP = brain natriuretic peptide   BrdU = bromodeoxyuridine   cGMP = cyclic guanosine monophosphate   EC50 = effective concentration at 50% relaxation   FCS = fetal calf serum   HAVSMC = human aortic vascular smooth muscle cell   NEP = neutral endopeptidase   NO = nitric oxide   NPR-A = natriuretic peptide A receptor   PGC = particulate guanylyl cyclase

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