Antihypertensive effect of glucagon-like peptide 1 in Dahl... : Journal of Hypertension (original) (raw)

Origianl papers: Metabolic aspects and diabetes

Yu, Minga; Moreno, Carola; Hoagland, Kimberly Ma; Dahly, Annettea; Ditter, Katiea; Mistry, Maheshb; Roman, Richard Ja

aDepartment of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin and bRestoragen Inc., Lincoln, Nebraska, USA

Sponsorship: This work was supported in part by grants HL29587 and 36279 from NIH in USA and a sponsored research award from Restoragen Inc., Lincoln, Nebraska, USA. C.M. was supported in part by a postdoctoral fellowship (EX2001) from the Spanish Ministry of Education, Culture and Sports and K.M.H. was supported by HL10364–02 from NRSA in USA.

See editorial commentary on page 1079

Correspondence and requests for reprints to Richard J. Roman, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA. Tel: +1 414 456 8723; fax: +1 414 456 6546; e-mail: [email protected]

Received 6 November 2002 Revised 10 February 2003 Accepted 21 February 2003

Abstract

Background

Dahl salt-sensitive (Dahl S) rats exhibit many phenotypic traits associated with salt-sensitive hypertension in man. Specifically, they are salt-sensitive, insulin-resistant and hyperlipidemic. They also develop endothelial dysfunction, cardiac injury and glomerulosclerosis. Insulin resistance is linked to hypertension, renal and cardiac damage and endothelial dysfunction. Thus, an agent that has diuretic action and can improve insulin resistance, like recombinant glucagon-like peptide-1(7-36)amide (rGLP-1), may have an antihypertensive effect.

Objective

To determine whether chronic administration of rGLP-1 attenuates the development of hypertension, endothelial dysfunction and/or hypertension-induced renal and cardiac end organ damage in Dahl S rats.

Methods

Mean arterial pressure (MAP) and urinary excretion of protein and albumin were measured in Dahl S rats before and after they were fed a 8% NaCl diet and infused with rGLP-1 (1 μg/kg per min, i.v.) or vehicle for 14 days. At the end of the study, the degree of renal and cardiac injury was histologically assessed and endothelium-dependent relaxing function was studied using aortic rings. In other rats, the effects of rGLP-1 on sodium and water balance and plasma glucose and insulin levels for the first 3 days following a step change in sodium intake from a 0.1% NaCl diet to 7.5 mEq/day were determined.

Results

rGLP-1 significantly attenuated the development of hypertension in Dahl S rats (136 ± 7 versus 174 ± 6 mmHg). This was associated with reduction in proteinuria (46 ± 7 versus 128 ± 15 mg/day) and albuminuria (46 ± 7 versus 86 ± 18 mg/day) and improvement of endothelial function and renal and cardiac damage. rGLP-1 markedly increased urine flow and sodium excretion for the first 3 days following elevation in sodium intake. It had no significant effects on plasma glucose and insulin concentrations.

Conclusion

rGLP-1 has antihypertensive and cardiac and renoprotective effects in Dahl S rats fed a high salt diet. The antihypertensive effect of rGLP-1 in Dahl S rats is due mainly to its diuretic and natriuretic effects, rather than an effect to improve insulin-resistance.