Antihypertensive effect of glucagon-like peptide 1 in Dahl salt-sensitive rats.
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 micro g/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.


CONCLUSIONS
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.
Yu
Ming
M
Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA.
Moreno
Carol
C
Hoagland
Kimberly M
KM
Dahly
Annette
A
Ditter
Katie
K
Mistry
Mahesh
M
Roman
Richard J
RJ
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000473:pathology; D001786:Blood Glucose / Q000187:drug effects; D004231:Diuresis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000473:pathology; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D006331:Heart Diseases / Q000473:pathology / Q000517:prevention & control; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D007328:Insulin / Q000097:blood; D007674:Kidney Diseases / Q000473:pathology / Q000517:prevention & control; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D012964:Sodium / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D014882:Water-Electrolyte Balance / Q000187:drug effects
D000959:Antihypertensive Agents; D001786:Blood Glucose; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D017673:Sodium Chloride, Dietary; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D012964:Sodium