Reversal of fructose-induced hypertension and insulin resistance by chronic losartan treatment is independent of AT2 receptor activation in rats.
OBJECTIVE
To examine whether angiotensin II type 2 receptors (AT2R) are involved in the reversal of fructose-induced hypertension and insulin resistance after chronic angiotensin II type 1 receptor (AT1R) blockade.


METHODS
Sprague-Dawley rats on fructose-enriched or regular diets were pretreated with losartan, an AT1R antagonist, or vehicle for 2 weeks before two-step glucose and insulin clamp experiments with [3-3H]glucose infusion. The hepatic glucose production (HGP) and whole-body glucose uptake (WBGU) were calculated during basal, euglycemic and euglycemic hyperinsulinemic periods. Blood pressure was measured before and after acute losartan (10 mg/kg, i.v. bolus), alone or in combination of PD123319 (PD, 50 microg/kg per min), an AT2R antagonist, or CGP42112 (2 microg/kg per min), an AT2R agonist, during the clamp study.


RESULTS
In rats on a regular diet, acute infusion of losartan alone or in combination with PD, an AT2R blocker, did not alter blood pressure and glucose metabolism during experiments. Fructose feeding for 6 weeks significantly increased blood pressure and attenuated insulin-mediated suppression of HGP and stimulation of WBGU. Both acute and chronic administration of losartan suppressed fructose-induced hypertension. Concomitant treatment with PD and losartan blunted the acute but not chronic losartan-mediated depressor effect. Acute losartan treatment further reduced insulin-induced suppression of HGP, but simultaneously increased insulin-stimulated WBGU. These acute metabolic effects of losartan were eliminated when PD was co-administered with losartan. Conversely, chronic losartan pretreatment significantly enhanced suppression of HGP and increased stimulation of WBGU by insulin, which were not altered when PD or CGP 42112 was superimposed on losartan during the clamp experiments.


CONCLUSIONS
These results suggest that reversal of high fructose-induced hypertension and insulin resistance by chronic losartan treatment is not dependent on AT2R activation and that functional activation of AT1R plays a major role in the pathogenesis of high fructose-induced hypertension and insulin resistance.
Hsieh
Po-Shiuan
PS
Department of Physiology and Biophysics, National Defense Medical Center, National Defense University, Taipei, Taiwan. pshsieh@hotmail.com
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology; D005632:Fructose / Q000633:toxicity*; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000959:Antihypertensive Agents; D007093:Imidazoles; D009842:Oligopeptides; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; C060894:CGP 42112A; C073402:PD 123319; D005632:Fructose; D005947:Glucose; D019808:Losartan