Subpressor Dose of L-NAME Unmasks Hypertensive Effect of Chronic Hyperinsulinemia

Abstract

Abstract-We previously found that chronic exogenous hyperinsulinemia without sugar supplementation does not elevate blood pressure. This may be partially explained by the ability of insulin to release nitric oxide and cause vasodilatation.To test this hypothesis, we studied 4 groups of rats: 9 rats (body weight, 213Ϯ14 g) treated with a gradual increase of a sustained-release subcutaneous insulin pellet; 9 rats (body weight, 213Ϯ9 g) treated with N G -nitro-L-arginine methyl ester (L-NAME) in drinking water 50 mg/L; 19 rats (body weight, 217Ϯ11 g) treated with the combination of L-NAME and insulin; and 9 control rats (body weight, 218Ϯ11 g). Blood pressure was followed weekly for 6 weeks, and then rats were studied in metabolic cages. Weight gain was not different during the 6 weeks. Renal function did not differ between the 4 groups, but 24-hour urinary nitrite/nitrate excretion was lower (PϽ0.02) in L-NAME-treated and higher in insulin-treated rats. Plasma insulin doubled (PϽ0.002) in the insulin-treated rats, but there was no hypoglycemia and, by week 6, fructosamine levels were 2.1Ϯ0.2, 2.1Ϯ0.2, 2.3Ϯ0.1, and 2.3Ϯ0.2 mmol/L in control rats and rats treated with L-NAME, insulin, and L-NAME plus insulin, respectively. Systolic blood pressure, which did not differ at baseline, at week 3 was 122Ϯ17, 118Ϯ17, and 118Ϯ24 mm Hg in the control, L-NAME, and insulin groups and 136Ϯ14 mm Hg (PϽ0.03) in the combination group. At week 6, systolic blood pressure was 128Ϯ14, 127Ϯ15, and 118Ϯ13 mm Hg in the control, L-NAME, and insulin groups, respectively, and 150Ϯ14 mm Hg (PϽ0.0005) in the combination group. In a subsequent experiment, L-arginine 2 g/L abrogated the effects of L-NAME and insulin combination. In conclusion, chronic exogenous hyperinsulinemia does not affect blood pressure but may cause hypertension when endothelial function is compromised. Key Words: insulin Ⅲ nitric oxide Ⅲ sodium Ⅲ nitrites Ⅲ nitrates H yperinsulinemia was found to be common in essential hypertension even without obesity and is the foundation for the concept of the metabolic syndrome X. However, the manner in which insulin elevates blood pressure is unclear. Sympathetic activation, 1,2 sodium retention, 3 and vascular hypertrophy have been suggested 4 but never proven in a chronic model of hyperinsulinemia. Indeed, because of the vasodilatory effects of insulin, 2 it has been suggested the vasodilation may mask a prohypertensive effect. More recently it was found that, in part, insulin-induced vasodilation may be related to increase in nitric oxide synthase (NOS) activity. 5 There have been several attempts to produce hypertension in rats by way of chronic exogenous hyperinsulinemia. 6 -10 In most of these studies, increase in carbohydrate consumption (intravenous glucose or oral sucrose) was combined with insulin to prevent hypoglycemia. We previously devised a method for producing chronic exogenous hyperinsulinemia in normal rats, without sugar supplementation and without hypoglycemia, that did not affect blood pressure. 10 However, whe...

Association of Capillary Density and Function Measures With Blood Pressure, Fasting Plasma Glucose, and Insulin Sensitivity

“…46 Another possibility, based on rat studies, is that chronic hyperinsulinemia may not universally affect BP but may cause hypertension when endothelial dysfunction is present. 47 The relationship between capillary function ⁄ density and hypertension, IS, and EF is in need of further exploration in future studies.…”

Regional Hemodynamic Effects of the N-(2-Benzoylphenyl)-l-tyrosine Peroxisome Proliferator-Activated Receptor-γ Ligand, GI 262570 [(S)-2-(2-Benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic Acid], in Conscious Rats

“…This is somewhat surprising, considering that insulin increases vascular NO production, although such an effect would not be expected to have been confined to the hindquarters (Hilzenrat et al, 2001). But, although an NO-dependent component of the vasodilator action of insulin is widely acknowledged (see Hsueh and Law, 1999, for review; Bursztyn et al, 2000;Molinari et al, 2001), there is evidence that the vasodilator action of thiazolidenediones on rat coronary vessels (Uchida et al, 2000) and the human forearm (Fujishima et al, 1998) is NO-independent. In fact, there is evidence that PPAR-␥ ligands may suppress inducible nitric-oxide synthase expression while increasing heme oxygenase-1 expression in rat glial cells (Kitamura et al, 1999).…”

Chronic insulin treatment suppresses PTP1B function, induces increased PDGF signaling, and amplifies neointima formation in the balloon-injured rat artery

“…Hyperinsulinemia was implemented by following a previously published procedure (6). Briefly, rats received a 2-mm segment of a 7-mm blank or sustained-release bovine insulin-releasing pellet (the expected delivery rate of insulin was 0.6 U/day for Ͼ40 days as indicated by the manufacturer of the pellet) under short-term isoflurane anesthesia (model 100 vaporizer, Surgivet).…”

“…Some studies (4,27) have reported an association between experimental hyperinsulinemia and hypertension or hypertriglyceridemia. We used a model of insulin infusion in the rat on the basis of a report (6) indicating that the use of an implantable insulin-impregnated pellet, in two stages, induces modest hyperinsulinemia without eliciting significant hypertension or hypertriglyceridemia. As shown in Fig.…”