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BACKGROUND Insulin resistance is associated with hypertension. The relative influences of hyperinsulinaemia and high blood pressure on vascular hypertrophy and carotid distensibility is unclear in patients with longstanding hypertension. METHODS In 88 unmedicated patients with stage II-III hypertension and left ventricular hypertrophy on electrocardiogram we measured blood pressure, minimal forearm vascular resistance (MFVR) using plethysmography, intima-media thickness (IMT) and the wall distensibility of the common carotid arteries using ultrasound, and insulin sensitivity using a 2-h isoglycaemic hyperinsulinaemic clamp. RESULTS IMT was positively correlated to systolic blood pressure (r= 0.26, P < 0.05), whole body glucose uptake index (M/IG; r= 0.22, P< 0.05), age (r= 0.24, P< 0.05) and negatively correlated to body mass index (r= -0.24, P < 0.05); IMT did not correlate to fasting serum insulin (r= -0.14, NS). In men (n = 64) MFVR was positively correlated to systolic blood pressure (r = 0.30, P < 0.05), but was unrelated to M/G and serum insulin. The distensibility of the common carotid arteries was negatively correlated to systolic blood pressure (r = -0.40, P< 0.001) and in untreated patients (n = 22) positively correlated to M/IG (r = 0.47, P < 0.05). CONCLUSIONS High systolic blood pressure was related to vascular hypertrophy, whereas hyperinsulinaemia and insulin resistance were not, suggesting that longstanding high blood pressure is a far more important determinant for structural vascular changes than insulin resistance at this stage of the hypertensive disease. However, hyperinsulinaemia and insulin resistance were associated with low distensibility of the common carotid arteries in the subgroup of never treated hypertensive patients.

An intravenous glucose tolerance test (IVGTT) was performed on 16 spontaneously hypertensive rats (SHR) and 15 Wistar-Kyoto rats (WKY) by challenging them with an intravenous glucose load of 0.125 g/100 g body weight. Serum glucose and insulin were measured at 0, 15, 30, 60, 120, and 240 min. In a second experiment, oral glucose tolerance testing (OGTT) was performed with a glucose load of 170 mg/100 g body weight. Serum glucose and insulin were measured at 0, 30, 60, 120, and 240 min. A third experiment examined in vivo insulin-stimulated peripheral glucose uptake via the insulin suppression test. Glucose (8 mg/kg/min), insulin (2.5 to 4.0 mU/kg/min), and somatostatin (1 ng/kg/min) were infused for 3 h. Steady state serum glucose (SSSG) and serum insulin (SSSI) were determined at 0, 140, 160, and 180 min. IVGTT data indicated that serum glucose values were significantly increased in the WKY compared to the SHR at 15, 30, 60, and 120 min. Glucose clearance rates between 15 and 60 min were significantly (P less than .0001) lower in WKY (0.65 +/- 0.07%/min) compared to SHR (1.91 +/- 0.17%/min). The SHR exhibited an exaggerated 15-min peak in insulin secretion that was lacking in the WKY in response to an intravenous glucose load. OGTT data also indicated that the area under the serum insulin curves was higher in the WKY than in the SHR (P less than .017). Peripheral insulin sensitivity showed that despite comparable SSSI levels between the two strains, SSSG values were 31% higher in the SHR compared to the WKY (P less than .001). Thus, it appears that the WKY has a diminished insulin secretory capacity in response to a glucose load, while the SHR has lower tissue responsiveness to insulin's action.

A positive association exists between insulin resistance, dyslipidemia, and hypertension, specifically salt-sensitive hypertension. A subgroup of salt-sensitive normal and high renin hypertensives called nonmodulators (NM) manifest an inability to modulate the adrenal and renal blood flow responses to a change in dietary sodium. Therefore, we tested the hypothesis that the NM subgroup would be insulin resistant and dyslipidemic when compared with normal and high renin hypertensives, in whom modulation is intact (M). Forty-six nondiabetic hypertensive individuals were evaluated and their modulation status defined by either renal or adrenal criteria. Fasting blood was drawn for measurement of several metabolic factors. Since the NM group had a greater body mass index (BMI) it was subdivided into a “lean” subgroup that matched the BMI of the M group. The fasting insulin levels in both the total NM and lean NM groups was significantly higher than in the M group ( P =.013 and .04, respectively). There were no differences in age, blood pressure, or plasma/serum levels of glucose, triglycerides, total cholesterol, or potassium. NM had elevated fasting insulin levels compared to M, compatible with an insulin resistant state, but this insulin resistance was not accompanied by higher lipid levels, suggesting that dyslipidemia and insulin resistance are dissociable in the hypertensive population.

Abstract The intrarenal production of angiotensin II (Ang II) as a local hormone, suggested by multiple lines of investigation, has been difficult to buttress with evidence of functional significance in humans. During studies designed to assess the renal vascular responses to the renin inhibitor enalkiren, an agent (like others in its class) with great substrate specificity, we noted in some subjects that the time course of the effect of enalkiren on renal plasma flow was not congruent with the time course of its influence on the renin-angiotensin system in the plasma compartment. We pursued this discrepancy in the current study of 18 healthy men and 9 men with essential hypertension, who each received one or more doses of enalkiren while on a fixed sodium diet. Plasma enalkiren and Ang II concentration and renal plasma flow were measured in each subject at intervals during and after discontinuation of the enalkiren infusion. Plasma enalkiren concentration fell progressively in each subject after administration was discontinued, the fall becoming evident 10 minutes after discontinuation without exception. In plasma samples obtained 90 minutes after the end of the infusion, drug levels were generally less than half of their peak value. Plasma Ang II concentration, at nadir levels by the end of the enalkiren administration, rose consistently during recovery. Renal plasma flow, in contrast, rose during infusion but did not begin to fall when enalkiren was discontinued. In 26 of 31 studies, renal plasma flow remained at peak level or even continued to rise; this discordance in the effects on plasma Ang II concentration and on renal plasma flow after discontinuation of enalkiren was highly significant ( P

To test the hypothesis that the hypertension associated with insulin resistance is secondary to an altered responsiveness of the vasculature to pressor agents, we evaluated the relationship between insulin resistance and pressor responses to angiotensin II (AII) in 21 hypertensive (HT) and 8 normotensive (NT) subjects on both a high (200 meq) and a low (10 meq) sodium diet. When sodium balance was achieved, each supine fasting subject underwent an AII infusion at a rate of 3 ng/kg per min for 60 min, with blood pressure monitored every 2 min. On the next day under similar conditions, a euglycemic hyperinsulinemic clamp was performed, with plasma glucose clamped at 90 mg/dl for 120 min. There was no significant relationship between the glucose disposal rate (M) or the insulin sensitivity index (M divided by the mean insulin level [M/I]) and blood pressure response to AII in the NTs, but a highly significant (P < 0.019) negative correlation (r = -0.55) in the HTs. Furthermore, in eight lean HTs whose body mass index was identical to that observed in the NTs, the relationship was even more striking (P < 0.008; r = -0.85). The results on high and low salt diets were similar; however, the M and M/I were significantly increased (P < 0.05) in the NTs but not HTs with sodium restriction. In conclusion, HTs but not NTs display a striking correlation between pressor response to AII and insulin resistance. This relationship is independent of the level of sodium intake. Furthermore, sodium intake modifies insulin sensitivity in NTs but not HTs. These results strongly suggest that a primary change in pressor response to vasoactive agents in insulin-resistant subjects can contribute to their elevated blood pressure.

BACKGROUND Recent clinical trial data indicate that the use of angiotensin converting enzyme (ACE) inhibitors among patients with left ventricular dysfunction results in reduced rates of coronary thrombosis, a provocative finding that suggests a potential interaction between the renin-angiotensin system and fibrinolytic function. METHODS AND RESULTS In four normotensive subjects and six hypertensive patients, we investigated whether infusion of angiotensin II (Ang II) affected circulating levels of plasminogen activator inhibitor-1 (PAI-1), the most important physiological inhibitor of tissue-type plasminogen activator (t-PA). Overall, mean levels of PAI-1 antigen increased significantly from 20.1 ng/mL before Ang II infusion to 36.0 ng/mL at the end of Ang II infusion (p = 0.008), whereas no change in PAI-1 was observed for control subjects infused with 5% dextrose (p = 0.46). Among the normotensive subjects for whom graded doses of Ang II were infused at 0, 1, 3, and 10 ng.kg-1.min-1, mean PAI-1 levels increased sequentially from 14.7 ng/mL to 23.0, 26.8, and 33.5 ng/mL, a dose-response relation that, compared with controls, was highly significant (p < 0.001). Among the hypertensive patients for whom a single 45-minute infusion of Ang II was given at a dose of 3 ng.kg-1.min-1, PAI-1 levels increased from 23.7 to 37.7 ng/mL, whereas PAI-1 levels among control subjects infused with 5% dextrose decreased from 16.9 to 10.8 ng/mL (p = 0.04). Finally, when compared with infusion of 5% dextrose solution, infusion of Ang II appeared to have little effect on circulating levels of t-PA antigen. CONCLUSIONS These in vivo data suggest that infusion of Ang II results in a rapid increase in circulating levels of PAI-1, a finding that may help to explain clinical observations linking the renin-angiotensin system and thrombotic risk.

To determine the reliability of the National Institutes of Health (NIH)-modified semiquantitative histologic scoring system for lupus nephritis.Cross-sectional study, repeated after 8 to 9 months.Four community hospitals and one university medical center.Five pathologists, all experienced in reading renal biopsy specimens, assessed 25 specimens that had been obtained from patients with a clinical diagnosis of systemic lupus erythematosus and showed diffuse proliferative glomerulonephritis.Biopsy specimens were scored independently and blindly by pathologists for components of nephritis chronicity and activity. Reliability was measured by percentage agreement, intraclass correlation coefficient or kappa statistic, and individual reader effect on the group arithmetic mean.As scored by the readers, the mean chronicity index score varied from 2.3 to 4.8 on a 12-point scale (P = 0.001) and the mean activity index score varied from 5.8 to 11.4 on a 24-point scale (P = 0.0001). Pairs of readers gave scores within 1 point for the chronicity index and within 2 points for the activity index in 50% of cases, and risk group assignments based on chronicity index (three strata) and activity index (two strata) were concordant in 59% and 76% of cases, respectively. Intraclass correlation coefficients for inter-reader agreement were 0.58 for the chronicity index (P0.01) and 0.52 for the activity index (P0.01). Intrareader agreement was uniformly higher than inter-reader agreement, but mean intraclass correlation coefficients exceeded 0.70 for only 1 of the 10 index components. Repeated readings yielded chronicity index scores that were more than 1 point discordant in 45% of cases and activity index scores that were more than 2 points discordant in 43% of cases. Risk group assignment changed on the basis of chronicity index and activity index in 36% and 21% of cases, respectively.In a nonreferral setting, the NIH-modified scoring system for lupus nephritis is only moderately reproducible and, if used to prognosticate renal outcome, may result in erroneous predictions of risk for renal failure and response to therapy.