Ivar Eide

Increased sympathetic reactivity may predict insulin resistance: an 18-year follow-up study

Insulin resistance and sympathetic activity are related by a positive feedback system. However, which precedes the other still remains unclear. The present study aimed to investigate the predictive role of sympathoadrenal activity in the development of insulin resistance in an 18-year follow-up study. We also examined whether reactivity to 2 different stress tests, a cold pressor test and a mental stress test, would differ in their predictive power. The 2 tests are supposed to represent different reactivity mechanisms: alpha- and beta-adrenergic responses, respectively. At entry, arterial plasma epinephrine and norepinephrine concentrations were measured in 99 healthy men (age, 19.3 +/- 0.4 years, mean +/- SD) during rest, a mental stress test, and a cold pressor test. Fasting plasma glucose concentration was measured at entry and at follow-up. Insulin resistance at follow-up was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR). Eighty subjects (81%) were eligible for follow-up after 18.0 +/- 0.9 years (mean +/- SD). The norepinephrine responses to cold pressor test at entry predicted plasma glucose concentration (r = 0.301, P = .010) and HOMA-IR (r = 0.383, P = .004) at follow-up in univariate analyses. In multiple regression analyses, corrected for fasting glucose at entry, family history of diabetes, blood pressure-lowering medication, body mass index at entry, and level of exercise, norepinephrine response to cold pressor test was found to be a positive predictor of future HOMA-IR (P = .010). This is the first long-term follow-up study in white subjects showing that sympathetic reactivity predicts future insulin resistance 18 years later. These findings may provide further insights into the pathophysiologic mechanisms of insulin resistance.

Evidence of increased peripheral catecholamine release in patients with long-standing, untreated essential hypertension

In 20 middle-aged men with untreated sustained essential hypertension for more than 5 years, both plasma adrenaline and noradrenaline were positively and significantly correlated with blood pressure. In both hypertensives and 19 normotensive control subjects supine arterial adrenaline concentrations were more than twice the venous concentrations consistent with adrenal production of this catecholamine. Adrenaline a--v(arterial-venous)differences(mean +/- SE) were significantly higher in the hypertensive group (82 +/- 15 pg/ml) than in the controls (50 +/- 5 pg/ml) indicating increased release of adrenaline in the hypertensives (P less than 0.05). Similarly, v-a(venous-arterial) differences of noradrenaline were significantly higher in the hypertensive (44 +/- 20 pg/ml) than in the control group (-10 +/- 16 pg/ml) indicating peripheral noradrenaline release in patients with essential hypertension. The findings are compatible with increased forearm noradrenaline and adrenal adrenaline release in these patients with long-standing untreated essential hypertension.

Double-blind, parallel, comparative study on quality of life during treatment with amlodipine or enalapril in mild or moderate hypertensive patients : a multicentre study

Objective: To compare tolerance, antihypertensive efficacy and impact on quality of life of amlodipine and enalapril in patients with mild or moderate hypertension. Design: Multicentre, double-blind, double-dummy, comparative trial in general practice. Three phases were conducted: 4 weeks on placebo, 12 weeks of dose adjustment (amlodipine or enalapril) and a 38-week maintenance period. Patients: Four hundred and sixty-one patients of both sexes were enrolled; 451 were available for efficacy evaluation at the end of the trial. Treatment: The patients were allocated to either amlodipine (231) or enalapril (230) treatment. If at the end of dose adjustment (amlodipine 5-10mg/day, enalapril 10—40 mg/day) diastolic blood pressure was >95mmHg, hydrochlorothiazide (25—50 mg/day) was added (27 amlodipine patients and 45 enalapril patients). Main outcome measures: Blood pressure changes after 1 year of treatment; between- and within-group changes in quality of life as assessed by psychological general well-being, social and sexual functioning, health-risk perception, alertness, behaviour, and impact of symptom and side effects. Results: Indices on quality of life were unchanged or increased (2-9%) in both groups. Blood pressure was normalized or reduced by >10mmHg in 204 (90%) and 190 (85%) patients on amlodipine and enalapril, respectively. Cough was the most frequently reported adverse event in the enalapril group (13%) and oedema in the amlodipine group (22%). Only eight (4%) patients on amlodipine and nine (4%) on enalapril were withdrawn because of drug-related adverse events. Conclusion: At similar blood pressure reduction in mild and moderate hypertension, quality of life is equally well maintained on amlodipine and enalapril therapy.

The Effect of Angiotensin II Receptor Blockade on Insulin Sensitivity and Sympathetic Nervous System Activity in Primary Hypertension

The objective of this study was to investigate the effect of Losartan (NK-954, DuP-753), a new selective angiotensin II receptor antagonist, on insulin sensitivity and sympathetic nervous system activity in patients with severe primary hypertension. Five patients with a record of diastolic blood pressure (DBP) > or = 115 mmHg, currently either untreated or with DBP > 95 mmHg on antihypertensive treatment, were examined in an open study with the euglycemic glucose clamp examination before and after being treated with Losartan for an average of 6 weeks. The glucose disposal rate increased from 6.2 +/- 2.6 to 7.9 +/- 2.6 mg/kg x min (27%, p < 0.05) during treatment with Losartan. The insulin sensitivity index (glucose disposal rate divided by mean insulin concentration during clamp) increased from 7.7 +/- 4.5 to 10.1 +/- 4.1 arbitrary units (30%, p < 0.05). Plasma noradrenaline decreased from 1.87 +/- 0.53 to 1.11 +/- 0.13 nmol/l (40%, p < 0.05), while plasma adrenaline was unchanged (0.23 +/- 0.10 vs. 0.22 +/- 0.11 nmol/l, n.s.). Mean blood pressure decreased from 132 +/- 10 to 119 +/- 13 mmHg (p < 0.05) and heart rate was unchanged during treatment with Losartan. Thus, antihypertensive treatment with the new selective angiotensin II receptor antagonist Losartan seems to improve insulin sensitivity. A decrease in plasma noradrenaline on Losartan suggests a sympathicolytic effect which together with vasodilation may explain the fall in blood pressure and the improvement in insulin sensitivity.

Insulin sensitivity, sympathetic activity, and cardiovascular reactivity in young men

The present study was undertaken to examine the relationships between insulin sensitivity, blood pressure (BP), and cardiovascular reactivity, and to assess sympathetic nervous system influence. Insulin sensitivity (GDR/I; euglycemic glucose clamp technique) was related to BP and heart rate (HR) in different situations in 40 healthy young men: in the laboratory, during a mental arithmetic stress test, and during baseline conditions at home. GDR/I correlated with supine diastolic BP in the laboratory and with maximum diastolic BP during mental stress (r = -0.46, P = .003; r = -0.62, P = .0001, respectively), but not so strongly with diastolic BP measured at home (r = -0.29, P = .09). Diastolic BP during stress and body mass index were the only independent explanatory variables of GDR/I in multiple regression analysis (multiple R = 0.71, R2 = 0.50, P < .0001). GDR/I and systolic BP were not significantly correlated at any time. GDR/I correlated negatively with HR in the laboratory and with maximum HR during mental stress, but not with HR at home. Maximum plasma epinephrine during stress correlated with stress BP and HR (r = 0.53, P = .001; r = 0.70, P < .0001, respectively) and negatively with GDR/I (r = -0.36, P < .05). In the present study, GDR/I is related to diastolic but not to systolic BP, and more closely correlated to diastolic BP and HR measured during mental stress than to diastolic BP and HR during baseline conditions at home.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathetic Activity and Cardiovascular Risk Factors in Young Men in the Low, Normal, and High Blood Pressure Ranges

We hypothesized that resting blood pressure is related to sympathetic activity in young men who are unaware of their blood pressure status in high, normal, and low ranges and that there is a relationship between sympathetic activity and coronary risk factors. Forty-three healthy, young men from the 1st [group 1, 106/52±2/2 mm Hg (±SEM), n=15], 50th (group 2, 129/79±2/1 mm Hg, n=15), and 98th to 99th percentile (group 3, 166/97±3/1 mm Hg, n=13) at a blood pressure screening were studied with intraarterial blood pressure, heart rate, and arterial plasma catecholamine responses to a mental, cold pressor, and orthostatic stress test. At baseline, group 3 had significant higher blood pressure (137/74±3/2 mm Hg) than group 2 (126/66±3/2 mm Hg; P<0.01) and group 1 (116/62±2/1 mm Hg; P<0.001). Group 1 had lower systolic blood pressure than group 2 (P=0.007). Baseline epinephrine and norepinephrine showed a clear positive linear trend (P<0.05), with the lowest values being in group 1 and highest in group 3. High-density lipoprotein was negatively related to epinephrine (r=−0.387; P=0.010). Mental stress was the only test that showed significant differences in cardiovascular and sympathetic responses among the groups, where group 3 had a more pronounced response in systolic and diastolic blood pressure and heart rate compared with group 1 (P<0.001) and group 2 (P<0.01). Furthermore, we found significant positive linear trends for &Dgr;catecholamines during mental stress across the groups (&Dgr;epinephrine P=0.001 and &Dgr;norepinephrine P=0.026, ANOVA). We conclude that resting blood pressure reflects both variation in resting arterial catecholamines and variation in cardiovascular and sympathetic responses specifically to mental stress.

Mechanism of renin release during acute ureteral constriction in dogs.

The relationship between renal arterial pressure and renin release was examined in anesthetized dogs during complete or partial ureteral constriction. During complete ureteral occlusion ureteral pressure rose to 95 ± 4 mm Hg and renin release increased from 1.7 ± 0.7 to 22.3 ± 3.1 &mgr;g/min; renal blood flow (RBF) was not significantly changed. Renin release was not further increased during subsequent renal arterial constriction; RBF fell in proportion to perfusion pressure, indicating maximum autoregulated arteriolar dilation. During partial ureteral constriction to a ureteral pressure of 65 ± 6 mm Hg, renin release was moderately raised but release mechanisms became fully stimulated when renal arterial pressure was reduced to 104 ± 3 mm Hg. By further constriction of the renal artery, RBF fell in proportion to perfusion pressure and renin release remained high and constant. In control experiments without ureteral constriction, renal arterial pressure had to be reduced to below 65 ± 8 mm Hg to fully stimulate renin release (22.0 ±3.8 jug/min which is not different from 22.3 ±3.1 &mgr;g/min during ureteral occlusion). During partial ureteral constriction, saline infusion (0.9% NaCl at 40 ml/min) raised urine flow, sodium excretion, renal pelvic pressure, and renin release. Thus, the stimulatory effect on renin release of a rise in ureteral pressure exceeded the inhibitory effect of increased sodium excretion. This observation, together with maximum renin release coinciding with complete arteriolar dilation during various combinations of renal arterial and ureteral constriction, is compatible with the conclusion that arteriolar dilation is the predominating stimulus to renin release during ureteral constriction.

Increased platelet and vascular smooth muscle reactivity to low-dose adrenaline infusion in mild essential hypertension

During low-dose adrenaline infusion, platelet count, platelet size, plasma beta-thromboglobulin (BTG) and forearm vascular resistance (FVR) were measured in twelve 40-year-old men with mild, untreated hypertension. The average platelet count increased from 195 to 226 X 10(9)/l (P less than 0.001), platelet size from 7.31 to 7.53 X 10(-15)/l (P less than 0.01), BTG from 0.61 to 1.08 nmol/l (P less than 0.02) and FVR decreased from 97 to 58 (arbitrary units; P less than 0.001) during the infusion. The change in platelet count reflects splenic release of platelets, the change in plasma BTG reflects platelet release reaction, while the reduced FVR reflects vascular smooth muscle cell relaxation. In 11 normotensive men aged 40 years, platelet count increased from 187 to 201 X 10 g/l (P less than 0.01) during an equal low-dose adrenaline infusion. This increase in platelet count is significantly less than in the hypertensive group (P less than 0.01). There was statistically no significant change in platelet size, BTG or FVR in the normotensive group. Arterial adrenaline rose from 0.5 to 2.5 nmol/l in the hypertensive and from 0.5 to 2.4 nmol/l in the normotensive group. A third group of 12 normotensive men received saline infusion: neither platelet parameters nor FVR changed in this group. Thus, a small and equal dose of adrenaline elicited a greater increase in platelet count, an enhanced platelet release reaction and a more pronounced forearm vasodilation in hypertensive than in normotensive subjects.

Increased Platelet Size and Release Reaction in Essential Hypertension

Basal platelet function was measured in 35 40-year-old men with untreated mild essential hypertension and compared with 44 age-matched normotensive men. The groups differed significantly with respect to platelet size in venous blood (hypertensive, 7.46 ± 0.10 x 10-15 I versus normotensive, 7.11 ± 0.09 x 10-15 I; P = 0.01) and arterial concentration of the platelet-specific protein β-thromboglobulin (hypertensive, 1.11 ± 0.23 nmol/l versus normotensive, 0.59 ± 0.04 nmol/l; P = 0.02). The normotensive subjects had significantly higher β-thromboglobulin (BTG) in venous than in arterial blood (P < 0.01). The hypertensive men showed no such difference. In contrast to the normotensive subjects, the hypertensive group had reduced arterial compared with venous platelet count (P < 0.01). This may reflect an increased liability in the hypertensive subjects to lose platelets through adherence to the cannula during arterial blood sampling. The above findings point to increased platelet activity in essential hypertension, particularly in arterial blood.

Renal Hypertension in Rabbits Immunized with Angiotensin - II

In 9 rabbits immunized with angiotensin II and in 3 control rabbits, renal hypertension was produced by wrapping one kidney in silk saturated with turpentine, and removing the other kidney 4 weeks later; both groups developed hypertension within a few days. Intravenous injections of renin and angiotensin had no effect in the immunized rabbits, but raised blood pressure in hypertensive controls. Serum from immunized rabbits was highly potent in binding of radioactively-labelled angiotensin, and could neutralize the pressor effect of large amounts of angiotensin. We conclude that renal hypertension induced in the immunized rabbits is not dependent on the acute pressor effect of angiotensin and renin.