IntroductionThe reason why hyperinsulinemia is associated with essential hypertension is not known. To test the hypothesis of a pathophysiologic link mediated by the sympathetic nervous system, we measured the changes in forearm norepinephrine release, by using the forearm perfusion technique in conjunction with the infusion of tritiated NE, in patients with essential hypertension and in normal subjects receiving insulin intravenously (1 mU/ kg per min) while maintaining euglycemia.Hyperinsulinemia (50-60 jsU/ml in the deep forearm vein) evoked a significant increase in forearm NE release in both groups of subjects. However, the response of hypertensives was threefold greater compared to that of normotensives (2.28±45 ng. liter-' * min' in hypertensives and 0.80±0.27 ng. liter-' in normals; P < 0.01). Forearm Although the coexistence ofhyperinsulinemia and essential hypertension has long been recognized (1-3), the nature and the significance of this association are far from being completely elucidated. A critical question is whether hyperinsulinemia is causally related to the development of hypertension and, if so, what mechanism underlies insulin action on blood pressure regulation. The question is under active investigation but the data available so far are not entirely consistent. Substantial evidence favoring a causal role of insulin comes essentially from the studies in fructose-fed rats (4-6). In this model, insulin resistance, hyperinsulinemia, and hypertension develop and this sequence may be interrupted by preventing either insulin resistance with physical exercise or hyperinsulinemia with somatostatin (5, 6).The relationship between insulin and human hypertension has been extensively investigated on epidemiological ground, less so from a mechanistic standpoint. The available clinical data, however, tend to support the concept that the two factors must be linked by pathophysiologic mechanisms. Particularly relevant is the observation that a program of physical activity or body weight control leads to a parallel reduction of hyperinsulinemia and blood pressure levels (7). Of interest is also the recent observation that in the offspring of essential hypertensive parents insulin resistance and hyperinsulinemia are demonstrable before the development of high blood pressure (8).Among the various factors considered as potential links between insulin and blood pressure, the sympathetic nervous system is indicated as a prime candidate for a number of reasons: (a) in hypertensive patients, glucose intolerance and insulin resistance with attendant hyperinsulinemia have been amply demonstrated (3, 9, 10); (b) in normal individuals, insulin evokes sympathetic overactivity (1 1, 12); (c) increased sympathetic activity in essential hypertension, particularly in the mild form of young hypertensives, has been documented by a variety of approaches (13,14); and (d) sympathetic overactivity may be potentially responsible for elevated blood pressure (15) and may antagonize insulin action (16)(17)(18)(19)(20). Ba...

These results show a reduced ability to excrete a sodium load and early abnormalities of cardiac and hemodynamic adaptations to salt excess in patients with mild heart failure and no signs or symptoms of congestion.

We assessed in normal subjects the effects of an acute increase in forearm norepinephrine (NE) release, evoked by -20 mmHg lower body negative pressure (LBNP), on insulin-mediated muscle glucose uptake. Seven normal subjects underwent the following two insulin euglycemic clamps in random sequence: one during application of LBNP and the other without LBNP (control study). In the control study, hyperinsulinemia (approximately 60 microU/ml) produced a significant increment in forearm NE release, measured by using the forearm perfusion technique combined with infusion of tritiated NE (from 4.91 +/- 1 to 7.94 +/- 1.33 ng.l-1.min-1; P < 0.05). Forearm glucose uptake rose from 0.97 +/- 0.13 to 5.2 +/- 0.2 mg.l-1.min-1 in response to insulin infusion. When the insulin clamp was performed during LBNP, forearm NE release rose to significantly higher values than those of the control study (from 4.33 +/- 0.52 to 12.7 +/- 1.46 ng.l-1.min-1; P < 0.01 vs. control). Under these conditions, the stimulatory effect of insulin on forearm glucose uptake was markedly reduced (from 0.78 +/- 0.10 to 3.2 +/- 0.7 mg.l-1.min-1; P < 0.02 vs. control). Forearm blood flow and plasma epinephrine and free fatty acid concentrations were comparable in the two study sessions. These data demonstrate that an acute activation of endogenous NE release antagonizes insulin-mediated glucose uptake in forearm skeletal muscle, probably accounted for by a direct metabolic effect of NE.

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The selective in vivo stimulation of alpha 2-adrenoceptors produces a reduction in coronary blood flow and diameter in humans with angiographically normal coronary arteries. alpha 2-Adrenergic blockade does not change coronary blood flow in subjects with angiographically normal coronary arteries (suggesting no resting alpha 2-adrenergic vasoconstrictor tone), whereas in patients with coronary artery stenosis, regional coronary blood flow decreases after alpha 2-receptor blockade. Finally, our data also suggest that alpha 2-adrenoceptors participate in the modulation of sympathetic neuronal norepinephrine release in the human heart.