Nine hypertensive patients with body mass indexes between 24-27 kg/m2 and normal glucose tolerance with at least a postchallenge plasma insulin level greater than 360 pmol/L were recruited for a double blind, cross-over study with metformin (850 mg, twice daily) and placebo. (J Clin Endocrinol i&tab 81: 1568-1574, 1996) I NSULIN RESISTANCE and hyperinsulinemia are common features in patients with essential hypertension and normal glucose tolerance (1, 2). It has been suggested that these features may play a causative role in blood pressure elevation rather than representing an accompanying phenomenon. Hyperinsulinemia may indeed affect blood arterial pressure via several mechanisms: 1) an increase in renal sodium reabsorption (3), 2) activation of cation membrane countertransports (4), 3) stimulation of the adrenergic nervous system (5), and 4) enhancement of vessel wall cell proliferation and reactivity (6).Based on these considerations, it can be hypothesized that an improvement in insulin sensitivity may result in a reduction in the overall plasma insulin concentration and a reduction in arterial blood pressure. Thus, in overweight hyperinsulinemic women, a 6-month physical activity program was associated with a reduction in fasting plasma insulin concentration and lower blood pressure (7). In normal weight subjects, diet and exercise might not be as successful as in obese patients, and a drug affecting insulin resistance without causing hypoglycemia could be used in an attempt to define the relationship between insulin action and blood pressure. Metformin seems to be a likely therapeutic candidate. In an uncontrolled study, Landin et al. (8) reported a significant improvement in arterial blood pressure in essential hypertensive subjects with normal glucose tolerance. However, in a more recent study (9), metformin administration in insulin-resistant hypertensive subjects did not affect blood pressure. We, therefore, designed a placebo-controlled study with the aim to 1) define the possible mechanisms of action of metformin in normal weight patients with essential hypertension and normal glucose tolerance, 2) assess whether changes in insulin action induced by metformin would affect blood pressure, and 3) test whether changes in insulin sensitivity can be paralleled by variations in arterial blood pressure, renal and red cell cation handling, and/or other factors involved in blood pressure regulation. Subjects Subjects and MethodsNine patients (five men and four women) with essential hypertension participated in the study. They had an average body mass index of 24.6 kg/m (range, 21.0-27.4), and their mean age was 44.5 yr old (range,

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The kinetic properties of sodium-proton exchange are abnormal in human red blood cells of hypertensive patients and it has been demonstrated that the transport protein undergoes post-translational modifications able to affect its kinetic properties. Protein kinase C (PKC) activation decreases the affinity constant for intracellular protons while insulin increases the maximal rate of proton translocation. The present study therefore aimed to examine the relationships among PKC activity, fasting insulin levels and the kinetic behaviour of sodiumproton exchange in red blood cells from 20 normotensives and 36 hypertensives.In comparison with normotensive subjects, hypertensive patients had higher body mass index (26.2 ؎ 0.7 vs 23.6 ؎ 0.6 kg/m 2 , P Ͻ 0.05), higher fasting insulin levels (93.2 ؎ 10.8 vs 38.6 ؎ 2.9 pmol/L), increased maximal velocity of proton translocation (37.9 ؎ 2.7 vs 27.6 ؎ 1.9 mmol/L per cell ؋ h, P Ͻ 0.05), and reduced Hill's coefficient (1.6 ؎ 0.1 vs 2.0 ؎ 0.1, P Ͻ 0.01) of sodiumproton exchange.Basal PKC activity of the cytosol and membrane was similar in the study groups. However, after treatment

These data provide evidence for the hypothesis that plasma factor(s) affect ion transport in patients with these two syndromes. Since FSLE estimates Na+-K+-2Cl- cotransport the data suggest that plasma factor(s) contribute(s) to K+ wasting, hypokalemia, and hypotension by inhibiting cotransport in patients with these syndromes. The increase of Na+/Li+ exchange is most likely a secondary phenomenon associated with the hypermineralocorticoid state.