The presence of insulin resistance in many patients with hypertension has become a well-recognized phenomenon. However, the mechanism of this association remains enigmatic. We have hypothesized that abnormal cellular calcium handling, particularly elevations in cytosolic free calcium concentrations, may represent a common intracellular abnormality (a missing link) that is responsible for the frequent co-existence of insulin resistance and hypertension. We have shown recently that sustained elevations of cytosolic free calcium in insulin target cells, such as are observed in patients with obesity and non-insulin-dependent diabetes mellitus and in some patients with hypertension, may lead to the development of insulin resistance. Although the mechanisms that lead to such increases are not yet well understood, they appear to include an enhanced influx of calcium via calcium channels. We found that the presence of the calcium antagonist nitrendipine in the incubation medium prevented increases in cytosolic free calcium concentration and ameliorated the insulin resistance induced by various mechanisms. To further evaluate the existence of an association between elevated levels of cytosolic calcium and diminished cellular sensitivity to insulin in patients with essential hypertension, we studied insulin sensitivity in vivo and in vitro in isolated adipocytes from older hypertensive, nondiabetic subjects. Obese hypertensive individuals demonstrated marked hyperinsulinemia and significantly reduced submaximally stimulated adipocyte 2-deoxyglucose uptake. One month of therapy with nitrendipine (10 mg twice daily) reduced blood pressure in hypertensive subjects, reduced plasma insulin to control values in obese hypertensive individuals, and restored adipocyte 2-deoxyglucose uptake at at submaximally effective insulin concentrations to control values in both obese hypertensive subjects and those of normal weight.(ABSTRACT TRUNCATED AT 250 WORDS)