Diabetes mellitus and hypertension: a physiologic basis for a rational therapeutic approach. The basic mechanisms that initiate and sustain hypertension in the diabetic population are poorly understood. Obesity, insulin, genetic factors, and abnormalities in calcium homeostasis may contribute, and could be related to an elevated Na+/H+ antiport activity. In the first study described in this investigation, hypertensive subjects with insulin-dependent diabetes mellitus (IDDM) who had an elevated Na+/Li+ countertransport activity were found to have a lower whole body glucose utilization, a lower insulin-stimulated forearm carbohydrate oxidation, larger ultrasound kidney volume, and increased left ventricular mass index when compared with hypertensive IDDM subjects with a normal Na+/Li+ countertransport activity or normotensive IDDM subjects. Thus an elevated Na+/Li+ countertransport activity appears to identify a subset of IDDM patients who are more susceptible to the development of the renal and cardiac complications associated with hypertension. This underlines the importance of choosing an appropriate antihypertensive therapy that will not produce a deterioration in glucose and lipid metabolism. In the second part of the report, results are presented for the treatment of hypertensive patients with non-insulin-dependent diabetes mellitus with doxazosin. The selective alpha 1-inhibitor produced a significant reduction in blood pressure, together with favorable changes in the serum lipid profile. As a result, the calculated risk of developing coronary heart disease was significantly reduced. Throughout the study no patients required a dose reduction or discontinuation of doxazosin because of side effects, and no clinically significant changes in laboratory tests were apparent. Thus doxazosin could be considered a useful antihypertensive agent in hypertensive patients with IDDM who are insulin-resistant and who have renal and cardiac abnormalities. 