Calcium Metabolism in Hypertension and Allied Metabolic Disorders

Abstract

Data suggest a critical role for Ca metabolism in the pathophysiology of hypertensive disease. Intracellularly, all hypertension displays elevated cytosolic free-Ca²⁺ and suppressed free-Mg²⁺ levels. Extracellularly, however, heterogeneous defects in Ca and Mg metabolism are observed. This apparent divergence may be explained by considering all hypertension as the expression, in varying degrees, of two underlying Ca-related mechanisms: one (salt sensitive, low renin, Ca²⁺-antagonist sensitive) dependent on inappropriate cellular Ca²⁺ uptake from the extracellular space and the other (salt insensitive, renin dependent, Ca²⁺-antagonist insensitive) dependent on increased cellular Ca²⁺ release from intracellular sites. Recent work highlights the role of 1,25-dihydroxyvitamin D₃ and the newly described parathyroid hypertensive factor in volume-dependent low-renin forms of hypertension. Altered cellular ion handling may also explain metabolic and clinical correlates of hypertension, e.g., peripheral insulin resistance, hyperinsulinemia, obesity, and non-insulin-dependent diabetes mellitus (NIDDM). Thus, all subjects with NIDDM, whether hypertensive or not, display the same elevated cytosolic free-Ca²⁺ and suppressed free-Mg²⁺ levels observed in hypertension. Furthermore, adiposity, the level of blood pressure, and fasting and postglucose hyperinsulinemia are all closely and quantitatively related to intracellular free-Ca²⁺, free-Mg²⁺, and pH levels. This suggests a broader hypothesis, in which hypertension, obesity, insulin resistance, and NIDDM, each usually considered a distinct clinical entity, represent different clinical expressions of a common defect in cellular ion handling, hence explaining their frequent clinical coexistence in the general population.