Cellular calcium and magnesium metabolism in the pathophysiology and treatment of hypertension and related metabolic disorders.
We have investigated the cellular basis for the clinical and epidemiologic linkage of hypertension, left ventricular hypertrophy (LVH), obesity, and non-insulin-dependent diabetes mellitus (NIDDM) and have studied cytosolic free calcium and free magnesium levels in these syndromes. Specifically, intracellular free calcium is elevated and free magnesium is deficient in hypertension, and both are related (directly and inversely, respectively) to the ambient level of blood pressure, to LV mass index (and thus to the degree of cardiac hypertrophy), and to the hyperinsulinemia and insulin resistance of essential hypertension. Dynamically, the ability of dietary salt loading to elevate blood pressure corresponds to its ability to elevate cytosolic free calcium and reciprocally to suppress free magnesium levels. Conversely, the ability of calcium channel blockade to reverse salt-induced hypertension is related to its ability to prevent these transmembrane ionic effects. Higher steady-state free calcium or lower free magnesium, or both, are also observed in clinical states linked to hypertension, such as obesity and NIDDM. Oral glucose loading in normal subjects itself elevates free calcium and suppresses free magnesium levels, as does hyperglycemia in vitro. These data suggest an ionic hypothesis of cardiovascular and metabolic disease, in which a generalized defect in cell ion handling is present in all tissues, resulting in higher steady-state free calcium and lower free magnesium levels. In pancreatic beta cells, this would produce hyperinsulinemia; in fat and skeletal muscle, cause peripheral insulin resistance; and in renal tissue, increase proximal sodium resorption and increase urinary calcium excretion--all features of essential hypertension. In vascular smooth muscle, high cytosolic free calcium would increase smooth muscle tone and cause vasoconstriction, and in heart muscle, independent of blood pressure, would increase contractility and predispose to LVH. Therefore, what may appear clinically to be the separate syndromes of hypertension, obesity, and NIDDM may pathophysiologically be different manifestations of the same underlying cellular defect, thus explaining their frequent clinical coexistence. Therapeutically, reversal of this excess free calcium accumulation and/or free magnesium deficit with ion-specific agents, such as calcium channel blocking drugs, may thus ameliorate not only the elevated blood pressure of hypertension but also the concurrent excess morbidity and mortality of the concurrent cardiac, vascular, and metabolic aspects of the hypertensive state.
Resnick
L M
LM
Cardiovascular Center, New York Hospital, Cornell Medical Center, New York, New York 10021.
D000450:Aldosterone / Q000502:physiology; D001786:Blood Glucose; D001794:Blood Pressure / Q000502:physiology; D002118:Calcium / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006332:Cardiomegaly / Q000453:epidemiology / Q000378:metabolism* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000378:metabolism* / Q000503:physiopathology; D004040:Dietary Carbohydrates / Q000009:adverse effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006946:Hyperinsulinism / Q000453:epidemiology / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000453:epidemiology / Q000378:metabolism* / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D007424:Intracellular Fluid / Q000737:chemistry / Q000378:metabolism*; D007477:Ions; D008274:Magnesium / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D009765:Obesity / Q000453:epidemiology / Q000378:metabolism* / Q000503:physiopathology; D012084:Renin-Angiotensin System / Q000502:physiology; D012982:Sodium, Dietary / Q000009:adverse effects
D001786:Blood Glucose; D002121:Calcium Channel Blockers; D004040:Dietary Carbohydrates; D007328:Insulin; D007477:Ions; D012982:Sodium, Dietary; D000450:Aldosterone; D008274:Magnesium; D002118:Calcium