Ionic Basis of Hypertension, Insulin Resistance, Vascular Disease, and Related Disorders The Mechanism of “Syndrome X”

Great pathophysiological significance has recently been placed on the association of metabolic abnormalities, such as hyperinsulinemia, insulin resistance, obesity, and frank diabetes mellitus, with essential hypertension and coronary artery disease, and the clinical coincidence of these features has been termed "syndrome X." Despite the suggestion that insulin itself mediates this clinical linkage, the specific mechanisms underlying this syndrome remain poorly understood. We have attempted to understand these phenomena at the cellular level, and have investigated the role of cellular mineral ion species such as cytosolic free calcium (Cai), free magnesium (Mgi), and intracellular pH (pHi) in various insulin resistant states, including essential hypertension, obesity, and type II (non-insulin-dependent) diabetes mellitus (NIDDM). Utilizing nuclear magnetic resonance spectroscopic techniques to noninvasively assess intracellular concentrations of these ions, we observed that each of these disease states is characterized, in whole or in part, by common abnormalities of cellular ion metabolism, including elevated Cai levels and suppressed levels of Mgi and pHi. Furthermore, despite the predominant use of red cells as a tissue source, the measured levels of Cai, Mgi, and pHi were closely related to the ambient blood pressure, the degree of cardiac hypertrophy, and to the hyperinsulinemic response to oral glucose challenge. Altogether, these data suggest an integrated "ionic hypothesis" in which the frequent clinical coexistence of hypertension and altered insulin metabolism derives from common abnormalities of cellular ion handling, resulting in excess steady-state levels of Cai, reciprocal depletion of Mgi, and lowered pHi. These cellular ion alterations would be expected to have tissue-specific consequences, appearing in vascular tissue as vasoconstriction and elevated blood pressure, in skeletal muscle and fat as insulin resistance, in pancreatic beta-cells as hyperinsulinemia, and in neural tissue as potentiated neurotransmitter release and increased sympathetic nerve activity. Thus, according to this hypothesis, essential hypertension, insulin resistance, hyperinsulinemia, and NIDDM are in reality different clinical components of what should be better designated as "generalized cardiovascular-metabolic disease" (GCMD).