Digitalislike circulating factor in hypertension: Potential messenger between salt balance and intracellular sodium

Abstract

Sodium chloride has no clearly established local direct action on blood vessels to produce constriction; on the contrary, it has an immediate local indirect action via osmolality, which produces vasodilation. Thus in order to explain salt-induced hypertension, a delayed remote indirect vasoconstrictor action must be postulated. This indirect vasoconstrictor action is apparently the result of volume expansion. Acute volume expansion imparts three physiologic properties to the plasma; these are the ability to inhibit Na,K-ATPase and the Na−K pump, to cause natriuresis, and to sensitize blood vessels to vasoconstrictor agents. Similarly, lowrenin, volume-expanded hypertension endows the plasma with the capacity to inhibit the Na,K-ATPase pump, to sensitize blood vessels to vasoconstrictor agents, and to raise blood pressure. These properties apparently result from a circulating digitalislike substance(s), perhaps derived from the hypothalamus and/or adrenals. We here review the considerable effort expended in identifying the agent or agents, and conclude that both steroidal and peptidic structure must be considered. Regardless of its structure, we hypothesize that when sodium excretion does not keep pace with sodium intake, its release leads to increased contractile activity of cardiac and vascular smooth muscle and hence hypertension. Inhibition of the Na−K pump increases the intracellular sodium concentration, particularly when superimposed on genetic- or aldosterone-induced increased sodium permeability, resulting in depolarization and increased calcium influx (vascular smooth muscle) or altered Na⁺−Ca²⁺ exchange and decreased calcium efflux (heart muscle). The increased intracellular calcium concentration then accounts for the increased contractile activity. Depolarization may also increase the sensitivity of vascular smooth muscle to vasoconstrictor agents such as norepinephrine. There may also be more norepinephrine in the neuromuscular cleft since norepinephrine uptake into adrenergic nerve terminals decreases with Na,K-ATPase inhibition.