Signaling mechanisms that link salt retention to hypertension: Endogenous ouabain, the Na+ pump, the Na+/Ca2+ exchanger and TRPC proteins

Abstract

Salt retention as a result of chronic, excessive dietary salt intake, is widely accepted as one of the most common causes of hypertension. In a small minority of cases, enhanced Na+ reabsorption by the kidney can be traced to specific genetic defects of salt transport, or pathological conditions of the kidney, adrenal cortex, or pituitary. Far more frequently, however, the salt retention may be the result of minor renal injury or small genetic variation in renal salt transport mechanisms. How the salt retention actually leads to the increase in peripheral vascular resistance (the hallmark of hypertension) and the elevation of blood pressure remain an enigma. Here we review the evidence that endogenous ouabain (an adrenocortical hormone), arterial smooth muscle α2 Na+ pumps, type-1 Na/Ca exchangers, and receptor- and store-operated Ca2+ channels play key roles in the pathway that links salt to hypertension. We discuss cardenolide structure-function relationships in an effort to understand why prolonged administration of ouabain, but not digoxin, induces hypertension, and why digoxin is actually anti-hypertensive. Finally, we summarize recent observations which indicate that ouabain upregulates arterial myocyte Ca2+ signaling mechanisms that promote vasoconstriction, while simultaneously downregulating endothelial vasodilator mechanisms. In sum, the reports reviewed here provide novel insight into the molecular mechanisms by which salt retention leads to hypertension.

A role of the sodium pump in spreading ischemia in rats

“…Whereas a 1 represents the housekeeping enzyme expressed by all cells, most cell types additionally express NaKA with another a isoform: astrocytes, endothelial cells, and VSMCs express a 2 whereas most neurons express a 3 . 25 Interestingly, Hajek and colleagues reported that prolonged increase of [K þ ] o significantly reduced NaKA activity in astrocytic culture. Therefore, we investigated whether NaKA activity is reduced by increase of [K þ ] ACSF to a level that was previously found to induce SI.…”

“…87 Another limitation is that the concept of intracellular Ca 2þ regulation by high affinity NaKAs has been partially based on other vascular beds than the cerebral circulation. 25,56 More research is thus needed to investigate these mechanisms in the brain.…”

Expression of rat Na-K-ATPase α2 enables ion pumping but not ouabain-induced signaling in α1-deficient porcine renal epithelial cells

“…Recent studies have revealed major differences in the physiological functions of each isoform. For example, the ␣2 isoform appears to possess the unique ability to regulate intracellular Ca 2ϩ levels in myocytes and coresides with the Na ϩ /Ca 2ϩ exchanger (5,24). In addition, recent experiments using SWAP mice (ouabainsensitive ␣1 Na-K-ATPase mutant and ouabain-resistant ␣2 Na-K-ATPase mutant) suggest that the ␣2 isoform plays a more prominent role in calcium release in cardiac and smooth muscle myocytes than ␣1 (12).…”

Attenuated renal vascular responses to acute angiotensin II infusion in smooth muscle-specific Na+/Ca2+exchanger knockout mice

“…Effects of acute ANG II infusions on urine flow and U Na V. Before acute ANG II infusions, there were no significant differences in urine flow ( (1,3,5). The latter are composed, at least in part, of C-type transient receptor potential (TRPC) channel proteins (3,5).…”

“…The latter are composed, at least in part, of C-type transient receptor potential (TRPC) channel proteins (3,5). Additionally, NCX plays a role in smooth muscle Ca homeostasis; in particular, NCX-mediated Ca 2ϩ entry is important for the maintenance of vascular tone (1,3,5).…”