The links between cellular Ca2+ and the antiport in the pathophysiology of essential hypertension.

Essential hypertension is marked by dysfunctional regulation (dysregulation) of Ca2+ and Na+ at the cellular level. Since essential hypertension is a polygenic disorder, ionic dysregulation may independently arise from primary abnormalities in regulatory pathways of Ca2+ and Na+. Alternatively, primary abnormalities resulting from the regulation of one of these ions may be expressed by secondary (adaptive) alterations in the regulations of the other ion. Understanding the links between the regulatory elements of cellular Ca2+ and Na+ is therefore the key to deciphering the underlying etiology of dysfunctional Ca2+ and Na+ regulation in essential hypertension. Moreover, the distinction between primary vs secondary ionic dysregulation is a crucial step in elucidating the genetic origin of essential hypertension. Recent studies have shown that the activity of the antiport (NHE-1) is enhanced in a subset of patients with essential hypertension and that this phenotype is maintained in immortalized lymphoblasts from these patients. Primary abnormalities (i.e., mutations) in the NHE-1 gene have been ruled out in essential hypertension. Thus, a higher antiport activity in essential hypertension probably reflects alterations in the cellular regulation of this transport system. A number of systems participate in the control of the activity of the antiport, including Ca2+ dependent protein kinases and calmodulin. These systems are closely linked to cellular Ca2+ regulation. It is therefore logical to conclude that altered antiport activity is the signature of Ca2+ dysregulation in essential hypertension.