Can the Na+/H+ exchange serve as an intermediate phenotype for essential hypertension?

In this issue of the journal, Kessler t al. [1] report that an acute saline infusion and an expansion of the extracellular volume altered the activity of the ubiquitous Na /H exchange (NHE) in lymphocytes of healthy volunteers. This finding and previous observations that in humans a chronic increase in salt intake [2] and a chronic ingestion of NH4Cl [3] augmented NHE activity in lymphocytes suggest that the environment might influence the activity of the NHE. Such a conclusion is relevant in that enhanced NHE activity has been shown in a number of cell types of patients with essential hypertension (reviewed in Ref. 4). Since essential hypertension is a polygenic disorder that expresses complex interaction with the environment [5], altered activity of the NHE in this disorder might be better appreciated in the context of environmental effects on phenotypic expression of variant genes that might harbour susceptibility for essential hypertension. These genes can be broadly stratified into two categories, namely genes that are strictly engaged in the intrinsic cellular machinery (e.g. genes encoding receptors, ion transporters, kinases/phosphatases, second messengers, such as cyclic nucleotides, G-proteins) and genes that regulate the levels of local (e.g. endothelin, nitric oxide) and circulating (e.g. angiotensin II, vasopressin) factors. These extracellular factors, in turn, modify the intrinsic cellular machinery. Environmental influences on cellular expression, such as the activity of the NHE, are likely to be exerted through the extracellular factors, e.g. a high salt intake would alter the circulating levels of elements of the renin–angiotensin–aldosterone systems, or modify the composition of the extracellular compartment. In the light of these considerations, the question arises as to whether the NHE can serve as an intermediate phenotype for essential hypertension, given that its activity is influenced by environmental factors. The answer to this question is probably in the affirmative, as long as we establish realistic expectations from intermediate phenotypes for essential hypertension. An ideal intermediate phenotype should be heritable and stable, be closely associated with the disease or biological phenomenon in question and be resistant to environmental effects. Phenotypes associated with monogenic forms of essential hypertension (e.g. Ref. 6) fit these characteristics quite well. A mutation that gives rise to a monogenic form of hypertension has such a profound effect that it overrides any environmental influence and attempts at the cellular and systemic levels to attenuate the deleterious impact of this mutation. However, phenotypes arising from variant genes that might play a role in essential hypertension are not as well defined as those expressed in monogenic forms of hypertension. These phenotypes appear to reflect not only the effect of variant genes but also secondary adaptive processes that are governed by principles of homeostasis. Practically any important biological parameter at the cellular and systemic levels is the product of an interactive network of regulatory systems so that a modest effect of a primary variation (i.e. a variant gene) in one system is modified by an adaptive response of interactive systems. This is one reason that the ‘candidate gene’ approach has been very effective in dissecting the genetics of monogenic diseases but less effective in identifying variant genes responsible for complex traits, such as essential hypertension. In a complex trait, variant genes leave convoluted and interactive pathways that may not be directly traced to altered phenotypic expressions. The activity of the NHE, for instance, is regulated by Ca / calmodulin, kinases/phosphatases, cytosolic pH, cellular osmolality and volume. Variations in any of these cellular parameters, and adaptive responses in the others, might be responsible for the final behaviour of the NHE. What then should we require from an intermediate phenotype for essential hypertension? First, it must be heritable. Secondly, it must be stable. Thirdly, it should be associated with hypertension or correlate with the blood pressure level. However, it is unrealistic to expect that the relations of the phenotype with essential hypertension European Journal of Clinical Investigation (1997)27, 566–567