The phenotypic patterns of essential hypertension are the key to identifying “high blood pressure” genes.

The genes that cause or increase susceptibility to essentialhypertension (EH) and related animal models remain unknown.Their identification is unlikely to be realized with current geneticapproaches, because of ambiguities in the genotype-phenotyperelationships in these polygenic disorders. In turn, the phenotypeis not just an aggregate of traits, but needs to be related tospecific components of the circulatory control system at differentstages of EH. Hence, clues about important genes must comethrough the phenotype, reversing the order of currentapproaches. A recent systems analysis has highlighted majordifferences in circulatory control in the two main syndromes ofEH: 1) stress-and-salt-related EH (SSR-EH) – a constrictorhypertension with low blood volume; 2) hypertensive obesity –SSR-EH plus obesity. Each is initiated through sensitization ofcentral synapses linking the cerebral cortex to the hypothalamicdefense area. Several mechanisms are probably involved,including cerebellar effects on baroreflexes. The result is asustained increase in sympathetic neural activity at stimuluslevels that have no effect in normal subjects. Subsequentprogression of EH is largely through interactions with non-neuralmechanisms, including changes in concentration of vascularautacoids (e.g. nitric oxide) and the amplifying effect of structuralchanges in large resistance vessels. The rising vasoconstrictionincreases heterogeneity of blood flow, causing rarefaction(decreased microvascular density) and deterioration of vitalorgans. SSR-EH also increases food intake in response to stress,but only 40% of these individuals develop hypertensive obesity.Their brain ignores the adiposity signals that normally reduceeating. Hyperinsulinemia masks the sympathetic vasoconstrictionthrough its dilator action, raises blood volume, whilst renalnephropathy and other diabetic complications are common. Ineach syndrome the neural and non-neural determinants ofhypertension provide targets for identifying high BP genes.Reading the genome from the phenotype will require newapproaches, such as those used in developmental genetics. Inaddition, transgenic technology may help verify hypotheses andexamine whether an observed effect is through single or multiplemechanisms. To obtain answers will require substantialcollaborative efforts between physiologists and geneticists.