Expression of altered alpha2-adrenergic phenotypic traits in normotensive humans at genetic risk of hereditary (essential) hypertension.

Abstract

Essential (hereditary) hypertension is a common, though complex, trait with substantial heritability, but a still-obscure mode of inheritance. In this disorder with relatively late onset, knowledge of phenotypes with earlier penetrance would aid genetic analyses, as well as assessment of risk. Because alpha2-adrenergic receptor alterations are among the most heritable in experimental genetic hypertension, we hypothesized enhanced expression of alpha2-adrenergic phenotypic traits in still-normotensive humans at genetic risk of hypertension. We evaluated hemodynamic (blood pressure, cardiac output, systemic vascular resistance, stroke volume, and cardiac contractility) and biochemical (plasma drug, catecholamine, renin, and chromogranin A levels) responses to alpha2-adrenergic blockade with intravenous yohimbine in 84 normotensive subjects stratified by genetic risk of essential hypertension (67 with positive family histories and 17 with negative family histories of hypertension), as well as 18 subjects with established essential hypertension. Results were evaluated by analysis of variance, normal likelihood ratio test, and by maximum likelihood analysis for bimodality (i.e. mixtures) of response distributions. Blood pressure rose (P<0.001) during alpha2-adrenergic blockade, with greater response (P<0.001) in members of the hypertensive than in members of the normotensive group. Hemodynamically, the rise in blood pressure resulted from an increase in cardiac output (P<0.001), with associated increases in stroke volume (P=0.002) and cardiac contractility (P=0.006), without an overall change in systemic vascular resistance. Biochemically, plasma norepinephrine (P<0.001), epinephrine (P=0.001), and chromogranin A (P=0.02) rose, suggesting augmentation of efferent exocytotic sympathoadrenal activity. Cardiac output and stroke volume responses were correlated to increments in plasma catecholamines (especially epinephrine) for the positive group, but not for the negative group. Baseline plasma catecholamines predicted increments of stroke volume after administration of yohimbine (P=0.003-0.007) for the positive but not for the negative group. Simultaneous comparison of means and variances of cardiac output and stroke volume alpha2-adrenergic responses, by using a normal likelihood ratio test, revealed highly significant (P=0.025 to P<0.0001) differences between the groups of subjects with and without family histories of hypertension. Frequency histogram suggested that there was a bimodal distribution of responses of stroke volume to alpha2-adrenergic blockade for the normotensive group with positive family histories of hypertension; maximum likelihood analysis strongly rejected the hypothesis of a unimodal distribution, whereas the hypothesis of bimodality could not be rejected (chi2=18.4, P=0.0004). The second (exaggerated) mode of response of stroke volume to alpha2-adrenergic blockade, defined by maximum likelihood analysis, was found for 9.5% of subjects in the normotensive group with positive family histories of hypertension, and was characterized by significantly different responses of cardiac output (P=0.001), stroke volume (P<0.001), contractility (P<0.001), heart rate (P=0.03), systemic vascular resistance (P<0.001), and epinephrine (P<0.001). Even prior to alpha2-adrenergic blockade, baseline stroke volume (P=0.01), heart rate (P=0.04), systemic vascular resistance (P=0.005), and catecholamine (P=0.001-0.005) values for this subgroup were different than control values. We conclude that heterogeneous, bimodally distributed hemodynamic responses to alpha2-adrenergic blockade in subjects with positive family histories of hypertension suggest a discrete subgroup with early expression of perhaps Mendelian traits associated with risk of later development of hypertension. Such phenotypic traits ('intermediate phenotypes'), with earlier penetrance than hypertension itself, can be