In white populations, a deletion polymorphism in the gene for angiotensin converting enzyme (ACE) appears to be associated with increased risk for myocardial infarction but not for hypertension. In a population-association study in African-Americans, we compared the frequency of the ACE deletion polymorphism in subjects with hypertension versus those with normal blood pressure. The frequency of the ACE deletion allele was greater in African-Americans with hypertension than in those with normal blood pressure (P < 0.05). These findings raise the possibility that in some patient subgroups, sequence variation in or near the ACE gene may contribute to the risk for hypertension.

We hypothesized that individual differences in autonomic responses to psychological, physiological, or environmental stresses are inherited, and exaggerated autonomic responsiveness may represent an intermediate phenotype that can contribute to the development of essential hypertension in humans over time. alpha(2)-Adrenergic receptors (alpha(2)-ARs), encoded by a gene on chromosome 10, are found in the central nervous system and also mediate release of norepinephrine from the presynaptic nerve terminals of the peripheral sympathetic nervous system and the exocytosis of epinephrine from the adrenal medulla. We postulated that, because this receptor mediates central and peripheral autonomic responsiveness to stress, genetic mutations in the gene encoding this receptor may explain contrasting activity of the autonomic nervous system among individuals. The restriction enzyme Dra I identifies a polymorphic site in the 3'-transcribed, but not translated, portion of the gene encoding the chromosome 10 alpha(2)-AR. Southern blotting of genomic DNA with a cDNA probe after restriction enzyme digestion results in fragments that are either 6.7 kb or 6.3 kb in size. Transfection studies of these two genotypes resulted in contrasting expression of a reporter gene, and it is suggested from these findings that this is a functional polymorphism. In a study of 194 healthy subjects, we measured autonomic responses to provocative motion, a fall in blood pressure induced by decreasing venous return and cardiac output, or exercise. Specifically, we measured reactions to 1) Coriolis stress, a strong stimulus that induces motion sickness in man; 2) heart rate responses to the fall in blood pressure induced by the application of graded lower body negative pressure; and 3) exercise-induced sweat secretion. In all of these paradigms of stress, subjective and objective evidence of increased autonomic responsiveness was found in those individuals harboring the 6.3-kb allele. Specifically, volunteers with the 6.3-kb allele had greater signs and symptoms of motion sickness mediated by the autonomic nervous system after off-axis rotation at increasing velocity (number of head movements a subject could complete during rotation before emesis +/- SE: 295 +/- 18 vs. 365 +/- 11; P = 0.001). They also had greater increases in heart rate in responses to the lower body negative pressure-induced fall in blood pressure (increase in heart rate +/- SE: 3.0 +/- 0.4 vs. 1.8 +/- 0.3; P = 0.012), and the 6.3-kb group had higher sweat sodium concentrations during exercise (mean sweat sodium concentration in meq/l over 30 min of exercise +/- SE: 43.2 +/- 7.1 vs. 27.6 +/- 3.4; P < 0.05). This single-nucleotide polymorphism may contribute to contrasting individual differences in autonomic responsiveness among healthy individuals.

alpha 2-Adrenergic receptors are found on presynaptic neurons of the central and peripheral nervous systems, on blood vessels, on platelets, on adipocytes, and in the kidney and pancreas. Activation of these ubiquitous adrenoreceptors results in decreased neuronal norepinephrine release, vasodilation, a fall in blood pressure, platelet aggregation, increased sodium excretion, and decreased insulin release. We hypothesized that defects in alpha 2-adrenergic receptors, or postreceptor defects, could explain the increased prevalence of hypertension in blacks. To test our hypothesis, we first determined whether or not a polymorphism of the alpha 2-adrenergic receptor gene was associated with pathologic elevations in blood pressure in American blacks. Dra-I identified a restriction fragment-length polymorphism (RFLP) of 6.3 and 6.7 kb of the alpha 2-adrenergic receptor gene on chromosome 10 in humans. Of 227 patients studied, 13/107 hypertensive subjects were homozygous for the 6.3-kb allele, whereas only 3/120 normotensive volunteers were homozygotes (P = .008). When analyzed by race, 13/82 black hypertensive subjects were homozygous for the 6.3-kb allele, whereas only 2/59 normotensive blacks were homozygous for the 6.3-kb alleles (P = .02). However, only 1/61 white normotensive and 0/25 white hypertensive subjects were homozygous for the 6.3-kb allele (P = 1.00). Ethnic variation among blacks may explain our findings. Alternatively, a genetic polymorphism in, or near, the alpha 2-adrenergic receptor on chromosome 10 can contribute to the development of hypertension in blacks.

It is likely that a number of independent heritable traits, each encoded by a singular gene, contribute to pathologic elevations in blood pressure in humans. Genetic polymorphisms of individual genes may result in intermediate phenotypes which, by themselves, do not raise blood pressure, but, coupled with environmental or epistatic forces, contribute to the prevalence of human hypertension. The gene for the alpha 2-adrenergic receptor encoded by chromosome 10 (C10 A2AR) is polymorphic, and Southern blotting with a cDNA probe following restriction enzyme digest of this gene results in fragments of either 6.3 kb or 6.7 kb in size. We reported an association between homozygosity for the 6.3 kb allele and hypertension in blacks. Blacks with hypertension also have an increased risk for thrombotic stroke, increased baroreceptor sensitivity, and decreased sodium excretion. We noted that the C10 A2AR, which modulates norepinephrine release in blood-pressure-regulating regions of the brain, is also expressed on platelets and in the kidney. We postulated that functional changes associated with the C10 A2AR gene polymorphism could be responsible for increased baroreceptor sensitivity, epinephrine-mediated platelet aggregation, and decreased sodium excretion in some individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the effect of yohimbine, a drug that inhibits presynaptic Oj-adrenergic receptors and increases the neuronal release of norepinephrine from the central and sympathetic nervous systems, on tolerance to cardiovascular stress in 10 untrained, healthy subjects. Using radioligand binding of tritiated yohimbine to platelets, these subjects were found to have a normal complement of a<2-adrenergic receptors (174±18 [±S£M] receptors/platelet) with normal X,, (1.93±0.17 nmol/1). Lower body negative pressure was used to test responses to cardiovascular stress in the subjects after they received either placebo or 20 mg yohimbine. Graded lower body negative pressure from 0 to -40 mm Hg significantly decreased systolic blood pressure from 116±3.7 to 106±5.8 mm Hg, increased heart rate from 54±3 to 68±7 beats/min, decreased forearm blood flow from 1.8 ±0.21 to 1.36±0.25 ml/100 ml/min, and increased forearm vascular resistance from 55.76±12.1 to 77.26±15.8 mm Hg/ml/min. Yohimbine increased the blood pressure at rest and during lower body negative pressure, but these changes were not significantly different from values recorded from the individuals when they were given placebo. Compared with placebo, however, yohimbine significantly increased forearm blood flow at rest (1.80±0.21 vs. 2.66±OJ1 ml/100 ml/min, p<0.05) and during -4 0 mm Hg of lower body negative pressure (U6±0.25 vs. 1.91±0.28 ml/100 ml/min, p<0.05). We also found that yohimbine significantly increased the plasma insulin concentration in these fasted subjects (9.4±2.4 vs. 14.5±1.4 ng/ml,/?<0.05) without inducing hypoglycemia. Because this agent increases forearm blood flow, yohimbine might be useful in treating the orthostatic hypotension and ischemic vascular disease that results from the autonomic insufficiency common in patients with diabetes mellitus. (Hypertension 1990;15:877-880) T he a-adrenergic receptors are found on presynaptic neurons of the central nervous system, the peripheral nervous system, and blood vessels. The a,-adrenergic receptors are found mainly on blood vessels, and when stimulated by endogenous ligands such as norepinephrine, cause vascular smooth muscle to contract and vascular resistance and blood pressure to increase. The a 2 -adrenergic receptors are found on platelets, in the vasculature, and on presynaptic neurons. Activation of presynaptic a 2 -adrenergjc receptors results in a decrease in catecholamine release from nerve terminals and the adrenal medulla and a decrease in blood pressure. Alternatively, antagonism Because increasing circulating and central catecholamines increases blood pressure, we hypothesized that pharmacological agents that increase catecholamine release could increase tolerance to cardiovascular stress experienced by patients with orthostatic hypotension or by fighter pilots who experience increased gravitational force (+Gz). We measured the effect of the oral a 2 -adrenergic receptor antagonist yohimbine on the blood pressure response to the unloading of cardiovascular baroreceptors with graded lowe...