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, encoded by a gene on chromosome 10 (C10 A2AR), are found in the central nervous system and they also mediate the release of norepinephrine from the pre-synaptic 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' prime transcribed, but not translated, portion of the gene encoding the C10 A2AR. Southern blotting of genomic DNA with a cDNA probe following 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 (LBNP), 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 "3 kb" allele had greater signs and symptoms of motion sickness mediated by the autonomic nervous system following off-axis rotation at increasing velocity (values expressed as number of head movements a subject could complete during rotation before emesis ± SEM, 295 ± 18 vs. 365 ± 11, p = 0.001). They also had greater increases in heart rate in responses to the LBNP-induced fall in blood pressure (values expressed as increase in heart rate ± SEM, vs. 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 (values expressed as mean sweat sodium concentration in mEq/L over 30 min exercise ±SEM, 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.