While hypertension affects a substantial portion of the American population, little is understood about the contributing role of specific genes in controlling blood pressure. This research proposal is directed toward the elucidation of the role of one such gene product, dopamine-beta-hydroxylase (DBH) in the control of blood pressure. DBH catalyzes the synthesis of norepinephrine (NE) from dopamine (DA). NE is the most critical peripheral determinant of minute-to-minute arterial pressure. Moreover, NE and its metabolite, epinephrine (E), are involved in the neural regulation of blood pressure in the brain and spinal cord. Any factor which alters the synthesis of NE and E will thus perturb blood pressure regulation at several interacting levels. In 1986, we reported the previously undescribed syndrome of complete DBH deficiency. In this disorder, NE and E appear to be absent in both the central nervous system and the periphery. Patients with this disorder present with debilitating hypotension, but with little if any intellectual or mood abnormality. Recognition that human beings can live without NE and E indicates that there are probably individuals with partial DBH deficiency who have hitherto gone unrecognized. One goal in these studies is to recognize and study such individuals and to determine the molecular basis of the abnormalities. The proposed investigations include (1) the development of clinical pharmacological tools (clonidine and alpha-methyldopa) to test for DBH deficiency in the central nervous system; (2) an evaluation of disulfiram and the role DBH inhibition plays in the drug's hemodynamic effect; (3) testing the hypothesis that clinical conditions such as vasoregulatory asthenia, disulfiram-induced hypotension in adults and unexplained shock in infants may be presentations of partial or complete DBH deficiency; and (4) Investigations to determine the molecular basis of complete and partial DBH deficiencies and the traits of low and high serum DBH levels. Knowledge of the genetic structural, regulatory, or processing defects causing DBH deficiency will lead to better clinical management of the disorder, reliable prenatal and postnatal diagnosis, and effective genetic counselling. These studies should also provide new information about the mechanisms of action of alpha-methyldopa and disulfiram. Finally, they should result in improved understanding of blood pressure regulation.
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