The studies described in this proposal are designed to extend the pilot experiment carried out in this laboratory which showed that chronic oral treatment with tyrosine protected renal hypertensive rats against an elevation of blood pressure to the level of untreated renal hypertensive controls. The studies described in this proposal will assess potential mechanisms may play a role in the protective effect of tyrosine and include: (a) cardiovascular (systolic, diastolic and mean blood pressures and heart rate) responsiveness of conscious rats to acute administration of graded doses of phenylephrine, norepinephrine, angiotensin II and isoproterenol; (b) metabolic and vascular responsiveness to Beta-adrenergic stimulation by four separate tests; (c) resting and stimulated (by isoproterenol) plasma renin activity; (d) resting as well as stress (acute cold exposure) stimulated urinary output of the major catecholamines and their metabolites; (e) plasma and brain concentrations of catecholamines; (f) sodium and potassium balances; (g) serum sodium, potassium, and calcium (total and ionized) concentrations; (h) vascular reactivity of aortic rings to KCl, phenylephrine and angiotensin II in vitro, and (i) an assessment of thyroid status (serum thyroxine, triiodothyronine, and TSH concentrations, thyroid weight and histology). The extent of protection against hypertension by treatment with tyrosine will be assessed by: (a) weekly measurement of blood pressure for 14 weeks; (b) tests of renal function (renal concentrating ability during a 24hr dehydration, serum creatinine concentration and blood urea nitrogen concentration), and (c) heart and renal weights and histology. Additional studies will be carried out to assess the effects of chronic oral treatment with tyrosine on the development of other experimentally induced hypertensions, including DOCA-induced and spontaneous hypertensions in rats. An additional objective is to determine the effect of chronic intracerebroventricular administration of tyrosine on the blood pressure of normotensive and hypertensive rats and on their brain levels of the major catecholamines and their metabolites. To assess the mechanism by which tyrosine may act, a decarboxylase inhibitor will be administered simultaneously to prevent formation of norepinephrine. The effect of the two compounds on blood pressure will be monitored. A final objective is to test the effect of chronic treatment with other neutral amino acids on the development of hypertension.
