Four projects are included. The goal of Project I """"""""Structure and Function of Dopamine (DA) Receptors"""""""" is to advance the knowledge of the chemical structures required for activation of 2 subsets of DA receptors, DA1 and DA2, with the ultimate objective to discover new orally effective agents for the treatment of hypertension, congestive heart failure, and renal failure. Compounds will be studied for action on DA1 and DA2 dopamine receptors and beta1-, beta2, alpha1- and alpha2-adrenoceptors. These studies will be conducted with measurements of blood flow in vascular beds of anesthetized dogs by electromagnetic flowmeters. Studies will also be conducted with isolated canine and rabbit blood vessels. The goals of Project II """"""""Role of Endogenous DA in Renal Function"""""""" are 1) to determine the effects of NaC1 loading on renal blood flow, glomerular filtration rate, and electrolyte and DA excretion in dogs before and after administration of DA1 and DA2 receptor antagonists and dopa decarboxylase inhibitors; 2) to perform similar studies with administration of amino acids. Both NaC1 and amino acids increase urinary excretion of sodium and DA in parallel. These studies are designed to determine whether endogenous DA contributes to the natriuresis by occupying DA receptors and by preventing DA synthesis by the kidney. Renal clearances will be measured by standard techniques. Levels of DA and 1-dopa will be measured by HPLC. The goal of Project III """"""""Behavioral Analysis of Central Nervous System DA Receptors"""""""" is to utilize the drug discrimination paradigm to determine potential differences in effects of DA1 and DA2 agonists and antagonists. Sprague Dawley male rats and rhesus monkeys will serve as experimental subjects. Most studies will be conducted in rats which will be trained to discriminate DA1 and DA2 agonists from saline in a 2-lever, food-reinforced drug discrimination paradigm. Intraperitoneal and intraventricular injections will be performed. The goal of Project IV """"""""Role of DA Receptors in Hypertension"""""""" is to determine whether levodopa can serve as a prodrug for DA and will reverse renal deterioration observed in hypertensive patients. Patients with hypertension and renal dysfunction will be treated initially with alpha- an beta-adrenoceptor blocking agents to antagonize the alpha- and beta-adrenoceptor activities of levodopa. The patients then will be divided into 2 groups; one group will received levodopa, and the other placebo. Each group of patients will receive i.v. infusions of DA to determine their renal responses. All patients will be followed for up to 5 years with repeated renal studies to determine whether levodopa therapy is beneficial.
