Parathyroid hormone (PTH), an 84 amino acid polypeptide hormone primarily associated with maintenance of plasma Ca++ homeostasis, has also been shown after exogenous administration to cause vasodilation of certain regional vascular beds and to lower mean arterial blood pressure. Recently, the applicant demonstrated for the first time that the aminoteminal 1-34 polypeptide fragment of PTH, i.e., PTH-(1-34), is a potent vasodilator of the coronary circulation. The dose-dependent coronary vasodilatory effect is obtained with both bovine and human synthetic fragments, is mimicked by the parent PTH hormone, and retains full potency in the presence of Beta- or Alpha-adrenergic blockade or muscarinic blockade. These collective observations have led us to hypothesize that PTH and/or PTH-(1-34), as naturally-occurring substances, may function as specific and potent dilators of the coronary circulation. Thus, we propose that coronary blood vessels represent a """"""""new"""""""" target site for parathyroid hormone. The overall aim of this proposal is to strengthen this hypothesis by characterizing the flow response in vivo and attempting to fit the response into a physiological and/or pharmacological context.
Our specific aims, to be carried out via protocols using acute thoracotomized and chronic instrumented dogs, are divided into three groups, each group for a given year of the project.
Our aims, in part, are directed toward a more comprehensive definition of the specificity of the PTH-(1-34)-induced cardiovascular responses; determining if calcitonin is vasoactive in the coronary circulation and whether this hypocalcemic peptide serves to antagonize the effects of PTH; an assessment of coronary and cardiac function in parathyroidectomized dogs and whether the responses to exogenous PTH administration are altered in these animals; and investigation of the effects of PTH and PTH-(1-34) on coronary blood flow and other elements of cardiovascular function in the chronic dog model. Achievement of the above aims and others cited in the proposal will enable a more comprehensive understanding of the function and importance of PTH in the cardiovascular system and provide a basis for our longer term aims directed toward the pathophysiology of the coronary circulation.
