Arginine-vasopressin (AVP) has dual effects; a vasopressor V1-receptor mediated action, attenuated in vivo by the sympathetic system, and an antidiuretic V2-receptor mediated action. A selective V1-inhibitor of AVP was used successfully in the past as a pharmacologic probe in normal man and patients with various types of hypertension or congestive heart failure. However, the V2-mediated renal and possibly non-renal effects may also be relevant in blood pressure regulation. In this proposal, in addition to studies in hypertension and heart failure with the selective V1 antagonist, we will study the cardiovascular and metabolic actions of the linear peptide CH3-CH2-COO-Tyr(Et)-Phe-Val-Asn-Abu-Pro-Arg-Arg-NH2, a dual V1 and V2 antagonist of AVP. First synthesized by Manning, this AVP inhibitor was prepared in our laboratory for use in humans under an IND exemption obtained from the FDA.
Specific aims of this proposal are: 1) To ascertain the efficacy of this compound as a dual V1 and V2 receptor antagonist in normal man and to define the minimum effective dose inhibiting each of these two functions; 2) To study the effects of selective V1 or dual V1V2 inhibition in various types of hypertension (including salt-sensitive and non-salt-sensitive essential hypertension, younger and older patients and patients with end-stage renal failure) and to separate the """"""""aquaretic"""""""", saluretic, and possibly other non-diuretic actions of the V2 function of AVP on blood pressure; 3) To investigate the influence of parasympathetic status on the V1 pressor action of AVP; 4) To investigate the therapeutic potential of the dual antagonist in the syndrome of inappropriate antidiuretic hormone secretion and later in edematous states with compensatory oversecretion of AVP; and 5) To further evaluate the role of the V1-mediated and V2-mediated effects of AVP in animals and humans with congestive heart failure, a condition with both inappropriate and compensatory oversecretion of AVP, by using either the selective V1 antagonist or the dual V1V2 antagonist.
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