Is there a cardiovascular rationale for the use of combined vasopressin V1a/V2 receptor antagonists?

Arginine vasopressin (AVP) signals predominantly through the V-1a receptor, which subserves vasoconstriction in the peripheral circulation, and is linked directly to stimulation of myocardial hypertrophic growth factors, and the V, receptor, the main function of which is to alter the expression of aquaporin channels in the renal collecting ducts, which leads to water retention. Agents that antagonize or block these receptors could be expected to reduce vascular tone (assuming sufficient V-1a signaling is present to be causing an effect), reduce direct mitogenic signaling in the myocardium (again assuming sufficient V-1a effect is present), and increase water excretion (assuming sufficient V-2 signaling is present). The case for antagonizing both sets of receptors depends on the clinical situation. Pure V-1a antagonists might be useful in treatment of hypertension or heart failure, but they are of little use in hyponatremia unless it is caused by heart failure. V-2 antagonists would be useful in any euvolemic or hypervolemic condition associated with hyponatremia and may help produce an effective and safe diuresis independent of serum sodium when used in conjunction with loop diuretics I in patients with heart failure. Selective blockade of either receptor could lead to increased signaling at the unblocked receptor sites, potentially a problematic result, especially in heart failure where disease progression is affected by increased afterload, preload, and the direct myocardial effects of neurohormonal imbalance. Therefore, a strong rationale exists for 'the use of combined vasopressin antagonists in patients with heart failure, particularly if the agents are used on a chronic basis. (c) 2006 Elsevier Inc. All rights reserved.