Mareo Naitoh

Vasopressin receptor antagonism — a therapeutic option in heart failure and hypertension

The precise role of vasopressin in the pathophysiology of cardiovascular disease is controversial, but this peptide hormone is important for several reasons. Firstly, circulating concentrations of vasopressin are elevated in heart failure and some forms of hypertension. Secondly, there is evidence that vasopressin is synthesized not only in the hypophysial‐pituitary axis but also in peripheral tissues including the heart where it acts as a paracrine hormone. Thirdly, vasopressin has vasoconstrictor, mitogenic, hyperplastic and renal fluid retaining properties which, by analogy with angiotensin II, may have deleterious effects when present in chronic excess. Finally, the availability of orally active non‐peptide vasopressin receptor antagonists allows vasopressin receptor antagonism to be considered as a therapeutic option in cardiovascular disease.

Neurohormonal antagonism in heart failure; beneficial effects of vasopressin V(1a) and V(2) receptor blockade and ACE inhibition.

OBJECTIVE To assess the long-term efficacy of vasopressin (AVP) V(1a) and V(2) receptor blockade with conivaptan, alone and in combination with angiotensin converting enzyme (ACE) inhibition on blood pressure, metabolic and neurohormonal parameters, and cardiovascular structure in a rat model of congestive heart failure (CHF). METHODS CHF was induced by left coronary artery ligation. CHF rats received conivaptan (1 mg/kg/day), ACE inhibition (captopril, 50 mg/kg/day), conivaptan and captopril (Combination) or vehicle for 4 weeks. Blood pressure was measured weekly, metabolic caging studies performed at 25 days, and rats killed and blood and tissue collected after 4 weeks treatment. RESULTS Combination treatment lowered blood pressure (P<0.01), and conivaptan and Combination caused an aquaresis (P<0.01). Combination decreased plasma natriuretic peptide (P<0.05), reduced left and right ventricular mass (P<0.01) and lung mass (P<0.05). CONCLUSIONS In CHF, blockade of vasopressin V(1a) and V(2) receptors was associated with increased water excretion, and the combination of conivaptan with ACE inhibition was the only treatment to reduce blood pressure, natriuretic peptide and pulmonary congestion. These results suggest conivaptan may be a useful addition to ACE inhibitors in the management of vasoconstriction and fluid retention that characterizes CHF.

In vivo and in vitro characterisation of a nonpeptide vasopressin V1A and V2 receptor antagonist (YM087) in the rat

This paper reports the in vitro and in vivo characterisation of a nonpeptide, orally active, vasopressin V(1A) and V(2) receptor antagonist, YM087 (methyl-1,4,5,6-tetrahydroimidazo[4, 5-d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide monohydrochloride) in the rat. YM087 dose dependently displaced the vasopressin V(1A) receptor antagonist radioligand, 125I-labelled [d(CH(2))(5),sarcosine(7)]vasopressin at vasopressin V(1A) receptors in liver and kidney medulla membranes and caused a concentration dependent displacement of the vasopressin V(2) receptor antagonist radioligand [3H]desGly-NH(2)(9)[d(CH(2))(5), D-Ile(2), Ile(4)]vasopressin at vasopressin V(2) receptors in kidney medulla membranes. In vitro binding kinetic studies showed YM087 acted as a competitive antagonist at liver V(1A) and kidney V(1A) and V(2) vasopressin receptors. Oral administration of YM087 (0.1-3 mg/kg) dose dependently inhibited vasopressin binding to liver V(1A) and kidney V(1A) and V(2) vasopressin receptors over 24 h. Oral YM087 (1-3 mg/kg/day) for 7 days in normotensive rats caused a dose dependent aquaresis with no effect on systolic blood pressure. These results show that YM087 is an orally effective vasopressin V(1A) and V(2) receptor antagonist that may be useful in the treatment of conditions characterised by vasoconstriction and fluid retention such as congestive heart failure.

NEW HORMONAL BLOCKADE STRATEGIES IN CARDIOVASCULAR DISEASE

The circulation is controlled by overlapping haemodynamic, structural and neurohumoral mechanisms. Many hormonal vasoactive substances, mostly derived from endothelial cells, are also growth regulators. Although neurohormonal systems are involved in normal physiological compensatory responses they often become maladaptive in conditions such as congestive heart failure. The success of blocking the renin angiotensin system by angiotensin converting enzyme (ACE) inhibitors has led to efforts to block other hormonal systems. Neutral endopeptidase (NEP), the major enzymatic pathway for degradation of natriuretic peptides, has a similar catalytic site to ACE. This has led to compounds that simultaneously inhibit both enzymes. Such dual ACE/NEP inhibitors show promise in experimental hypertension and heart failure. Similar dual NEP/ECE (endothelin converting enzyme) inhibitors are becoming available. The hormone vasopressin has dual actions on the vasculature and the kidney via specific membrane receptors. Specific orally active vasopressin receptor antagonists have been developed and their therapeutic potential in hypertension, heart failure and oedematous states are being explored.

Chronic Vasopressin Antagonism in Two-Kidney, One-Clip Renovascular Hypertension

The role of vasopressin (AVP) in the maintenance of hypertension in the rat model of two-kidney, one-clip (2K1C) Goldblatt hypertension was assessed using the nonpeptide orally effective V1a receptor antagonist, OPC-21268. Rats were studied eight weeks after surgery when mean arterial pressure (MAP) was significantly increased in 2K1C rats compared to SHAM operated controls (2K1C 139 +/- 6, SHAM 106 +/- 3, P < 0.01). Neither acute (OPC-21268, 30 mg/kg) nor chronic (OPC-21268, 30 mg/kg twice daily) V1a receptor blockade reduced blood pressure in either 2K1C or SHAM rats. The results of binding kinetic studies confirmed that OPC-21268 was effective at its putative site of action, the V1a receptor in both 2K1C and SHAM rats. These results indicate AVP is not involved in the maintenance of blood pressure in the 2K1C model of renovascular hypertension.

Effects of Chronic AVP V2R Blockade in Congestive Heart Failure in Sheep

The chronic effects of AVP V2 receptor (V2R) antagonism or ACE inhibition in conscious sheep with congestive heart failure (CHF) using the non-peptide V2R antagonist, OPC-31260 (1), and the ACE inhibitor, ramipril, were examined. Fifteen ovarectomised ewes equipped with epicardial right ventricular pacing leads and transonic cardiac output (CO) flow probe, had rapid ventricular pacing until the animal developed CHF. Then animals received oral OPC-31260 (10mg/kg twice daily, n=5), ramipril (1mg/kg daily, n=5) or vehicle (n=5) for 8 days. Throughout the experiment, animals were allowed free tap water. Oral OPC-31260 produced significant water diuresis, significant increase in CO (△CO; +0.92 L/min) and decrease in right atrial pressure (RAP) with significant increase in plasma osmolality and sodium concentration from 2 hours after first dosing; these hemodynamic effects were maintained throughout the treatment period without significant changes in systemic vascular resistance (SVR), although plasma osmolality and sodium concentration returned towards pre-treatment value on the last treatment day. Oral ramipril caused no significant changes with acute dosing but significant increases in CO (△CO; +0.88 L/min), urine volume and sodium excretion and decrease in SVR (ΔSVR; -22.8%) were observed after second treatment day. In vehicle-treated sheep, cardiac function, urine volume and sodium excretion remained lower. These results suggest V2R antagonism using OPC-31260 may be a novel therapeutic maneuver in CHF.