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We studied the hypotensive effects of OPC-21268, an orally effective nonpeptide vasopressin V1 receptor antagonist, in spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP). OPC-21268 was given intravenously to conscious, freely moving SHR and SHRSP. We used young and aged animals to examine the contribution of vasopressin to the development and maintenance of hypertension in both types of rats. In SHR, hypertension was fully established at 38 weeks of age, and intravenous injection of OPC-21268 produced slight hypotensive effects at either 38 or 70 weeks of age. In SHRSP, hypertension developed at 25 weeks of age, and blood pressure was sustained at a high level (approximately 250 mm Hg systolic blood pressure) thereafter. Intravenous administration of OPC-21268 did not cause hypotensive effects in young rats at 15 weeks, but at 25 weeks a significant decrease in blood pressure was observed. Furthermore, in the malignant state of SHRSP (35 to 41 weeks), OPC-21268 significantly decreased mean blood pressure by 32.4 +/- 7.9 mm Hg (mean +/- SEM) at 3 mg/kg IV, and the decrease was dose dependent (0.3 to 3.0 mg/kg). Plasma vasopressin concentrations were increased in a more malignant phase of SHRSP at 45 weeks of age, whereas at other ages of SHRSP or in SHR, plasma vasopressin levels were not increased. These results suggest that vasopressin plays an important role through V1 receptors in the maintenance of hypertension, at least in the malignant phase of SHRSP, and OPC-21268 may be therapeutically useful in the treatment of some types of hypertension.

We investigated the effects of tolvaptan, a vasopressin V(2)-receptor antagonist, on diuretic response and systemic and renal hemodynamic characteristics in conscious dogs with congestive heart failure (CHF). We also compared these effects with those of furosemide, a loop diuretic.CHF was induced by rapid right-ventricular pacing at 260 beats/min for at least 3 weeks, and maintained with a pacing rate of 220-240 beats/min. CHF dogs were orally given tolvaptan (10 mg/kg), furosemide (10 mg/kg) and vehicle in random order during the stable CHF state. Urine excretion, systemic and renal hemodynamic parameters, and plasma hormone levels were measured over 6-hour periods after drug administration.Tolvaptan induced aquaresis with an increase in free water clearance, resulting in a significant increase in serum sodium concentrations and a decrease in cumulative water balance. Tolvaptan also decreased pulmonary capillary wedge pressure without affecting systemic vascular resistance, glomerular filtration rate or renal blood flow. Tolvaptan tended to increase plasma arginine vasopressin concentrations but did not affect plasma renin activity. In contrast, furosemide induced clear saluresis with increased electrolyte excretion, resulting in decreased pulmonary capillary wedge pressure. However, furosemide also decreased serum potassium concentration and increased plasma arginine vasopressin concentrations and plasma renin activity.Tolvaptan elicited a potent aquaretic response and reduced the cardiac preload without unfavorable effects on systemic or renal hemodynamics, the renin-angiotensin-aldosterone system, or the sympathetic nervous system in CHF dogs. Thus, tolvaptan may offer a novel approach to remove excess water congestion from patients with CHF.

The therapeutic efficacy of tolvaptan (OPC-41061), a potent, selective nonpeptide vasopressin V2 receptor antagonist, on acute and chronic severe hyponatremia was assessed in rats. Experiments were designed to demonstrate the efficacy of tolvaptan reducing mortality in an acute model, and controlling the extent of serum sodium elevation without causing abnormal animal behavior suggesting neurological symptoms in a chronic model. In the acute model, rats developed rapidly progressive, severe hyponatremia by continuous sc infusion of [deamino-Cys1, d-Arg8]-vasopressin (10 ng/h) and forced water-loading (additional 10% initial body weight per day). By d 6, untreated rats had a 47% mortality rate. However, rats treated with repeated oral administrations of tolvaptan (1, 3, and 10 mg/kg) produced dose-dependent aquaresis (i.e. urine volume increased and urine osmolality decreased) that resulted in a gradual increase in plasma sodium concentration. Consequently, tolvaptan treatment reduced mortality and, at higher doses, resulted in no observed deaths. In the gradual model, rats receiving a continuous sc infusion of [deamino-Cys1, d-Arg8]-vasopressin (1 ng/h) combined with a liquid diet were induced to stable, severe hyponatremia (∼110 mEq/liter), which lead to increased organ weight and water content. Rats receiving dose titrations of tolvaptan (0.25, 0.5, 1, 2, 4, and 8 mg/kg) increased plasma sodium to healthy levels without causing abnormal animal behavior suggesting neurological symptoms or death, improved hyponatremia-driven increases in wet weight and water content in the organs. Thus, in animal models, analogous to the hyponatremia forms seen in humans, tolvaptan presents exciting therapeutic implications in the management of patients with severe hyponatremia.

We assessed the long-term effects of oral vasopressin V1 antagonist, OPC-21268 (1-1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl-3.4-dihydro-2(1H)quinolinone) in conscious dogs with regional myocardial damage by repetitive DC-shocks. Methods Study design includes three groups: without DC shock (•, C, n = 6). DC-shock (z, DC, n = 7). and DC-shock with OPC-21268 100 mg/kg twice daily (▴, V1A, n = 7). Cardiac catheterizations were performed at baseline and at 4 and 16 weeks 1 after DC shocks. At sacrifice LV was fixed with constant pressure and the cavity size was measured. Results LVEDP was higher in DC. Mean aortic pressure was lower in V1A. Stroke volume did not change among the groups. LV long axis and cross-sectional cavity area were larger in DC, however, they were significa ntly smaller in VlA Download : Download high-res image (69KB) Download : Download full-size image C DC V1A Long axis (cm/kg) 4.9 ± 04 6.1 ± 0.4 * 5.5 ± 0.4 # Cavity area (cm2/kg) 0.49 ± 0.04 0.72 ± 0.10 * 0.58 ± 0.12 # * p l 0.05 vs. C, # p l 0.05 vs. DC Conclusions Stroke volume was preserved through increased LV volume and elevated LVEDP in dogs with DC shocks. OPC-21268 effectively reduced preload and afterload, resulting in smaller LV cavity and normal LVEDP while maintaining stroke volume

An orally effective, nonpeptide, vasopressin V1 receptor antagonist, OPC-21268, has been identified. This compound selectively antagonized binding to the V1 subtype of the vasopressin receptor in a competitive manner. In vivo, the compound acted as a specific antagonist of arginine vasopressin (AVP)-induced vasoconstriction. After oral administration in conscious rats, the compound also antagonized pressor responses to AVP. OPC-21268 can be used to study the physiological role of AVP and may be therapeutically useful in the treatment of hypertension and congestive heart failure.