OPC-21268, a vasopressin V1 antagonist, produces hypotension in spontaneously hypertensive rats.

Abstract

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.

Effects of Nonpeptide and Selective V1 and V2 Antagonists on Blood Pressure Short-Term Variability in Spontaneously Hypertensive Rats

“…of the V 2 antagonist in 16-h dehydrated rats (to stimulate vasopressin secretion) increased in volume and decreased in osmolality (<500 mosmol / l). It is noteworthy mentioning that the selectivity and the efficacy of V 1 and V 2 vasopressin antagonists in SHR, in the doses we employed in this study, were also reported by others (22,30).…”

“…It is therefore important to emphasize that the receptor subtype selectivity and the functional separation between V 1 -and V 2 -receptor blockade is warranted even at doses ten times higher than the ones we employed (22,23,28,31,50). This minimizes the possibility that the effects of vasopressin antagonists in this study were due to inhibition of receptors other than the V 1 -and V 2 -receptor subtypes.…”

“…In SHR, plasma concentration of vasopressin was found to be elevated (20), V 1 receptor antagonists significantly reduce BP (22,23), and vascular responsiveness to exogenously applied arginine-vasopressin is potentiated in comparison to normotensive controls (24). In addition, in normotensive rats, chronic stimulation of V 1 receptors results in sustained hypertension (25,26).…”

Increased expression of ENaC subunits and increased apical targeting of AQP2 in the kidneys of spontaneously hypertensive rats

“…The effects of chronic blockade of the vasopressin receptors during hypertension of SHR appear controversial and the role of the V1 receptor in the pathogenesis of hypertension is unclear (51,52,55). It has been demonstrated that increased plasma vasopressin levels and enhanced binding capacity in the kidney tubules induce the decreased urine volume and increased urine osmolality (27,53) and that they play roles in the pathogenesis of hypertension by expanding effective circulating blood volume via the V2 receptor.…”

Small molecule ligands for oxytocin and vasopressin receptors

“…A hypotensive response for OPC-21268 was demonstrated in stroke-prone spontaneously hypertensive rats, suggesting a possible role of AVP in some forms of hypertension. 29 In addition, OPC-21268 improved renal function in a rat model (5/6 nephrectomized) of renal failure. 30 Significantly, the compound is orally active with an ID 50 of 2 mg/kg for inhibiting AVP-induced vasoconstriction in conscious rats and has been shown to produce drug plasma levels after oral administration to humans.…”