Lm. Burrell et al., BLOOD-PRESSURE-LOWERING EFFECT OF AN ORALLY-ACTIVE VASOPRESSIN V(1) RECEPTOR ANTAGONIST IN MINERALOCORTICOID HYPERTENSION IN THE RAT, Hypertension, 23(6), 1994, pp. 737-743
We studied the contribution of vasopressin to the maintenance of high
blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertension
in the rat using the nonpeptide orally effective vasopressin V1 recep
tor antagonist OPC-21268. Binding kinetic studies demonstrated that or
al OPC-21268 (30 mg/kg) acted as a competitive antagonist at the vasop
ressin V1 receptor in DOCA-salt and salt control rats. Basal mean intr
a-arterial blood pressure was 140 +/- 4 mm Hg (n=12) in DOCA-salt rats
compared with 111 +/- 2 mm Hg in salt control rats (n=18). Acute oral
OPC-21268 (30 mg/kg) significantly (P<.01) reduced mean intra-arteria
l pressure in DOCA-salt hypertension, with an average maximal decrease
of 24 +/- 3 mm Hg occurring at 2.5 +/- 0.7 hours after dosing. Systol
ic brood pressure (tail-cuff) in DOCA-salt rats was 178 +/- 2 mm Hg. C
hronic oral OPC-21268 (30 mg/kg) twice daily for 7 days significantly
(P<.01) reduced systolic blood pressure in DOCA-salt hypertension, wit
h an average maximal decrease of 27 +/- 5 mm Hg. The antihypertensive
effect was reversed 5 days after treatment with OPC-21268 was stopped.
In water control rats basal systolic pressure (120 +/- 1 mm Hg, n=20)
was unchanged by chronic oral OPC-21268 (30 mg/kg twice daily for 7 d
ays), and this was confirmed by direct measurement of mean intra-arter
ial pressure. After chronic oral OPC-21268 (30 mg/kg twice daily for 7
days) hepatic V1 receptor binding was significantly reduced for up to
10 hours (P<.05). The results of this study suggest that vasopressin
does not play a major role in the regulation of normal blood pressure
in the rat but support a role for vasopressin in the maintenance of mi
neralocorticoid hypertension in the rat. OPC-21268 may be of use in th
e treatment of hypertensive conditions associated with elevated vasopr
essin concentrations.