We investigated the
therapeutic effect of
MH-76 and
MH-79, which are non-
quinazoline α1-adrenoceptor antagonists with an additional ability to stimulate the
nitric oxide (NO)/cyclic
guanosine monophosphate (cGMP)/K + pathway, on
deoxycorticosterone acetate (
DOCA)-
salt induced
hypertension in rats.
Prazosin was used as a reference compound, as
quinazoline-based α1-adrenolytics may potentially exert unfavorable proapoptotic and necrotic effects.
DOCA-
salt hypertension was induced by
DOCA (20 mg/kg s.c., twice weekly) administration plus 1% NaCl and 0.2% KCl solutions in
drinking water for 12 weeks. The studied compounds
MH-76,
MH-79 (10 mg/kg i.p.) or
prazosin (0.4 mg/kg i.p.) were administered to the
DOCA-
salt-treated rats, starting from the 6th week of
DOCA-
salt treatment and continuing for 6 weeks. This study showed that the administration of
MH-79 and, to a lesser extent,
MH-76 decreased elevated systolic blood pressure and heart rate, reduced heart and kidney
hypertrophy, and reversed the histopathological alterations of the heart, kidney, and vessels in
DOCA-
salt hypertensive rats.
MH-79 reversed endothelial dysfunction, which reduced inflammatory cell infiltration, arteriosclerotic alterations in renal and coronary arteries, and tubulointerstitial
fibrosis.
Prazosin showed a potent hemodynamic effect and reduced cardiac and renal
fibrosis but exerted detrimental effects on blood vessels, potentiating fibroplasia of the media of the intrarenal artery and causing calcification of coronary arteries.
Prazosin did not reverse endothelial dysfunction. Our results show the beneficial effect of non-
quinazoline α1-adrenolytics on cardiac, vascular, and renal dysfunction in
DOCA-
salt hypertensive rats. Our findings also support the idea that targeting endothelial protection and endothelial integrity would yield beneficial effects against cardiac, blood vessel and renal injury related to
hypertension.