Reversal of cardiac, vascular, and renal dysfunction by non-quinazoline α1-adrenolytics in DOCA-salt hypertensive rats: a comparison with prazosin, a quinazoline-based α1-adrenoceptor antagonist.
Adrenergic alpha-1 Receptor Agonists
/ pharmacology
Animals
Antihypertensive Agents
/ pharmacology
Blood Pressure
/ drug effects
Body Weight
/ drug effects
Desoxycorticosterone Acetate
Drug Evaluation, Preclinical
Endothelium, Vascular
/ drug effects
Heart
/ drug effects
Heart Rate
/ drug effects
Hypertension
/ drug therapy
Kidney
/ drug effects
Lipid Peroxidation
/ drug effects
Male
Piperazines
/ pharmacology
Prazosin
/ pharmacology
Rats, Wistar
DOCA-salt hypertensive rats
endothelial dysfunction
nitric oxide
α1-adrenoceptor antagonist
Journal
Hypertension research : official journal of the Japanese Society of Hypertension
ISSN: 1348-4214
Titre abrégé: Hypertens Res
Pays: England
ID NLM: 9307690
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
23
10
2018
accepted:
03
02
2019
revised:
11
12
2018
pubmed:
16
3
2019
medline:
23
9
2020
entrez:
16
3
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30872813
doi: 10.1038/s41440-019-0239-1
pii: 10.1038/s41440-019-0239-1
doi:
Substances chimiques
Adrenergic alpha-1 Receptor Agonists
0
Antihypertensive Agents
0
MH-76 compound
0
MH-79 compound
0
Piperazines
0
Desoxycorticosterone Acetate
6E0A168OB8
Prazosin
XM03YJ541D
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1125-1141Références
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