Contribution of cytochrome P450 metabolites of arachidonic acid to hypertension and end-organ damage in spontaneously hypertensive rats treated with L-NAME.
1 The purpose of this study was to examine the effect of inhibition of the formation of cytochrome P450 metabolites of arachidonic acid with 1-aminobenzotriazole (ABT) on the development of hypertension and end-organ damage in spontaneously hypertensive rats (SHR) chronically treated with nitric oxide synthesis inhibitor L-NAME (SHR-L-NAME). 2 Administration of L-NAME in drinking water (80 mg l(-1)) to SHR for 3 weeks significantly elevated mean arterial blood pressure (MABP) (223 +/- 4 mmHg) as compared to SHR controls drinking regular water (165 +/- 3 mmHg). The administration of ABT (50 mg kg(-1) i.p. alt diem) for 6 days significantly attenuated elevation of blood pressure in SHR-L-NAME (204 +/- 4 mmHg). 3 L-NAME-induced increase in urine volume and protein was significantly lower in ABT-treated animals. 4 The impaired vascular responsiveness to noradrenaline and isoprenaline in the perfused mesenteric vascular bed of SHR-L-NAME-treated animals was significantly improved by ABT treatment. 5 Morphological studies of the kidneys and hearts showed that treatment with ABT minimized the extensive arterial fibrinoid necrosis, arterial thrombosis, significant narrowing of arterial lumen with marked arterial hyperplastic arterial changes that were observed in vehicle treated SHR-L-NAME. 6 In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischaemia was significantly better in ABT-treated SHR-L-NAME. 7 These results suggest that in hypertensive individuals with endothelial dysfunction and chronic NO deficiency, inhibitors of 20-HETE synthesis may be able to attenuate development of high blood pressure and end-organ damage.
Benter
I F
IF
Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait Univesity, P.O. box 24923, Safat 13110, Kuwait.
Francis
I
I
Cojocel
C
C
Juggi
J S
JS
Yousif
M H M
MH
Canatan
H
H
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D024061:Collagen Type III / Q000032:analysis; D003331:Coronary Vessels / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007545:Isoproterenol / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009638:Norepinephrine; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013152:Splanchnic Circulation / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents
D024061:Collagen Type III; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D014230:Triazoles; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C033020:1-aminobenzotriazole; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D007545:Isoproterenol; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine