Arginase inhibition reduces endothelial dysfunction and blood pressure rising in spontaneously hypertensive rats.
OBJECTIVE
A decrease in nitric oxide (NO) bioavailability has been proposed to contribute to endothelial dysfunction and increased peripheral resistances during essential arterial hypertension. Given that arginine is a substrate for both arginase and NO synthase, arginase activity may be a critical factor in NO bioavailability. To test this hypothesis, we evaluated the effects of the arginase inhibitor alpha-difluoromethylornithine (DFMO) in spontaneously hypertensive rats (SHR).


METHODS
Vascular reactivity experiments were performed on thoracic aortic rings from 10-week-old SHR and their normotensive counterparts, Wistar-Kyoto (WKY) rats. Blood pressure was measured by the tail-cuff method. DFMO treatment (30 mg/kg daily in drinking water) was started in 5-week-old SHR and maintained for 5 weeks. Aortic arginase I and arginase II expression as well as arginase activity were evaluated by western blotting and the spectrophotometric method, respectively.


RESULTS
DFMO (1.2 x 10 mol/l) enhanced the vascular response to acetylcholine both in SHR (+24%, P < 0.01) and WKY rats (+12%, P < 0.01), and reversed the effects of the NO synthase inhibitor N-nitro-L-arginine-methyl-ester. The vasorelaxant response to sodium nitroprusside on endothelium-denuded rings was not affected by DFMO, neither in SHR nor in WKY rats. In SHR, DFMO prevented the increase in blood pressure and improved the response of aortic rings to acetylcholine. Finally, as compared with WKY rats, SHR exhibited increased expression of vascular arginase I (+72%, P < 0.05) and arginase II (+91%, P < 0.05) as well as increased arginase activity (+26%, P < 0.05).


CONCLUSIONS
Our results showed that arginase inhibition reduced endothelial dysfunction and blood pressure rising in SHR.
Demougeot
Céline
C
Laboratoire de Physiologie-Pharmacologie-Nutrition Préventive Expérimentale, Faculté de Médecine-Pharmacie, Besancon, France. cdemouge@univ-fcomte.fr
Prigent-Tessier
Anne
A
Marie
Christine
C
Berthelot
Alain
A
D000818:Animals; D001011:Aorta / Q000201:enzymology; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D000518:Eflornithine / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D009955:Ornithine Decarboxylase / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D001119:Arginase; D009955:Ornithine Decarboxylase; D019331:NG-Nitroarginine Methyl Ester; D000518:Eflornithine