Inhibition of renin-angiotensin system ameliorates endothelial dysfunction associated with aging in rats.
OBJECTIVE
Endothelial vasodilator functions are progressively impaired with aging, which may account in part for the increased incidence of cardiovascular events in elderly people. We examined what treatment could ameliorate the endothelial dysfunction associated with aging in rats.


RESULTS
Aged (12-month-old) Wistar-Kyoto rats were treated with vehicle, temocapril, CS-866 (an angiotensin II type 1 receptor antagonist), cerivastatin, or hydralazine for 2 weeks. Endothelium-dependent relaxations (EDRs) of aortas from aged rats were markedly impaired compared with EDRs of aortas from young (3-month-old) rats. Indomethacin, NS-398 (a cyclooxygenase [COX]-2 inhibitor), and SQ-29548 (a thromboxane A2/prostaglandin H2 receptor antagonist) acutely restored EDRs in aged rats, suggesting an involvement of COX-2-derived vasoconstricting eicosanoids. Tiron, a superoxide scavenger, also partially improved EDRs, suggesting an involvement of superoxide. EDRs were significantly ameliorated in aged rats after long-term treatment with temocapril or CS-866 but not after treatment with cerivastatin or hydralazine. Indomethacin induced no further improvement of EDRs after treatment with temocapril or CS-866. COX-2 protein expression and superoxide production were increased in the aortas of aged rats and were also attenuated by treatment with temocapril or CS-866.


CONCLUSIONS
These results demonstrate that long-term inhibition of the renin-angiotensin system ameliorates endothelial dysfunction associated with aging through the inhibition of the synthesis of COX-2-derived vasoconstricting factors and superoxide anions.
Mukai
Yasushi
Y
Department of Cardiovascular Medicine, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan.
Shimokawa
Hiroaki
H
Higashi
Midoriko
M
Morikawa
Keiko
K
Matoba
Tetsuya
T
Hiroki
Junko
J
Kunihiro
Ikuko
I
Talukder
Hassan M A
HM
Takeshita
Akira
A
D000375:Aging / Q000187:drug effects* / Q000473:pathology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D051546:Cyclooxygenase 2; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology*; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D009578:Nitrobenzenes / Q000008:administration & dosage / Q000494:pharmacology; D000068557:Olmesartan Medoxomil; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology; D013841:Thiazepines / Q000008:administration & dosage / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007093:Imidazoles; D007527:Isoenzymes; D009578:Nitrobenzenes; D013449:Sulfonamides; D013777:Tetrazoles; D013841:Thiazepines; D013481:Superoxides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D000068557:Olmesartan Medoxomil; C045749:SQ 29548; C055603:temocapril hydrochloride; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin