title: Angiotensin-converting enzyme inhibitor prevents age-related endothelial dysfunction.
abstract: Vascular relaxation via endothelium-derived hyperpolarizing factor (EDHF) declines in association with aging and also with hypertension, and antihypertensive treatment improves the endothelial dysfunction connected with hypertension. We tested whether the angiotensin-converting enzyme inhibitor improves EDHF-mediated responses in normotensive rats, with special reference to the age-related process. Wistar-Kyoto rats (WKY) were treated with either 20 mg. kg(-1). d(-1) enalapril (WKY-E group) or a combination of 50 mg. kg(-1). d(-1) hydralazine and 7.5 mg. kg(-1). d(-1) hydrochlorothiazide (WKY-H group) from 9 to 12 months of age. Twelve-month-old WKY (WKY-O) and 3-month-old WKY (WKY-Y) served as controls (n=6 to 10 in each group). The 2 treatments lowered systolic blood pressure comparably. EDHF-mediated hyperpolarization to acetylcholine (ACh) in mesenteric arteries was significantly improved in WKY-E, but not in WKY-H, compared with WKY-O, and the hyperpolarization in WKY-E was comparable to that in WKY-Y (hyperpolarization to 10(-)(5) mol/L ACh in the presence of norepinephrine: WKY-O, -14+/-2 mV; WKY-E, -22+/-3 mV; WKY-H, -15+/-2 mV; and WKY-Y, -28+/-0 mV). EDHF-mediated relaxation, as assessed by relaxation to ACh in norepinephrine-precontracted rings in the presence of indomethacin and NO synthase inhibitor, was also significantly improved in WKY-E, but not in WKY-H, to a level comparable to that in WKY-Y (maximum relaxation: WKY-O, 45+/-6%; WKY-E, 63+/-8%; WKY-H, 43+/-4%; and WKY-Y, 72+/-4%). Hyperpolarization and relaxation to levcromakalim, an ATP-sensitive K(+) channel opener, were similar in all groups. These findings suggest that the angiotensin-converting enzyme inhibitor prevents the age-related decline in EDHF-mediated hyperpolarization and relaxation in normotensive rats, presumably through an inhibition of the renin-angiotensin system.
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Goto
authors.forename: K
authors.initials: K
authors.lastname: Fujii
authors.forename: U
authors.initials: U
authors.lastname: Onaka
authors.forename: I
authors.initials: I
authors.lastname: Abe
authors.forename: M
authors.initials: M
authors.lastname: Fujishima
mesh_terms: D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000284:Administration, Oral; D000375:Aging / Q000187:drug effects*; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D001685:Biological Factors / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006830:Hydralazine / Q000008:administration & dosage; D006852:Hydrochlorothiazide / Q000008:administration & dosage; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000959:Antihypertensive Agents; D001685:Biological Factors; C067410:endothelium-dependent hyperpolarization factor; D006852:Hydrochlorothiazide; D000804:Angiotensin II; D006830:Hydralazine; D004656:Enalapril; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D009638:Norepinephrine