title: Renin-angiotensin system blockade improves endothelial dysfunction in hypertension.
abstract: Angiotensin-converting enzyme (ACE) inhibitor improves the impaired hyperpolarization and relaxation to acetylcholine (ACh) via endothelium-derived hyperpolarizing factor (EDHF) in arteries of spontaneously hypertensive rats (SHR). We tested whether the angiotensin type 1 (AT(1)) receptor antagonist also improves EDHF-mediated responses and whether the combined AT(1) receptor blockade and ACE inhibition exert any additional effects. SHR were treated with either AT(1) receptor antagonist TCV-116 (5 mg. kg(-1). d(-1)) (SHR-T), enalapril (40 mg. kg(-1). d(-1)) (SHR-E), or their combination (SHR-T&E) from 8 to 11 months of age. Age-matched, untreated SHR (SHR-C) and Wistar Kyoto (WKY) rats served as controls (n=8 to 12 in each group). Three treatments lowered blood pressure comparably. EDHF-mediated hyperpolarization to ACh in mesenteric arteries in the absence or presence of norepinephrine was significantly improved in all treated SHR. In addition, the hyperpolarization in the presence of norepinephrine was significantly greater in SHR-T&E than in SHR-E (ACh 10(-5) mol/L with norepinephrine: SHR-C -7; SHR-T -19; SHR-E -15; SHR-T&E -22; WKY -14 mV). EDHF-mediated relaxation, assessed in the presence of indomethacin and N:(G)-nitro-L-arginine, was markedly improved in all treated SHR. Hyperpolarization and relaxation to levcromakalim, a direct opener of ATP-sensitive K(+)-channel, were similar in all groups. These findings suggest that AT(1) receptor antagonists are as effective as ACE inhibitors in improving EDHF-mediated responses in SHR. The beneficial effects of the combined AT(1) receptor blockade and ACE inhibition appears to be for the most part similar to those of each intervention.
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; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001562:Benzimidazoles / Q000008:administration & dosage*; D001685:Biological Factors / Q000378:metabolism; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D019806:Cromakalim / Q000008:administration & dosage; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000008:administration & dosage*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006973:Hypertension / Q000188:drug therapy*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D019335:Nitroarginine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013777:Tetrazoles
chemical_list: D057911:Angiotensin Receptor Antagonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001685:Biological Factors; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D015221:Potassium Channels; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; C067410:endothelium-dependent hyperpolarization factor; D019806:Cromakalim; D019335:Nitroarginine; D004656:Enalapril; D000109:Acetylcholine; C077793:candesartan cilexetil; D009638:Norepinephrine; D007213:Indomethacin