title: Factors involved in the effects of losartan on endothelial dysfunction induced by aging in SHR.
abstract: In the present study we investigated the effects of losartan (10 mg/kg/day; 12 weeks) on acetylcholine (Ach) induced relaxations in isolated mesenteric vascular beds (MVB) from adult and elderly spontaneous hypertensive rats (SHR). Experiments were done in absence or presence of either the NO synthesis inhibitor, L-NAME (10(-5) mol/liter), L-NAME + indomethacin (10(-5) mol/liter) or L-NAME + indomethacin + KCl (10(-5) mol/liter), to evaluate the participation of the factors (NO, PGs and EDHF, respectively) mediating Ach-relaxations. Systolic blood pressure levels were comparable in both groups. However, urinary nitrites excretion and Ach-response was lower in elderly than in adult SHR. The presence of L-NAME and L-NAME + indomethacin only reduced Ach-relaxations in untreated elderly SHR. Further addition of KCl to the perfusion media totally blunted Ach-relaxation in both groups. The calculated participation of endothelium-derived hyperpolarizing factor (EDHF) in Ach-relaxations was higher than that of nitric oxide (NO) and prostaglandins in both groups, although the EDHF component was lower in elderly when compared to adult SHR. Losartan treatment reduced blood pressure levels and enhanced dose-related Ach-relaxations and urinary nitrites in both groups. Presence of L-NAME and L-NAME + indomethacin blunted the enhancements induced by losartan on Ach-relaxations in both adult and elderly SHR. Further addition of KCl to the perfusion media totally blunted Ach-relaxation in both groups. The calculated participation of NO in Ach-relaxations was increased by losartan in both groups. Neither EDHF or prostanoids (PGs) components were clearly affected by losartan. In conclusion, (1) diminished EDHF availability accounts for the reduced Ach-relaxations produced by aging in MVB from SHR; (2) the enhancement of Ach-relaxations produced by losartan seems to be dependent on an increased NO availability; and (3) angiotensin II via angiotensin I type 1 receptor (AT1) plays an important role in the deleterious consequences of aging on endothelial function in SHR.
authors.affiliation: Department of Physiology, School of Medicine, Complutense University, Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Maeso
authors.forename: E
authors.initials: E
authors.lastname: Rodrigo
authors.forename: R
authors.initials: R
authors.lastname: Muñoz-García
authors.forename: J
authors.initials: J
authors.lastname: Navarro-Cid
authors.forename: L M
authors.initials: LM
authors.lastname: Ruilope
authors.forename: V
authors.initials: V
authors.lastname: Cachofeiro
authors.forename: V
authors.initials: V
authors.lastname: Lahera
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009573:Nitrites / Q000652:urine; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D009573:Nitrites; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010656:Phenylephrine; D011189:Potassium Chloride; D019808:Losartan; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester