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Renal and vascular effects of chronic nitric oxide synthase inhibition: involvement of endothelin 1 and angiotensin II.
Can J Physiol Pharmacol. 1999 Jan; 77(1):8-16.CJ

Abstract

Endothelin 1 (ET-1) is a potent vasoconstrictor implicated in the control of blood pressure and renal function. Its effects can be modulated by nitric oxide (NO), which inhibits ET-1 production and action. Recently, we reported that ET-1 production can also be modulated by angiotensin II (AngII) in vivo. To investigate the interactions between NO, ET-1, and AngII in hypertension and renal dysfunction, we assessed immunoreactive ET-1 (ir-ET-1) concentration in plasma and urine as well as in vascular and renal tissues of rats with chronic inhibition of NO synthesis, in the presence and the absence of the AngII type 1 receptor antagonist losartan. Normal (protocols A and B) and uninephrectomized rats (protocol C) received the L-arginine analog N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, 0.05% (protocol A) or 0.1% (protocols B and C), with or without losartan (20 mg x kg(-1) x day(-1)). After 6 weeks, systolic blood pressure was significantly increased in L-NAME rats compared with the controls (p < 0.01), while serum creatinine and urea, creatinine clearance, and proteinuria were similar to control values. However, ir-ET-1 concentration in plasma and in the thoracic aorta was augmented in animals receiving 0.1% L-NAME (1 < 0.01), while it was unchanged in the mesenteric arterial bed, preglomerular arteries, and glomeruli. In contrast, ir-ET-1 concentration was decreased in the renal papilla (p < 0.05) as well as in the urine of L-NAME rats (p < 0.01). Treatment with losartan significantly attenuated the rise in systolic blood pressure induced by L-NAME (p < 0.01). Losartan also normalized the increased ir-ET-1 concentration in plasma and in the thoracic aorta, but had no effect on tissues with normal or reduced ir-ET-1 levels. These results indicate that chronic inhibition of NO synthase with L-NAME induces hypertension without renal dysfunction. Increased ET-1 production in some blood vessels and elevated circulating ET-1 concentration may contribute to the maintenance of high blood pressure. The reduction of systolic blood pressure by losartan supports a role for AngII in the pathogenesis of this form of hypertension, which may be due, at least in part, to the modulation of ET-1 production.

Authors+Show Affiliations

Research Centre, Centre Hospitalier Universitaire de Québec (CHUQ), L'Hôtel-Dieu de Québec Hospital, Université Laval, Canada.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10535660

Citation

D'Amours, M, et al. "Renal and Vascular Effects of Chronic Nitric Oxide Synthase Inhibition: Involvement of Endothelin 1 and Angiotensin II." Canadian Journal of Physiology and Pharmacology, vol. 77, no. 1, 1999, pp. 8-16.
D'Amours M, Lebel M, Grose JH, et al. Renal and vascular effects of chronic nitric oxide synthase inhibition: involvement of endothelin 1 and angiotensin II. Can J Physiol Pharmacol. 1999;77(1):8-16.
D'Amours, M., Lebel, M., Grose, J. H., & Larivière, R. (1999). Renal and vascular effects of chronic nitric oxide synthase inhibition: involvement of endothelin 1 and angiotensin II. Canadian Journal of Physiology and Pharmacology, 77(1), 8-16.
D'Amours M, et al. Renal and Vascular Effects of Chronic Nitric Oxide Synthase Inhibition: Involvement of Endothelin 1 and Angiotensin II. Can J Physiol Pharmacol. 1999;77(1):8-16. PubMed PMID: 10535660.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Renal and vascular effects of chronic nitric oxide synthase inhibition: involvement of endothelin 1 and angiotensin II. AU - D'Amours,M, AU - Lebel,M, AU - Grose,J H, AU - Larivière,R, PY - 1999/10/27/pubmed PY - 1999/10/27/medline PY - 1999/10/27/entrez SP - 8 EP - 16 JF - Canadian journal of physiology and pharmacology JO - Can J Physiol Pharmacol VL - 77 IS - 1 N2 - Endothelin 1 (ET-1) is a potent vasoconstrictor implicated in the control of blood pressure and renal function. Its effects can be modulated by nitric oxide (NO), which inhibits ET-1 production and action. Recently, we reported that ET-1 production can also be modulated by angiotensin II (AngII) in vivo. To investigate the interactions between NO, ET-1, and AngII in hypertension and renal dysfunction, we assessed immunoreactive ET-1 (ir-ET-1) concentration in plasma and urine as well as in vascular and renal tissues of rats with chronic inhibition of NO synthesis, in the presence and the absence of the AngII type 1 receptor antagonist losartan. Normal (protocols A and B) and uninephrectomized rats (protocol C) received the L-arginine analog N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, 0.05% (protocol A) or 0.1% (protocols B and C), with or without losartan (20 mg x kg(-1) x day(-1)). After 6 weeks, systolic blood pressure was significantly increased in L-NAME rats compared with the controls (p < 0.01), while serum creatinine and urea, creatinine clearance, and proteinuria were similar to control values. However, ir-ET-1 concentration in plasma and in the thoracic aorta was augmented in animals receiving 0.1% L-NAME (1 < 0.01), while it was unchanged in the mesenteric arterial bed, preglomerular arteries, and glomeruli. In contrast, ir-ET-1 concentration was decreased in the renal papilla (p < 0.05) as well as in the urine of L-NAME rats (p < 0.01). Treatment with losartan significantly attenuated the rise in systolic blood pressure induced by L-NAME (p < 0.01). Losartan also normalized the increased ir-ET-1 concentration in plasma and in the thoracic aorta, but had no effect on tissues with normal or reduced ir-ET-1 levels. These results indicate that chronic inhibition of NO synthase with L-NAME induces hypertension without renal dysfunction. Increased ET-1 production in some blood vessels and elevated circulating ET-1 concentration may contribute to the maintenance of high blood pressure. The reduction of systolic blood pressure by losartan supports a role for AngII in the pathogenesis of this form of hypertension, which may be due, at least in part, to the modulation of ET-1 production. SN - 0008-4212 UR - https://www.unboundmedicine.com/medline/citation/10535660/Renal_and_vascular_effects_of_chronic_nitric_oxide_synthase_inhibition:_involvement_of_endothelin_1_and_angiotensin_II_ L2 - https://cdnsciencepub.com/doi/10.1139/cjpp-77-1-8?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -