RESUMO
BACKGROUND: We have previously shown that nitroglycerin (NTG) therapy increases vascular expression of endothelin 1 (ET-1) and stimulates vascular superoxide (O2.-) production via activation of NADH/NADPH oxidases. Both phenomena are stimulated by angiotensin II in vitro, and the renin-angiotensin system is activated during early nitrate therapy. We hypothesized that either angiotensin II or ET-1 may increase vascular O2.- production during nitrate therapy. METHODS AND RESULTS: In New Zealand White rabbits, 3 days of treatment with NTG patches increased plasma renin activity for the entire treatment period. After 24 hours of NTG treatment, angiotensin II type 1 (AT1) receptor expression and vascular ACE activity were significantly decreased. At this time, constrictions to angiotensin I and II were depressed, but there was no loss of NTG vasodilator potency. Within 3 days of continuous NTG treatment, relaxations to NTG were markedly blunted. This was associated with an increase in AT1 receptor mRNA expression, a return of ACE activity back to baseline, and a marked increase in constrictions to angiotensin I and II despite continuously increased plasma renin activity. Tolerance was associated with a 2-fold increase in vascular O2.-, as estimated by lucigenin-enhanced chemiluminescence. Concomitant treatment with the AT1 receptor antagonist losartan (5 to 25 mg. kg-1. d-1) dose-dependently normalized vascular O2.- and prevented tolerance to NTG and cross-tolerance to endogenous nitric oxide released by acetylcholine. The nonselective ET-1 receptor blocker bosentan (100 mg. kg-1. d-1) had similar but less pronounced effects. CONCLUSIONS: The positive effects of AT1 and ET-1 receptor blockade on tolerance and O2.- production imply a pathophysiological role for angiotensin II and to some extent for ET-1 in the development of nitrate tolerance.
Assuntos
Nitratos/metabolismo , Nitroglicerina/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Vasodilatadores/farmacologia , Angiotensina I/farmacologia , Angiotensina II/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Bosentana , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Endotélio Vascular/química , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Feminino , Expressão Gênica/efeitos dos fármacos , Losartan/farmacologia , Medições Luminescentes , Masculino , Complexos Multienzimáticos/metabolismo , NADH NADPH Oxirredutases/metabolismo , NADPH Oxidases/metabolismo , Óxido Nítrico/metabolismo , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/análise , Coelhos , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Receptores de Angiotensina/genética , Renina/sangue , Sulfonamidas/farmacologia , Superóxidos/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
Experiments in cultured vascular smooth muscle cells have shown that angiotensin II (Ang II) stimulates expression of endothelin-1. We sought to examine role of endothelin-1 in the effects of Ang II in vivo. Ang II infusion in rats (0.7 mg/kg per day for 5 days) was associated with marked increases in vascular smooth muscle endothelin-1 levels, as assessed by immunostaining. Administration of the selective endothelin type A (ET(A)) receptor antagonist PD 155080 (50 mg/kg per day) abrogated the hypertensive response to a 5-day infusion of Ang II (0.7 mg/kg per day), as did losartan (25 mg/kg per day). ET(A) receptor blockade during Ang II-mediated hypertension was associated with marked elevations of plasma endothelin-1 levels. Ang II-mediated hypertension was associated with heightened vascular responsiveness to a variety of vasoconstrictor agents except endothelin-1. Blockade of ET(A) receptor invariably corrected this vasoconstrictor hyperresponsiveness. We conclude that some of the vascular effects of Ang II thought to be unique to this hormone are likely mediated by endothelin-1.