RESUMEN
The vascular NAD(P)H oxidase contributes to endothelial dysfunction and high blood pressure in the spontaneously hypertensive rat by enhancing superoxide production. We investigated the effects of apocynin, a NAD(P)H oxidase inhibitor, on blood pressure and vascular radical and nitric oxide formation in SHR and compared its effects to the calcium channel blocker nifedipine. Apocynin (over four weeks) lowered systolic blood pressure significantly and as effectively as nifedipine. Both apocynin and nifedipine significantly reduced superoxide production. In parallel, vascular nitric oxide production and ecNOS activity was significantly increased by apocynin treatment. Therefore, apocynin may be an effective antihypertensive drug in essential hypertension.
Asunto(s)
Acetofenonas/farmacología , Inhibidores Enzimáticos/farmacología , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , NADPH Oxidasas/antagonistas & inhibidores , Animales , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Técnicas In Vitro , Masculino , Nifedipino/farmacología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas , Ratas Endogámicas SHR , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Vasoconstricción/efectos de los fármacosRESUMEN
Dihydropyridine calcium antagonists play an important role in the treatment of hypertension and angina pectoris. They lower blood pressure by a well-characterized mechanism of blocking L-type calcium channels in smooth muscle cells. Additionally, there is growing evidence that dihydropyridines also modulate endothelial functions by other mechanisms, since macrovascular endothelial cells do not express L-type calcium channels. A number of studies have demonstrated that dihydropyridine calcium antagonists enhance bioavailability of endothelial nitric oxide (NO). Endothelium-derived NO plays a pivotal role in the regulation of vasorelaxation, leukocyte adhesion and platelet aggregation and an impaired NO release is associated with the genesis and progression of atherosclerotic diseases. This review summarizes results from experimental findings that dihydropyridine calcium antagonists increase endothelial NO formation as well as studies which demonstrate these effects in vivo both in animals and humans. Moreover, the influence of dihydropyridine calcium antagonists on the progression of atherosclerosis is discussed. These pleiotropic effects of dihydropyridine calcium antagonists may underlie or contribute to antiatherosclerotic effects of this substance class.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Dihidropiridinas/farmacología , Endotelio Vascular , Óxido Nítrico , Animales , Arteriosclerosis/prevención & control , Disponibilidad Biológica , Bloqueadores de los Canales de Calcio/uso terapéutico , Dihidropiridinas/uso terapéutico , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiología , Humanos , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa/metabolismoRESUMEN
BACKGROUND: It has not been completely clarified whether selective estrogen receptor modulators (SERMs) such as raloxifene exert vasoprotective effects similar to those of estrogens. METHODS AND RESULTS: To investigate vascular effects of raloxifene, male spontaneously hypertensive rats were treated for 10 weeks with either raloxifene (10 mg x kg(-1) x d(-1)) or vehicle. Raloxifene improved endothelium-dependent vasodilatation but had no effect on either endothelium-independent vasorelaxation or phenylephrine-induced vasoconstriction. Raloxifene treatment increased the release of NO from the vessel wall by enhanced expression and activity of endothelial NO synthase. Blood pressure reduction after bradykinin infusion was more pronounced in animals treated with SERMs. The production of superoxide in intact aortic segments was decreased by raloxifene treatment. Administration of raloxifene had no effect on the expression of the essential NAD(P)H oxidase subunits p22phox and nox1 in the vasculature but reduced the activity and expression of vascular membrane-bound rac1, a GTPase required for the activation of the NAD(P)H oxidase. Finally, blood pressure levels were significantly decreased in spontaneously hypertensive rats treated with raloxifene. All SERM effects were also detected in healthy age-matched Wistar rats. In cultured rat aortic vascular smooth muscle cells, raloxifene inhibited angiotensin II-induced reactive oxygen species production dependent on estrogen receptor activation. CONCLUSIONS: Raloxifene treatment improves hypertension-induced endothelial dysfunction by increased bioavailability of NO. This is achieved by an increased activity of endothelial NO synthase and by an estrogen receptor-dependent reduction in release of reactive oxygen species from vascular cells. These vascular effects cause a profound blood pressure reduction and lead to decreased vascular damage in male spontaneously hypertensive rats.