RESUMEN
The role of androgens in vascular reactivity is controversial, particularly regarding their age-related actions. The objective of this study was to conduct a temporal evaluation of the vascular reactivity of resistance arteries of young male rats, as well as to understand how male sex hormones can influence the vascular function of these animals. Endothelium-mediated relaxation was characterized in third-order mesenteric arteries of 10-, 12-, 16-, and 18w (week-old) male rats. Concentration-response curves to acetylcholine (ACh, 0.1 nmol/L-10 µmol/L) were constructed in arteries previously contracted with phenylephrine (PE, 3 µmol/L), before and after the use of nitric oxide synthase or cyclooxygenase inhibitors. PE concentration-response curves (1 nmol/L-100 µmol/L) were also built. The levels of vascular nitric oxide, superoxide anion, and hydrogen peroxide were assessed and histomorphometry analysis was performed. The 18w group had impaired endothelium-dependent relaxation. All groups showed prostanoid-independent and nitric oxide-dependent vasodilatory response, although this dependence seems to be smaller in the 18w group. The 18w group had the lowest nitric oxide and hydrogen peroxide production, in addition to the highest superoxide anion levels. Besides functional impairment, 18w animals showed morphological differences in third-order mesenteric arteries compared with the other groups. Our data show that time-dependent exposure to male sex hormones appears to play an important role in the development of vascular changes that can lead to impaired vascular reactivity in mesenteric arteries, which could be related to the onset of age-related cardiovascular changes in males.
Asunto(s)
Óxido Nítrico , Superóxidos , Masculino , Ratas , Animales , Peróxido de Hidrógeno , Arterias , Hormonas Esteroides GonadalesRESUMEN
Lectins are proteins that recognize specific carbohydrates, and the vasorelaxant effect of legume lectins has been previously reported, for example the Dioclea rostrata lectin (DRL). This study evaluated major pathways of DRL-induced relaxation in different artery segments and the possible molecular interactions involved. Rat thoracic aorta, coronary and mesenteric resistance arteries were tested "in vitro" with concentration-response curves to DRL (0.01-100 µg/mL). L-NAME, indomethacin and high KCl were used to evaluate nitric oxide, cyclooxygenase and hyperpolarization-dependent effects. DRL promoted relaxation of all vessels throughout different mechanisms. L-NAME blunted DRL-induced effects only in the aorta and mesenteric resistance artery. By the use of depolarizing KCl solution, vasodilation was reduced in all arteries, while incubation with indomethacin indicated a role of cyclooxygenase-derived factors for DRL effects in mesenteric and coronary arteries, but not in the aorta. Molecular docking results suggested interactions between DRL and heparan sulphate, CD31 and other glycans present on the membrane surface. These data indicate that the mechanisms involved in DRL-mediated vasodilation vary between conductance and resistance arteries of different origins, and these effects may be related to the capacity of DRL to bind a diversity of glycans, especially heparan sulphate, a proposed mechanoreceptor for nitric oxide synthase and cyclooxygenase activation.
Asunto(s)
Arterias/efectos de los fármacos , Dioclea , Lectinas/metabolismo , Lectinas/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Arterias/fisiología , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiología , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiología , Simulación del Acoplamiento Molecular , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Ratas , Ratas WistarRESUMEN
Mercury is a heavy metal associated with cardiovascular diseases. Studies have reported increased vascular reactivity without changes in systolic blood pressure (SBP) after chronic mercury chloride (HgCl2) exposure, an inorganic form of the metal, in normotensive rats. However, we do not know whether individuals in the prehypertensive phase, such as young spontaneously hypertensive rats (SHRs), are susceptible to increased arterial blood pressure. We investigated whether chronic HgCl2 exposure in young SHRs accelerates hypertension development by studying the vascular function of mesenteric resistance arteries (MRAs) and SBP in young SHRs during the prehypertensive phase. Four-week-old male SHRs were divided into two groups: the SHR control group (vehicle) and the SHR HgCl2 group (4 weeks of exposure). The results showed that HgCl2 treatment accelerated the development of hypertension; reduced vascular reactivity to phenylephrine in MRAs; increased nitric oxide (NO) generation; promoted vascular dysfunction by increasing the production of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2); increased Gp91Phox protein levels and in situ levels of superoxide anion (O2·-); and reduced vasoconstrictor prostanoid production compared to vehicle treatment. Although HgCl2 accelerated the development of hypertension, the HgCl2-exposed animals also exhibited a vasoprotective mechanism to counterbalance the rapid increase in SBP by decreasing vascular reactivity through H2O2 and NO overproduction. Our results suggest that HgCl2 exposure potentiates this vasoprotective mechanism against the early establishment of hypertension. Therefore, we are concluding that chronic exposure to HgCl2 in prehypertensive animals could enhance the risk for cardiovascular diseases.
Asunto(s)
Presión Arterial/efectos de los fármacos , Peróxido de Hidrógeno/metabolismo , Hipertensión/inducido químicamente , Cloruro de Mercurio/toxicidad , Arterias Mesentéricas/efectos de los fármacos , Óxido Nítrico/metabolismo , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Arterias Mesentéricas/metabolismo , Arterias Mesentéricas/fisiopatología , NADPH Oxidasa 2/metabolismo , Prostaglandinas/metabolismo , Ratas Endogámicas SHR , Especies Reactivas de Oxígeno/metabolismo , Medición de Riesgo , Transducción de Señal , Factores de TiempoRESUMEN
During three decades, an enormous number of studies have demonstrated the critical role of nitric oxide (NO) as a second messenger engaged in the activation of many systems including vascular smooth muscle relaxation. The underlying cellular mechanisms involved in vasodilatation are essentially due to soluble guanylyl-cyclase (sGC) modulation in the cytoplasm of vascular smooth cells. sGC activation culminates in cyclic GMP (cGMP) production, which in turn leads to protein kinase G (PKG) activation. NO binds to the sGC heme moiety, thereby activating this enzyme. Activation of the NO-sGC-cGMP-PKG pathway entails Ca2+ signaling reduction and vasodilatation. Endothelium dysfunction leads to decreased production or bioavailability of endogenous NO that could contribute to vascular diseases. Nitrosyl ruthenium complexes have been studied as a new class of NO donors with potential therapeutic use in order to supply the NO deficiency. In this context, this article shall provide a brief review of the effects exerted by the NO that is enzymatically produced via endothelial NO-synthase (eNOS) activation and by the NO released from NO donor compounds in the vascular smooth muscle cells on both conduit and resistance arteries, as well as veins. In addition, the involvement of the nitrite molecule as an endogenous NO reservoir engaged in vasodilatation will be described.
Asunto(s)
Animales , Humanos , Ratas , Células Endoteliales/metabolismo , Donantes de Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Óxido Nítrico/biosíntesis , Compuestos de Rutenio/metabolismo , Endotelio Vascular/metabolismo , Hipertensión/fisiopatología , Músculo Liso Vascular/metabolismo , Óxido Nítrico/farmacología , Vasodilatación/fisiologíaRESUMEN
The investigation of resistance vessels is generally costly and difficult to execute. The present study investigated the diameters and the vascular reactivity of different segments of the rat tail artery (base, middle, and tail end) of 30 male Wister rats (EPM strain) to characterize a conductance or resistance vessel, using a low-cost simple technique. The diameters (mean ± SEM) of the base and middle segments were 471 ± 4.97 and 540 ± 8.39 µm, respectively, the tail end was 253 ± 2.58 µm. To test reactivity, the whole tail arteries or segments were perfused under constant flow and the reactivity to phenylephrine (PHE; 0.01-300 µg) was evaluated before and after removal of the endothelium or drug administration. The maximal response (Emax) and sensitivity (pED50) to PHE of the whole tail and the base segment increased after endothelium removal or treatment with 100 µM L-NAME, which suggests modulation by nitric oxide. Indomethacin (10 µM) and tetraethylammonium (5 mM) did not change the Emax or pED50 of these segments. PHE and L-NAME increased the pED50 of the middle and the tail end only and indomethacin did not change pED50 or Emax. Tetraethylammonium increased the sensitivity only at the tail end, which suggests a blockade of vasodilator release. Results indicate that the proximal segment of the tail artery possesses a diameter compatible with a conductance vessel, while the tail end has the diameter of a resistance vessel. In addition, the vascular reactivity to PHE in the proximal segment is nitric oxide-dependent, while the tail end is dependent on endothelium-derived hyperpolarizing factor.