) found that endothelin (ET) stimulated O 2 Ϫ production in sympathetic ganglion neurons in vitro by activating ETB receptors. The objective of the present study was to determine whether activation of ETB receptors in vivo elevates O 2 Ϫ levels in sympathetic ganglia. Because ET B receptor activation increases blood pressure, we also sought to determine whether alteration in O 2 Ϫ levels was a direct effect of ET B receptor activation on sympathetic ganglia or an indirect consequence of hypertension. Male Sprague-Dawley rats received intravenous infusions of either the specific ET B receptor agonist sarafotoxin 6c (S6c; 5 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) or isotonic saline at 0.01 ml/min (control) for 120 min. To measure O 2 Ϫ levels, we removed the inferior mesenteric ganglion immediately after infusion and stained it with dihydroethidine (DHE). Mean arterial pressure increased 26.6 Ϯ 1.7 mmHg in the S6c-treated rats and 3.65 Ϯ 6 mmHg in control rats. Measurements of average pixel intensity revealed that the DHE fluorescence in ganglionic neurons and surrounding glial cells were 96.7% and 160% greater in S6c-treated than in control rats, respectively. To evaluate the effect of elevated blood pressure on O 2 Ϫ production, a separate group of rats received phenylephrine (PE; 10 g ⅐ kg Ϫ1 ⅐ min Ϫ1 iv) for 2 h. MAP increased 31 Ϯ 1.2 mmHg in PE-infused rats. The DHE fluorescence intensity in ganglia of PEinfused rats was significantly greater than that of control rats, 137.7% in neurons and 104.6% in glia but significantly lower than in ganglia from S6c rats. We conclude that ETB receptor activation in vivo significantly enhances O 2 Ϫ levels in sympathetic ganglia, due to both pressor effects and direct stimulation of ET B receptors in ganglion cells. hypertension; sarafotoxin 6c; sympathetic nervous activity; oxidative stress; reactive oxygen species HYPERTENSION CAUSED BY NUMEROUS genetic and neurohumoral factors is associated with higher amounts of reactive oxygen species (ROS) in blood vessels, brain, and kidneys; examples include ANG II-mediated hypertension, deoxycorticosterone acetate (DOCA)-salt hypertension, mineralocorticoid hypertension, aortic banding-induced hypertension, renovascular hypertension, and endothelin-induced hypertension (1, 3, 18 -20, 23, 28, 36, 42). The best characterized ROS in tissues of hypertensive individuals is superoxide anion (O 2 Ϫ ). Reduction in O 2 Ϫ formation can lower blood pressure in some experimental models of hypertension (1,9,14,32,38), suggesting that increased production of ROS is an etiologic factor in hypertension. O 2 Ϫ can increase blood pressure by several mechanisms. In the vasculature, O 2 Ϫ causes vasoconstriction, in part by inducing endothelial cell dysfunction (5). Increased O 2 Ϫ in the kidney is associated with enhanced tubular reabsorption of sodium and water (27,33). In key brain regions, increased O 2 Ϫ leads to increased sympathetic nervous system activity (SNA) (7,(51)(52)(53). The focus of the work to be reported here, however, is on the peripheral sympa...
Distribution of the cAMP-specific phosphodiesterase PDE4A was examined in the accessory olfactory system by immunohistochemistry. Adjacent sections through the vomeronasal organ (VNO) and accessory olfactory bulb (AOB) were alternately immunostained with antibodies against PDE4A or the G-protein alpha subunit G(o) alpha, which labels basal VNO neurons, in order to determine whether PDE4A occurs preferentially in one of two segregated VNO pathways. We found that PDE4A strongly labeled apical VNO neurons and rostral AOB glomeruli. There was virtually no overlap in G(o) alpha and PDE4A staining, and there were no regions of the VNO neuroepithelium or AOB glomeruli not labeled by either antibody. These results identify a potential member of the pheromone transduction cascade in apical neurons, and provide further evidence that the VNO consists of functionally distinct pathways.
Loss of endothelial cell-derived nitric oxide (NO) in hypertension is a hallmark of arterial dysfunction. Experimental hypertension created by the removal of NO, however, involves mechanisms in addition to decreased arterial vasodilator activity. These include augmented endothelin-1 (ET-1) release, increased sympathetic nervous system activity, and elevated tissue oxidative stress. We hypothesized that increased venous smooth muscle (venomotor) tone plays a role in Nomega-nitro-L-arginine (LNNA) hypertension through these mechanisms. Rats were treated with the NO synthase inhibitor LNNA (0.5 g/L in drinking water) for 2 weeks. Mean arterial pressure of conscious rats was 119 +/- 2 mm Hg in control and 194 +/- 5 mm Hg in LNNA rats (P<0.05). Carotid arteries and vena cava were removed for measurement of isometric contraction. Maximal contraction to norepinephrine was modestly reduced in arteries from LNNA compared with control rats whereas the maximum contraction to ET-1 was significantly reduced (54% control). Maximum contraction of vena cava to norepinephrine (37% control) also was reduced but no change in response to ET-1 was observed. Mean circulatory filling pressure, an in vivo measure of venomotor tone, was not elevated in LNNA hypertension at 1 or 2 weeks after LNNA. The superoxide scavenger tempol (30, 100, and 300 micromol kg(-1), IV) did not change arterial pressure in control rats but caused a dose-dependent decrease in LNNA rats (-18 +/- 8, -26 +/- 15, and -54 +/- 11 mm Hg). Similarly, ganglionic blockade with hexamethonium caused a significantly greater fall in LNNA hypertensive rats (76 +/- 9 mm Hg) compared with control rats (35 +/- 10 mm Hg). Carotid arteries, vena cava, and sympathetic ganglia from LNNA rats had higher basal levels of superoxide compared with those from control rats. These data suggest that while NO deficiency increases oxidative stress and sympathetic activity in both arterial and venous vessels, the impact on veins does not make a major contribution to this form of hypertension.
Abstract-Endothelin (ET) exerts powerful pressor actions primarily through activation of the ET A receptor subtype. The ET B receptor (ET B R) subtype, on the other hand, is generally thought to initiate physiological actions that decrease arterial pressure. Such actions include clearing ET from the bloodstream, initiating endothelium-mediated vasodilation, and facilitating renal sodium and water excretion. The effect of long-term activation of the ET B R on arterial pressure, however, never has been directly tested. In this study we evaluated cardiovascular responses to chronic (5-day) activation of ET B R in male rats using continuous intravenous infusion of the selective agonist sarafotoxin 6c. Surprisingly, we found that sarafotoxin 6c caused a sustained increase in arterial pressure that rapidly reversed on termination of infusion. The hypertension was associated with increased renal excretion of sodium and water and decreased plasma volume. Alterations in daily sodium intake did not affect the magnitude of the hypertension. Hemodynamic studies revealed a decreased cardiac output and increased total peripheral resistance during sarafotoxin 6c infusion. Infusion of sarafotoxin 6c caused a small increase in plasma ET levels. Nevertheless, the hypertension was not affected by coadministration of a selective ET A receptor antagonist (atrasentan) but was completely prevented by treatment with a combined ET A receptor and ET B R antagonist (A186280). These experiments reveal for the first time that chronic activation of ET B R in rats causes sustained hypertension. (Hypertension. 2007;50:512-518.)Key Words: endothelin Ⅲ ET B receptor Ⅲ salt Ⅲ hemodynamics E ndothelins (ETs) have powerful effects on arterial blood pressure regulation and contribute to the genesis of human and experimental hypertension. 1 Most ET-mediated pressor actions result from stimulation of the ET A receptor (ET A R) found in vascular smooth muscle, kidney, heart, adrenal gland, and other tissues. 1 The influence of ET B receptor (ET B R) on arterial pressure (AP) regulation has been more controversial, but the bulk of evidence supports an antihypertensive function. Knockout of the ET B R gene causes salt-sensitive hypertension in rats 2 and mice, 3,4 as does chronic pharmacological blockade of ET B R in a variety of species. 5-8 One important antihypertensive mechanism associated with ET B R activation may be enhanced renal sodium and water excretion, because renal-collecting, duct-specific knockout of ET B R causes hypertension. 9 Other studies, however, do not support a critical role for renal ET B R in controlling AP. 2 ET B Rs on endothelial cells act as plasma ET clearance receptors, 10 and their absence or blockade produces increased plasma ET levels that can activate ET A R to cause hypertension. 6 In addition, ET B Rs located on endothelial cells promote vasodilation by releasing NO and prostanoids. Nevertheless, endothelial cell ET B Rs do not seem necessary for chronic AP regulation, because their selective deletion does not cause...
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