The circulating doxycycline levels of the patients are comparable with those achieved in mice. Doxycycline accounts for an inhibition of 33% to 66% of the aortic growth. The findings suggest that standard doxycycline doses could inhibit AAA growth in humans.
The paraventricular nucleus (PVN) of the hypothalamus is known to be involved in the control of sympathetic outflow. The goal of the present study was to examine the role of nitric oxide within the PVN in the regulation of renal sympathetic nerve activity. Renal sympathetic nerve discharge (RSND), arterial blood pressure, and heart rate in response to the microinjection of nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 50, 100, and 200 pmol) into the PVN were measured in male Sprague-Dawley rats. Microinjection of L-NMMA elicited an increase in RSND, arterial blood pressure, and heart rate. Administration of NG-monomethyl-D-arginine (D-NMMA, 50-200 pmol) into the PVN did not change RSND, arterial pressure, or heart rate. Similarly, microinjection of another nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 100 nmol) also elicited an increase in RSND, arterial blood pressure, and heart rate. L-Arginine (100 nmol) reversed the effects of L-NAME in the PVN. Furthermore, microinjection of sodium nitroprusside (SNP; 50, 100, and 200 nmol) into the PVN elicited a significant decrease in RSND, arterial blood pressure, and heart rate. These effects of L-NMMA, L-NAME, and SNP on RSND and arterial blood pressure were not mediated by their vasoactive action because microinjection of phenylephrine and hydralazine did not elicit similar respective changes. In conclusion, our data indicate that endogenous nitric oxide within the PVN regulates sympathetic outflow via some inhibitory mechanisms. Altered nitric oxide mechanisms within the PVN may contribute to elevated sympathetic nerve activity observed during various diseases states such as heart failure and hypertension.
It appears that the expression of vascular endothelial growth factor (VEGF) is increased during brain injury and thus may contribute to disruption of the blood-brain barrier (BBB) during cerebrovascular trauma. The first goal of this study was to determine the effect of VEGF on permeability of the BBB in vivo. The second goal was to determine possible cellular mechanisms by which VEGF increases permeability of the BBB. We examined the pial microcirculation in rats using intravital fluorescence microscopy. Permeability of the BBB [clearance of FITC-labeled dextran of molecular mass 10,000 Da (FITC-dextran-10K)] and diameter of pial arterioles were measured in absence and presence of VEGF (0.01 and 0.1 nM). During superfusion with vehicle (saline), clearance of FITC-dextran-10K from pial vessels was minimal and diameter of pial arterioles remained constant. Topical application of VEGF (0.01 nM) did not alter permeability of the BBB to FITC-dextran-10K or arteriolar diameter. However, superfusion with VEGF (0.1 nM) produced a marked increase in clearance of FITC-dextran-10K and a modest dilatation of pial arterioles. To determine a potential role for nitric oxide and stimulation of soluble guanylate cyclase in VEGF-induced increases in permeability of the BBB and arteriolar dilatation, we examined the effects of N G-monomethyl-l-arginine (l-NMMA; 10 μM) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1.0 μM), respectively.l-NMMA and ODQ inhibited VEGF-induced increases in permeability of the BBB and arteriolar dilatation. The findings of the present study suggest that VEGF, which appears to be increased in brain tissue during cerebrovascular trauma, increases the permeability of the BBB via the synthesis/release of nitric oxide and subsequent activation of soluble guanylate cyclase.
We studied disruption of the blood-brain barrier (BBB) by acute hypertension and a hyperosmolar solution. The goals were to determine whether 1) disruption of the BBB occurs primarily in arteries, capillaries, or veins, and 2) transport of different-sized molecules is homogeneous or size dependent. Sprague-Dawley rats were studied using intravital fluorescent microscopy of pial vessels and fluorescein-labeled dextrans (FITC-dextran, mol wt = 70,000, 20,000, and 4,000 daltons). The site of disruption was determined by the appearance of microvascular leaky sites. Transport of different-sized molecules was calculated from clearance of FITC-dextran. During gradual hypertension and osmotic disruption, all leaky sites were venular. Rapid hypertension produced venular leaky sites and, in some experiments, diffuse arteriolar extravasation of FITC-dextran. Clearance of different-sized molecules was homogeneous during acute hypertension. In contrast, clearance of molecules during osmotic disruption was size dependent. The findings suggest that 1) venules and veins are the primary sites of disruption following acute hypertension and a hyperosmolar solution; 2) transport of different-sized molecules is homogeneous following acute hypertension, which suggests a vesicular mechanism; and 3) transport following hyperosmolar disruption is size dependent, which suggests that hyperosmolar disruption may involve formation of pores as well as vesicular transport.
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