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Background and Purpose: Superoxide anions can reduce the bioavailability and actions of endothelium‐derived NO. In human resistance‐sized arteries, endothelium‐dependent vasodilatation can be mediated by H2O2 instead of NO. Here, we tested the hypothesis that in resistance arteries from patients with cardiovascular disease, endothelium‐dependent vasodilatation is mediated by a reactive oxygen species and not impaired by oxidative stress. Experimental Approach Small arteries were isolated from biopsies of the parietal pericardium of patients undergoing elective cardiothoracic surgery and were studied using immunohistochemical and organ chamber techniques. Key Results: NO synthases 1, 2 and 3, superoxide dismutase 1 and catalase proteins were observed in the microvascular wall. Relaxing responses to bradykinin were endothelium dependent. During submaximal depolarization‐induced contraction, bradykinin‐mediated relaxations were inhibited by inhibitors of NO synthases (NOS) and soluble guanylyl cyclase (sGC) but not by scavengers of NO or HNO, inhibitors of cyclooxygenases, neuronal NO synthase, superoxide dismutase or catalase, or by exogenous catalase. During contraction stimulated by endothelin‐1, these relaxations were not reduced by any of these interventions except DETCA, which caused a small reduction. Conclusion and Implications: In resistance arteries from patients with cardiovascular disease, endothelium‐dependent relaxations seem not to be mediated by NO, HNO or H2O2, although NOS and sGC can be involved. These vasodilator responses continue during excessive oxidative stress. [ABSTRACT FROM AUTHOR]

Kidney fibrosis is the common pathophysiological mechanism in end-stage renal disease characterized by excessive accumulation of myofibroblast-derived extracellular matrix. Natriuretic peptides have been demonstrated to have cyclic guanosine monophosphate (cGMP)-dependent anti-fibrotic properties likely due to interference with pro-fibrotic tissue growth factor ß (TGF-ß) signaling. However, in vivo, natriuretic peptides are rapidly degraded by neutral endopeptidases (NEP). In a unilateral ureteral obstruction (UUO) mouse model for kidney fibrosis we assessed the anti-fibrotic effects of SOL1, an orally active compound that inhibits NEP and endothelin-converting enzyme (ECE). Mice (n=10 per group) subjected to UUO were treated for 1 week with either solvent, NEP-/ECE-inhibitor SOL1 (two doses), reference NEP-inhibitor candoxatril or the angiotensin II receptor type 1 (AT1)-antagonist losartan. While NEP-inhibitors had no significant effect on blood pressure, they did increase urinary cGMP levels as well as endothelin-1 (ET-1) levels. Immunohistochemical staining revealed a marked decrease in renal collagen (~55% reduction, P<0.05) and α-smooth muscle actin (a-SMA; ~40% reduction, P<0.05). Moreover, the number of a-SMA positive cells in the kidneys of SOL1-treated groups inversely correlated with cGMP levels consistent with a NEP-dependent anti-fibrotic effect. To dissect the molecular mechanisms associated with the anti-fibrotic effects of NEP inhibition, we performed a 'deep serial analysis of gene expression (Deep SAGE)' transcriptome and targeted metabolomics analysis of total kidneys of all treatment groups. Pathway analyses linked increased cGMP and ET-1 levels with decreased nuclear receptor signaling (peroxisome proliferator-activated receptor [PPAR] and liver X receptor/retinoid X receptor [LXR/RXR] signaling) and actin cytoskeleton organization. Taken together, although our transcriptome and metabolome data indicate metabolic dysregulation, our data support the therapeutic potential of NEP inhibition in the treatment of kidney fibrosis via cGMP elevation and reduced myofibroblast formation. [ABSTRACT FROM AUTHOR]

Le Noble, Ferdinand A. C., Karin Ruijtenbeek, Susanne Gommers, Jo G. R. De Mey, and Carlos E. Blanco. Contractile and relaxing reactivity in carotid and femoral arteries of chicken embryos. Am J Physiol Heart Circ Physiol 278: H1261-H1268, 2000.--In the embryo, hypoxemia causes redistribution of cardiac output from the periphery toward the heart and the brain. In view of this, we investigated developmental changes in the contractile and relaxing properties of the peripheral femoral artery (Fem) and the more central carotid artery (Car) at 0.7, 0.8, and 0.9 of the chicken embryo incubation time. Isolated arteries were studied :in myographs and were exposed to norepinephrine or phenylepihrine. High [K.sup.+] (125 mM) and electrical field stimulation (0.25-16 Hz) were used to induce receptor-independent and neurogenic contractions. Relaxing responses to ACh were evaluated in the absence and presence of the nitric oxide (NO) synthase inhibitor [N.sub.G]-nitro-L-arginine methyl ester (L-NAME) and before and after endothelium removal. [[Alpha].sub.1]-Adrenergic contractile responses increased in a time-dependent manner and were significantly larger in Fern than in Car. Neurogenic contractions and adrenergic nerves could only be demonstrated in Fem at 0.9 incubation. ACh caused relaxation in both Fem and Car at 0.7, 0.8, and 0.9 incubation. The NO-independent part of the relaxation was more pronounced in Car than in Fem at all developmental stages. We conclude that the chicken embryo is a useful model to investigate the development of vasomotor control and vascular heterogeneity. The observed regional vascular differences may contribute to cardiac output redistribution during hypoxia in the embryo and might result from endothelial and neurogenic influences on vascular smooth muscle differentiation. catecholamines; vascular smooth muscle; sympathetic nerves; endothelium; regional heterogeneity; chemoreflex

Van Gorp, Ad W., Dorette S. Van Ingen Schenau, Arnold P. G. Hoeks, Harry A. J. Struijker Boudier, Jo G. R. De Mey, and Robert S. Reneman. In spontaneously hypertensive rats alterations in aortic wall properties precede development of hypertension. Am J Physiol Heart Circ Physiol 278: H1241-H1247, 2000.--In hypertension arterial wall properties do not necessarily depend on increased blood pressure alone. The present study investigates the relationship between the development of hypertension and thoracic aortic wall properties in 1.5-, 3-, and 6-mo-old spontaneously hypertensive rats (SHR); Wistar-Kyoto rats (WKY) served as controls. During ketamine-xylazine anesthesia, compliance and distensibility were assessed by means of a noninvasive ultrasound technique combined with invasive blood pressure measurements. Morphometric measurements provided in vivo media cross-sectional area and thickness, allowing the calculation of the incremental elastic modulus. Extracellular matrix protein contents were determined as well. Blood pressure was not significantly different in 1.5-mo-old SHR and WKY, but compliance and distensibility were significantly lower in SHR. Incremental elastic modulus was not significantly different between SHR and WKY at this age. Media thickness and media cross-sectional area were significantly larger in SHR than in WKY, but there was no consistent difference in collagen density and content between the strains. Blood pressure was significantly higher in 3- and 6-mo-old SHR than in WKY, and compliance was significantly lower in SHR. The findings in this study show that in SHR, in which hypertension develops over weeks, alterations in functional aortic wall properties precede the development of hypertension. The decrease in compliance and distensibility at a young age most likely results from media hypertrophy rather than a change in intrinsic elastic properties. arterial wall tracking; compliance; distensibility; incremental elastic modulus; wall structure; collagen; elastin