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Aamand R, Dalsgaard T, Jensen FB, Simonsen U, Roepstorff A, Fago A. Generation of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilation. Am J Physiol Heart Circ Physiol 297: H2068-H2074, 2009. First published October 9, 2009; doi: 10.1152/ajpheart.00525.2009.--In catalyzing the reversible hydration of C[O.sub.2] to bicarbonate and protons, the ubiquitous enzyme carbonic anhydrase (CA) plays a crucial role in C[O.sub.2] transport, in acid-base balance, and in linking local acidosis to [O.sub.2] unloading from hemoglobin. Considering the structural similarity between bicarbonate and nitrite, we hypothesized that CA uses nitrite as a substrate to produce the potent vasodilator nitric oxide (NO) to increase local blood flow to metabolically active tissues. Here we show that CA readily reacts with nitrite to generate NO, particularly at low pH, and that the NO produced in the reaction induces vasodilation in aortic rings. This reaction occurs under normoxic and hypoxic conditions and in various tissues at physiological levels of CA and nitrite. Furthermore, two specific inhibitors of the C[O.sub.2] hydration, dorzolamide and acetazolamide, increase the CA-catalyzed production of vasoactive NO from nitrite. This enhancing effect may explain the known vasodilating effects of these drugs and indicates that C[O.sub.2] and nitrite bind differently to the enzyme active site. Kinetic analyses show a higher reaction rate at high pH, suggesting that anionic nitrite participates more effectively in catalysis. Taken together, our results reveal a novel nitrous anhydrase enzymatic activity of CA that would function to link the in vivo main end products of energy metabolism (C[O.sub.2]/[H.sup.+]) to the generation of vasoactive NO. The CA-mediated NO production may be important to the correlation between blood flow and metabolic activity in tissues, as occurring for instance in active areas of the brain. acetazolamide; dorzolamide; acidosis; neurovascular coupling doi: 10.1152/ajpheart.00525.2009

Background: To decrease the morbidity associated with cut-downs during endovascular aneurysm repair, some authors have suggested the totally percutaneous endovascular repair (PEVAR). The goal of this report is to evaluate and describe our centre's experience with the total percutaneous endovascular aneurysm repair (PEVAR) for aortic abdominal aneurysm (AAA). Methods: We performed a retrospective analysis of 15 consecutive patients with AAA, including 1 with right common iliac artery aneurysm. Results: There were 12 men and 3 women with a mean age of 74 (standard deviation [SD] 2) years who underwent PEVAR with a Perclose ProGlide suture-mediated closure system between July 2007 and July 2008. All surgeries were elective. Forty percent of patients had a history of smoking, 73% were hypertensive, 33% were diabetic, 20% had chronic obstructive pulmonary disease and 40% had coronary artery disease. Fourteen patients had bilateral deployment for bifurcated devices (7 bifurcated Gore Excluder, 7 bifurcated Cook Zenith grafts), and 1 patient had unilateral deployment for a Cook Zenith device. The outer diameter of the sheaths used for puncture sites was on average 18.1-Fr (SD 0.6), with main bodies being 21.1-Fr (SD 0.3) and contralateral sides 15-Fr (SD 0.3). Procedural success was 93%, with 1 patient requiring a femoral artery cut-down because of failure of the Perclose device to deploy in the groin. Another patient had persistent venous bleeding in 1 puncture site that stopped with skin suturing. Endovascular aneurysm repair was 100% with no conversion to open surgery and no type-I endoleaks. The mean length of stay in hospital was 2.2 (SD 0.4) days. There were no long-term groin complications at 6 (SD 1) months' follow-up. Conclusion: To our knowledge, this is the first Canadian report of experience with PEVAR using the Perclose device. The technique is safe, reliable and allows discharge of patients soon after surgery. Contexte : Afin de reduire la morbidite associee aux denudations au cours de la reparation d'un anevrisme par voie endovasculaire, des auteurs ont suggere d'utiliser la reparation endovasculaire entierement percutanee (PEVAR). Ce rapport vise a evaluer et a decrire l'experience, a notre centre, de la reparation d'un anevrisme de l'aorte abdominale (AAA) par voie endovasculaire entierement percutanee (PEVAR). Methodes : Nous avons procede a une analyse retrospective de 15 patients consecutifs qui ont subi un AAA, dont un anevrisme de l'artere iliaque commune droite. Resultats : Les 12 hommes et 3 femmes avaient en moyenne 74 (ecart-type [ET] 2) ans et ont subi une reparation PEVAR pratiquee au moyen du systeme d'obturation vasculaire par suture Perclose ProGlide entre juillet 2007 et juillet 2008. Toutes les interventions chirurgicales ont ete electives. Quarante pour cent des patients avaient des antecedents de tabagisme, 73%, de l'hypertension, 33%, le diabete, 20%, une maladie pulmonaire obstructive chronique et 40%, une coronaropathie. Quatorze patients avaient des dispositifs bifurques bilateraux (7 Gore Excluder bifurques, 7 greffons Cook Zenith bifurques) et 1 patient avait un dispositif Cook Zenith a deploiement unilateral. Le diametre exterieur des gaines utilisees au point de perforation s'etablissait en moyenne a 18,1-Fr (ET 0,6), les corps principaux ayant 21,1-Fr (ET 0,3) et les cotes contralateraux, 15-Fr (ET 0,3). Les interventions ont reussi a 93%; il a fallu pratiquer une incision dans l'artere femorale d'un patient parce que le dispositif Perclose ne s'etait pas deploye dans l'aine. Un autre patient avait un saignement veineux persistant a un point de perforation, qui s'est arrete apres la suture de la peau. La reparation de l'anevrisme s'est faite entierement par voie endovasculaire et il n'y a eu aucune conversion en chirurgie sanglante ni aucune endofuite de type I. La duree moyenne du sejour a l'hopital a ete de 2,2 (ET 0,4) jours. Il n'y a eu aucune complication a long terme a l'aine a 6 (ET 1) mois. Conclusion : Sauf erreur, il s'agit du premier rapport canadien portant sur une experience d'intervention PEVAR pratiquee avec le systeme Perclose. La technique, securitaire et fiable, permet de donner son conge au patient peu apres l'intervention chirurgicale., Abdominal aortic aneurysms (AAAs) were traditionally treated with open surgical repair until the development of endovascular aneurysm repair (EVAR), as described by Parodi in 1991. (1) Since then, many studies [...]

Epoxyeicosatrienoic acids (EETs) are potent vasodilators produced from arachidonic acid by cytochrome P-450 (CYP) epoxygenases and metabolized to vicinal diols by soluble epoxide hydrolase (sEH). In the brain, EETs are produced by astrocytes and the vascular endothelium and are involved in the control of cerebral blood flow (CBF). Recent evidence, however, suggests that epoxygenases and sEH are present in perivascular vasodilator nerve fibers innervating the cerebral surface vasculature. In the present study, we tested the hypothesis that EETs are nerve-derived relaxing factors in the cerebral circulation. We first traced these fibers by retrograde labeling in the rat to trigeminal ganglia (TG) and sphenopalatine ganglia (SPG). We then examined the expression of CYP epoxygenases and sEH in these ganglia. RT-PCR and Western blot analysis identified CYP2J3 and CYP2J4 epoxygenase isoforms and sEH in both TG and SPG, and immunofluorescence double labeling identified CYP2J and sEH immunoreactivity in neuronal cell bodies of both ganglia. To evaluate the functional role of EETs in neurogenic vasodilation, we elicited cortical hyperemia by electrically stimulating efferent cerebral perivascular nerve fibers and by chemically stimulating oral trigeminal fibers with capsaicin. Cortical blood flow responses were monitored by laser-Doppler flowmetry. Local administration to the cortical surface of the putative EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (30 [micro]mol/l) attenuated CBF responses to electrical and chemical stimulation. These results suggest that EETs are produced by perivascular nerves and play a role in neurogenic vasodilation of the cerebral vasculature. The findings have important implications to such clinical conditions as migraine, vasospasm after subarachnoid hemorrhage, and stroke. cerebral blood flow regulation; cytochrome P-450 epoxygenase; epoxyeicosatrienoic acid; soluble epoxide hydrolase; perivascular nerves

In septic shock, systemic vasodilation and myocardial depression contribute to the systemic hypotension observed. Both components can be attributed to the effects of mediators that are released as part of the inflammatory response. We previously found that lysozyme (Lzm-S), released from leukocytes, contributed to the myocardial depression that develops in a canine model of septic shock. Lzm-S binds to the endocardial endothelium, resulting in the production of nitric oxide (NO), which, in turn, activates the myocardial soluble guanylate cyclase (sGC) pathway. In the present study, we determined whether Lzm-S might also play a role in the systemic vasodilation that occurs in septic shock. In a phenylephrine-contracted canine carotid artery ring preparation, we found that both canine and human Lzm-S, at concentrations similar to those found in sepsis, produced vasorelaxation. This decrease in force could not be prevented by inhibitors of NO synthase, prostaglandin synthesis, or potassium channel inhibitors and was not dependent on the presence of the vascular endothelium. However, inhibitors of the sGC pathway prevented the vasodilatory activity of Lzm-S. In addition, Aspergillus niger catalase, which breaks down [H.sub.2][O.sub.2], as well as hydroxyl radical scavengers, which included hydroquinone and mannitol, prevented the effect of Lzm-S. Electrochemical sensors corroborated that Lzm-S caused [H.sub.2][O.sub.2] release from the carotid artery preparation. In conclusion, these results support the notion that when Lzm-S interacts with the arterial vasculature, this interaction results in the formation of [H.sub.2][O.sub.2], which, in turn, activates the sGC pathway to cause relaxation. Lzm-S may contribute to the vasodilation that occurs in septic shock. reactive oxygen species; catalase; compound I; hydroxyl radical; septic shock; hypotension

Muscarinic receptor agonists have primarily been used to characterize endothelium-dependent vasodilator dysfunction with overweight/obesity. Reliance on a single class of agonist, however, yields limited, and potentially misleading, information regarding endothelial vasodilator capacity. The aims of this study were to determine 1) whether the overweight/obesity-related reduction in endothelium-dependent vasodilation extends beyond muscarinic receptor agonists and 2) whether the contribution of nitric oxide (NO) to endothelium-dependent vasodilation is reduced in overweight/obese adults. Eighty-six middle-aged and older adults were studied: 42 normal-weight (54 [+ or -] 1 yr, 21 men and 21 women, body mass index = 23.4 [+ or -] 0.3 kg/[m.sup.2]) and 44 overweight/obese (54 [+ or -] 1 yr, 28 men and 16 women, body mass index = 30.3 [+ or -] 0.6 kg/[m.sup.2]) subjects. Forearm blood flow (FBF) responses to intra-arterial infusions of acetylcholine in the absence and presence of the endothelial NO synthase inhibitor [N.sup.G]-monomethyl-L-arginine, methacholine, bradykinin, substance P, isoproterenol, and sodium nitropmsside were measured by strain-gauge plethysmograplay. FBF responses to each endothelial agonist were significantly blunted in the overweight/obese adults. Total FBF (area under the curve) to acetylcholine (50 [+ or -] 5 vs. 79 [+ or -] 4 ml/100 ml tissue), methacholine (55 [+ or -] 4 vs. 86 [+ or -] 5 ml/100 ml tissue), bradykinin (62 [+ or -] 5 vs. 85 [+ or -] 4 ml/100 ml tissue), substance P (37 [+ or -] 4 vs. 57 [+ or -] 5 ml/100 ml tissue), and isoproterenol (62 [+ or -] 4 vs. 82 [+ or -] 6 ml/100 ml tissue) were 30%-40% lower in the overweight/obese than normal-weight adults. [N.sup.G]-monomethyl-L-arginine significantly reduced the FBF response to acetylcholine to the same extent in both groups. There were no differences between the groups in the FBF responses to sodium nitroprusside. These results indicate that agonist-stimulated endothelium-dependent vasodilation is universally impaired with overweight/obesity. Moreover, this impairment appears to be independent of NO. cell surface receptors; intracellular signaling pathways; nitric oxide