A reduction in L-arginine availability has been implicated in the impairment of endothelium-dependent nitric oxide (NO)-mediated vasodilation by ischemia-reperfusion (I/R). However, the mechanisms contributing to dysregulation of the L-arginine pool remain unknown. Because endothelial cells can metabolize L-arginine via two major enzymes, that is, NO synthase (NOS) and arginase, we hypothesized that up-regulation of arginase during I/R reduces L-arginine availability to NOS and thus impairs NO-mediated vasodilation. To test this hypothesis, a local I/R was produced in the porcine heart by occlusion of a small branch of left anterior descending artery for 30 min, followed by reperfusion for 90 min. Arterioles (60-110 microm) isolated from non-ischemic and ischemic regions of subepicardium were cannulated and pressurized without flow for in vitro study. Vessels from both regions developed similar levels of basal tone. Although the dilation of I/R vessels to endothelium-independent agonist sodium nitroprusside was not altered, the endothelium-dependent NO-mediated dilations to adenosine and serotonin were attenuated. I/R not only inhibited arteriolar production of NO but also increased arteriolar arginase activity. Arginase inhibitor alpha-difluoromethylornithine enhanced NO production/dilation in normal vessels and also restored the NO-mediated function in I/R vessels. Treating I/R vessels with L-arginine also restored vasodilations. Immunohistochemical data revealed that I/R up-regulated arginase but down-regulated NOS expression in the arteriolar endothelium. Pretreating the animals with protein synthesis inhibitor cycloheximide prevented I/R-induced arginase up-regulation and also preserved NO-mediated vascular function. These results suggest that one mechanism by which I/R inhibits NO-mediated arteriolar dilation is through increased arginase activity, which limits the availability of L-arginine to NOS for NO production. In addition, the inability of arginase blockade or L-arginine supplementation to completely restore vasodilatory function may be attributable to the down-regulation of endothelial NOS expression.
Thengchaisri, Naris, and Lih Kuo. Hydrogen peroxide induces endothelium-dependent and -independent coronary arteriolar dilation: role of cyclooxygenase and potassium channels. Am J Physiol Heart Circ Physiol 285: H2255-H2263, 2003;; 10.1152/ajpheart.00487.2003.-Hydrogen peroxide, a relatively stable reactive oxygen species, is known to elicit vasodilation, but its underlying mechanism remains elusive. Here, we examined the role of endothelial nitric oxide (NO), prostaglandin, cytochrome P-450-derived metabolites, and smooth muscle potassium channels in coronary arteriolar dilation to abluminal H 2O2. Pig subepicardial coronary arterioles (50-100 m) were isolated and pressurized without flow for in vitro study. Arterioles developed basal tone and dilated dose dependently to H 2O2 (1-100 M). Disruption of th endothelium and inhibition of cyclooxygenase (COX) by indomethacin produced identical attenuation of vasodilation to H 2O2. Conversely, the vasodilation to H 2O2 was not affected by either the NO synthase inhibitor N G -nitro-L-arginine methyl ester or the cytochrome P-450 enzyme blocker miconazole. Inhibition of the COX-1, but not the COX-2 pathway, attenuated H 2O2-induced dilation similarly to indomethacin. The production of prostaglandin E 2 (PGE2), but not prostaglandin I2, from coronary arterioles was significantly increased by H 2O2. Furthermore, inhibition of PGE 2 receptors with AH-6809 attenuated vasodilation to H 2O2 similar to that produced by indomethacin. In the absence of a functional endothelium, H 2O2-induced dilation was attenuated, in an identical manner, by a depolarizing agent KCl and a calcium-activated potassium (K Ca) channel inhibitor iberiotoxin. However, PGE 2-induced dilation was not affected by iberiotoxin. The endothelium-independent dilation to H 2O2 was also insensitive to the inhibition of guanylyl cyclase, lipoxygenase, ATP-sensitive potassium channels, and inward rectifier potassium channels. These results suggest that H 2O2 induces endothelium-dependent vasodilation through COX-1-mediated release of PGE 2 and also directly relaxes smooth muscle by hyperpolarization through K Ca channel activation. oxidative stress; prostaglandins; smooth muscle; hyperpolarization
Objective-Overproduction of reactive oxygen species such as hydrogen peroxide (H 2 O 2 ) has been implicated in various cardiovascular diseases. However, mechanism(s) underlying coronary vascular dysfunction induced by H 2 O 2 is unclear. We studied the effect of H 2 O 2 on dilation of coronary arterioles to endothelium-dependent and endothelium-independent agonists. Methods and Results-Porcine coronary arterioles were isolated and pressurized without flow for in vitro study. All vessels developed basal tone and dilated dose-dependently to activators of nitric oxide (NO) synthase (adenosine and ionomycin), cyclooxygenase (arachidonic acid), and cytochrome P450 monooxygenase (bradykinin). Intraluminal incubation of vessels with H 2 O 2 (100 mol/L, 60 minutes) did not alter basal tone but inhibited vasodilations to adenosine and ionomycin in a manner similar as that by NO synthase inhibitor L-NAME. H 2 O 2 affected neither endothelium-dependent responses to arachidonic acid and bradykinin nor endothelium-independent dilation to sodium nitroprusside. The inhibited adenosine response was not reversed by removal of H 2 O 2 but was restored by excess L-arginine. Inhibition of L-arginine consuming enzyme arginase by ␣-difluoromethylornithine or N -hydroxy-nor-Larginine also restored vasodilation. Administering deferoxamine, an inhibitor of hydroxyl radical production, prevented the H 2 O 2 -induced impairment of vasodilation to adenosine. Western blot and reverse-transcription polymerase chain reaction results indicated that arginase I was upregulated after treating vessels with H 2 O 2 . Key Words: endothelium Ⅲ free radicals Ⅲ hydrogen peroxide Ⅲ nitric oxide R eactive oxygen species (ROS) from mitochondria and other subcellular sources have been regarded as toxic byproducts of metabolism, especially when excessive production of ROS outstrips endogenous antioxidant defense mechanisms. 1 However, ROS are also known to influence the expression of a number of genes and signal transduction pathways 2 and are thought to act as subcellular messengers for certain growth factors. 3 Interestingly, several cardiovascular diseases with diverse etiologies, such as atherosclerosis, 4 hypertension, 5 vascular complications in diabetes, 6 and after ischemia/reperfusion injury 7 are associated with the common hallmarks of increased oxidative stress and endothelial cell dysfunction. 8 Although the molecular basis of endothelial dysfunction is not completely understood, numerous studies point to the reduction of nitric oxide (NO) biosynthesis and/or bioactivity as a major mechanism. 9 However, the underlying cellular mechanisms contributing to the reduction of NO-mediated effects remain unclear. Conclusions-H See page 1931Perfusion of coronary artery with H 2 O 2 has recently been shown to impair vasodilation in response to NO-mediated agonists; 10 however, the studies suggested that endothelial dysfunction caused by H 2 O 2 was not mediated by the disruption of arginine-NO pathway. 11 In fact, NO synthase (NOS) activity and its exp...
BackgroundThe relationship between overall obesity and fat distribution in dogs and the development of heart disease is unclear. In the present study we evaluated the association between overall obesity and fat distribution and clinical heart disease by morphometric and computed tomography (CT)-based measurements. Body condition score (BCS), modified body mass index (MBMI, kg/m2), waist-to-hock-to-stifle distance ratio (WHSDR), waist-to-ilium wing distance ratio (WIWDR), and waist-to-truncal length ratio (WTLR) were compared between dogs with (n = 44) and without (n = 43) heart disease using receiver operating characteristic (ROC) analysis. Intra-abdominal fat (IAF) and subcutaneous fat (SQF) were measured in dogs with (n = 8) and without (n = 9) heart disease at the center of the fourth and fifth lumbar vertebrae by CT.ResultsBCS was similar between heart disease and healthy groups (3.6 ± 0.2 vs. 3.3 ± 0.1, P = 0.126). The following morphometric measurements were greater in the heart disease group compared with healthy canines: MBMI (65.0 ± 4.5 vs. 52.5 ± 3.7 kg/m2, respectively, P = 0.035); WIWDR (4.1 ± 0.1 vs. 3.1 ± 0.1, P < 0.01); and WTLR (1.25 ± 0.04 vs. 1.05 ± 0.04, P < 0.01). However, there was no significant difference in WHSDR (3.6 ± 0.1 vs. 3.7 ± 0.2, P = 0.875). Interestingly, IAF was significantly increased in dogs with heart disease compared with healthy dogs (23.5 ± 1.5% vs. 19.4 ± 1.2%, P = 0.039) whereas SQF was similar between two groups (35.5 ± 2.7% vs. 38.6 ± 3.5%, P = 0.496). Of the five morphometric indices studied, WIWDR and WTLR provided acceptable discrimination for diagnosing heart disease in dogs, with areas under the ROC curve of 0.778 (95% confidence interval [CI]:0.683-0.874) and 0.727 (95% CI:0.619-0.835), respectively.ConclusionsOur data indicate that abdominal obesity, rather than overall obesity, is associated with heart disease in dogs. Measurements of both WIWDR and WTLR are particular useful for detection of an abdominal obesity in dogs.
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