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Biomedical subjects

Akos Koller

Publications and source records attributed to Akos Koller.

At least 19 recordsLinked to original sources
PubMed2007

Hyperhomocysteinemia alters cardiac substrate metabolism by impairing nitric oxide bioavailability through oxidative stress.

BACKGROUND: Hyperhomocysteinemia (HHcy) has been considered a vascular disease associated with increased levels of oxidative stress that results in scavenging of NO. However, little is known of the impact of HHcy on cardiac function and especially myocardial metabolism. METHODS AND RESULTS: L-Homocysteine was intravenously infused into conscious dogs, and the dogs were fed methionine to increase plasma homocysteine to 10 micromol/L for acute and 24 micromol/L for chronic HHcy. There was no significant change in hemodynamics with HHcy. Veratrine-induced, NO-dependent, coronary vasodilation (Bezold-Jarisch reflex) was reduced by 32% but was restored by simultaneous intravenous infusion of ascorbic acid or apocynin. Acute and chronic HHcy significantly increased uptake of glucose and lactate and decreased uptake of free fatty acid by the heart. HHcy significantly decreased bradykinin- or carbachol-induced reduction of myocardial oxygen consumption in vitro, and this effect was completely restored by coincubation with ascorbic acid, Tempol, or apocynin. Western blot analysis indicated an increase in Nox2 (82%) and a reduction in endothelial nitric oxide synthase (39%), phospho-endothelial nitric oxide synthase (39%), and superoxide dismutase-1 (45%). Microarray analysis of gene expression in heart tissue from chronic HHcy indicated a switch in cardiac phenotype to enzymes that metabolize glucose. CONCLUSIONS: HHcy directly modulates substrate use by the heart independent of changes in hemodynamics or ventricular function by reducing NO bioavailability through the generation of superoxide. The progression of cardiac or coronary heart disease associated with HHcy should be evaluated in light of the impact of alterations in the regulation of cardiac metabolism and substrate use.

Animals↗
PubMed2006

H2O2 increases production of constrictor prostaglandins in smooth muscle leading to enhanced arteriolar tone in Type 2 diabetic mice.

Our previous study showed that arteriolar tone is enhanced in Type 2 diabetes mellitus (T2-DM) due to an increased level of constrictor prostaglandins. We hypothesized that, in mice with T2-DM, hydrogen peroxide (H(2)O(2)) is involved in the increased synthesis of constrictor prostaglandins, hence enhanced basal tone in skeletal muscle arterioles. Isolated, pressurized gracilis muscle arterioles ( approximately 100 microm in diameter) of mice with T2-DM (C57BL/KsJ-db(-)/db(-)) exhibited greater basal tone to increases in intraluminal pressure (20-120 mmHg) than that of control vessels (at 80 mmHg, control: 25 +/- 5%; db/db: 34 +/- 4%, P < 0.05), which was reduced back to control level by catalase (db/db: 24 +/- 4%). Correspondingly, in carotid arteries of db/db mice, the level of dichlorofluorescein-detectable and catalase-sensitive H(2)O(2) was significantly greater. In control arterioles, exogenous H(2)O(2) (0.1-100 micromol/l) elicited dilations (maximum, 58 +/- 10%), whereas in arterioles of db/db mice H(2)O(2) caused constrictions (-28 +/- 8%), which were converted to dilations (maximum, 16 +/- 5%) by the thromboxane A(2)/prostaglandin H(2) (TP) receptor antagonist SQ-29548. In addition, arteriolar constrictions in response to the TP receptor agonist U-46619 were not different between the two groups of vessels. Endothelium denudation did not significantly affect basal tone and H(2)O(2)-induced arteriolar responses in either control or db/db mice. Also, in arterioles of db/db mice, but not in controls, 3-nitrotyrosine staining was detected in the endothelial layer of vessels. Thus we propose that, in mice with T2-DM, arteriolar production of H(2)O(2) is enhanced, which leads to increased synthesis of the constrictor prostaglandins thromboxane A(2)/prostaglandin H(2) in the smooth muscle cells, which enhance basal arteriolar tone. These alterations may contribute to disturbed regulation of skeletal muscle blood flow in Type 2 diabetes mellitus.

Animals↗
PubMed2006

Increased cyclooxygenase-2 expression and prostaglandin-mediated dilation in coronary arterioles of patients with diabetes mellitus.

Based on findings of experimental models of diabetes mellitus (DM) showing increased expression of vascular cyclooxygenase-2 (COX-2), we hypothesized that in patients with DM changes in COX-2-dependent prostaglandin synthesis affect vasomotor responses of coronary arterioles. Arterioles were dissected from the right atrial appendages obtained at the time of cardiac surgery of patient with DM(+) or without documented diabetes DM(-). Isolated arterioles (89+/-15 microm in diameter) were cannulated and pressurized (at 80 mm Hg), and changes in diameter were measured with video microscopy. After spontaneous tone developed [DM(-): 32+/-7%; DM(+): 37+/-5%; P=NS], arteriolar responses to bradykinin were investigated. Dilations to bradykinin (0.1 nmol/L to 1 micromol/L) were significantly (P<0.05) greater in DM(+) than DM(-) patients (10 nmol/L: 77+/-10% versus 38+/-14%). In both groups, dilations were similar to the NO-donor, sodium nitroprusside. In arterioles of DM(+), but not those of DM(-), patients' bradykinin-induced dilations were reduced by the nonselective COX inhibitor indomethacin or by the selective COX-2 inhibitor NS-398 (DM(+) at 10 nmol/L: to 20+/-4% and 29+/-7%, respectively). Correspondingly, a marked COX-2 immunostaining was detected in coronary arterioles of DM(+), but not in those of DM(-) patients. We conclude that in coronary arterioles of diabetic patients bradykinin induces enhanced COX-2-derived prostaglandin-mediated dilation. These findings are the first to show that in humans diabetes mellitus increases COX-2 expression and dilator prostaglandin synthesis in coronary arterioles, which may serve to increase dilator capacity and maintain adequate perfusion of cardiac tissues.

Aged↗
PubMed2006

High-fat diet-induced reduction in nitric oxide-dependent arteriolar dilation in rats: role of xanthine oxidase-derived superoxide anion.

Obesity frequently leads to the development of hypertension. We hypothesized that high-fat diet (HFD)-induced obesity impairs the endothelium-dependent dilation of arterioles. Male Wistar rats were fed with normal (control) or HFD (60% of saturated fat, for 10 wk). In rats with HFD, body weight, mean arterial blood pressure, and serum insulin, cholesterol, and glucose were elevated. In isolated gracilis muscle arterioles (diameter: approximately 160 microm) of HFD, rat dilations to ACh (at 1 microM, maximum: 83 +/- 3%) and histamine (at 10 microM, maximum: 16 +/- 4%) were significantly (P < 0.05) decreased compared with those of control responses (maximum: 90 +/- 2 and 46 +/- 4%, respectively). Dilations to the NO donor sodium nitroprusside were similar in the two groups. Inhibition of NO synthesis by N(omega)-nitro-l-arginine methyl ester reduced ACh- and histamine-induced dilations in control arterioles but had no effect on microvessels of HFD rats. The superoxide dismutase mimetic Tiron or xanthine oxidase inhibitor allopurinol enhanced ACh (maximum: 90 +/- 2 and 93 +/- 2%, respectively)- and histamine (maximum: 30 +/- 7 and 37 +/- 8%, respectively)-induced dilations in HFD arterioles, whereas the NAD(P)H oxidase inhibitor apocynin had no significant effect. Correspondingly, in carotid arteries of HFD rats, an enhanced superoxide production was shown by lucigenin-enhanced chemiluminescence, in association with an increased xanthine oxidase, but not NAD(P)H oxidase activity. In addition, a marked xanthine oxidase immunostaining was detected in the endothelial layer of the gracilis arterioles of HFD, but not in control rats. These findings suggest that, in obese rats, NO mediation of endothelium-dependent dilation of skeletal muscle arterioles is reduced because of an enhanced xanthine oxidase-derived superoxide production. These alterations demonstrate substantial dysregulation of arteriolar tone by the endothelium in HFD-induced obesity, which may contribute to disturbed tissue blood flow and development of increased peripheral resistance.

Acetylcholine↗
PubMed2005

Correlation of flow mediated dilation with inflammatory markers in patients with impaired cardiac function. Beneficial effects of inhibition of ACE.

Impaired cardiac function is frequently accompanied by peripheral vascular dysfunction and a pro-inflammatory condition, which may be associated with elevated levels of angiotensin II. We hypothesized that the magnitude of flow mediated dilatation (FMD) of the brachial artery of post myocardial infarction patients will correlate with serum levels of tumor necrosis factor alpha (TNFalpha) and C-reactive protein (CRP), and that treatment with angiotensin converting enzyme inhibitors (ACEI) will increase FMD by reducing TNFalpha and CRP. Patients were treated with low dose (10 mg/day) quinapril (Q) or enalapril (E) and their effects on FMD and inflammatory markers were evaluated after 8 and 12 weeks. Before treatment, in both groups FMD showed a low value (Q: 2.95+0.42% and E: 3.3+/-0.33%), whereas TNF-alpha (Q: 31.65+/-8.23 pg/ml and E: 29.5+/-5.9 pg/ml) and CRP (Q: 7.28+/-2.96 mg/ml and E: 7.08+/-3.02 mg/ml) were elevated. In the Q group, but not in the E group FMD increased significantly, (to 5.96+1.10%), whereas TNF-alpha (19.0+/-12.21 pg/ml) and CRP (to 3.91+/-1.82 mg/L) significantly decreased after 8 and 12 weeks of Q treatment. Moreover, the magnitude of FMD showed a strong inverse correlation with serum levels of TNF-alpha and CRP after Q treatment. Thus, in post myocardial infarction patients endothelial dysfunction assessed by FMD correlates with elevated levels of plasma inflammatory markers, and low dose quinapril improves endothelial function, likely by reducing vascular inflammation.

Adult↗
PubMed2005

Type 2 diabetic mice have increased arteriolar tone and blood pressure: enhanced release of COX-2-derived constrictor prostaglandins.

OBJECTIVE: Type 2 diabetes mellitus (T2-DM) is frequently associated with vascular dysfunction and elevated blood pressure, yet the underlying mechanisms are not completely understood. We hypothesized that in T2-DM, the regulation of peripheral vascular resistance is altered because of changes in local vasomotor mechanisms. METHODS AND RESULTS: In mice with T2-DM (C57BL/KsJ-(db-)/db-), systolic and mean arterial pressures measured by the tail cuff method were significantly elevated compared with those of control (db+/db-) animals (db/db, 146+/-5 and 106+/-2 mm Hg versus control, 133+/-4 and 98+/-4 mm Hg, respectively; P<0.05). Total peripheral resistance, calculated from cardiac output values (measured by echocardiography) and mean arterial pressure were significantly elevated in db/db mice (db/db, 25+/-6 versus control, 15+/-1 mm Hg[middot]mL(-1)[middot]min(-1)). In isolated, pressurized gracilis muscle arterioles (diameter approximately 80 microm) from db/db mice, stepwise increases in intraluminal pressure (from 20 to 120 mm Hg) elicited a greater reduction in diameter than in control vessels at each pressure step (at 80 mm Hg, db/db, 66+/-4% versus control, 79+/-3%). The passive diameters of arterioles (obtained in Ca2+-free solution) and the calculated myogenic index were not significantly different in the 2 groups. The presence of the prostaglandin H2/thromboxane A2 receptor antagonist SQ29548 did not affect arteriolar diameters of control mice but reduced the enhanced arteriolar tone of db/db mice back to control levels (at 80 mm Hg, 80+/-4%). The inhibitor of cyclooxygenase-1 (COX-1), SC-560, did not affect the basal tone of arterioles, whereas NS-398, an inhibitor of COX-2, caused a significant shift in the arteriolar pressure-diameter curve of vessels from db/db mice (at 80 mm Hg, 76+/-3%) but not in those of control mice. Also, in aortas of db/db mice, expression of COX-2 was enhanced compared with controls. CONCLUSIONS: Collectively, these findings suggest that in mice with T2-DM, the basal tone of skeletal muscle arterioles is increased because of an enhanced COX-2-dependent production of constrictor prostaglandins. These alterations in microvascular prostaglandin synthesis may contribute to the increase in peripheral resistance and blood pressure in T2-DM.

Animals↗
PubMed2005

PECAM-1 mediates NO-dependent dilation of arterioles to high temporal gradients of shear stress.

OBJECTIVE: In response to changes in wall shear stress (WSS) the vascular endothelium releases several factors, among others nitric oxide. On the basis of studies of endothelial cells in culture, suggesting that platelet endothelial cell adhesion molecule-1 (PECAM-1) is specifically involved in sensing and coupling high temporal gradients of fluid shear stress with activation of eNOS, we hypothesized that dilations of isolated skeletal muscle arterioles from PECAM-1 knockout mice (PECAM-KO) will be reduced to rapid increases in WSS elicited by increases in perfusate flow. METHODS AND RESULTS: Small and large step increases in flow resulted in substantial dilations in arterioles of WT mice (45+/-4%), but they were markedly reduced in arterioles of PECAM-KO mice (22+/-5%). The initial slope of dilations, when WSS increased rapidly, was greater in vessels of WT than those of PECAM-KO mice (slopes: 0.378 and 0.094, respectively), whereas the second phase of dilations, when flow/shear stress was steady, was similar in the 2 groups (slopes: 0.085 and 0.094, respectively). Inhibition of eNOS significantly reduced the initial phase of dilations in arterioles from WT, but not from those of PECAM-KO mice. The calcium ionophore A23187 elicited similar NO-mediated dilation in both WT and PECAM-KO mice. CONCLUSIONS: In isolated arterioles of PECAM-KO mice activation of eNOS and consequent dilation by agonists is maintained, but the dilation to high temporal gradients of wall shear stress elicited by increases in perfusate flow is reduced. Thus, we propose that PECAM-1 plays an important role in the ability of the endothelium to sense and couple high temporal gradients of wall shear stress to NO-mediated arteriolar dilation during sudden changes in blood flow in vivo.

Animals↗
PubMed2005

Hyperhomocysteinemia, a cardiac metabolic disease: role of nitric oxide and the p22phox subunit of NADPH oxidase.

BACKGROUND: Hyperhomocysteinemia (HHcy) is a reliable indicator of cardiovascular disease, in part because of the production of superoxide and scavenging of nitric oxide (NO). The present study assessed the impact of HHcy on the NO-dependent control of cardiac O2 consumption and examined enzymatic sources of superoxide. METHODS AND RESULTS: Rats and mice were fed methionine in drinking water for 5 to 9 weeks to increase plasma homocysteine, a process that did not cause significant changes in hemodynamic function. The ability of the NO agonists bradykinin and carbachol to reduce myocardial O2 consumption in vitro was impaired by approximately 40% in methionine-fed rats, and this impairment was proportional to their individual plasma homocysteine concentration. However, responses were restored in the presence of ascorbic acid, tempol, and apocynin, which inhibits NADPH oxidase assembly. Western blots showed no difference in Cu/Zn or Mn superoxide dismutase, endothelial NO synthase, or inducible NO synthase protein, but HHcy caused a 100% increase in the p22phox subunit of NADPH oxidase. Western blots with plasma membrane-enriched fractions of cell lysate detected elevated levels of p22phox, p67phox, and rac-1, which indicates increased oxidase assembly. Finally, mice lacking a functional gp91phox subunit of NADPH oxidase demonstrated normal NO-dependent regulation of myocardial O2 consumption after methionine feeding. CONCLUSIONS: In HHcy, superoxide produced by NADPH oxidase reduces the ability of NO to regulate mitochondrial function in the myocardium. The severity of this effect is proportional to the increase in homocysteine.

Animals↗
PubMed2005

Regulation of bone morphogenetic protein-2 expression in endothelial cells: role of nuclear factor-kappaB activation by tumor necrosis factor-alpha, H2O2, and high intravascular pressure.

BACKGROUND: Recent studies suggest that bone morphogenetic protein-2 (BMP-2), a transforming growth factor-beta superfamily member cytokine, plays an important role both in vascular development and pathophysiological processes, including endothelial activation that is likely to contribute to the development of coronary atherosclerosis, yet the factors that regulate arterial expression of BMP-2 are completely unknown. We tested the hypothesis that BMP-2 expression in endothelial cells is governed by an H2O2 and nuclear factor (NF)-kappaBeta-dependent pathway that can be activated by both proinflammatory and mechanical stimuli. METHODS AND RESULTS: The proinflammatory cytokine tumor necrosis factor (TNF)-alpha induced NF-kappaBeta activation and elicited significant increases in BMP-2 mRNA and protein in primary coronary arterial endothelial cells and human umbilical vein endothelial cells that were prevented by NF-kappaBeta inhibitors (pyrrolidine dithiocarbamate and SN-50), silencing of p65 (siRNA), or catalase. Administration of H2O2 also elicited NF-kappaBeta activation and BMP-2 induction. In organ culture, exposure of rat arteries to high pressure (160 mm Hg) elicited H2O2 production, nuclear translocation of NF-kappaBeta, and upregulation of BMP-2 expression. Although high pressure upregulated TNF-alpha, it appears that it directly regulates BMP-2 expression, because upregulation of BMP-2 was also observed in vessels of TNF-alpha knockout mice. CONCLUSIONS: Vascular BMP-2 expression can be regulated by H2O2-mediated activation of NF-kappaBeta both by inflammatory stimuli and by high intravascular pressure.

Animals↗
PubMed2004

Nitric oxide and H2O2 contribute to reactive dilation of isolated coronary arterioles.

The role of metabolic factors derived from cardiac muscle in the development of reactive hyperemia after brief occlusions of the coronary circulation seems to be well established. However, the contribution of occlusion-induced changes in hemodynamic forces to eliciting reactive hyperemia is less known. We hypothesized that in isolated coronary arterioles changes in intraluminal pressure and flow, during and after release of occlusion (O/R), themselves via activating intrinsic mechanosensitive mechanisms, elicit release of vasoactive factors resulting in reactive dilations. Thus in isolated coronary arterioles (diameter: 88 +/- 8 microm) changes in diameter to changes in pressure or pressure plus flow (P+F) during and after a brief period (30, 60, and 120 s) of O/R of cannulating tube were measured by videomicroscopy. In response to both types of O/R, diameter first decreased, then, subsequently increased during occlusions. When only pressure was changed (from 80-10-80 mmHg), after release of occlusion, peak dilations increased as a function of the duration of occlusions. After flow was established (30 microl/min), O/R elicited changes in both pressure and flow (from 80-10-80 mmHg and from 0 to 30 microl/min). In these conditions, after the release of occlusions, not only the peak but also the duration of reactive dilation increased significantly as a function of the length of occlusions. The dilations during, and peak dilations after occlusions both in pressure and P+F protocols were significantly reduced by the inhibition of NO synthase with Nomega-nitro-L-arginine-methyl-ester (L-NAME) or by endothelium removal, whereas duration of postocclusion dilations were reduced by L-NAME or by endothelium removal only in P+F protocols. Furthermore, in both protocols, catalase significantly reduced the peak but not the duration of reactive dilations. Thus, mechanosensitive mechanisms that are sensitive to deformation, pressure, stretch, and wall shear stress elicit release of NO and H2O2, resulting in reactive dilation of isolated coronary arterioles.

Animals↗
PubMed2004

Biphasic effect of hydrogen peroxide on skeletal muscle arteriolar tone via activation of endothelial and smooth muscle signaling pathways.

We hypothesized that hydrogen peroxide (H2O2) has a role in the local regulation of skeletal muscle blood flow, thus significantly affecting the myogenic tone of arterioles. In our study, we investigated the effects of exogenous H2O2 on the diameter of isolated, pressurized (at 80 mmHg) rat gracilis skeletal muscle arterioles (diameter of approximately 150 microm). Lower concentrations of H2O2 (10(-6)-3 x 10(-5) M) elicited constrictions, whereas higher concentrations of H2O2 (6 x 10(-5)-3 x 10(-4) M), after initial constrictions, caused dilations of arterioles (at 10(-4) M H2O2, -19 +/- 1% constriction and 66 +/- 4% dilation). Endothelium removal reduced both constrictions (to -10 +/- 1%) and dilations (to 33 +/- 3%) due to H2O2. Constrictions due to H2O2 were completely abolished by indomethacin and the prostaglandin H2/thromboxane A2 (PGH2/TxA2) receptor antagonist SQ-29548. Dilations due to H2O2 were significantly reduced by inhibition of nitric oxide synthase (to 38 +/- 7%) but were unaffected by clotrimazole or sulfaphenazole (inhibitors of cytochrome P-450 enzymes), indomethacin, or SQ-29548. In endothelium-denuded arterioles, clotrimazole had no effect, whereas H2O2-induced dilations were significantly reduced by charybdotoxin plus apamin, inhibitors of Ca(2+)-activated K+ channels (to 24 +/- 3%), the selective blocker of ATP-sensitive K+ channels glybenclamide (to 14 +/- 2%), and the nonselective K(+)-channel inhibitor tetrabutylammonium (to -1 +/- 1%). Thus exogenous administration of H2O2 elicits 1) release of PGH2/TxA2 from both endothelium and smooth muscle, 2) release of nitric oxide from the endothelium, and 3) activation of K+ channels, such as Ca(2+)-activated and ATP-sensitive K+ channels in the smooth muscle resulting in biphasic changes of arteriolar diameter. Because H2O2 at low micromolar concentrations activates several intrinsic mechanisms, we suggest that H2O2 contributes to the local regulation of skeletal muscle blood flow in various physiological and pathophysiological conditions.

Animals↗
PubMed2004

Ghrelin induces vasoconstriction in the rat coronary vasculature without altering cardiac peptide secretion.

We administered ghrelin, a novel growth hormone-releasing hormone, to isolated perfused rat hearts, coronary arterioles, and cultured neonatal cardiomyocytes to determine its effects on coronary vascular tone, contractility, and natriuretic peptide secretion and gene expression. We also determined cardiac levels of ghrelin and whether the heart is a source of the circulating peptide. Ghrelin dose dependently increased coronary perfusion pressure (44 +/- 9%, P < 0.01), constricted isolated coronary arterioles (12 +/- 2%, P < 0.05), and significantly enhanced the pressure-induced myogenic tone of arterioles. These effects were blocked by diltiazem, an L-type Ca(2+) channel blocker, and bisindolylmaleimide (Bis), a protein kinase C (PKC) inhibitor. Interestingly, coinfusion of ghrelin with diltiazem completely restored myocardial contractile function that was decreased 30 +/- 3% (P < 0.01) by diltiazem alone. In contrast, combination of ghrelin with diltiazem or Bis did not significantly alter atrial natriuretic peptide (ANP) secretion, which was decreased 40% (P < 0.01) and 50% (P < 0.05) by these agents alone, respectively. Administration of ghrelin to cultured cardiomyocytes had no effect on ANP or B-type natriuretic peptide secretion or gene expression. Detectable amounts of low-molecular-weight ghrelin were present in cardiac tissue extracts but not in isolated heart perfusate. Thus we provide the first evidence that ghrelin has a coronary vasoconstrictor action that is dependent on Ca(2+) and PKC. Furthermore, the data obtained from diltiazem infusion suggest that ghrelin has a role in regulation of contractility when L-type Ca(2+) channels are blocked. Finally, the observation that immunoreactive ghrelin is found in cardiac tissue suggests the presence of a local cardiac ghrelin system.

Animals↗
PubMed2004

Microvascular dysfunction after transient high glucose is caused by superoxide-dependent reduction in the bioavailability of NO and BH(4).

We hypothesized that transient high-glucose concentration interferes with mediation by nitric oxide (NO) of flow-induced dilation (FID) of arterioles due to enhanced production of superoxide. In isolated, pressurized (80 mmHg) rat gracilis muscle arterioles ( approximately 130 microm) after transient high-glucose treatment (tHG; incubation with 30 mM glucose for 1 h), FID was reduced (maximum: control, 38 +/- 4%; after tHG, 17 +/- 3%), which was not further diminished by the NO synthase (NOS) inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME; 18 +/- 2%). Correspondingly, an enhanced polyethylene-glycol-SOD (PEG-SOD)-sensitive superoxide production was detected after tHG in carotid arteries by dihydroethydine (DHE) staining. Presence of PEG-SOD during tHG prevented the reduction of FID (41 +/- 3%), which could be inhibited by l-NAME (20 +/- 4%). Administration of PEG-SOD after tHG did not prevent the reduction of FID (22 +/- 3%). Sepiapterin, a precursor of the NO synthase cofactor tetrahydrobiopterin (BH(4)), administered during tHG did not prevent the reduction of FID (maximum, 15 +/- 5%); however, it restored FID when administered after tHG (32 +/- 4%). Furthermore, inhibition of either glycolysis by 2-deoxyglucose or mitochondrial complex II by 2-thenoyltrifluoroacetone reduced the tHG-induced DHE-detectable enhanced superoxide production in carotid arteries and prevented FID reduction in arterioles (39 +/- 5 and 35 +/- 2%). Collectively, these findings suggest that in skeletal muscle arterioles, a transient elevation of glucose via its increased metabolism, elicits enhanced production of superoxide, which decreases the bioavailability of NO and the level of the NOS cofactor BH(4), resulting in a reduction of FID mediated by NO.

Animals↗
PubMed2004

Proinflammatory phenotype of coronary arteries promotes endothelial apoptosis in aging.

Previously we demonstrated that aging in coronary arteries is associated with proinflammatory phenotypic changes and decreased NO bioavailability, which, we hypothesized, promotes vascular disease by enhancing endothelial apoptosis. To test this hypothesis we characterized proapoptotic alterations in the phenotype of coronary arteries of aged (26 mo old) and young (3 mo old) F344 rats. DNA fragmentation analysis and TUNEL assay showed that in aged vessels there was an approximately fivefold increase in the number of apoptotic endothelial cells. In aged coronary arteries there was an increased expression of TNFalpha, TNFbeta, and caspase 9 (microarray, real-time PCR), as well as increased caspase 9 and caspase 3 activity, whereas expression of TNFR1, TNFalpha-converting enzyme (TACE), Bcl-2, Bcl-X(L), Bid, Bax, caspase 8, and caspase 3 were unchanged. In vessel culture (18 h) incubation of aged coronary arteries with a TNF blocking antibody or the NO donor S-nitroso-penicillamine (SNAP) decreased apoptotic cell death. Incubation of young arteries with exogenous TNFalpha increased caspase 9 activity and elicited endothelial apoptosis, which was attenuated by SNAP. Inhibition of NO synthesis in cultured young coronary arteries also induced apoptotic cell death and potentiated the apoptotic effect of TNFalpha. Thus we propose that age-related upregulation of TNFalpha and caspase 9 and decreased bioavailability of NO promote endothelial apoptosis in coronary arteries that may lead to impaired endothelial function and ischemic heart disease in the elderly.

ADAM Proteins↗
PubMed2004

Chronic high pressure-induced arterial oxidative stress: involvement of protein kinase C-dependent NAD(P)H oxidase and local renin-angiotensin system.

Regardless of the underlying pathological mechanisms oxidative stress seems to be present in all forms of hypertension. Thus, we tested the hypothesis that chronic presence of high pressure itself elicits increased arterial O(2)(.-) production. Hypertension was induced in rats by abdominal aortic banding (Ab). Rats with Ab had elevated pressure in vessels proximal and normal pressure in vessels distal to the coarctation, yet both vascular beds were exposed to the same circulating factors. Compared to normotensive hind limb arteries (HLAs) hypertensive forelimb arteries (FLAs) exhibited 1) impaired dilations to acetylcholine and the nitric oxide donor S-nitroso-N-acetyl-D,L-penicillamine that were restored by administration of superoxide dismutase; 2) an increased production of O(2)(.-) (measured by lucigenin chemiluminescence and ethidium bromide fluorescence) that was inhibited or reduced by superoxide dismutase, the NAD(P)H oxidase inhibitors diphenyleneiodonium and apocynin, or the protein kinase C (PKC) inhibitors chelerythrine and staurosporine or by the angiotensin-converting enzyme (ACE) inhibitor captopril; and 3) increased ACE activity. In organ culture, exposure of isolated arteries of normotensive rats to high pressure (160 mmHg, for 24 hours) significantly increased O(2)(.-) production compared to that in arteries exposed to 80 mmHg. High pressure-induced O(2)(.-) generation was reduced by inhibitors of ACE and PKC. Incubation of cultured arteries with angiotensin II elicited significantly increased O(2)(.-) generation that was inhibited by chelerythrine. Thus, we propose that chronic presence of high pressure itself can elicit arterial oxidative stress, primarily by activating directly a PKC-dependent NAD(P)H oxidase pathway, but also, in part, via activation of the local renin-angiotensin system.

Acetophenones↗
PubMed2004

Nitric oxide and prostaglandins modulate pressure-induced myogenic responses of intramural coronary arterioles.

The myogenic response, an active constriction and dilation of vessels to changes in intravascular pressure, can play an important role in the regulation of coronary blood flow. The characteristics of the myogenic response and its modulation by endothelium-derived factors are organ and location specific and have not been studied extensively in intramural coronary arterioles. Thus, distal intramural branches (approximately 100 and approximately 170 microm active and passive diameter, respectively) of the left anterior descending coronary artery of rats were isolated and cannulated. Step increases in intraluminal pressure from 0 to 40 mm Hg elicited increases in diameter, whereas further increases in pressure from 50 to 150 mm Hg resulted in constrictions. In control, the pressure-induced myogenic tone of coronary arterioles was 67.3 +/- 2.7% of passive diameter (PD, obtained in Ca2+-free solution) at 60 mm Hg. Nomega-nitro-L-arginine (L-NNA, 10(-5) M), an inhibitor of nitric oxide synthase, reduced the initial arteriolar diameter (by 44.8 +/- 5.1 microm at 2 mm Hg, P < 0.05) and significantly mitigated increases in diameter to lower pressures and constrictions to higher pressures (41.1 +/- 5.6% of PD at 60 mm Hg). Administration of adenosine restored the initial diameter in the presence of l-NNA, but the increase in diameter to lower pressures and the decrease in diameter to higher pressures observed under control conditions remained greatly inhibited. Inhibition of prostaglandin synthesis, or PGH2/TxA2 receptors significantly reduced the constrictions to higher pressures as compared with control (indomethacin: from 57.9 +/- 4.8% of PD to 67.0 +/- 4.7% of PD at 150 mm Hg). Thus, because in isolated intramural coronary arterioles of rats a negative slope for the pressure-diameter curve develops only in the presence of nitric oxide and constrictor prostaglandins, they seem to be essential for the normal development of the myogenic response.

Adenosine↗
PubMed2003

PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes.

We tested the hypothesis that short-term treatment of mice with Type 2 diabetes mellitus (DM) with rosiglitazone (ROSI), an agonist of peroxisome proliferator-activated receptor-gamma, ameliorates the impaired coronary arteriolar dilation by reducing oxidative stress via a mechanism unrelated to its effect on hyperglycemia and hyperinsulinemia. Control and Type 2 DM (db/db) mice were treated with ROSI (3 mg x kg(-1) x day(-1)) for 7 days, which did not significantly affect their serum concentration of glucose and insulin. Compared with controls, in db/db mice serum levels of 8-isoprostane and dihydroethydine-detectable superoxide production in carotid arteries were significantly elevated and were reduced by ROSI treatment. In coronary arterioles (diameter, approximately 80 microm) isolated from db/db mice, the reduced dilations to ACh, the nitric oxide (NO) donor NONOate, and increases in flow were significantly augmented either by in vitro administration of apocynin, an inhibitor of NAD(P)H-oxidase, or by in vivo ROSI treatment, responses that were then significantly reduced by the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester. In aortas of db/db mice, activity of SOD and catalase was reduced, whereas NAD(P)H oxidase activity was enhanced. ROSI treatment enhanced catalase and reduced NAD(P)H oxidase activity but did not affect the activity of SOD. These findings suggest that ROSI treatment enhances NO mediation of coronary arteriolar dilations due to the reduction of vascular NAD(P)H oxidase-derived superoxide production and enhancement of catalase activity. Thus, in addition to the previously revealed beneficial metabolic effects, the antioxidant action of rosiglitazone may protect coronary arteriolar function in Type 2 DM.

Acetylcholine↗