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David D Gutterman

Publications and source records attributed to David D Gutterman.

At least 37 records · Page 2Linked to original sources
PubMed2004

Role of hydrogen peroxide in ACh-induced dilation of human submucosal intestinal microvessels.

The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several mediators of vasodilation, which include prostacyclin (PGI(2)), nitric oxide, and endothelium-derived hyperpolarizing factor (EDHF). We have recently defined the role of nitric oxide and PGI(2) in the dilation of submucosal intestinal arterioles from patients with normal bowel function. However, significant endothelium-dependent dilator capacity to ACh remained after inhibiting both these mediators. The current study was designed to examine the potential role of EDHF in human intestinal submucosal arterioles. ACh elicited endothelium-dependent relaxation in the presence of inhibitors of nitric oxide synthase and cyclooxygenase (23 +/- 10%, n = 6). This ACh-induced relaxation was inhibited and converted to constriction by catalase (-53 +/- 10%, n = 6) or KCl (-30 +/- 3%, n = 7), whereas 17-octadecynoic acid and 6-(2-propargylloxyphenyl) hexanoic acid, two inhibitors of cytochrome P450 monooxygenase, had no significant effect (3 +/- 1% and 20 +/- 8%, n = 5, respectively). Exogenous H(2)O(2) elicited dose-dependent relaxation of intact microvessels (52 +/- 10%, n = 7) but caused frank vasoconstriction in arterioles denuded of endothelium (-73 +/- 8%, n = 7). ACh markedly increased the dichlorofluorescein fluorescence in intact arterioles in the presence of nitric oxide synthase and cyclooxygenase inhibitors compared with control and compared with catalase-treated microvessels (363.6 +/- 49, 218.8 +/- 10.6, 221.9 +/- 27.9, respectively, P < 0.05 ANOVA, n = 5 arbitrary units). No changes in the dichlorofluorescein fluorescence were recorded in vessels treated with ACh alone. These results indicate that endothelial production of H(2)O(2) occurs in response to ACh in human gut mucosal arterioles but that H(2)O(2) is not an EDHF in this tissue. Rather, we speculate that it stimulates the release of a chemically distinct EDHF.

Acetylcholine↗
PubMed2004

Nitration and functional loss of voltage-gated K+ channels in rat coronary microvessels exposed to high glucose.

Coronary microvessels generate reactive oxygen species in response to high glucose (HG), resulting in vasodilator defects involving an impaired function of vascular K(+) channels. Inhibition of voltage-gated K(+) (K(v)) channels by peroxynitrite (ONOO(-)), formed by the interaction of superoxide and nitric oxide, may contribute to impaired dilation. The present study investigated whether HG induces ONOO(-) formation to mediate nitration and impairment of K(v) channels in rat small coronary arteries (RSCAs). Exposure to ONOO(-) reduced the dilator influence of K(v) channels in RSCAs. Patch-clamp studies revealed that ONOO(-) diminished whole-cell and unitary K(v) currents attributable to the K(v)1 gene family in smooth muscle cells. Subsequently, immunohistochemically detected enhancement of nitrotyrosine residues in RSCAs that were cultured in HG (23 mmol/l) compared with normal glucose (5.5 mmol/l) for 24 h correlated with the nitration of K(v)1.2 channel alpha-subunits. HG-induced nitrotyrosine formation was partially reversed by scavenging ONOO(-). Finally, RSCAs that were exposed to HG for 24 h showed a loss of K(v) channel dilator influence that also was partially restored by the ONOO(-) scavengers urate and ebselen. We conclude that ONOO(-) generated by HG impairs K(v) channel function in coronary microvessels, possibly by nitrating tyrosine residues in the pore-forming region of the K(v) channel protein.

Animals↗
PubMed2003

Mitochondrial sources of H2O2 generation play a key role in flow-mediated dilation in human coronary resistance arteries.

We previously showed that hydrogen peroxide (H2O2) contributes to flow-induced dilation in human coronary resistance arteries (HCRAs); however, the source of this H2O2 is not known. We hypothesized that the H2O2 is derived from superoxide (O2*-) generated by mitochondrial respiration. HCRAs were dissected from right atrial appendages obtained from patients during cardiac surgery and cannulated with micropipettes. H2O2-derived radicals and O2*- were detected by electron spin resonance (ESR) using BMPO as the spin trap and by histofluorescence using hydroethidine (HE, 5 micromol/L) and dichlorodihydrofluorescein (DCFH, 5 micromol/L). Diameter changes to increases in pressure gradients (20 and 100 cm H2O) were examined in the absence and the presence of rotenone (1 micromol/L), myxothiazol (100 nmol/L), cyanide (1 micromol/L), mitochondrial complex I, III, and IV inhibitors, respectively, and apocynin (3 mmol/L), a NADPH oxidase inhibitor. At a pressure gradient of 100 cm H2O, ubisemiquinone and hydroxyl radicals were detected from effluents of vessels. Including superoxide dismutase and catalase in the perfusate reduced the ESR signals. Relative ethidium and DCFH fluorescence intensities in HCRAs exposed to flow were enhanced (1.45+/-0.15 and 1.57+/-0.12, respectively compared with no-flow) and were inhibited by rotenone (0.87+/-0.17 and 0.95+/-0.07). Videomicroscopic studies showed that rotenone and myxothiazol blocked flow-induced dilation (% max. dilation at 100 cm H2O: rotenone, 74+/-3% versus 3+/-13%; myxothiazol, 67+/-3% versus 28+/-4%; P<0.05). Neither cyanide nor apocynin altered flow-induced dilation. These results suggest that shear stress induced H2O2 formation, and flow-induced dilation is derived from O2*- originating from mitochondrial respiration.

Coronary Circulation↗
PubMed2003

Coronary vascular dysfunction associated with direct current shock injury.

OBJECTIVE: To determine if cardiac injury following DC shocks includes impairment of coronary vascular reactivity. METHODS: 36 dogs (18-32 kg) were anesthetized and a thoracotomy was performed. Either antioxidant enzymes, superoxide dismutase (SOD, 15,000 U/kg) plus catalase (55,000 U/kg) or the NO synthase inhibitor N(G)-nitro-L-arginine (L-NNA, 5 mg/kg) was administered IV prior to sham (no shocks) or DC shock treatment, and the results were compared to dogs which did not receive SOD/catalase or L-NNA. In sham dogs, electrodes cradled the heart, but no shocks were delivered. In shock dogs, three 20 Joule DC shocks were delivered to the epicardium using hand-held paddles. Other dogs were allowed a 3-hour recovery period after the shocks. Epicardial microvessels and conduit rings were studied in vitro. Antagonists were not added to the bath of the study vessel. Internal diameter was measured in microvessels after constriction with endothelin. Tension of conduit arteries was measured after constriction with PGF(2alpha). Responses to acetylcholine (Ach, 10(-10)-10(-4) M), bradykinin (10(-14)-10(-6) M), the calcium ionophore A23187 (A23187, 10(-12)-10(-4) M) or nitroprusside (SNP, 10(-10)-10(-4) M) were measured. RESULTS: Bradykinin, A23187 and SNP dependent dilation was not different between vessels from sham and shocked animals. Dilation to Ach was attenuated in vessels from shocked dogs. Superoxide production probably contributed to the impaired dilation to Ach since treatment with SOD/catalase improved dilation. Treatment with L-NNA also improved vascular function after DC shock. CONCLUSION: DC shocks cause endothelial dysfunction, as demonstrated by impaired dilation to acetylcholine, in both canine coronary microvascular and conduit arteries. Since pretreatment with either SOD/catalase or L-NNA protects against this damage, a free radical mechanism, possibly involving eNOS, may contribute to endothelial dysfunction.DC shocks for cardioversion and defibrillation cause myocardial injury that may be free radical mediated.

Acetylcholine↗
PubMed2003

Enhancement of antral contractions and vagal afferent signaling with synchronized electrical stimulation.

Gastric filling activates vagal afferents involved in peripheral signaling to the central nervous system (CNS) for food intake. It is not known whether these afferents linearly encode increasing contractions of the antrum during antral distension (AD). The aim of this study was to investigate effects of AD and electrically enhanced antral contractions on responses of vagal afferents innervating the antrum. Single-fiber recordings were made from the vagal afferents in anesthetized male Long-Evans rats. Antral contractions were measured with a solid-state probe placed in the antrum. A nonexcitatory electrical stimulation (NES) inducing no smooth muscle contractions was applied during the ascending phase of antral contractions to enhance subsequent antral contractions. Fifty-six fibers identified during AD (1 ml for 30 s) were studied through different types of mechanical stimuli. Under normal conditions, one group of fibers exhibited rhythmic firing in phase with antral contractions. Another group of fibers had nonrhythmic spontaneous firing. Responses of 15 fibers were tested with NES during multiple-step distension (MSD). NES produced a mean increase in antral contraction amplitude (177.1 +/- 35.3%) and vagal afferent firing (21.6 +/- 2.6%). Results show that both passive distension and enhanced antral contractions activate distension-sensitive vagal afferents. Responses of these fibers increase linearly to enhanced antral contraction induced by NES or MSD up to a distending volume of 0.6 ml. However, responses reached a plateau at a distending volume >0.8 ml. We concluded that enhanced contraction of the antrum can activate vagal afferents signaling to the CNS.

Animals↗
PubMed2003

Elevated glucose impairs cAMP-mediated dilation by reducing Kv channel activity in rat small coronary smooth muscle cells.

Hyperglycemia impairs endothelium-dependent vasodilation. In this study, we examined the effect of high glucose (HG) on vascular smooth muscle function. Rat small coronary arteries were freshly isolated or incubated for 24 h with normal glucose (NG; 5.5 mmol/l) or HG (23 mmol/l). In freshly isolated arteries, dilation to isoproterenol (Iso) was reduced by 3 mmol/l 4-aminopyridine (4-AP; 44 +/- 10% vs. 77 +/- 4%; P < 0.05) and further reduced by 4-AP + iberiotoxin (IbTX; 100 nmol/l; 17 +/- 2%). Dilation to forskolin was abolished by 4-AP (-3 +/- 17 vs. 73 +/- 9%). cAMP production was similar in NG and HG vessels. Dilations to Iso and forskolin were significantly reduced in HG arteries (Iso, 41 +/- 5% vs. 70 +/- 6%; forskolin, 40 +/- 4% vs. 75 +/- 4%) compared with NG arteries. A similar reduction was also observed to the dilation to papaverine. Endothelial denudation had no effect on Iso-induced dilation. In HG vessels, the reduced 4-AP-sensitive component of Iso-induced dilation was greater compared with the IbTX-sensitive component. Iso increased whole cell K+ current in NG cells but had little effect in HG cells. Similarly, 4-AP-, but not IbTX-sensitive, K+ currents were reduced in HG cells. These results suggest that HG impairs cAMP-mediated dilation primarily by reducing Kv channel function. We speculate that in addition to the endothelial dysfunction, altered smooth muscle function may also contribute to the reduced coronary vasodilation in diabetes.

4-Aminopyridine↗
PubMed2003

L-4F, an apolipoprotein A-1 mimetic, dramatically improves vasodilation in hypercholesterolemia and sickle cell disease.

BACKGROUND: Hypercholesterolemia and sickle cell disease (SCD) impair endothelium-dependent vasodilation by dissimilar mechanisms. Hypercholesterolemia impairs vasodilation by a low-density lipoprotein (LDL)-dependent mechanism. SCD has been characterized as a chronic state of inflammation in which xanthine oxidase (XO) from ischemic tissues increases vascular superoxide anion (O2*-) generation. Recent reports indicate that apolipoprotein (apo) A-1 mimetics inhibit atherosclerosis in LDL receptor-null (Ldlr-/-) mice fed Western diets. Here we hypothesize that L-4F, an apoA-1 mimetic, preserves vasodilation in hypercholesterolemia and SCD by decreasing mechanisms that increase O2*- generation. METHODS AND RESULTS: Arterioles were isolated from hypercholesterolemic Ldlr-/- mice and from SCD mice that were treated with either saline or L-4F (1 mg/kg per day). Vasodilation in response to acetylcholine was determined by videomicroscopy. Effects of L-4F on LDL-induced increases in endothelium-dependent O2*- generation were determined on arterial segments via the hydroethidine assay and on stimulated endothelial cell cultures via superoxide dismutase-inhibitable ferricytochrome c reduction. Effects of L-4F on XO bound to pulmonary arterioles and content in livers of SCD mice were determined by immunofluorescence. Hypercholesterolemia impaired vasodilation in Ldlr-/- mice, which L-4F dramatically improved. L-4F inhibited LDL-induced increases in O2*- in arterial segments and in stimulated cultures. SCD impaired vasodilation, increased XO bound to pulmonary endothelium, and decreased liver XO content. L-4F dramatically improved vasodilation, decreased XO bound to pulmonary endothelium, and increased liver XO content compared with levels in untreated SCD mice. CONCLUSIONS: These data show that L-4F protects endothelium-dependent vasodilation in hypercholesterolemia and SCD. Our findings suggest that L-4F restores vascular endothelial function in diverse models of disease and may be applicable to treating a variety of vascular diseases.

Anemia, Sickle Cell↗
PubMed2003

Diabetes mellitus impairs vasodilation to hypoxia in human coronary arterioles: reduced activity of ATP-sensitive potassium channels.

ATP-sensitive K+ channels (K(ATP)) contribute to vasomotor regulation in some species. It is not fully understood the extent to which K(ATP) participate in regulating vasomotor tone under physiological and pathophysiological conditions in the human heart. Arterioles dissected from right atrial appendage were studied with video microscopy, membrane potential recordings, reverse transcription-polymerase chain reaction, and immunohistochemistry. Hypoxia produced endothelium-independent vasodilation and membrane hyperpolarization of vascular smooth muscle cells, both of which were attenuated by glibenclamide. Aprikalim, a selective K(ATP) opener, also induced a potent endothelium-independent and glibenclamide-sensitive vasodilation with membrane hyperpolarization. Reverse transcription-polymerase chain reaction detected mRNA expression for K(ATP) subunits, and immunohistochemistry confirmed the localization of the inwardly rectifying Kir6.1 protein in the vasculature. In patients with type 1 or type 2 diabetes mellitus (DM), vasodilation was reduced to both aprikalim (maximum dilation, DM(+) 90+/-2% versus DM(-) 96+/-1%, P<0.05) and hypoxia (maximum dilation, DM(+) 56+/-8% versus DM(-) 85+/-5%, P<0.01) but was not altered to sodium nitroprusside or bradykinin. Baseline myogenic tone and resting membrane potential were not affected by DM. We conclude that DM impairs human coronary arteriolar dilation to K(ATP) opening, leading to reduced dilation to hypoxia. This reduction in K(ATP) function could contribute to the greater cardiovascular mortality and morbidity in DM.

Adenosine Triphosphate↗
PubMed2003

Role for hydrogen peroxide in flow-induced dilation of human coronary arterioles.

Flow-induced dilation (FID) is dependent largely on hyperpolarization of vascular smooth muscle cells (VSMCs) in human coronary arterioles (HCA) from patients with coronary disease. Animal studies show that shear stress induces endothelial generation of hydrogen peroxide (H2O2), which is proposed as an endothelium-derived hyperpolarizing factor (EDHF). We tested the hypothesis that H2O2 contributes to FID in HCA. Arterioles (135+/-7 micro m, n=71) were dissected from human right atrial appendages at the time of cardiac surgery and cannulated with glass micropipettes. Changes in internal diameter and membrane potential of VSMCs to shear stress, H2O2, or to papaverine were recorded with videomicroscopy. In some vessels, endothelial H2O2 generation to shear stress was monitored directly using confocal microscopy with 2',7'-dichlorofluorescin diacetate (DCFH) or using electron microscopy with cerium chloride. Catalase inhibited FID (%max dilation; 66+/-8 versus 25+/-7%; P<0.05, n=6), whereas dilation to papaverine was unchanged. Shear stress immediately increased DCFH fluorescence in the endothelial cell layer, whereas treatment with catalase abolished the increase in fluorescence. Electron microscopy with cerium chloride revealed shear stress-induced increase in cerium deposition in intimal area surrounding endothelial cells. Exogenous H2O2 dilated (%max dilation; 97+/-1%, ED50; 3.0+/-0.7x10(-5) mol/L) and hyperpolarized HCA. Dilation to H2O2 was reduced by catalase, 40 mmol/L KCl, or charybdotoxin plus apamin, whereas endothelial denudation, deferoxamine, 1H-(1,2,4)-oxadiazole-[4,3-a]quinoxalin-1-one, or glibenclamide had no effect. These data provide evidence that shear stress induces endothelial release of H2O2 and are consistent with the idea that H2O2 is an EDHF that contributes to FID in HCA from patients with heart disease. The full text of this article is available at http://www.circresaha.org.

Apamin↗
PubMed2003

Acquired microvascular dysfunction in inflammatory bowel disease: Loss of nitric oxide-mediated vasodilation.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD; i.e., Crohn's disease, ulcerative colitis) is characterized by refractory inflammatory ulceration and damage to the intestine. Mechanisms underlying impaired healing are not defined. Because microvascular dysfunction resulting in diminished vasodilatory capacity and tissue hypoperfusion is associated with impaired wound healing, we hypothesized that microvascular dysfunction may also occur in chronic IBD. METHODS: Intact submucosal arterioles from control, involved, and uninvolved IBD specimens were assessed using in vitro videomicroscopy to assess endothelium-dependent vasodilation in response to acetylcholine (Ach) and fluorescence microscopy to detect oxyradicals. RESULTS: Normal microvessels dilated in a dose-dependent and endothelium-dependent manner to Ach (maximum, 82% +/- 2%; n = 34). Inhibition of nitric oxide synthase with N(G)-nitro-L-arginine methyl ester (L-NAME) reduced maximal dilation to 54% +/- 6% (P < 0.05, n = 7), and further reduction was observed after inhibiting cyclooxygenase (indomethacin; 23% +/- 10%, n = 6). Chronically inflamed IBD microvessels showed significantly reduced Ach-induced vasodilation (maximum, 15% +/- 2%; n = 33), with no effect of L-NAME. Indomethacin eliminated the remaining Ach-induced vasodilation, resulting in frank vasoconstriction (-54% +/- 9%, n = 6). Uninvolved IBD gut vessels and non-IBD inflammatory controls responded in a fashion similar to normal vessels. IBD-involved microvessels generated significantly higher levels of reactive oxygen species compared with control and uninvolved IBD vessels (P < 0.01). CONCLUSIONS: Human intestinal microvessels from chronically inflamed IBD show microvascular endothelial dysfunction, characterized by loss of NO-dependent dilation that may contribute to reduced perfusion, poor wound healing, and maintenance of chronic inflammation.

Acetylcholine↗
PubMed2003

Mechanism of dilation to reactive oxygen species in human coronary arterioles.

We tested whether reactive oxygen species (ROS) generated from treatment with xanthine (XA) and xanthine oxidase (XO) alter vascular tone of human coronary arterioles (HCA). Fresh human coronary arterioles (HCA) from right atrial appendages were cannulated for video microscopy. ROS generated by XA (10(-4) M) + XO (10 mU/ml) dilated HCA (99 +/- 1%, 20 min after application of XA/XO). This dilation was not affected by denudation or superoxide dismutase (150 U/ml). Catalase (500 U/ml or 5,000 U/ml) attenuated the dilation early on, but a significant latent vasodilation appeared after 5 min peaking at 20 min (51 +/- 1%, 20 min after application of XA/XO + 500 U/ml catalase, P < 0.01 vs. control). KCl (40 mM) reduced the early and sustained vasodilation to XA/XO in the absence of catalase but 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 5 x 10(-5) M), diethyldithiocarbamate trihydrate (DDC, 10(-2) M), and deferoxamine (DFX, 10(-3) M) had no effect. In contrast, the catalase-resistant vasodilation was significantly attenuated by DDC, ODQ, and DFX as well as polyethylene-glycolated catalase (5,000 U/ml), but KCl had no effect. Confocal microscopy revealed that even in the presence of catalase, 2',7'-dichlorodihydrofluoresein diacetate fluorescence was observed in the vascular smooth muscle, but this was abolished by DDC. These data indicate that the exogenously generated superoxide anion (O2-*) by XA/XO is spontaneously converted to H2O2, which dilates HCA through vascular smooth muscle hyperpolarization. O2-* is also converted to H2O2 likely by superoxide dismustase within vascular cells and dilates HCA through a different pathway involving the activation of guanylate cyclase. These findings suggest that exogenously and endogenously produced H2O2 may elicit vasodilation by different mechanisms.

Arterioles↗
PubMed2003

Is there an association between athletic amenorrhea and endothelial cell dysfunction?

PURPOSE: To test the hypothesis that young females with athletic amenorrhea and oligomenorrhea show signs of early cardiovascular disease manifested by decreased endothelium-dependent dilation of the brachial artery. METHODS: Ten women with athletic amenorrhea (mean +/- SE, age 21.9 +/- 1.2 yr), 11 with oligomenorrhea (age 20.8 +/- 1.1 yr), and 11 age-matched controls (age 20.2 +/- 1.1 yr) were studied. Study subjects were amenorrheic an average of 2.3 (range 0.6-5) yr and oligomenorrheic an average of 6.2 yr. All ran a minimum of 25 miles.wk. They were nonpregnant and free of metabolic disease. Brachial artery flow-mediated dilation (endothelium-dependent) was measured with a noninvasive ultrasound technique in each group. RESULTS: Endothelium-dependent brachial artery dilation was reduced in the amenorrheic group (1.08 +/- 0.91%) compared with oligomenorrheic (6.44 +/- 1.3%; P< 0.05) and eumenorrheic (6.38 +/- 1.4%; P< 0.05) groups. CONCLUSION: Athletic amenorrhea is associated with reduced endothelium-dependent dilation of the brachial artery. This may predispose to accelerated development of cardiovascular disease.

Adolescent↗
PubMed2003

The association of hypertension and secondary cardiovascular disease with sleep-disordered breathing.

We present a review of the English-language literature from 1972 through 2000 pertaining to systemic high BP in patients with sleep-disordered breathing (SDB). We reviewed studies assessing the relationship between obstructive sleep apnea, central sleep apnea or periodic breathing, and systemic high BP, and present an approach to the management of these patients. Complications of obesity and the role of the sympathetic nervous system are reviewed as well. It is the aim of these reviews to draw qualified conclusions, based on the current literature, with regard to SDB as a causative or contributory factor in systemic hypertension.

Cardiovascular Diseases↗
PubMed2002

Mechanism of thrombin-induced vasodilation in human coronary arterioles.

Thrombin (Thromb), activated as part of the clotting cascade, dilates conduit arteries through an endothelial pertussis toxin (PTX)-sensitive G-protein receptor and releases nitric oxide (NO). Thromb also acts on downstream microvessels. Therefore, we examined whether Thromb dilates human coronary arterioles (HCA). HCA from right atrial appendages were constricted by 30-50% with endothelin-1. Dilation to Thromb (10(-4)-1 U/ml) was assessed before and after inhibitors with videomicroscopy. There was no tachyphylaxis to Thromb dilation (maximum dilation = 87.0%, ED(50) = 1.49 x 10(-2)). Dilation to Thromb was abolished with either hirudin or denudation but was not affected by PTX. Neither N(omega)-nitro-l-arginine methyl ester (n = 7), indomethacin (n = 9), (1)H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (n = 6), tetraethylammonium chloride (n = 5), nor iberiotoxin (n = 4) reduced dilation to Thromb. However, KCl (maximum dilation = 89 +/- 5 vs. 20 +/- 10%; P < 0.05; n = 7), tetrabutylammonium chloride (maximum dilation = 79 +/- 7 vs. 21 +/- 4%; P < 0.05; n = 5), and charybdotoxin (maximum dilation = 89 +/- 4 vs. 10 +/- 2%; P < 0.05; n = 4) attenuated dilation to Thromb. In contrast to animal models, Thromb-induced dilation in human arterioles is independent of G(i)-protein activation and NO release. However, Thromb dilation is endothelium dependent, is maintained on consecutive applications, and involves activation of K(+) channels. We speculate that an endothelium-derived hyperpolarizing factor contributes to Thromb-induced dilation in HCA.

Adult↗
PubMed2002

Peroxynitrite inhibits Ca2+-activated K+ channel activity in smooth muscle of human coronary arterioles.

We examined the hypothesis that ONOO-, a product of the interaction between superoxide (O2*-) and nitric oxide (NO), inhibits calcium-activated K+ (KCa) channel activity in vascular smooth muscle cells (VSMCs) of human coronary arterioles (HCAs), thereby reducing hyperpolarization-mediated vasodilation. HCAs were dissected from right atrial appendages. The interaction of ONOO- with microvessels was determined by immunohistochemistry using a nitrotyrosine antibody. Strong staining was observed in arteries exposed to authentic ONOO- or to sodium nitroprusside (SNP)+xanthine (XA)+xanthine oxidase (XO). Dilation to 10(-8) mol/L bradykinin (BK) was abolished in vessels exposed to ONOO- (-2.5+/-8%; P<0.05) but not DC-ONOO- (65+/-8%). Reduced dilation to BK was also observed after application of XO and SNP. Dilation to NS1619 (KCa channel opener) was reduced in endothelial denuded arterioles treated with ONOO-. In isolated VSMCs, whole-cell peak K+ current density was reduced by ONOO- (control 65+/-15 pA/pF; ONOO- 42+/-9 pA/pF; P<0.05). Iberiotoxin had no further effect on whole-cell K+ current. In inside-out patches, ONOO- but not DC-ONOO- decreased open state probability (NP(o)) of KCa channel by 50+/-12%. O2*- generated by XA+XO had no effect on BK-induced dilation and NP(o) of KCa channels. These results suggest that ONOO-, but not O2*-, inhibits KCa channel activity in VSMCs possibly by a direct effect. This mechanism may contribute to impaired EDHF-mediated dilation in conditions such as ischemia/reperfusion where increased activity of NO synthase occurs in the presence of excess of O2*-.

Animals↗
PubMed2002

The coronary circulation in diabetes: influence of reactive oxygen species on K+ channel-mediated vasodilation.

Enhanced oxidative stress, particularly an excess production of superoxide, has been implicated in the altered vasomotor responsiveness observed in diabetes mellitus (DM). Recent evidence suggests that an altered regulation of K+ channel activity by enhanced oxidative stress may participate in the abnormal vascular responses. This review examines the mechanism of hyperglycemia-induced superoxide production and describes the consequences on hyperpolarization-mediated vasodilation. Several pathways have been proposed as mechanisms for hyperglycemia-induced superoxide overproduction, including increased flux through the polyol pathway, depletion of nicotinamide adenine dinucleotide phosphate (NADPH), altered endogenous antioxidant enzymes, and reduced availability of tetrahydrobiopterin, an essential cofactor for nitric oxide synthase (NOS). The resulting excess production of superoxide has been implicated in the impaired dilator responses to ATP-sensitive K+ (KATP) channel openers in aorta and in mesenteric and cerebral arteries of streptozotocin-induced diabetic rats. This may have important implications for ischemia-mediated vasodilation. Potential alterations in voltage-sensitive K+ (KV) channel regulation also have been implicated in the vascular pathogenesis of DM. For example, incubation of small rat coronary arteries in high glucose for 24 h greatly reduces KV channel activity and functional responses, both of which can be partially restored by antioxidant treatment. However, not all K+ channels are adversely affected by reactive oxygen species (ROS). For example, high-conductance Ca(2+)-activated K+ (BKCa) channels may compensate for the loss of other vasodilator mechanisms in disease states such as atherosclerosis where ROS generation is increased. Therefore, BKCa channels may be refractory to superoxide, providing a compensatory mechanism for partially reversing the reduced dilator responses attributed to the dysfunction of other K+ channel types. In summary, determining the effect of ROS on K+ channel-mediated dilation will be important for understanding the pathophysiology of diabetic vascular dysfunction and for developing therapies to improve tissue perfusion in this disease.

Animals↗
PubMed2002

Oxidative stress and potassium channel function.

1. Modulation of K+ channel activities by cellular oxidative stress has emerged as a significant determinant of vasomotor function in multiple disease states. 2. Evidence from in vitro and in vivo studies suggest that superoxide (O2-) and hydrogen peroxide (H2O2) enhance BKCa channel activity in rat and cat cerebral arterioles; however, activity is decreased by peroxynitrite (ONOO-) in rat cerebral arteries. The mechanisms of changes in BKCa channel properties are not fully understood and may involve oxidation of cysteine residues that are located in the cell membranes. 3. Studies further suggest that O2- increases KATP channel activity in guinea-pig cardiac myocytes, but decreases opening in cerebral vasculature. Both H2O2 and ONOO- enhance KATP channel activity in the myocardium and in coronary, renal, mesenteric and cerebral vascular beds. Alteration of KATP channels by free radicals may be due to oxidation of SH groups or changes in the cytosolic concentration of ATP. 4. It does appear that O2- produced by either reaction of xanthine and xanthine oxidase or elevated levels of glucose reduces Kv channel activity and the impairments can be partially restored by free radical scavengers, superoxide dismutase and catalase. 5. Thus, redox modulation of potassium channel activity is an important mechanism regulating cell vascular smooth muscle membrane potential.

Animals↗