Akos Koller

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Papers by Akos Koller

Molecular Pathomechanisms of Impaired Flow-Induced Constriction of Cerebral Arteries Following Traumatic Brain Injury: A Potential Impact on Cerebral Autoregulation

International Journal of Molecular Sciences, Jun 21, 2021

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Estrogen Maintains Nitric Oxide Synthesis in Arterioles of Female Hypertensive Rats

Hypertension, Jun 1, 1997

We hypothesized that in female spontaneously hypertensive rats (SHR), estrogen moderates the dysf... more We hypothesized that in female spontaneously hypertensive rats (SHR), estrogen moderates the dysfunction of arterioles by preserving nitric oxide synthesis. To this end, we conducted experiments on isolated gracilis muscle arterioles (approximately 55 μm in diameter) of 12-week-old SHR divided into four groups: females (fSHR), ovariectomized females (fSHR-OV), ovariectomized females with estrogen replacement (fSHR-OV+ES, 50 μg/kg SC 17β-estradiol benzoate every 48 hours), and males (mSHR). Arteriolar diameter in the presence of perfusion pressures of 60, 80, 100, and 120 mm Hg were obtained, and diameter changes were measured (at 80 mm Hg) in response to various concentrations of substance P (10 −9 to 5×10 −8 mol/L), sodium nitroprusside (10 −8 to 10 −6 mol/L), and A23187 (5×10 −8 to 10 −6 mol/L). The pressure-induced diameter of mSHR and fSHR-OV arterioles was significantly less (by approximately 10%) than that of fSHR and fSHR-OV+ES arterioles. N ω -nitro- l -arginine (10 −4 mol/L), a nitric oxide synthase inhibitor, elicited a significant decrease in basal arteriolar diameter of fSHR (by approximately 19%) and fSHR-OV+ES (by approximately 17%), thereby eliminating the differences in tone among the various groups. Dilations of fSHR and fSHR-OV+ES arterioles to substance P were significantly greater (by 140% at a concentration of 5×10 −8 mol/L) than those of mSHR and fSHR-OV arterioles, whereas dilations to sodium nitroprusside were not different among the groups. A23187 (a nitric oxide releaser) elicited dilations in arterioles of fSHR (5.9±1.5%, 13.0±1.8%, and 19.2±2.1%) and fSHR-OV+ES (4.3±1.0%, 10.3±2.4%, and 15.0±4.0%) but constrictions in those of mSHR (−7.5±1.6%, −25.3±39%, and −36.9±4.1%) and fSHR-OV (−2.6±1.7%, −7.4±3.3%, and −11.5±6.1%). We conclude that estrogen in fSHR is responsible for the preservation of nitric oxide synthesis in skeletal muscle arterioles, resulting in a greater modulation of pressure-induced myogenic tone than in mSHR and maintenance of nitric oxide–mediated dilations.

Role of endothelial [Ca2+]i in activation of eNOS in pressurized arterioles by agonists and wall shear stress

American Journal of Physiology-heart and Circulatory Physiology, Aug 1, 2001

In cultured endothelial cells, Ca 2ϩ-dependent and-independent activation of nitric oxide (NO) sy... more In cultured endothelial cells, Ca 2ϩ-dependent and-independent activation of nitric oxide (NO) synthesis to agonists and flow/wall shear stress (WSS) has been demonstrated. However, the presence and function of these pathways are less well known in microvessels that can be exposed to a high level of WSS. We hypothesized that the role of changes in endothelial intracellular calcium concentration ([Ca 2ϩ ]i) is different in agonist-and WSS-induced release of NO. Thus changes in endothelial [Ca 2ϩ ]i and diameter of intact pressurized (ϳ100 m at 80 mmHg) gracilis skeletal muscle arterioles of rats were measured by fluorescent videomicroscopy. Acetylcholine (ACh) and increases in WSS (by increasing intraluminal flow) elicited dilations (maximum 91 Ϯ 2% and 34 Ϯ 4%) that could be inhibited by N-nitro-Larginine methyl ester (L-NAME), a NO synthase blocker. In diameter-clamped arterioles, ACh caused substantial increases in the endothelial calcium fluorescence ratio (ERCa, maximum 43 Ϯ 5%), which was significantly greater than changes in ERCa (maximum ϳ10%) to increases in WSS. The Ca 2ϩ ionophore A-23187 also substantially increased ERCa (maximum 38 Ϯ 5%) and elicited significant L-NAME-sensitive arteriolar dilations (maximum 45 Ϯ 7%). Intraluminal administration of the tyrosine kinase inhibitor genistein had no effect on dilations induced by ACh or the NO donor sodium nitroprusside, whereas it eliminated WSS-induced dilations. Collectively, our data suggest that, in endothelium of skeletal muscle arterioles, NO synthesis is activated by shear stress without a substantial increase in [Ca 2ϩ ]i, most likely by activation of tyrosine kinase pathways, whereas NO release by ACh and A-23187 is associated with substantial increases in [Ca 2ϩ ]i.

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Increases in endothelial Ca2+activate KCachannels and elicit EDHF-type arteriolar dilation via gap junctions

American Journal of Physiology-heart and Circulatory Physiology, May 1, 2002

Ungvari, Zoltan, Anna Csiszar, and Akos Koller. Increases in endothelial Ca 2ϩ activate KCa chann... more

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Gender difference in flow-induced dilation and regulation of shear stress: role of estrogen and nitric oxide

American Journal of Physiology-regulatory Integrative and Comparative Physiology, Nov 1, 1998

Previous studies show that agonist-induced, nitric oxide (NO)-mediated arteriolar dilations are g... more Previous studies show that agonist-induced, nitric oxide (NO)-mediated arteriolar dilations are greater in female than in male rats. Thus we hypothesized that flowdependent arteriolar dilation, which is in part mediated by NO, is also greater in females than in males. Gracilis muscle arterioles from 12-wk-old female and male Wistar rats were isolated, cannulated, and pressurized. At 80 mmHg of perfusion pressure, the active diameter and passive diameter (PD) of arterioles of female and male rats were 58.3 Ϯ 3.4 and 53.2 Ϯ 2.6 µm as well as 103.6 Ϯ 4.0 and 115.3 Ϯ 4.8 µm, respectively. Dilations to step increases in perfusate flow from 0 to 25 µl/min were significantly greater in arterioles of female rats and ovariectomized rats with estrogen replacement (OVE) than in male and ovariectomized female (OV) rats (98.6 Ϯ 0.6 and 97.4 Ϯ 1.1% vs. 72.6 Ϯ 3.3 and 72.5 Ϯ 3.6% of PD at 25 µl/min). Calculation of wall shear stress (WSS) revealed that the maintained WSS was significantly lower in arterioles of female than in those of male rats (ϳ20 vs. ϳ35 dyn/cm 2). After indomethacin pretreatment, N-nitro-L-arginine methyl ester (L-NAME; 10 Ϫ4 M) eliminated flowdependent dilation in arterioles of male and OV rats but only attenuated (by ϳ50%) the responses in arterioles of female and OVE rats. In vessels of these latter two groups of rats, the remaining flow-induced dilation was completely eliminated by administration of 10 Ϫ5 M Hb or 10 Ϫ3 M L-NAME. The greater flow/shear stress-induced dilation of arterioles of female rats indicates a gender difference in the regulation of WSS, which is likely to be due to the greater release of NO in female vessels requiring the chronic presence of estrogen. These findings suggest an important role for estrogen in the regulation of peripheral resistance in females.

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Hyperhomocysteinemia Alters Cardiac Substrate Metabolism by Impairing Nitric Oxide Bioavailability Through Oxidative Stress

Circulation, Jan 16, 2007

Background-Hyperhomocysteinemia (HHcy) has been considered a vascular disease associated with inc... more 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 mol/L for acute and 24 mol/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. (Circulation. 2007;115:255-262.

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17β-Estradiol Restores Endothelial Nitric Oxide Release to Shear Stress in Arterioles of Male Hypertensive Rats

Circulation, Jan 4, 2000

Background-Endothelial nitric oxide (NO)-mediated responses are impaired in arterioles of male sp... more Background-Endothelial nitric oxide (NO)-mediated responses are impaired in arterioles of male spontaneously hypertensive rats (SHR), but they are still present in female SHR. We hypothesized that in vitro incubation of arterioles of male SHR with estrogen will restore NO-mediated responses by upregulation of endothelial NO synthase. Methods and Results-Responses to increases in perfusate flow (from 0 to 25 L/min) and to the calcium ionophore A23187 (5ϫ10 Ϫ8 to 10 Ϫ6 mol/L), norepinephrine (NE; 10 Ϫ7 to 3ϫ10 Ϫ7 mol/L), sodium nitroprusside (SNP; 10 Ϫ8 to 10 Ϫ6 mol/L), and adenosine (ADO; 10 Ϫ6 to 5ϫ10 Ϫ5 mol/L) were studied in cannulated and pressurized gracilis muscle arterioles (Ϸ75 m in diameter) isolated from 12-week-old male SHR before and after incubation with 10 Ϫ9 mol/L 17␤-estradiol (17␤-E 2) for 16 to 18 hours. After incubation with 17␤-E 2 , basal diameter of arterioles was significantly increased (by Ϸ10%), and flow-induced dilation was significantly enhanced (79.8Ϯ2.9 versus 103.7Ϯ3.7 m at 25 L/min), resulting in a lowered shear stress (62.0Ϯ9.1 versus 32.5Ϯ4.2 dyne/cm 2). Also, vasoconstrictions to A23187 were reversed to dilations (Ϫ18.7Ϯ2.2 versus 18.8Ϯ1.7 m), and constrictions to NE were significantly attenuated (Ϫ30.7Ϯ3.0 versus Ϫ21.2Ϯ2.8 m). These alterations were eliminated by ICI 182,780 (10 Ϫ7 mol/L), an estrogen receptor antagonist; 5,6-dichloro-1-␤-D-ribofuranosylbenzimidazole (10 Ϫ5 mol/L), a transcription inhibitor; or N-nitro-L-arginine methyl ester (10 Ϫ4 mol/L), an inhibitor of NO synthase, whereas they were not affected by aminoguanidine (5ϫ10 Ϫ5 mol/L), a specific inhibitor of inducible NO synthase. Arteriolar responses were not altered by incubation with 17␣-estradiol. Conclusions-Estrogen, via a receptor-mediated pathway, upregulates endothelial NO synthase gene expression, leading to increased NO production, and restores the regulation of wall shear stress in arterioles of male SHR. (Circulation. 2000;101:94-100.

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Increased myogenic tone in skeletal muscle arterioles of diabetic rats. Possible role of increased activity of smooth muscle Ca2+ channels and protein kinase C

Cardiovascular Research, Sep 1, 1999

The diabetes mellitus-induced microangiopathy is still not clearly characterized. In this study w... more The diabetes mellitus-induced microangiopathy is still not clearly characterized. In this study we aimed to elucidate the effect of streptozotocin (STZ)-induced diabetes on myogenic response of isolated rat skeletal muscle arterioles and the mechanisms responsible for its alterations. Methods: Male rats were divided into two groups: (1) control rats (C, plasma glucose: 6.460.5 mmol / l, n540) 2) diabetic rats (DM, 65 mg / kg STZ iv, plasma glucose: 25.760.7 mmol / l, n540). Changes in diameter of isolated, cannulated gracilis skeletal muscle arterioles (|130 mm in diameter) were measured by video-microscopy. Results: Step increases in perfusion pressure (PP; from 10 to 140 mmHg) elicited significantly greater constrictions in DM than in C gracilis arterioles, in the presence of the endothelium (E). Also, a step increase in PP (from 40 to 100 mmHg) elicited greater and faster constrictions in DM vs. C arterioles. There 21 were no significant differences in the pressure-passive diameter (in Ca free solution) curves of arterioles. Dilations to acetylcholine 29 28 were impaired in arterioles of DM as compared to those of C rats (EC , C: 4.060.9310 mol / l, DM: 4.862.0310 mol / l (p,0.01), 50 24 and unaffected by inhibition of nitric oxide synthesis with L-NNA (10 mol / l). Arteriolar constrictions to norepinephrine (NE) were 27 28 significantly greater in DM compared to those of C rats (EC , C: 6.260.6310 mol / l, DM: 8.062.0 310 mol / l, p,0.01) both in 50 21 the presence and absence of E. In the absence of the E, constrictions to increases in pressure, or Ca (0.25-7.5 mmol / l), or the 21 210 29 voltage-dependent Ca-channel agonist Bay K 8644 (EC ; DM: 4.261.5310 mol / l, C: 1.760.8310 mol / l, p,0.05) or the 50 29 28 protein kinase C activator phorbol 12-myristate 13-acetate (PMA, EC ; DM: 662310 mol / l, C: 261310 mol / l, p,0.05) were 50 significantly greater in arterioles of DM compared to those of C rats. Conclusion: The novel findings of our study are that in diabetes mellitus the myogenic response of rat skeletal muscle arterioles is enhanced, which seems to be independent from the impaired endothelial 21 function present simultaneously, and likely due to the increased activity of voltage-dependent Ca channels and / or upregulation of protein kinase C in arteriolar smooth muscle.

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Neuronal NOS-dependent dilation to flow in coronary arteries of male eNOS-KO mice

American Journal of Physiology-heart and Circulatory Physiology, Feb 1, 2002

Flow-induced dilation was examined in isolated coronary arteries of endothelial nitric oxide (NO)... more Flow-induced dilation was examined in isolated coronary arteries of endothelial nitric oxide (NO) synthase knockout mice (eNOS-KO) and wild-type (WT) mice. The basal tone of arteries (percentage of passive diameter) was significantly greater in eNOS-KO than in WT mice; their flow-induced dilations, however, were similar. Endothelial removal eliminated the dilations in vessels of both strains of mice. In arteries of WT mice, N-nitro-L-arginine methyl ester (L-NAME) (10 Ϫ4 M) or indomethacin (10 Ϫ5 M) alone, inhibited flow-induced dilation by ϳ50%, whereas their simultaneous administration abolished the responses. In arteries of eNOS-KO mice, flow-induced dilation was inhibited by ϳ40% with L-NAME. The residual portion (60%) of the response was eliminated by the additional administration of indomethacin. 7-Nitroindazole (10 Ϫ4 M) attenuated flow-induced dilation by ϳ40% in arteries of eNOS-KO mice, but did not affect responses in those of WT mice. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (3 ϫ 10 Ϫ5 M) inhibited the L-NAME/7-nitroindazole-sensitive portion of the responses in arteries of eNOS-KO mice. Immunohistochemical evidence confirms the presence of neuronal NOS (nNOS) in the arterial endothelium of eNOS-KO mice. In conclusion, nNOSderived NO, via activation of cGMP, together with prostaglandins, maintains flow-induced dilation in coronary arteries of male eNOS-KO mice.

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Dysfunction of Nitric Oxide Mediation in Isolated Rat Arterioles With Methionine Diet–Induced Hyperhomocysteinemia

Arteriosclerosis, Thrombosis, and Vascular Biology, Aug 1, 1999

In humans, increased plasma homocysteine (Hcy) has been shown to be correlated with occlusive art... more In humans, increased plasma homocysteine (Hcy) has been shown to be correlated with occlusive arterial diseases and atherosclerosis. Studies of isolated conductance vessels of experimental animals suggest that Hcy may interfere with local vasoregulatory mechanisms, yet the effect of hyperhomocysteinemia (HHcy) on the function of microvessels, such as skeletal muscle arterioles, has not been investigated. Male Wistar rats were divided into 2 groups: control rats (C; plasma Hcy, 7.1Ϯ0.3 mol/L; nϭ25), and rats made HHcy by 1 g/kg body weight daily intake of methionine in the drinking water for 4 weeks (plasma Hcy, 23.6Ϯ2.9 mol/L; PϽ0.01 versus C; nϭ25). First-order arterioles (Ϸ130 m in diameter) were isolated from gracilis muscle, cannulated, and pressurized (80 mm Hg, no-flow conditions). Changes in diameter were observed by videomicroscopy. Arteriolar constrictions to norepinephrine (NE; 3ϫ10 Ϫ7 mol/L) were significantly (PϽ0.01) greater in HHcy compared with C rats (C, 37.7Ϯ4.9%; HHcy, 59.5Ϯ5.2%). Removal of the endothelium (-E) augmented NE-induced constrictions only in arterioles from C rats, whereas it had no effect on responses of arterioles from HHcy rats (C-E, 55.9Ϯ6.9%; HHcy-E, 56.5Ϯ7.0%). Dilations to cumulative doses of acetylcholine (ACh; 10 Ϫ8 mol/L) were significantly reduced in arterioles from HHcy rats (C, 64.0Ϯ5.2%; HHcy, 24.1Ϯ6.8%). Inhibition of nitric oxide (NO) synthesis with N-nitro-L-arginine (L-NNA; 10 Ϫ4 mol/L) significantly decreased ACh-induced dilations of C arterioles, whereas it did not affect HHcy arterioles. Similar alterations were found in arteriolar dilations to histamine, another known NO-dependent agonist. Endothelium-independent dilations to the NO donor sodium nitroprusside were not different in arterioles from C and HHcy rats, either in the presence or absence of L-NNA. Presence of superoxide dismutase and catalase (scavenger of reactive oxygen metabolites) did not affect HHcy-induced alterations in the ACh response. We conclude that hyperhomocysteinemia reduces rat skeletal muscle arteriolar dilations in response to ACh and histamine, and enhances constrictions to NE, alterations that are likely to be caused by the reduced mediation of these responses by NO. The reduced activity of NO in arterioles may contribute to the microvascular impairment described in HHcy.

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Superoxide Released to High Intra-arteriolar Pressure Reduces Nitric Oxide–Mediated Shear Stress– and Agonist-Induced Dilations

Circulation Research, Nov 2, 1998

It is thought that elevated levels of reactive oxygen metabolites contribute to the dysfunction o... more It is thought that elevated levels of reactive oxygen metabolites contribute to the dysfunction of vascular endothelium in hypertension. We hypothesized that high intravascular pressure itself elicits production of superoxide, which then interferes with nitric oxide (NO)-mediated responses of arterioles. Thus, isolated arterioles (Ϸ80 m in diameter) from gracilis muscle of normotensive Wistar rats were cannulated and exposed to 140 mm Hg perfusion pressure for 30 minutes (in the absence of perfusate flow). After high intravascular pressure treatment, dilations to increases in perfusate flow (0 to 30 L/min) were significantly reduced (from 39Ϯ2.2 to 19Ϯ2.1 m at 30 L/min), eliciting an increase in wall shear stress from Ϸ20 to Ϸ60 dyne/cm 2. N-nitro-L-arginine (10 Ϫ4 mol/L) did not affect, whereas indomethacin eliminated, flow-induced dilations after pressure treatment. In control, substance P (SP, 10 Ϫ9 to 5ϫ10 Ϫ8 mol/L), sodium nitroprusside (SNP, 10 Ϫ8 to 10 Ϫ6 mol/L), and adenosine (ADO, 10 Ϫ6 to 5ϫ10 Ϫ5 mol/L) elicited dilations (SP: 31.5Ϯ1.9 m, SNP: 45.6Ϯ4 m, and ADO: 37.2Ϯ4.1 m, at maximum concentrations, respectively). After pressure treatment, maximum dilations to SP and SNP were significantly reduced (by 49% and 39%, respectively), whereas responses to ADO were not affected. Presence of superoxide dismutase (120 U/mL) and catalase (80 U/mL), but not catalase alone, in the perfusate solution prevented the reduction in dilation of arterioles to flow and agonists after pressure treatment by restoring NO mediation. We conclude that high intravascular pressure per se elicits the release of superoxide, which then interferes with NO, a mechanism that contributes to the elevation of wall shear stress and peripheral resistance in hypertension. (Circ Res. 1998;83:960-965.

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In eNOS knockout mice skeletal muscle arteriolar dilation to acetylcholine is mediated by EDHF

American Journal of Physiology-heart and Circulatory Physiology, Mar 1, 2000

The mechanisms that account for acetylcholine (ACh)-induced responses of skeletal muscle arteriol... more The mechanisms that account for acetylcholine (ACh)-induced responses of skeletal muscle arterioles of mice lacking endothelial nitric oxide (NO) synthase (eNOS-KO) were investigated. Isolated, cannulated, and pressurized arterioles of gracilis muscle from male eNOS-KO (74.1 Ϯ 2.3 µm) and wild-type (WT, 87.2 Ϯ 2.1 µm) mice developed spontaneous tone accounting for 63 and 61% of their passive diameter (116.8 Ϯ 3.4 vs. 143.2 Ϯ 2.8 µm, respectively) and dilated dose-dependently to ACh (10 Ϫ9-10 Ϫ7 M). These dilations were significantly smaller in vessels of eNOS-KO compared with WT mice (29.2 Ϯ 2.0 µm vs. 46.3 Ϯ 2.1 µm, at maximum concentration) but responses to the NO donor, sodium nitrite (NaNO 2 , 10 Ϫ6-3 ϫ 10 Ϫ5 M), were comparable in the vessels of the two strains. N G-nitro-L-arginine (L-NNA, 10 Ϫ4 M), an inhibitor of eNOS, inhibited AChinduced dilations by 60-90% in arterioles of WT mice but did not affect responses in those of eNOS-KO mice. In arterioles of eNOS-KO mice, dilations to ACh were not affected by indomethacin but were essentially abolished by inhibitors of cytochrome P-450, clotrimazole (CTZ, 2 ϫ 10 Ϫ6 M) or miconazole (MCZ, 2 ϫ 10 Ϫ6 M), as well as by either high K ϩ (40 mM) or iberiotoxin [10 Ϫ7 M, a blocker of Ca 2ϩ-dependent K ϩ channels (K Ca channels)]. On the other hand, in WT arterioles CTZ or MCZ inhibited ACh-induced dilations only by ϳ10% and only in the presence of L-NNA. These results indicate that in arterioles of eNOS-KO mice, endothelium-derived hyperpolarizing factor (EDHF), synthesized via cytochrome P-450, accounts entirely for the mediation of ACh-induced dilation via an increase in K Ca-channel activity. In contrast, in arterioles of WT mice, endothelium-derived NO predominantly mediates ACh-induced dilation in which participation of EDHF becomes apparent only after inhibition of NO synthesis. nitric oxide; endothelium; cytochrome P-450; potassium channels; arteriolar smooth muscle

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Corelease of nitric oxide and prostaglandins mediates flow-dependent dilation of rat gracilis muscle arterioles

American Journal of Physiology-heart and Circulatory Physiology, Jul 1, 1994

We have studied the mechanisms responsible for the mediation of flow (shear stress)-induced dilat... more We have studied the mechanisms responsible for the mediation of flow (shear stress)-induced dilation of isolated arterioles of rat gracilis muscle. Active diameter of arterioles at a constant perfusion pressure (PP, 80 mmHg) was approximately 92 microns, while their passive diameter (Ca(2+)-free solution) was approximately 165 microns. At a constant PP the stepwise increase in flow of the perfusion solution (PS, 0-60 microliters/min in 10-microliters/min steps) elicited a gradual increase in diameter up to approximately 140 microns. Flow-induced dilations were eliminated by the removal of the endothelium of arterioles (by air). Dilations were significantly reduced by the cyclooxygenase blocker, indomethacin (Indo, 10(-5) M), by the nitric oxide synthase blocker, N omega-nitro-L-arginine (L-NNA, 10(-4) M), or by the endothelium-derived relaxing factor inhibitor, oxyhemoglobin (Hb, 10(-5) M), as indicated by the significant changes in the slope of the regression lines of the flow-diameter curves. For example, during administration of the inhibitors, dilation to 60 microliters/min perfusate flow was reduced by 41.1, 54.3, and 39.3%, respectively. Combined application of Indo and L-NNA almost completely eliminated flow-induced dilation. Arteriolar dilation maintained calculated wall shear stress close to control values (approximately 30 dyn/cm2 at 60 microliters/min) despite increases in flow, but when the dilation was inhibited by removal of the endothelium or by the combined administration of Indo and L-NNA, wall shear stress was greatly increased as a function of increases in flow of the PS (approximately 125 dyn/cm2).(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced Release of Prostaglandins Contributes to Flow-Induced Arteriolar Dilation in eNOS Knockout Mice

Circulation Research, Aug 6, 1999

Nitric oxide and prostaglandins were shown to contribute to the endothelial mediation of flow-ind... more Nitric oxide and prostaglandins were shown to contribute to the endothelial mediation of flow-induced dilation of skeletal muscle arterioles of rats. Thus, we hypothesized that flow-induced dilation and its mediation are altered in gracilis muscle arterioles of mice deficient in the gene for endothelial nitric oxide synthase (eNOS-KO) compared with control wild-type (WT) mice. Gracilis muscle arterioles (Ϸ80 m) of male mice were isolated, then cannulated and pressurized in a vessel chamber. The increases in diameter elicited by increases in perfusate flow from 0 to 10 L/min were similar in arterioles from eNOS-KO (nϭ28) and WT (nϭ22) mice (Ϸ20 m at 10 L/min flow). Removal of the endothelium eliminated flow-induced dilations in vessels of both strains of mice. N-nitro-L-arginine (L-NNA, 10 Ϫ4 mol/L) significantly inhibited flow-induced dilation in arterioles of WT mice by Ϸ51% but had no effect on responses of arterioles from eNOS-KO mice. Indomethacin (INDO, 10 Ϫ5 mol/L) inhibited flow-induced dilation of WT mice by Ϸ49%, whereas it completely abolished this response in arterioles of eNOS-KO mice. Simultaneous administration of INDO and L-NNA eliminated flow-induced responses in arterioles of WT mice. Dilations to carbaprostacyclin were similar at concentrations of 10 Ϫ8 and 3ϫ10 Ϫ8 mol/L but decreased significantly at 10 Ϫ7 mol/L in arterioles of eNOS-KO compared with those of WT mice. These findings demonstrate that, despite the lack of nitric oxide mediation, flow-induced dilation is close to normal in arterioles of eNOS-KO mice because of an enhanced release of endothelial dilator prostaglandins and suggest that this vascular adaptation may contribute to the regulation of peripheral resistance in eNOS-KO mice.

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P331Are there gender specific differences in elderly regarding exercise treatment of cardiovasular diseases?

Cardiovascular Research, 2018

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Guía ESC/EACTS 2018 sobre revascularización miocárdica

Revista Espanola De Cardiologia, 2019

Autores/miembros del Grupo de Trabajo: Franz-Josef Neumann* (coordinador de la ESC) (Alemania), M... more Autores/miembros del Grupo de Trabajo: Franz-Josef Neumann* (coordinador de la ESC) (Alemania), Miguel Sousa-Uva*,◊ (coordinador de la EACTS) (Portugal), Anders Ahlsson◊ (Suecia), Fernando Alfonso (España), Adrian P. Banning (Reino Unido), Umberto Benedetto◊ (Reino Unido), Robert A. Byrne (Alemania), Jean-Philippe Collet (Francia), Volkmar Falk◊ (Alemania), Stuart J. Head◊ (Países Bajos), Peter Jüni (Canadá), Adnan Kastrati (Alemania), Akos Koller (Hungría), Steen D. Kristensen (Dinamarca), Josef Niebauer (Austria), Dimitrios J. Richter (Grecia), Petar M. Seferovic (Serbia), Dirk Sibbing (Alemania), Giulio G. Stefanini (Italia), Stephan Windecker (Suiza), Rashmi Yadav◊ (Reino Unido) y Michael O. Zembala◊ (Polonia)

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A hemodinamikai erők által aktivált normális éa kóros vaszkuláris mechanizmusok = Haemodynamic forces-activated normal and pathological vascular mechanisms

A hemodinamikai erők altal aktivalt normalis es koros vaszkularis mechanizmusok tisztazasat tűztu... more A hemodinamikai erők altal aktivalt normalis es koros vaszkularis mechanizmusok tisztazasat tűztuk ki celul. Főbb eredmenyek: 1) A nitrogen-monoxid (NO) befolyasolja a miogen valasz es az erfal mechanikus viselkedese kozti kapcsolatot patkany koronaria arteriolakban. Tovabba, az NO jelenlete szukseges disztenzibilitas fenntartasahoz. 2) 2-es tipusu diabeteses egerekben az arteriolak tonusa es vernyomasa emelkedett, melyben a COX-2 eredetű konstriktor prosztaglandin fokozott felszabadulasa szerepet jatszhat. 3) A PECAM-1 medialja az arteriolak magas fali nyiroerőgradiens-indukalta NO-fuggő dilataciojat. 4) Izolalt ereket oxidativ stressznek kiteve, az Ang II-re adott konstrikcios valaszok fokozodtak. 5) Az asszimetrikus dimetilarginin (ADMA) izolalt vazizom arteriolakban nem csak az NO szinteziset csokkenti, hanem szuperoxid termelest is indukal, amelyek modositjak a rezisztencia erek vazomotor műkodeset. Tovabba, a vaszkularis RAS-t aktivalva fokozza az NAD(P)H oxidaz aktivasat, ami...

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Platelet-derived extracellular vesicles may contribute to the hypercoagulable state in preeclampsia

Journal of Reproductive Immunology, 2021

It has previously been shown that preeclampsia is associated with disturbed hemostasis and that e... more It has previously been shown that preeclampsia is associated with disturbed hemostasis and that extracellular vesicles (EVs) play important role in the regulation of hemostatic homeostasis. Thus, we hypothesized that the altered procoagulant characteristics of circulating platelet-derived EVs may contribute to the disturbed hemostasis in preeclampsia. Using multicolor flow cytometry, we have analyzed both tissue factor expressing procoagulant EVs and platelet-derived EV subpopulations derived from resting and activated thrombocytes by examining them in plasma samples of preeclamptic patients and pregnancy-matched healthy individuals. Compared to pregnancy-matched healthy individuals in preeclamptic patients a significantly (p < 0.05) higher ratio of Annexin-V positive activated platelets and a higher number of CD142 + tissue factor bearing procoagulant EVs were found, whereas the absolute amount of circulating CD41a + platelet-derived EVs and CD62P + /CD41a + EVs produced by activated thrombocytes was significantly lower in the plasma of preeclamptic women. In the plasma samples, there was no significant difference in the amount of CD63 + platelet-derived EVs. We propose that increased platelet activation and tissue factor expression of platelet derived extracellular vesicles may contribute to the hypercoagulable state observed in preeclampsia.

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Post-sports career healthy ageing: The Janus-faced, high-performance sport

Developments in Health Sciences, 2020

By now, there is no doubt that regular physical exercise has an overall beneficial effect on each... more By now, there is no doubt that regular physical exercise has an overall beneficial effect on each organ of the body. However, the effects of highly competitive sports (HCS) are more complex, as they exert greater demands on the cardiovascular and metabolic systems, among others. Strength, athletic, and aesthetic sport types each has a different exercise intensity and nutritional loading, as well as a different prevalence of cardiometabolic diseases at a later age. HCS athletes experience hypertension and mental stress during competitions and high nutritional loads between them. The post-career effects of this behaviour on the heart, arteries, cellular metabolism, and risk of obesity, are not well known and are not often the focus of research. In this review, we aimed to summarize the post-career effects of HCS. Based on data in the literature, we propose that athletes involved in highly competitive strength sports progressively develop metabolic syndrome and sustained elevated blood...

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Molecular Pathomechanisms of Impaired Flow-Induced Constriction of Cerebral Arteries Following Traumatic Brain Injury: A Potential Impact on Cerebral Autoregulation

International Journal of Molecular Sciences, Jun 21, 2021

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Estrogen Maintains Nitric Oxide Synthesis in Arterioles of Female Hypertensive Rats

Hypertension, Jun 1, 1997