Neuro- and Cardioprotective Effects of Blockade of Nitric Oxide Action by Administration of Methylene Blue

Exercise promotes cardioprotection in both humans and animals not only by reducing risk factors associated with cardiovascular disease but by reducing myocardial infarction and improving survival following ischemia. This article will define the role that nitric oxide and β-adrenergic receptors play in mediating the cardioprotective effects of exercise in the setting of ischemia-reperfusion injury.

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The Mechanisms Underlying Methylene Blue-Mediated Attenuation of Nitric Oxide-induced Vasodilatation

Journal of Emergency Medicine ◽

10.1016/j.jemermed.2020.10.059 ◽

2021 ◽

Vol 60 (5) ◽

pp. 679

Author(s):

Ju-Tae Sohn

Keyword(s):

Nitric Oxide ◽

Methylene Blue

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Comparison of the hemodynamic effects of nitric oxide and endothelium-dependent vasodilators in intact lungs

Journal of Applied Physiology ◽

10.1152/jappl.1990.68.2.735 ◽

1990 ◽

Vol 68 (2) ◽

pp. 735-747 ◽

Cited By ~ 51

Author(s):

S. L. Archer ◽

K. Rist ◽

D. P. Nelson ◽

E. G. DeMaster ◽

N. Cowan ◽

...

Keyword(s):

Nitric Oxide ◽

Methylene Blue ◽

Pulmonary Hypertension ◽

Feedback Inhibition ◽

Pressor Response ◽

Pulmonary Vasculature ◽

Hemodynamic Effects ◽

Isolated Lung

The effects of endothelium-dependent vasodilation on pulmonary vascular hemodynamics were evaluated in a variety of in vivo and in vitro models to determine 1) the comparability of the hemodynamic effects of acetylcholine (ACh), bradykinin (BK), nitric oxide (NO), and 8-bromo-guanosine 3′,5′-cyclic monophosphate (cGMP), 2) whether methylene blue is a useful inhibitor of endothelium-dependent relaxing factor (EDRF) activity in vivo, and 3) the effect of monocrotaline-induced pulmonary hypertension on the responsiveness of the pulmonary vasculature to ACh. In isolated rat lungs, which were preconstricted with hypoxia, ACh, BK, NO, and 8-bromo-cGMP caused pulmonary vasodilation, which was not inhibited by maximum tolerable doses of methylene blue. Methylene blue did not inhibit EDRF activity in any model, despite causing increased pulmonary vascular tone and responsiveness to various constrictor agents. There were significant differences in the hemodynamic characteristics of ACh, BK, and NO. In the isolated lung, BK and NO caused transient decreases of hypoxic vasoconstriction, whereas ACh caused more prolonged vasodilation. Pretreatment of these lungs with NO did not significantly inhibit ACh-induced vasodilation but caused BK to produce vasoconstriction. Tachyphylaxis, which was agonist specific, developed with repeated administration of ACh or BK but not NO. Tachyphylaxis probably resulted from inhibition of the endothelium-dependent vasodilation pathway proximal to NO synthesis, because it could be overcome by exogenous NO. Pretreatment with 8-bromo-cGMP decreased hypoxic pulmonary vasoconstriction and, even when the hypoxic pressor response had largely recovered, subsequent doses of ACh and NO failed to cause vasodilation, although BK produced vasoconstriction. These findings are compatible with the existence of feedback inhibition of the endothelium-dependent relaxation by elevation of cGMP levels. Responsiveness to ACh was retained in lungs with severe monocrotaline-induced pulmonary hypertension. Many of these findings would not have been predicted based on in vitro studies and illustrate the importance for expanding studies of EDRF to in vivo and ex vivo models.

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Is nitric oxide the only endothelium-derived relaxing factor in canine femoral veins?

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1989.257.6.h1910 ◽

1989 ◽

Vol 257 (6) ◽

pp. H1910-H1916 ◽

Cited By ~ 2

Author(s):

V. M. Miller ◽

P. M. Vanhoutte

Keyword(s):

Nitric Oxide ◽

Methylene Blue ◽

Superoxide Dismutase ◽

Sodium Nitroprusside ◽

Femoral Vein ◽

Pulmonary Veins ◽

Chemical Properties ◽

Relaxing Factor ◽

Endothelium Derived Relaxing Factor ◽

Ly 83583

Nitric oxide may be an endothelium-derived relaxing factor in systemic arteries and pulmonary veins. The endothelium-derived relaxing factor of systemic veins has not been characterized. Experiments were designed to determine whether the endothelium-derived relaxing factor of systemic veins shared chemical properties and mechanisms of action with nitric oxide. Rings of the canine femoral vein with and without endothelium were suspended in organ chambers for the measurement of isometric force. In rings without endothelium, relaxations to nitric oxide were augmented by superoxide dismutase plus catalase and were inhibited by hemoglobin, methylene blue, and LY 83583. The endothelium-dependent relaxations to acetylcholine and A23187 were not augmented by superoxide dismutase plus catalase but were inhibited by hemoglobin and only moderately reduced by either methylene blue or LY 83583. Relaxations to sodium nitroprusside were not inhibited by methylene blue and LY 83583. Relaxations to sodium nitroprusside were inhibited by ouabain and K+-free solution; those to nitric oxide were not. These results indicate that although the endothelium-derived relaxing factor released from canine systemic veins shares some chemical properties with nitric oxide, the mechanism by which relaxations are induced by the two differ. A factor dissimilar to nitric oxide but acting like sodium nitroprusside may be released by the endothelium of canine systemic veins.

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Melatonin potentiates contractile responses to serotonin in isolated porcine coronary arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.280.1.h76 ◽

2001 ◽

Vol 280 (1) ◽

pp. H76-H82 ◽

Cited By ~ 20

Author(s):

Qiong Yang ◽

Elizabeth Scalbert ◽

Philippe Delagrange ◽

Paul M. Vanhoutte ◽

Stephen T. O'Rourke

Keyword(s):

Nitric Oxide ◽

Methylene Blue ◽

Smooth Muscle ◽

Coronary Arteries ◽

Isometric Tension ◽

Maximal Response ◽

Melatonin Receptor ◽

Vasomotor Tone ◽

Vasoconstrictor Response ◽

Coronary Vasomotor Tone

The present study was designed to determine the effects of melatonin on coronary vasomotor tone. Porcine coronary arteries were suspended in organ chambers for isometric tension recording. Melatonin (10−10-10−5 M) itself caused neither contraction nor relaxation of the tissues. Serotonin (10−9-10−5 M) caused concentration-dependent contractions of coronary arteries, and in the presence of melatonin (10−7 M) the maximal response to serotonin was increased in rings with but not without endothelium. In contrast, melatonin had no effect on contractions produced by the thromboxane A2 analog U-46619 (10−10-10−7 M). The melatonin-receptor antagonist S-20928 (10−6 M) abolished the potentiating effect of melatonin on serotonin-induced contractions in endothelium-intact coronary arteries, as did treatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10−5 M), methylene blue (10−5 M), or NG -nitro-l-arginine (3 × 10−5 M). In tissues contracted with U-46619, serotonin caused endothelium-dependent relaxations that were inhibited by melatonin (10−7 M). Melatonin also inhibited coronary artery relaxation induced by sodium nitroprusside (10−9-10−5 M) but not by isoproterenol (10−9-10−5 M). These results support the hypothesis that melatonin, by inhibiting the action of nitric oxide on coronary vascular smooth muscle, selectively potentiates the vasoconstrictor response to serotonin in coronary arteries with endothelium.

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Simvastatin Restores Ischemic Preconditioning in the Presence of Hyperglycemia through a Nitric Oxide–mediated Mechanism

Anesthesiology ◽

10.1097/aln.0b013e3181672590 ◽

2008 ◽

Vol 108 (4) ◽

pp. 634-642 ◽

Cited By ~ 22

Author(s):

Weidong Gu ◽

Franz Kehl ◽

John G. Krolikowski ◽

Paul S. Pagel ◽

David C. Warltier ◽

...

Keyword(s):

Nitric Oxide ◽

Cardiovascular Risk ◽

Methyl Ester ◽

Infarct Size ◽

Ischemic Preconditioning ◽

Myocardial Infarct ◽

Coronary Artery Occlusion ◽

Myocardial Infarct Size ◽

Protective Effects ◽

Cardioprotective Effects

Background A growing body of evidence indicates that statins decrease perioperative cardiovascular risk and that these drugs may be particularly efficacious in diabetes. Diabetes and hyperglycemia abolish the cardioprotective effects of ischemic preconditioning (IPC). The authors tested the hypothesis that simvastatin restores the beneficial effects of IPC during hyperglycemia through a nitric oxide-mediated mechanism. Methods Myocardial infarct size was measured in dogs (n = 76) subjected to coronary artery occlusion and reperfusion in the presence or absence of hyperglycemia (300 mg/dl) with or without IPC in separate groups. Additional dogs received simvastatin (20 mg orally daily for 3 days) in the presence or absence of IPC and hyperglycemia. Other dogs were pretreated with N-nitro-l-arginine methyl ester (30 mg intracoronary) with or without IPC, hyperglycemia, and simvastatin. Results Ischemic preconditioning significantly (P < 0.05) reduced infarct size (n = 7, 7 +/- 2%) as compared with control (n = 7, 29 +/- 3%). Hyperglycemia (n = 7), simvastatin (n = 7), N-nitro-l-arginine methyl ester alone (n = 7), and simvastatin with hyperglycemia (n = 6) did not alter infarct size. Hyperglycemia (n = 7, 24 +/- 2%), but not N-nitro-l-arginine methyl ester (n = 5, 10 +/- 1%), blocked the protective effects of IPC. Simvastatin restored the protective effects of IPC in the presence of hyperglycemia (n = 7, 14 +/- 1%), and this beneficial action was blocked by N-nitro-l-arginine methyl ester (n = 7, 29 +/- 4%). Conclusions The results indicate that simvastatin restored the cardioprotective effects of IPC during hyperglycemia by nitric oxide-mediated signaling. The results also suggest that enhanced cardioprotective signaling could be a mechanism for statin-induced decreases in perioperative cardiovascular risk.

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Methylene blue inhibits hippocampal nitric oxide synthase activity in vivo

Brain Research ◽

10.1016/s0006-8993(99)01253-6 ◽

1999 ◽

Vol 826 (2) ◽

pp. 303-305 ◽

Cited By ~ 42

Author(s):

Vallo Volke ◽

Gregers Wegener ◽

Eero Vasar ◽

Raben Rosenberg

Keyword(s):

Nitric Oxide ◽

Methylene Blue ◽

Nitric Oxide Synthase ◽

Oxide Synthase ◽

Nitric Oxide Synthase Activity

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Modulation of vasoactive intestinal peptide pulmonary relaxation by NO in tracheally superfused guinea pig lungs

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1993.265.4.l410 ◽

1993 ◽

Vol 265 (4) ◽

pp. L410-L415 ◽

Cited By ~ 6

Author(s):

C. M. Lilly ◽

J. S. Stamler ◽

B. Gaston ◽

C. Meckel ◽

J. Loscalzo ◽

...

Keyword(s):

Nitric Oxide ◽

Methylene Blue ◽

Confidence Interval ◽

Guinea Pig ◽

Vasoactive Intestinal Peptide ◽

Inhibitory Effect ◽

Lung Perfusion ◽

Perfusion Fluid ◽

Oxide Synthase ◽

Dependent Mechanism

The mechanism of vasoactive intestinal peptide (VIP)-induced pulmonary relaxation in tracheally perfused guinea pig lungs was defined with the use of inhibitors of nitric oxide synthase (NOS) and by direct measurement of nitric oxide (NO) equivalents recovered from lung perfusion fluid. Lungs treated with 200 microM NG-nitro-L-arginine were resistant to the relaxant effects of VIP in these lungs; the 50% inhibitory dose (ID50) for VIP was 32 nmol/kg (95% confidence interval, 16–79), which was approximately 100-fold greater than the ID50 of control lungs which was 0.39 nmol/kg, (0.16–0.79, P < 0.0001). This inhibitory effect could be overcome with excess L- but not D-arginine. In contrast, VIP-induced relaxation of isolated guinea pig trachea was not modified by inhibitors of NOS. To confirm that VIP infusion resulted in NO generation in whole lungs, we measured NO equivalents in lung effluent by two distinct technologies. We found that VIP injection caused a significant increase in NO equivalents from 0.11 +/- 0.04 microM to 0.78 +/- 0.15 microM (P < 0.05) and that this increase preceded VIP-induced pulmonary relaxation. Lungs pretreated with the putative guanylyl cyclase inhibitor methylene blue were less responsive to VIP [ID50 4.0 nmol/kg (1.5–10), P < 0.005 compared with control lungs], consistent with a physiologically significant guanosine 3',5'-cyclic monophosphate-dependent mechanism. Our data demonstrate that VIP has the capacity to relax whole lungs in part by stimulating the generation of NO.

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Inhibition of vascular nitric oxide-cGMP pathway by plasma from ischemic hindlimb of rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.1.h254 ◽

1995 ◽

Vol 269 (1) ◽

pp. H254-H261 ◽

Cited By ~ 1

Author(s):

J. S. Jin ◽

R. C. Webb ◽

L. G. D'Alecy

Keyword(s):

Nitric Oxide ◽

Methylene Blue ◽

Superoxide Dismutase ◽

Contractile Activity ◽

Femoral Vein ◽

Guanylate Cyclase Activity ◽

Cgmp Pathway ◽

Induced Hypertension ◽

Control Plasma

The hypothesis was tested that plasma from ischemic hindlimbs facilitates hypertension. Ischemia-induced hypertension was generated in rats by infrarenal aortic cross clamping for 5 h after which plasma was obtained from femoral vein blood. In vitro contractile activity of naive aortic rings incubated for 2 h in plasma collected from ischemic rats demonstrated reduced relaxation to acetylcholine and nitroglycerin. Methylene blue (10(-5) M) induced greater contraction in rings incubated in control vs. ischemic plasma, suggesting that endogenous guanylate cyclase activity is decreased by ischemic plasma. However, 8-bromo-guanosine 3',5'-cyclic monophosphate (cGMP) relaxed equally strips incubated in ischemic or control plasma. Acetylcholine-induced nitrite release was significantly lower in ischemic vs. control plasma-incubated strips (8.6 +/- 2.7 vs. 28.2 +/- 2.3 ng/10 mg tissue wt, respectively). The impaired relaxation to acetylcholine in ischemic plasma-incubated rings was significantly increased by L-arginine but not by prior treatment of ischemic plasma with heating or superoxide dismutase and catalase. These findings suggest the impaired relaxation is mediated through inhibition of the nitric oxide-cGMP pathway. Prolonged blunting of vasodilation by ischemic plasma may therefore contribute to maintenance of a sustained vasoconstriction and ischemic hypertension.

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Pharmacological differentiation of epithelium-derived relaxing factor from nitric oxide

Journal of Applied Physiology ◽

10.1152/jappl.1990.69.2.665 ◽

1990 ◽

Vol 69 (2) ◽

pp. 665-670 ◽

Cited By ~ 42

Author(s):

M. Munakata ◽

Y. Masaki ◽

I. Sakuma ◽

H. Ukita ◽

Y. Otsuka ◽

...

Keyword(s):

Nitric Oxide ◽

Methylene Blue ◽

Smooth Muscle ◽

Vascular System ◽

Serosal Side ◽

Epithelial Surface ◽

Relaxing Factor ◽

Complete Relaxation ◽

Osmotic Stimulus ◽

Endothelium Dependent Relaxation

We examined the possibility that nitric oxide is one of the epithelium-derived relaxing factors in guinea pig airways. First we studied whether nitric oxide could relax isolated tracheal strips, and then we examined the effects of known inhibitors of endothelium-dependent relaxation (EDR) in the vascular system [hemoglobin, methylene blue, and NG-monomethyl-L-arginine (L-NMMA)] on epithelium-dependent relaxation (EpDR) induced by hyperosmotic stimuli in perfused whole tracheal preparations. Mannitol (160 mM in Krebs-Henseleit solution) applied to the epithelial surface was used as an osmotic stimulus to induce EpDR after carbachol-induced contraction (2 microM, serosal side). Nitric oxide produced concentration-dependent and complete relaxation of epithelium-denuded tracheal strips. Preincubation of the whole trachea with hemoglobin significantly inhibited osmotic-induced EpDR (P less than 0.05), but preincubation with methylene blue and L-NMMA did not. Hemoglobin introduced into the epithelial side after EpDR induced by hyperosmotic stimuli reversed relaxation, but methylene blue and L-NMMA did not. These results suggest that, although EpDR and vascular EDR have some pharmacological similarities and nitric oxide can relax airway smooth muscle, nitric oxide is not responsible for osmotic-induced EpDR.

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