INT34742

Context Info Confidence 0.67 First Reported 1986 Last Reported 2010 Negated 1 Speculated 1 Reported most in Body Documents 44 Total Number 45 Disease Relevance 6.83 Pain Relevance 5.65

signal transduction (Gnat3) GTPase activity (Gnat3) cytoplasm (Gnat3) signal transducer activity (Gnat3)

Anatomy Link Frequency plasma 3 Sublingual 2 coronary artery 1 Gnat3 (Mus musculus)

Pain Link Frequency Relevance Heat transdermal 18 100.00 headache 27 99.96 Migraine 11 99.44 tolerance 266 98.92 Angina 48 98.56 Bile 22 97.36 addiction 70 93.60 Bioavailability 75 92.96 Osteoarthritis 45 90.64 Piles 3 90.00

Disease Link Frequency Relevance Heat Headache 34 99.96 Pancreatitis 140 99.16 Angina 20 98.56 Cv General 3 Under Development 29 97.32 Coronary Artery Disease 39 96.92 Increased Venous Pressure Under Development 87 94.92 Pressure Volume 2 Under Development 16 92.24 Osteoarthritis 50 90.64 Anorectal Disorders 3 90.00 Hypotension 2 89.48

Sentences Mentioned In

Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

After administration of GTN, SBP was decreased significantly from 157 +/- 25 to 142 +/- 23 mmHg (P < 0.01), while DBP did not change (83 +/- 13 vs 84 +/- 15 mmHg).

Gene_expression (administration) of GTN

1) Confidence 0.67 Published 1993 Journal Angiology Section Abstract Doc Link 8285372 Disease Relevance 0.59 Pain Relevance 0.22

CONCLUSION: Sodium valproate and GTN are well tolerated and provide significant improvement in pain scores as well as in electrophysiological parameters.

Gene_expression (tolerated) of GTN

2) Confidence 0.58 Published 2009 Journal Diabetes Res. Clin. Pract. Section Body Doc Link 19208440 Disease Relevance 0.05 Pain Relevance 0

Sublingual GTN produced effects similar to those with 0.4 and 0.8 mg of GTN spray, but exceeded the response to 0.2 mg of GTN spray.

Gene_expression (produced) of GTN in Sublingual

3) Confidence 0.52 Published 1986 Journal Am. J. Cardiol. Section Abstract Doc Link 3079939 Disease Relevance 0.56 Pain Relevance 0.56

This study evaluated the systemic absorption profile of GTN, and correlation between plasma GTN levels, RAP, haemodynamic variables and side-effects.

Gene_expression (levels) of GTN in plasma

4) Confidence 0.49 Published 2001 Journal Br J Surg Section Abstract Doc Link 11736974 Disease Relevance 0.18 Pain Relevance 0.14

There was no correlation between plasma GTN concentration, RAP, and the onset, duration or intensity of headaches.

Gene_expression (concentration) of GTN in plasma

5) Confidence 0.49 Published 2001 Journal Br J Surg Section Body Doc Link 11736974 Disease Relevance 0 Pain Relevance 0

RESULTS: GTN was detected in the plasma 10 min to 3 h after topical application.

Gene_expression (detected) of GTN in plasma

6) Confidence 0.44 Published 2001 Journal Br J Surg Section Body Doc Link 11736974 Disease Relevance 0 Pain Relevance 0

Adverse effect of using GTN

Gene_expression (using) of GTN

7) Confidence 0.41 Published 2010 Journal BMC Gastroenterol Section Body Doc Link PMC2921391 Disease Relevance 0.52 Pain Relevance 0.26

When just analyzing the effect of sublingual GTN on the incidence of PEP, we revealed a significant difference between the two groups (OR 0.34, 95% CI: 0.16 to 0.75, P = 0.007), but there was no statistical difference found between the two groups when we just analyzed the effect of transdermal GTN on the incidence of PEP (OR 0.64, 95% CI: 0.40 to 1.01, P = 0.05).

Spec (analyzed) Gene_expression (effect) of GTN in sublingual associated with transdermal and pancreatitis

8) Confidence 0.41 Published 2010 Journal BMC Gastroenterol Section Body Doc Link PMC2921391 Disease Relevance 0.62 Pain Relevance 0.17

GTN was consistent in producing headache and migraine that resembled the patients' usual spontaneous migraine.

Gene_expression (producing) of GTN associated with migraine and headache

9) Confidence 0.35 Published 2004 Journal Cephalalgia Section Abstract Doc Link 15377319 Disease Relevance 1.55 Pain Relevance 1.27

Importantly, ALDH2-catalyzed GTN reduction was partly inactivated by preincubation with GTN, suggesting that the inactivation of GTN reduction is also partly irreversible.

Gene_expression (reduction) of GTN

10) Confidence 0.33 Published 2008 Journal The Journal of Biological Chemistry Section Abstract Doc Link PMC2576553 Disease Relevance 0 Pain Relevance 0

To determine the dose of GTN that produces significant anti-anginal effects, symptom limited exercise testing has been undertaken in seven patients with stable angina.

Gene_expression (produces) of GTN associated with angina

11) Confidence 0.31 Published 1987 Journal Eur. Heart J. Section Abstract Doc Link 3115779 Disease Relevance 0.48 Pain Relevance 0.51

Interestingly, inhibition of GTN reduction by ALDH2 also required more than 1000-fold higher concentrations of acetaldehyde than might have been expected (9).

Gene_expression (reduction) of GTN

12) Confidence 0.29 Published 2008 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2576553 Disease Relevance 0 Pain Relevance 0.04

One attractive characteristic of the proposal that mitochondrial ALDH is responsible for GTN biotransformation is the fact that it can accommodate one of the more common explanations for nitrate tolerance in a slightly modified version.

Gene_expression (biotransformation) of GTN associated with tolerance

13) Confidence 0.29 Published 2008 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2576553 Disease Relevance 0.08 Pain Relevance 0.28

SCHEME 1.Irreversible inactivation of ALDH-catalyzed GTN reduction.

Gene_expression (reduction) of GTN

14) Confidence 0.29 Published 2008 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2576553 Disease Relevance 0 Pain Relevance 0

The model correctly predicts that the fraction of ALDH2 that is irreversibly inactivated by GTN in the absence of DTT will depend on the GTN concentration but not on the concentrations of DTT and acetaldehyde applied to reactivate the enzyme.

Gene_expression (concentration) of GTN

15) Confidence 0.29 Published 2008 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2576553 Disease Relevance 0 Pain Relevance 0

Mitochondria (0.8 mg/ml) were preincubated with GTN (100 ?

Gene_expression (preincubated) of GTN

16) Confidence 0.29 Published 2008 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2576553 Disease Relevance 0 Pain Relevance 0

One major unresolved question concerns the identity of the physiological reductant, because ALDH2-catalyzed GTN reduction is supported by the non-physiological thiol dithiothreitol (DTT) but not by glutathione (GSH), the most abundant physiological low-molecular weight thiol.

Gene_expression (reduction) of GTN

17) Confidence 0.29 Published 2008 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2576553 Disease Relevance 0.12 Pain Relevance 0.05

Importantly, ALDH2-catalyzed GTN reduction was partly inactivated by preincubation with GTN, suggesting that the inactivation of GTN reduction is also partly irreversible.

Gene_expression (reduction) of GTN

18) Confidence 0.29 Published 2008 Journal The Journal of Biological Chemistry Section Abstract Doc Link PMC2576553 Disease Relevance 0 Pain Relevance 0

For GTN concentrations in the physiological range (0.01–0.1 ?

Gene_expression (concentrations) of GTN

19) Confidence 0.29 Published 2008 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2576553 Disease Relevance 0 Pain Relevance 0.11

In summary, the present study allows the following conclusions: (i) in the absence of DTT, GTN oxidizes the active site thiol of mitochondrial ALDH resulting in complete inactivation of dehydrogenation, ester hydrolysis, and GTN reduction; (ii) the rate of inactivation is affected by the concentrations of substrate and inhibitor, indicative of competitive binding, but the apparent dissociation constants (in the order of 10-4 m) are much higher than reported Km values for the respective reactions, which suggests that competition takes place outside of the high-affinity binding site; (iii) dehydrogenase activity is only restored to a modest extent by DTT, indicating that a large fraction of inactivation is irreversible; (iv) GTN reduction is irreversibly inactivated in a similar fashion as dehydrogenase activity, suggesting a role for irreversible ALDH2 inactivation in the development of nitrate tolerance.

Gene_expression (reduction) of GTN associated with tolerance

20) Confidence 0.29 Published 2008 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2576553 Disease Relevance 0 Pain Relevance 0.11

General Comments

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