INT11196
From wiki-pain
|
|
|
|
|
Sentences Mentioned In
| Key: | Protein | Mutation | Event | Anatomy | Negation | Speculation | Pain term | Disease term |
| Twenty patients with chronic, stable, exercise-induced angina pectoris were studied after receiving lingual sprays that delivered 0.2, 0.4 and 0.8 mg of nitroglycerin (GTN). | |||||||||||||||
| |||||||||||||||
|
| The purpose of this study was to investigate whether pre-treatment with prednisolon could decrease this effect of GTN. | |||||||||||||||
| |||||||||||||||
|
| 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). | |||||||||||||||
| |||||||||||||||
|
The activity in the
absence of DTT corresponded to approximately one turnover (280 nm 1,2-GDN were formed by 332 nm ALDH), in line with the proposal that reduction of GTN results in oxidation of active site cysteine residues. | |||||||||||||||
| |||||||||||||||
|
mol/mg/min before and after enzyme recovery,
respectively; ester hydrolysis: 0.219 ± 0.003 and 0.223 ± 0.004 nmol/mg/min before and after enzyme recovery, respectively), which rules out that partial inactivation of GTN reduction was an artifact. | |||||||||||||||
| |||||||||||||||
|
Because decomposition of GTN by ALDH2 results in oxidation
of the active site thiol that must subsequently be reduced to sustain
catalysis, the proposed involvement of ALDH2 in the bioactivation of GTN
revived the early proposal that ascribed nitrate tolerance to thiol depletion
(34).
| |||||||||||||||
| |||||||||||||||
|
| SCHEME 1.Irreversible inactivation of ALDH-catalyzed GTN reduction. | |||||||||||||||
| |||||||||||||||
|
Importantly, ALDH2-catalyzed GTN
reduction was partly inactivated by preincubation with GTN, suggesting that
the inactivation of GTN reduction is also partly irreversible.
| |||||||||||||||
| |||||||||||||||
|
GTN reduction was determined in the absence or presence
of DTT (pre-column activity). | |||||||||||||||
| |||||||||||||||
|
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. | |||||||||||||||
| |||||||||||||||
|
| SCHEME 1.Irreversible inactivation of ALDH-catalyzed GTN reduction. | |||||||||||||||
| |||||||||||||||
|
We also determined the effect of incubation time in experiments of the type
described in Fig. 5, in which we preincubated the enzyme in the presence and absence of GTN (0.18 mm) and DTT (2 mm) for different lengths of time, and then measured the dehydrogenase activity after 15-fold dilution. | |||||||||||||||
| |||||||||||||||
|
Interestingly, inhibition
of GTN reduction by ALDH2 also required more than 1000-fold higher concentrations of acetaldehyde than might have been expected (9). | |||||||||||||||
| |||||||||||||||
|
A
substantial decrease of the dissociation constant for GTN in the presence of NAD+ seems to be an implausible explanation.4 It is more likely that NAD+ binding exposes a target to GTN that is poorly accessible in the absence of the cofactor. | |||||||||||||||
| |||||||||||||||
|
In the absence of DTT the enzyme turned over only once and
after recovery no more GTN was reduced, in line with the hypothesis that the reaction with GTN results in oxidation of the active site thiol. | |||||||||||||||
| |||||||||||||||
|
A crucial question regarding the physiological significance of irreversible
ALDH2 inactivation concerns the applicability of the observations to GTN reduction. | |||||||||||||||
| |||||||||||||||
|
FIGURE 7.Effect of preincubation of ALDH2 with GTN on the ALDH2-catalyzed
reduction of GTN. | |||||||||||||||
| |||||||||||||||
|
One candidate
inactivating agent is nitroxyl (NO-), which has been proposed to be a product of GTN metabolism (31), and which was reported to cause partially irreversible inhibition of ALDH, presumably by the formation of sulfinamides (32). | |||||||||||||||
| |||||||||||||||
|
The role of impaired GTN
bioactivation depends on the physiologically relevant mechanism of GTN biotransformation. | |||||||||||||||
| |||||||||||||||
|
| Our hypothesis was disproved, as Az did not decrease GTN-induced headache. | |||||||||||||||
| |||||||||||||||
|
General Comments
This test has worked.
