Chronic protection against ischemia and reperfusion-induced endothelial dysfunction during therapy with different organic nitrates.
BACKGROUND
Ischemic and pharmacologic preconditioning have great clinical potential, but it remains unclear whether their effects can be maintained over time during repeated exposure.We have previously demonstrated that the acute protective effect of nitroglycerin (GTN) is attenuated during repeated daily administration. Pentaerythrityl tetranitrate (PETN) is an organic nitrate with different hemodynamic and biochemical properties. The purpose of the current experiment was to study the preconditioning-like effects of PETN and GTN during repeated daily exposure.


RESULTS
In a randomized, investigator-blind parallel trial, 30 healthy (age 25-32) volunteers were randomized to receive (1) transdermal GTN (0.6 mg/h) administered for 2 h a day for 6 days; (2) oral PETN (80 mg) once a day for 6 days; or (3) no therapy. One week later, endothelium-dependent flow-mediated dilation was assessed before and after exposure to ischemia and reperfusion (IR). IR caused a significant blunting of the endothelium-dependent relaxation in the control group (FMD before IR: 5.8 ± 2.1%; after IR 1.0 ± 2.1%; P < 0.01). Daily, 2-h exposure to GTN partially prevented IR-induced endothelial dysfunction (FMD before IR: 7.7 ± 2.4%; after IR 4.3 ± 3.0%; P < 0.01 compared to before IR). In contrast, daily PETN administration afforded greater protection from IR-induced endothelial injury (FMD before IR: 7.9 ± 1.7%; after IR 6.4 ± 5.3%, P = ns; P < 0.05 ANOVA across groups). In vitro, incubation of human endothelial cells with GTN (but not PETN) was associated with inhibition (P < 0.01) of aldehyde dehydrogenase, an enzyme that is important for both nitrate biotransformation and ischemic preconditioning.


CONCLUSIONS
We previously showed that upon repeated administration, the preconditioning-like effects of GTN are attenuated. The present data demonstrate a gradient in the extent of protection afforded by the two nitrates, suggesting that PETN-induced preconditioning is maintained after prolonged administration in a human in vivo model of endothelial dysfunction induced by ischemia. Using isolated human endothelial cells, we propose a mechanistic explanation for this observation based on differential effects of GTN versus PETN on the activity of mitochondrial aldehyde dehydrogenase.
Department of Clinical Medicine and Immunological Sciences, University of Siena, Siena, Italy.
Monica
M
Lisi
Matthias
M
Oelze
Saverio
S
Dragoni
Andrew
A
Liuni
Sebastian
S
Steven
Mary-Clare
MC
Luca
Dirk
D
Stalleicken
Thomas
T
Münzel
Franco
F
Laghi-Pasini
Andreas
A
Daiber
John D
JD
Parker
Tommaso
T
Gori
D000328:Adult; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000704:Analysis of Variance; D002478:Cells, Cultured; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D006801:Humans; D019194:Ischemic Preconditioning / Q000379:methods*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology*; D010417:Pentaerythritol Tetranitrate / Q000008:administration & dosage / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D016037:Single-Blind Method; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology
D014665:Vasodilator Agents; D010417:Pentaerythritol Tetranitrate; D000444:Aldehyde Dehydrogenase; D005996:Nitroglycerin