Coadministration of carvedilol attenuates nitrate tolerance by preventing cytochrome p450 depletion.
BACKGROUND
Long-term administration of nitroglycerin (NTG) causes tolerance secondary to increased vascular formation of reactive oxygen species. Carvedilol, which has potent antioxidant activity in addition to functioning as an adrenergic blocker, prevents nitrate tolerance by a still to be elucidated mechanism. The present study investigated how carvedilol attenuates nitrate tolerance, particularly with reference to cytochrome P450 (CYP), an enzyme involved in the development of tolerance.


RESULTS
Male Wistar rats were subjected to 48-h continuous infusion of NTG alone (0.5 mg/h) or NTG with concomitant carvedilol (20 or 100 microg/h), and then compared with vehicle-treated rats (4 groups; n=6 in each group). Following the continuous administration, nitrate tolerance, assessed by bolus NTG injections, was hemodynamically prevented by coadministration of carvedilol. Levels of CYP1A1/1A2, superoxide production, and phosphorylated vasodilator-stimulated phosphoprotein at serine 239 (P-VASP) were examined in the aortic wall and heart tissue. When NTG alone was continuously administered, vascular superoxide was produced, there was a decrease in the cardiac CYP1A1/1A2 level, and depletion of P-VASP. However, each of these changes induced by continuous NTG administration was significantly attenuated by coadministration of carvedilol and the extent of attenuation was more pronounced at the higher dose (100 microg/h).


CONCLUSIONS
Coadministration of carvedilol attenuates nitrate tolerance through maintenance of NO/cGMP pathway activity by preventing free radical generation and CYP depletion.
Nakahira
Atsushi
A
Department of Cardiovascular Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan.
Minamiyama
Yukiko
Y
Takemura
Shigekazu
S
Hirai
Hidekazu
H
Sasaki
Yasuyuki
Y
Okada
Shigeru
S
Funae
Yoshihiko
Y
Suehiro
Shigefumi
S
D000818:Animals; D002227:Carbazoles / Q000008:administration & dosage* / Q000494:pharmacology; D000077261:Carvedilol; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000187:drug effects*; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D005609:Free Radicals / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D005996:Nitroglycerin / Q000008:administration & dosage* / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D011412:Propanolamines / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D013481:Superoxides; D000098662:Vasodilator-Stimulated Phosphoprotein
D002227:Carbazoles; D015815:Cell Adhesion Molecules; D005609:Free Radicals; D008840:Microfilament Proteins; D010750:Phosphoproteins; D011412:Propanolamines; D000098662:Vasodilator-Stimulated Phosphoprotein; D000077261:Carvedilol; D013481:Superoxides; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; D005996:Nitroglycerin; D006152:Cyclic GMP