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CLINICAL STUDIES

Preventive effects of carvedilol on nitrate tolerance—a randomized, double-blind, placebo-controlled comparative study between carvedilol and arotinolol

Hideki Watanabe, MD^*, Masaaki Kakihana, MD, Sadanori Ohtsuka, MD and Yasuro Sugishita, MD, FACC

^* Department of Cardiology, KINU Medical Association Hospital Mitsukaido, Ibaraki, Japan
Ibaraki Prefectural University of Health Sciences, Ami, Ibaraki, Japan
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

Manuscript received November 24, 1997; revised manuscript received June 8, 1998, accepted July 17, 1998.

Address for correspondence: Hideki Watanabe, Department of Cardiology, KINU Medical Association Hospital, 13 - 3 Araigi-cho, Mitsukaido City, Ibaraki 303-0016, Japan
wata-h{at}xa2.so-net.ne.jp

Objectives. This study was designed to compare the preventive effect of nitrate tolerance between carvedilol with antioxidant properties and arotinolol without antioxidant properties.

Background. The attenuation of cyclic guanosine monophosphate (cGMP) production due to inactivation of guanylate cyclase by increased superoxide has been reported as a mechanism of nitrate tolerance. Carvedilol has been known to combine alpha- and beta-blockade with antioxidant properties.

Methods. To evaluate the preventive effect of nitrate tolerance, 24 patients with untreated hypertension were randomized to receive either carvedilol (10 mg twice a day [carvedilol group, n = 8]), arotinolol (10 mg twice a day [arotinolol group, n = 8]), or placebo (placebo group, n = 8). Vasodilatory response to nitroglycerin (NTG) was assessed with forearm plethysmography by measuring the change in forearm blood flow (FBF) before and 5 min after sublingual administration of 0.3 mg NTG, and at the same time blood samples were taken from veins on the opposite side to measure platelet cGMP. Plethysmography and blood sampling were obtained serially at baseline (day 0), 3 days after carvedilol, arotinolol or placebo administration (day 3) and 3 days after application of a 20 mg/24 h NTG tape concomitantly with carvedilol, arotinolol or placebo (day 6).

Results. There was no significant difference in the response of FBF (%FBF) and cGMP (%cGMP) to sublingual administration of NTG on days 0 and 3 among the three groups. On day 6, %FBF and %cGMP were significantly lower in the arotinolol group and the placebo group than days 0 and 3, but these parameters in the carvedilol group were maintained.

Conclusions. The results indicated that carvedilol with antioxidant properties may prevent the development of nitrate tolerance during continuous therapy with NTG compared with arotinolol without antioxidant properties.

Abbreviations and Acronyms   cGMP = cyclic guanosine monophosphate   FBF = forearm blood flow   NTG = nitroglycerin

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