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HEART FAILURE

An inhibitor of inducible nitric oxide synthase decreases forearm blood flow in patients with congestive heart failure

Yutaka Ishibashi, MD^*,*, Toshio Shimada, MD^*, Yo Murakami, MD^*, Nobuyuki Takahashi, MD^*, Takeshi Sakane, MD^*, Takashi Sugamori, MD^*, Shuzo Ohata, MD^*, Shin-ichi Inoue, MD^*, Yoko Ohta, MD^*, Ko Nakamura, MD^*, Hiromi Shimizu, MD^*, Harumi Katoh, MD^* and Michio Hashimoto, MD

^* Fourth Department of Internal Medicine, Izumo, Japan
Department of Physiology, Shimane Medical University, Izumo, Japan

Manuscript received February 12, 2001; revised manuscript received June 18, 2001, accepted July 12, 2001.

^* Reprint requests and correspondence: Dr. Yutaka Ishibashi, Fourth Department of Internal Medicine, Shimane Medical University, 89-1 Enyacho, Izumo City, 693-8501, Japan
yuyu{at}shimane-med.ac.jp

OBJECTIVES

The functional activation of inducible nitric oxide synthase (iNOS) was evaluated as a source of nitric oxide (NO) in the forearm of patients with heart failure.

BACKGROUND

Although endogenous NO is normally produced by constitutive NO synthase (cNOS) in patients with congestive heart failure (CHF), expression of iNOS provides an additional source of NO. However, there are no in vivo studies showing functional activation of iNOS in humans.

METHODS

A nonselective NOS inhibitor, N^G-monomethyl-L-arginine (L-NMMA), and a selective inhibitor of iNOS, aminoguanidine, were administered intra-arterially in graded doses into the brachial arteries of 13 patients with CHF and 10 normal control subjects. Forearm blood flow (FBF) was measured simultaneously in the infused and noninfused arms by plethysmography. Arterial and venous plasma concentrations of nitrite/nitrate (NOx) were measured at baseline and at the highest dose of each drug.

RESULTS

L-NMMA significantly reduced the FBF ratio between the infused and noninfused arms in both the control and patient groups (35 ± 12% and 34 ± 10%, respectively; both p < 0.001). Aminoguanidine at the same concentration significantly reduced the ratio in the patient group (15 ± 9%, p < 0.01), with no change in the control group. The arterial NOx concentration was not affected by either drug; however, venous NOx concentrations were significantly decreased in both the control and patient groups by L-NMMA (18 ± 5% and 18 ± 17%, respectively; both p < 0.05) and in the patient group only by aminoguanidine (7 ± 6%, p < 0.05).

CONCLUSIONS

These findings suggest that NO production in the forearms of patients with CHF is induced partly by iNOS activation, whereas in normal subjects, it can be ascribed to cNOS activation.

Abbreviations and Acronyms   ANP = atrial natriuretic peptide   BNP = B-type natriuretic peptide   CHF = congestive heart failure   cNOS = constitutive nitric oxide synthase   FBF = forearm blood flow   iNOS = inducible nitric oxide synthase   L-NAME = NG-nitro-L-arginine methyl ester   L-NMMA = NG-monomethyl-L-arginine   NO = nitric oxide   NOS = nitric oxide synthase   Nox = nitrite/nitrate   TNF = tumor necrosis factor

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