Chronic infusion of adrenomedullin reduces pulmonary hypertension and lessens right ventricular hypertrophy in rats administered monocrotaline

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Abstract

A novel vasorelaxant peptide, adrenomedullin, its messenger ribonucleic acid (mRNA), and the mRNA for its receptor are highly expressed in the lung, suggesting that adrenomedullin may play a role in the regulation of the pulmonary circulation. We investigated whether the chronic infusion of rat adrenomedullin would affect pulmonary hypertension and right ventricular hypertrophy produced by the administration of monocrotaline. Four-week-old male Wistar rats received a single subcutaneous injection of 60 mg/kg monocrotaline and were then chronically and subcutaneously infused with rat adrenomedullin (PH+AM group, n=8) or saline (PH group, n=10) by an osmotic minipump for a period of 21 days. Plasma levels of adrenomedullin were significantly higher in the PH vs. the control group. The chronic infusion of adrenomedullin in rats with pulmonary hypertension increased the plasma levels of adrenomedullin to a value 94% greater than that of the control group and 55% greater than that of the untreated PH group. Chronic infusion of adrenomedullin significantly lessened the increase in right ventricular systolic pressure and the ratio of right ventricular weight to body weight seen after monocrotaline treatment. Histological examination revealed that adrenomedullin also attenuated the medial thickening of the pulmonary artery. These results suggest that chronic infusion of adrenomedullin attenuates the pulmonary hypertension and right ventricular hypertrophy seen in rats treated with monocrotaline.

Introduction

Adrenomedullin, a potent vasorelaxant peptide, was isolated from pheochromocytoma tissue (Kitamura et al., 1993a). Human adrenomedullin messenger ribonucleic acid (mRNA) is highly expressed in several other normal tissues including lung (Kitamura et al., 1993b). The concentration of adrenomedullin in the lung is several-fold higher than that in the cardiac ventricle and the kidney (Ichiki et al., 1994; Sakata et al., 1994). In addition, binding sites for adrenomedullin are abundant in rat lung (Owji et al., 1995), and the mRNA for the adrenomedullin receptor is highly expressed in lung tissue (Kapas et al., 1995). The presence of adrenomedullin receptors in the lung make it likely that adrenomedullin may act as an autocrine and paracrine factor.

It has been previously reported that adrenomedullin injections decrease pulmonary vascular resistance in a dose-dependent manner (Lippton et al., 1994; DeWitt et al., 1994) under conditions of elevated pulmonary vascular tone (Lippton et al., 1994). With regard to the mechanism for pulmonary vasorelaxation by adrenomedullin, Nossaman et al. (1996)previously reported that the pulmonary vasodilator response to adrenomedullin is dependent on the release of nitric oxide from the endothelium in the rat, but that the response to adrenomedullin is endothelium independent in the pulmonary vascular bed of the cat. In addition, Champion et al. (1997)demonstrated that adrenomedullin dilates the hindlimb vascular bed of the cat by an adenosine 3′,5′-cyclic monophospate-dependent mechanism. Thus, these findings suggest that the mechanisms by which adrenomedullin dilates the vascular bed are not same in different vessels or in different species. However, plasma adrenomedullin levels previously have been reported to be elevated in patients with primary and secondary pulmonary hypertension and to correlate with pulmonary arterial pressure, suggesting the involvement of adrenomedullin in the regulation of the pulmonary circulation (Yoshibayashi et al., 1997; Nishikimi et al., 1997a).

The administration of monocrotaline to rats induces vascular endothelial cell damage, medial thickening of the muscular pulmonary arteries, and neomuscularization of the nonmuscular distal arteries, leading to pulmonary hypertension and right ventricular hypertrophy (Meyrick et al., 1980; Ghodsi and Will, 1981). A previous report demonstrated that the concentrations of adrenomedullin in the right ventricle and plasma, and the expression of adrenomedullin mRNA in the right ventricle were significantly higher in monocrotaline-treated rats than in controls (Shimokubo et al., 1995). While it has been suggested that adrenomedullin could counteract monocrotaline-induced pulmonary hypertension, it has not been investigated whether adrenomedullin can inhibit the progression of pulmonary hypertension and right ventricular hypertrophy in such a model at pathophysiological levels.

The purpose of the present study was to study whether adrenomedullin in pathophysiological concentrations attenuates the development and progression of the cardiopulmonary changes in rats induced by monocrotaline. To accomplish this, we measured plasma adrenomedullin levels in monocrotaline-treated rats, control animals and those given monocrotaline and receiving a chronic infusion of adrenomedullin. We also measured and compared cardiovascular parameters and the degree of medial thickening of the small pulmonary arteries these groups of animals.

Section snippets

Materials and methods

The study was performed in accordance with the guidelines of the Animal Care Committee of the National Cardiovascular Center Research Institute.

Plasma adrenomedullin concentrations

Plasma adrenomedullin levels were significantly higher in the PH group than in the control group (Fig. 1). Chronic infusion of rat adrenomedullin significantly increased the plasma adrenomedullin levels more than those of the control group and the PH group (6.8±1.1 vs. 3.5±0.8 or 4.4±0.6 pmol/l, P<0.001, respectively).

Effects of chronic adrenomedullin infusion on hemodynamics, cardiac hypertrophy, and alteration of lung vascular morphology in monocrotaline-treated rats

There were no significant differences in the heart rate between the three groups at 21 days after injection of monocrotaline (Fig. 2A). Mean arterial pressure in the PH group was

Discussion

To investigate whether chronic infusion of rat adrenomedullin attenuates the progressive pulmonary hypertension, right ventricular hypertrophy and pulmonary arterial medial thickening seen in monocrotaline-treated rats, we measured right ventricular systolic pressure, RV/BW and % wall thickness in these animals and compared these values with those obtained from normal control and monocrotaline-treated control animals. Chronic infusion of adrenomedullin significantly attenuated the increase in

Acknowledgements

This work was supported in part by Special Coordination Funds for Promoting Science and Technology (Encouragement System of COE) from the Science and Technology Agency of Japan, the Ministry of Health and Welfare, and the Human Science Foundation of Japan. We thank Yoko Saito for her technical assistance.

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