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Different angiotensin II-forming pathways in human and rat vascular tissues

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Abstract

We studied the angiotensin II-forming pathways in extracts from human and rat vascular tissues. In the extract from human artery, angiotensin I mainly converted to two products, angiotensin-(1–9) and angiotensin II, while in the extract from rat artery, the major angiotensin I products were angiotensin II and angiotensin-(5–10). The concentrations of angiotensin II and angiotensin-(1–9) generated in the human extract (1 mg protein/ml) after incubation for 30 min were 3.2 and 2.5 nmol, respectively, and that of angiotensin II and angiotensin-(5–10) generated in the rat extract (1 mg protein/ml) were 0.28 and 2.3 nmol, respectively. In the extract from human vascular tissues, the angiotensin II formation was inhibited by 8% with lisinopril and by 95% with chymostatin. The other product, angiotensin-(1–9) was inhibited completely by carboxypeptidase inhibitor. In the extract from rat vascular tissues, the angiotensin II formation was suppressed to 4% by lisinopril, but not by chymostatin. The angiotensin-(5–10) formation was completely inhibited by chymostatin. These findings suggest clearly that human vascular tissues contain two angiotensin II-forming enzymes, angiotensin-converting enzyme and chymase, but rat vascular tissues have no chymase-dependent angiotensin II-forming pathway.

Introduction

Angiotensin II plays an important role in the regulation of vascular homeostasis. It is known that angiotensin II is generated from angiotensin I by angiotensin-converting enzyme. However, in human vascular tissues, an alternative angiotensin II-forming enzyme was identified as chymase [1], and the possible roles of two angiotensin II-forming enzymes, angiotensin-converting enzyme and chymase, in human vascular tissues have been reported [2], [3]. In isolated human artery, angiotensin I-dependent vascular contractile response was partially suppressed by captopril, an angiotensin-converting enzyme inhibitor, but the remainder was blocked by chymostatin, a chymase inhibitor [2]. These findings suggest that chymase in human vascular tissue plays a functional role in converting angiotensin I to angiotensin II. On the other hand, in isolated rat artery, angiotensin I-induced vascular contractile responses were completely inhibited by an angiotensin-converting enzyme inhibitor [2], suggesting that rat vascular tissues contain angiotensin-converting enzyme only as an angiotensin II-forming enzyme. However, a recent paper reported that angiotensin II-forming enzyme in extract from rat vascular tissues was mainly chymase, but not angiotensin-converting enzyme [4].

In the present study, we wanted to clarify whether or not extract from human and rat vascular tissues has chymase-dependent angiotensin II-forming pathway.

Section snippets

Vascular tissue

Human gastroepiploic arteries were isolated from the surgically resected stomachs of four male and two female patients aged 34–58 years (average age 43.8 years). These patients suffered from gastric cancer or ulcers, but not hypertension or diabetic vasculopathy. The protocol of this study complies with the principles of the Helsinki Declaration. A total of six male Sprague–Dawley rats weighing 200–300 g were purchased from Japan SLC (Shizuoka, Japan). The experimental procedures for animals

Results

Fig. 1 shows the degradation of 4 mmol/l angiotensin I after incubation of the extract (1 mg protein/ml) from rat and human vascular tissues for 30 min. In the extract from human vessels, the major angiotensin I products constituted two peaks, one eluting at 10.1 min and the other eluting at 23.3 min (Fig. 1A). The angiotensin I substrate eluted at 36.1 min. The peaks at 10.1 and 23.3 min were identified as angiotensin-(1–9) and angiotensin II by amino-terminal sequence analysis. In the extract

Discussion

In the present study, angiotensin I in the extract from human vascular tissues was primarily converted to angiotensin II and angiotensin-(1–9). The angiotensin II formation was inhibited by 8% with lisinopril and by 95% with chymostatin. These findings suggest that angiotensin II formation is predominantly dependent on chymase in the extract from human vascular tissues. On the other hand, the angiotensin-(1–9) formation in the extract from human vascular tissues was completely inhibited by

Acknowledgments

This study was supported in part by Grant-in-Aid for Encouragement of Young Scientists 12770048 and by Grant-in-Aid for Scientific Research (B) 11470027 from the Ministry of Education, Science, Sports and Culture, Japan.

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