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Colforsin-induced vasodilation in chronic hypoxic pulmonary hypertension in rats

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Abstract

Purpose

Colforsin, a water-soluble forskolin derivative, directly activates adenylate cyclase and thereby increases the 3′,5′-cyclic adenosine monophosphate (cAMP) level in vascular smooth muscle cells. In this study, we investigated the vasodilatory action of colforsin on structurally remodeled pulmonary arteries from rats with pulmonary hypertension (PH).

Methods

A total of 32 rats were subjected to hypobaric hypoxia (380 mmHg, 10% oxygen) for 10 days to induce chronic hypoxic PH, while 39 rats were kept in room air. Changes in isometric force were recorded in endothelium-intact (+E) and -denuded (−E) pulmonary arteries from the PH and control (non-PH) rats.

Results

Colforsin-induced vasodilation was impaired in both +E and −E arteries from PH rats compared with their respective controls. Endothelial removal did not influence colforsin-induced vasodilation in the arteries from control rats, but attenuated it in arteries from PH rats. The inhibition of nitric oxide (NO) synthase did not influence colforsin-induced vasodilation in +E arteries from controls, but attenuated it in +E arteries from PH rats, shifting its concentration–response curve closer to that of −E arteries from PH rats. Vasodilation induced by 8-bromo-cAMP (a cell-permeable cAMP analog) was also impaired in −E arteries from PH rats, but not in +E arteries from PH rats, compared with their respective controls.

Conclusions

cAMP-mediated vasodilatory responses without β-adrenergic receptor activation are impaired in structurally remodeled pulmonary arteries from PH rats. In these arteries, endothelial cells presumably play a compensatory role against the impaired cAMP-mediated vasodilatory response by releasing NO (and thereby attenuating the impairment). The results suggest that colforsin could be effective in the treatment of PH.

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Acknowledgments

Supported in part by grants (14370484, 16390449) from the Ministry of Education, Science, and Culture of Japan. Dr. Jiang was supported by a FY2002 JSPS (Japan Society for the Promotion of Science) postdoctoral fellowship for foreign researchers.

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Authors and Affiliations

  1. Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, University of Mie, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Ayumu Yokochi, Erquan Zhang, Baohua Jiang & Kazuo Maruyama

  2. Department of Physiology, Faculty of Medicine, University of Mie, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Junko Maruyama

  3. Department of Pediatrics, Faculty of Medicine, University of Mie, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Yoshihide Mitani

  4. Department of Internal Medicine, Nabari City Hospital, 178 Yurigaoka-Nishi-1ban-cho, Nabari, Mie, 518-0481, Japan

    Hiroo Itoh

  5. Faculty of Engineering, Tokyo University of Science, 1-14-6 Kudankita, Chiyoda-ku, Tokyo, 102-0073, Japan

    Chikuma Hamada

Authors
  1. Ayumu Yokochi
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  2. Hiroo Itoh
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  3. Junko Maruyama
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  8. Kazuo Maruyama
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Correspondence to Ayumu Yokochi.

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Yokochi, A., Itoh, H., Maruyama, J. et al. Colforsin-induced vasodilation in chronic hypoxic pulmonary hypertension in rats. J Anesth 24, 432–440 (2010). https://doi.org/10.1007/s00540-010-0912-7

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  • DOI: https://doi.org/10.1007/s00540-010-0912-7

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