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(Circulation Research. 2006;99:767.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Sustained Elevation of Serum Cortisol Level Causes Sensitization of Coronary Vasoconstricting Responses in Pigs In Vivo

A Possible Link Between Stress and Coronary Vasospasm

Takatoshi Hizume, Keiko Morikawa, Aya Takaki, Kohtaro Abe, Kenji Sunagawa, Mutsuki Amano, Kozo Kaibuchi, Chiharu Kubo, Hiroaki Shimokawa

From the Departments of Cardiovascular Medicine (T.H., K.M., A.T., K.A., K.S., H.S.) and Psychosomatic Medicine (T.H., C.K.), Kyushu University Graduate School of Medical Sciences, Fukuoka; Department of Cell Pharmacology (M.A., K.K.), Nagoya University Graduate School of Medicine; Department of Cardiovascular Medicine (A.T., H.S.), Tohoku University Graduate School of Medicine, Sendai; and Japan Science and Technology Agency (H.S.), Core Research for Evolutional Science and Technology, Tokyo.

Correspondence to Hiroaki Shimokawa, MD, PhD, Professor and Chairman, Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. E-mail shimo{at}cardio.med.tohoku.ac.jp

Vasospastic angina is induced by stress, for which cortisol secreted by activated hypothalamic/pituitary/adrenal axis may play an important role. However, direct evidence for this notion is still lacking. In this study, we examined whether sustained elevation of serum cortisol level sensitizes coronary vasoconstricting responses in pigs in vivo and, if so, whether Rho-kinase, which we found is a key molecule of coronary vasospasm, is involved. Oral administration of cortisol (20 mg/kg per day) increased its serum level to that seen in restraint stress in pigs. Thus, we examined coronary vasomotor responses in the following 4 groups: (1) control (without cortisol); (2) cortisol (20 mg/kg per day, PO) for 9 days; (3) cortisol plus RU38486 (a glucocorticoids receptor antagonist, 10 mg/kg per day, PO) for 9 days; and (4) cortisol for 9 days followed by 6-week withdrawal. Coronary angiography showed that intracoronary serotonin caused coronary hyperconstriction and reduction in coronary blood flow associated with ischemic ECG changes (coronary vasospasm) in only the cortisol group. All of these responses were abolished by hydroxyfasudil, a specific Rho-kinase inhibitor, in vivo. Organ chamber experiments demonstrated that serotonin concentration-dependently caused hypercontractions of coronary vascular smooth muscle associated with Rho-kinase activation (as evidenced by the enhanced phosphorylation of myosin binding subunit, a substrate of Rho-kinase) in only the cortisol group. All of these responses were again inhibited by hydroxyfasudil in vitro. These results indicate that sustained elevation of serum cortisol level sensitizes coronary vasoconstricting responses through Rho-kinase activation, suggesting the link between stress and coronary vasospasm.

Key Words: Rho-kinase • coronary vasospasm • cortisol • myocardial ischemia • stress

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