Jpn. J. Pharmacol. 85 (3), 313-321 (2001)

Blood Pressure and Heart Rate Are Increased by AF-DX 116, a Selective M2 Antagonist, in Autonomic Imbalanced and Hypotensive Rats Caused by Repeated Cold Stress

Taeko Hata1,*, Eiji Itoh1, Yoshinori Funakami1, Katsushi Ishida1 and Shuji Uchida2

1Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan
2Kawanishi Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 3-10-1 Yatoi, Kawanishi 666-0131, Japan
*Corresponding author. FAX: +81-6-6721-2353

Abstract: Rats exposed to SART (specific alternation of rhythm in temperature) stress, which are ideal animal models for vagotonia-type dysautonomia, show various changes in cardiac and circulatory systems. In this study, attention was directed to cholinergic function in the SART-stressed rat heart and the effects of AF-DX 116, a specific muscarinic M2 antagonist, on blood pressure and heart rate. The results were compared with those obtained for atropine and pirenzepine. In SART-stressed rats, systolic and diastolic blood pressures (SBP and DBP) were lower than in unstressed rats. Oral AF-DX 116 resulted in greater elevation of DBP than SBP in unstressed rats. In stressed rats, greater and more prolonged elevation of SBP than in unstressed rats was noted, particularly at higher doses. A dose-dependent SBP change in stressed rats, caused by intravenous AF-DX 116, was shifted upward in parallel with that in unstressed groups, unlike with oral administration. The positive chronotropic effect of this drug was smaller in stressed rats than in unstressed rats, in contrast to the pressor effect. SART-stressed rats may thus have an enhanced sympathetic tone in the heart, as well as changes in muscarinic M2 receptors at sympathetic nerve endings and at the heart muscle. The effects of AF-DX 116 on blood pressure and heart rate thus may arise from peripheral action and AF-DX 116 may be useful for treating hypotension related to autonomic imbalance of the vagotonia type.

Keywords: Stress, Blood pressure, AF-DX 116, Hypotension, M2 antagonist

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