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

Abstract

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 M 2 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 Blood pressure (BP) is related to sympathetic tone and physical and/ or psychological stress (1 -7). In general, stress is thought to induce hypertension in humans and experimental animals. Rats subjected to SART (specific alternation of rhythm in environmental temperature) stress (8) showed hypotension (9) in a manner different from hypertension in animals subjected to other types of stress such as cold and restraint (10 -12).SART stress is induced through sudden drops in environmental temperature and is a type of repeated or intermittent cold stress in rodents. Experimental animals subjected to SART stress are accepted as animal models of vagotoniatype dysautonomia in consideration of the results of Aschner and Mecholyl tests (13). The stressed animals exhibit pathophysiological abnormalities such as an abnormal galvanic skin response (GSR) (8) and electroencephalogram (EEG) (14), hyperalgesia (15), thrombocytopenia (16), as well as hypotension (9). In cardiac and circulatory systems, the animals show tachycardia, short PQ and long QRS intervals and high voltage in R waves on electrocardiograms (ECG) (17), and blood flow either increases or decreases in the arteries (9, 18). In the cholinergic system, a decrease in acetylcholine (ACh) content and an elevation of the synthesis and hydrolysis of ACh in the brain (19) were noted in addition to an increase in ACh content, a decrease in ACh-esterase activity and the number of muscarinic ACh receptors in the small intestine (20).SART-stres...

Effects of Some .BETA.-Adrenoceptor Antagonists on Orthostatic Hypotension in Repeatedly Cold- (SART-) Stressed Rats

“…In the manifestation of severe OH in SARTstressed rats, in particular, along with the already reported association with vagus nerve and M 2 -receptors, 18) changes in sympathetic stimulation to the heart, changes in the sensitivity of b 1 -adrenoceptors in heart and changes in b 2 -adrenoceptors in peripheral blood vessels seem to play roles. In other words, the balance of the autonomic nervous system seems to function poorly in the nervous reflex in head up tilting in SART-stressed rats.…”

“…Basic items had the similar results as in the previous reports. 1,2,15,18,19) Effects of drugs are summarized in Fig. 7 for the discussion.…”

“…1 and Table 1 based on mean blood pressure and heart rate that were mea-sured automatically by Fluclet, were similar to data based on systolic blood pressure obtained in analog processing reported in previous studies. 1,2,18,19) Roles Played by the Autonomic Nervous System on OH Figure 2 shows changes in blood pressure and heart rate in HUT following administration of hexamethonium. In unstressed rats, decreases in blood pressure after standing were greater than those without hexamethonium, the time-related curve moved downward, and the recovery of blood pressure was poor.…”

“…18,19) Effects of hexamethonium, an autonomic ganglion blocker, isoproterenol, a b-adrenoceptor stimulant and badrenoceptor antagonists on OH induced by HUT were studied using the above-described SART-stressed rats. Results of the study were obtained in mean blood pressure measured automatically using an electrocardiogram and blood pressure-waveform recognition frequency change analysis software (Fluclet ® ).…”

Effects of AF-DX116 and Other Muscarinic Receptor Antagonists on Orthostatic Hypotension in Autonomic Imbalanced (SART-Stressed) Rats

“…In addition, our recent studies found that the SART-stressed rats had marked OH, suggesting the rats could be an OH model animal (9). In order to elucidate the mechanism of OH, we investigated the effect of AF-DX116, a selective muscarinic M 2 -receptor antagonist, which has been observed to remarkably improve hypotension in SART-stressed rats (10). Effects of other muscarinic receptor antagonists were investigated and compared with that of AF-DX116.…”