UL-FS 49 (Zatebradine) Does Not Affect Arterial Baroreflex in Conscious Normal or Aortic-Constricted Rats

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Heart-rate reduction is an important element of patient management during cardiac bypass surgery and in therapeutic measures for combating ischemia and relieving pain in patients with angina. UL-FS 49 is a novel bradycardic agent that purportedly acts solely on the sinoatrial node without potentially deleterious effects on arterial pressure and cardiac inotropism. However, little is known about influences of this agent on neuronal tissue and cardiovascular reflexes. Moreover, left ventricular hypertrophy, which often accompanies cardiovascular disease, is known to attenuate the arterial baroreflex and could have effects interactive with those of UL-FS 49. In this study, the effects of UL-FS 49 on the arterial baroreflex were tested in normal rats (N), rats with left ventricular hypertrophy 14 days after abdominal aortic constriction (AC), and sham-operated controls (SH). Arterial baroreflex sensitivity (BRS) was estimated as the slope of the relation between mean arterial pressure (independent variable) and the RR interval (dependent variable). At the time of study, the AC group had significantly greater mean arterial pressure than either SH or N (159 ± 2, 122 ± 3, and 124 ± 3 mm Hg, respectively; mean ± SEM, p < 0.01) and significantly greater left ventricular mass to body mass ratio than did SH (3.73 ± 0.11, 2.33 ± 0.11 mg/g; p < 0.01). As expected, BRS was significantly depressed in AC, compared with either SH or N (0.52 ± 0.16, 1.48 ± 0.12, 1.69 ± 0.25 ms/mm Hg, respectively; p < 0.01). Despite its potent dose-dependent bradycardic effects in all three groups, UL-FS 49 did not affect BRS significantly in any group. These results show that the arterial baroreflex is largely unaffected by UL-FS 49 in both normal rats and rats with systemic hypertension and left ventricular hypertrophy.

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