Effects of a sinus node inhibitor on the normal and failing rabbit heart.
The effects on cardiac function of slowed frequency produced by a sinus node inhibitor (zatebradine, or UL-FS 49) were studied in the conscious rabbit under control conditions (n = 16) and after heart failure was produced by rapid atrial pacing for an average of 18.5 days (n = 8). Echocardiography was used to verify severe left ventricular (LV) dysfunction, and high-fidelity micromanometry and cardiac output measurements (Doppler echo) were performed. Echocardiographic fractional shortening was 40.3 +/- 4.1 % (SD) in controls; in heart failure it was 18.0 +/- 1.6 %, and the LV was enlarged. In controls, as heart rate (HR) was decreased from 279 beats per minute (bpm) by incremental doses of zatebradine (up to 0.75 mg/kg), maximal changes occurred when the heart reached 218 bpm with a maximum decrease of the first derivative of LV pressure (LV dP/dtmax) of 15.9 %; LV enddiastolic pressure (EDP) increased from 4.3 to 8.4 mmHg along with a significant decrease in cardiac index (CI) of 15.2 %, while LV systolic pressure (SP) was stable. In heart failure, LV dP/dtmax and CI were markedly reduced compared to controls and with reduction of HR from 257 to 221 bpm LV dP/dtmax was unchanged, LVEDP increased slightly (NS), LVSP was unchanged and CI fell by 13.5 % at the highest dose. In subgroups (control n = 9, failure n = 6), in order to eliminate the hemodynamic effects of cardiac slowing by zatebradine the sinus rate present before zatebradine was matched by atrial pacing; this procedure eliminated all hemodynamic abnormalities accompanying cardiac slowing in both groups. In conclusion, slowed HR due to a sinus node inhibitor was well tolerated in severe heart failure, and all negative hemodynamic responses in both controls and in heart failure were due entirely to a negative forcefrequency effect, without a direct depressant action of zatebradine on the myocardium.
Ryu
K H
KH
Department of Medicine, University of California San Diego, La Jolla 92093-0613, USA.
Tanaka
N
N
Ross
J
J
D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy*; D001552:Benzazepines / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004452:Echocardiography / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D011817:Rabbits; D012849:Sinoatrial Node / Q000503:physiopathology
D001552:Benzazepines; D002316:Cardiotonic Agents; C043636:zatebradine