The role of ANG II and endothelin-1 in exercise-induced diastolic dysfunction in heart failure

The diastolic dysfunction present at rest in congestive heart failure (CHF) is exacerbated during exercise (Ex). Increases in circulating ANG II and e ndothelin-1 (ET-1) during Ex may contribute to this response. We assessed t he effect of Ex on circulating plasma levels of ANG II and ET-1 and left ve ntricular (LV) dynamics before and after pacing-induced CHF at rest and dur ing Ex in nine conscious, instrumented dogs. Before CHF, there were modest increases in circulating levels of ANG II (but not ET-1) during Ex. LV dias tolic performance was enhanced during Ex with decreases in the time constan t of LV relaxation (tau), LV end-systolic volume (V-ES), and LV minimum pre ssure with a downward shift of the LV early diastolic portion of the pressu re-volume (P-V) loop. This produced an increase in peak LV filling rate wit hout an increase in mean left atrial (LA) pressure. After CHF, the resting values of ANG II and ET-1 were elevated and increased to very high levels d uring Ex. After CHF, mean LA pressure, tau, and LV minimum pressure were el evated at rest and increased further during Ex. Treatment with L-754,142, a potent ET-1 antagonist, or losartan, an ANG II AT(1)-receptor blocker, dec reased these abnormal Ex responses in CHF more effectively than an equally vasodilatory dose of sodium nitroprusside. Combined treatment with both ANG II- and ET-1-receptor blockers was more effective than either agent alone. We conclude that in CHF, circulating ANG II and ET-1 increase to very high levels during Ex and exacerbate the diastolic dysfunction present at rest.