Chronic therapy with an ETA/B receptor antagonist in conscious dogs duringprogression of congestive heart failure - Intracellular Ca2+ regulation and nitric oxide mediated coronary relaxation

Background: Although it is known that endothelin (ET-1) is elevated in hear t failure (HF), it remains unclear if chronic ETA/B receptor antagonism aff ects the progression of HF, particularly by affecting coronary vasoactivity and left ventricular (LV) diastolic function. Methods: We examined the eff ects of an ETA/B receptor antagonist, L-753,037 (oral bid for 6 weeks, n=7) , and vehicle (n=8) in conscious dogs with previously implanted aortic, cor onary sinus and left atrial catheters, LV pressure gauge, aortic flow probe , LV dimension crystals and pacers. Results: Baseline hemodynamics were sim ilar in the two groups. During the development of rapid pacing-induced HF, treatment with the ETA/B antagonist significantly reduced total peripheral resistance and increased cardiac output compared to vehicle. After 2 weeks of paring, LV diastolic function (tau) was improved (P<0.05) in the ETA/B a ntagonist group (+6+/-2 ms) compared to the vehicle group (+12+/-2 ms). In addition, ETA/B antagonist treatment attenuated the increase in mean left a trial pressure and LV end-diastolic pressure that occurred during heart fai lure in vehicle-treated animals. However, LV systolic function (LV dP/dt, f ractional shortening and Vcfc) neither at rest nor in response to dobutamin e was altered by ETA/B antagonist treatment. Also, ETA/B antagonist treatme nt did not affect the progressive increases in LV dimension. After 6 weeks of pacing, maximal Ca2+ transport in isolated cardiac sarcoplasmic reticulu m (SR) was reduced (P<0.02) in the vehicle-treated compared to the ETA/B an tagonist-treated dogs (1.34+/-0.09 vs. 1.60+/-0.06 mu mol/mg/min, respectiv ely;). The improvement in SR function in the ETA/B antagonist-treated dogs was associated with a significant attenuation of the reduction in protein e xpression of SERCA2a and calsequestrin observed in the vehicle-treated dogs . Coronary arteries isolated from the dogs treated with the ETA/B antagonis t exhibited enhanced (P<0.01) coronary endothelium-dependent relaxation com pared to the vehicle group, while coronary responses to an NO donor were id entical in the two groups. Plasma NO levels in the coronary sinus during th e late stage of I-TT; were higher (P<0.05) in the ETA/B antagonist group (4 0+/-2 muM) compared to the vehicle group (18+/-2 muM). Conclusions: We conc lude that in conscious dogs during the development of HF induced by rapid p acing, chronic inhibition of ETA/B receptors does not affect resting myocar dial contractile function nor reserve, but reduces vascular resistance and improves LV diastolic function. After 6 weeks of pacing, the reduction in i ntracellular Ca2+ regulation by the SR is also attenuated, and endothelium- dependent coronary relaxation is improved, which appears to be related to t he preservation of coronary NO levels. (C) 2000 Elsevier Science B.V. All r ights reserved.