Specific endothelin-1 receptor antagonism markedly lowers blood pressure in experimental hypertension but is less effective on blood pressure of healthy animals. This suggests that endothelin-1 plays a role in the pathophysiology of hypertension but contributes to a lesser extent to the maintenance of normal blood pressure. This role of endothelin-1 is unrelated to its plasma levels. The increase of plasma endothelin-1 with bosentan, due either to a displacement of endothelin-1 from its receptor or to a feedback mechanism, does not prevent this blood pressure reduction.

Bosentan produces an additional hypotensive effect to that of ACEI, which opens new therapeutic perspectives.

A fourfold increase of plasma endothelin-1 obtained after doubling the infusion rate suggests a reduction in endothelin-1 clearance or endothelin-1 endogenous production. The biphasic response of heart rate is consistent with baroreflex-mediated effects resulting from vasodilation at the pathophysiological level and vasoconstriction at the pharmacological level. Hemodynamic data suggest an increase followed by a decrease in contractility at both levels, respectively. Finally, endothelin-1 is a stimulator of atrial natriuretic factor.

The cumulative hypotensive effect of bosentan suggests that, besides angiotensin II, endothelin-1 is independently involved in the pathophysiology of hypertension, which presents new therapeutic perspectives.

Beta3-AR stimulation exerts hypotensive effects, increases cardiac contractility and stimulates lipolysis in hypertensive dogs.

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Relations between shortening, velocity of shortening, and relaxation of inflow and outflow segments of the right ventricular (RV) free wall (FW) were examined during ejection in 12 open-chest dogs after pharmacologic blockade by recording RV pressures, RVFW dimensions (piezoelectric crystals), and pulmonary blood flow. At heart rates of 113 +/0 8 (SD) beats/min, investigated segments remained isometric or even lengthened before the end of ejection. Tension-length data in the outflow tract converged at the time of peak systolic tension toward a common linear relation (average slope 65 +/- 10 cmH2O/mm, average intercept 5.9 +/- 0.9 mm), but markedly deviated from this line at the end of ejection. Consistent relations between peak tension and mean velocity of shortening were only observed during the first part of ejection. In addition the rate of segmental isometric relaxation, estimated from RV pressure fall was load dependent (e.g., +60% increase in relaxation rate when RVFW end-diastolic segment length increased from 12.9 +/- 0.8 to 13.5 +/- 0.8 mm). We conclude that under normal conditions, the tension-velocity-length relations of the RVFW are comparable to those of the left ventricle during the first part of ejection only. We also conclude that RV relaxation is load dependent and that a significant part of RV ejection occurs during RVFW relaxation.