ENDOTHELIN-1 RECEPTOR ANTAGONISM DOES NOT INFLUENCE MYOCARDIAL-FUNCTION IN HYPERTENSIVE DOGS

Background As endothelin-l exerts positive inotropic effects, the pres ent study evaluated whether the hypotensive effects of the endothelin- 1 receptor antagonist bosentan were partially related to a decrease in myocardial performance.Methods. In group I, eight anaesthetized open- chest dogs with perinephritic hypertension received four cumulative do ses of bosentan (B1-B4). In group II, eight animals received the same doses of bosentan after autonomic blockade. Indices of heart function were derived from the pressure-length loops obtained during vena cava occlusion. Results In group I, bosentan decreased left ventricular sys tolic pressure (LVSP) and mean. aortic pressure (MAP) dose dependently , reaching 21% and 23% respectively at B4 (LVSP from 190 +/- 8 to 150 +/- 5 mmHg, P < 0.001; MAP from 167 +/- 7 to 128 +/- 5 mmHg, P < 0.001 ). These effects were only related to peripheral vasodilatation, witho ut depression of myocardial contractility, as systemic vascular resist ance dropped (from 670 +/- 83 to 446 +/- 53 mmHgmL(-1) min(-1) x 10(4) ; P < 0.05), and the end-systolic pressure-length relationship (ESPLR) remained unchanged (4.0 +/- 0.4 vs. 4.3 +/- 0.7 mmHgmm(-1) kg(-1)). C oncomitantly with pressure decline, heart rate tended to increase in t his group (from 150 +/- 4 to 156 +/- 6 beats min(-1)).When autonomic s ystem was blocked (group LT), administration of bosentan induced simil ar hypotensive effects as in group I (26% and 28% reduction in LVSP an d MAP respectively, P < 0.001) whereas ESPLR did not change (3.0 +/- 0 .9 vs. 3.1 +/- 0.5 mmHg(-1) mm kg(-1)). Under these sympathetically bl ocked conditions, heart rate significantly fell after bosentan infusio n (from 120 +/-4 to 110 +/- 6 beats min(-1), P < 0.001). Conclusions W ithout influencing heart function, bosentan is an efficient and safe t herapy that opens up new therapeutic perspectives in human essential h ypertension.