Pharmacology of two novel mixed ET_A/ET_B receptor antagonists, BQ‐928 and 238, in the carotid and pulmonary arteries and the perfused kidney of the rabbit

Abstract

1 In the present study, we have pharmacologically characterized two novel mixed endothelin ET A /ET B receptor antagonists, namely BQ-928 and BQ-238, in ET A and ET B preparations, the rabbit carotid artery (RbCA) and the rabbit pulmonary artery (RbPA), respectively. These two antagonists were compared to established ET A (BQ-123 and BMS 182874), ET B (BQ-788) and mixed ET A /ET B (SB 209670) receptor antagonists. 2 In the RbCA, the ET A monoreceptor preparation, BQ-238 and BQ-928 had apparent a nities (pA 2 ) of 7.42+0.22 and 7.22+0.18, respectively, BQ-788 being inactive in this preparation. In the ET B monoreceptor preparation, the RbPA (when IRL-1620 was used as an ET B receptor agonist), the pA 2 for BQ-238 was 7.05+0.14 and for BQ-928 was 8.43+0.04. BQ-123 and BMS 182874 were inactive in this preparation. Similar to SB 209670, BQ-238 but not BQ-928 had a higher a nity for the ET A than the ET B receptor. 3 All of the antagonists were tested for their ability to block and reverse endothelin-1-induced vasoconstrictions in the rabbit perfused kidney. In this preparation endothelin-1-induced increases in vascular resistance have been shown to be mediated solely by ET A receptors. All compounds (except BQ-788) blocked the pressor e ects of endothelin within the kidney; the calculated IC 50 values for BQ-123, BMS 182874, SB 209670, BQ-928 and BQ-238 were 0.4 mM, 2 mM, 0.01 mM, 0.4 mM and 0.09 mM, respectively. 4 In all experiments in the rabbit perfused kidney, endothelin-1 was readministered for a third time, 60 min following cessation of infusion of the above-mentioned antagonists. The response to the third infusion of endothelin-1 following cessation of infusion of BQ-123, BMS 182874 and SB 209670 was not signi®cantly di erent from that to the third infusion of endothelin in control conditions. However, the response to endothelin-1 was signi®cantly higher than control in tissues pre-infused with BQ-788 or BQ-928 (56+9 and 41.6+15%, respectively, n=8 each, P50.05). 5 Our results suggest that in a system where ET A receptor activation is responsible for vasoconstriction and ET B -receptor activation for vasodilatation, ET A receptor selective antagonists or mixed ET A /ET B receptor antagonists which possess high a nity for ET A receptors do not induce hyperresponsiveness to endothelin-1. In contrast, ET B selective antagonists or mixed antagonists possessing a high a nity for ET B receptors (such as BQ-928) interfere with the ET B -receptor-dependent physiological antagonism of endothelin-1-induced pressor responses in these same tissues.

Comparison of the contractile and calcium‐increasing properties of platelet‐activating factor and endothelin‐1 in the rat mesenteric artery and vein

“…The fact that the ET A /ET B receptor antagonist SB209670 decreased ET‐1‐induced increase of tension and [Ca] i to the same extent as BQ‐123 or BQ‐788, could be due to the fact that the former antagonist possesses a higher affinity for ET A (pA 2 for 9.22) than ET B receptors (pA 2 for 8.09) (Maurice et al ., 1997). It is possible that the further decrease of tension and absence of effect on [Ca] i simultaneous blockade of ET A and ET B receptors by BQ‐123 and BQ‐788 could be due to the higher affinity of the mixture for ET B receptors (pA 2 of BQ‐788 9.01) than ET A receptors (pA 2 of BQ‐123 6.41) (Maurice et al ., 1997). Finally, the superior effect of the mixture of BQ‐123 and BQ‐788 may not be due to a lack of selectivity of BQ‐788, since that particular antagonist did not affect at all the contraction of ET‐1 on the mesenteric artery in the present study.…”

“…Both receptor types (ET A on the arterial, ET A and ET B receptors on the venous side) contribute to the increased [Ca] i level and tension. The fact that the ET A /ET B receptor antagonist SB209670 decreased ET-1-induced increase of tension and [Ca] i to the same extent as BQ-123 or BQ-788, could be due to the fact that the former antagonist possesses a higher anity for ET A (pA 2 for 9.22) than ET B receptors (pA 2 for 8.09) (Maurice et al, 1997). It is possible that the further decrease of tension and absence of eect on [Ca] i simultaneous blockade of ET A and ET B receptors by BQ-123 Figure 8 Cross-sectional view of a 3-D reconstructed isolated vascular smooth muscle cell from arterial (A to D) and venous origin (E to J).…”

“…This ®gure is representative of three other experiments. and BQ-788 could be due to the higher anity of the mixture for ET B receptors (pA 2 of BQ-788 9.01) than ET A receptors (pA 2 of BQ-123 6.41) (Maurice et al, 1997). Finally, the superior eect of the mixture of BQ-123 and BQ-788 may not be due to a lack of selectivity of BQ-788, since that particular antagonist did not aect at all the contraction of ET-1 on the mesenteric artery in the present study.…”

Pressor and pulmonary responses to ET‐1(1–31) in guinea‐pigs

“…We have previously shown that a similar phenomenon occurs with respect to the influence of selective versus mixed (i.e. combined ET A /ET B receptor blockade) ET receptor antagonists against ET‐1‐induced vasoconstriction in the rabbit perfused kidney (Maurice et al ., 1997).…”

Distortion of KB estimates of endothelin‐1 ETA and ETB receptor antagonists in pulmonary arteries: Possible role of an endothelin‐1 clearance mechanism

“…The conclusions provide a theoretical framework to test for the “ideal” dual ET A and ET B receptor antagonist if significant antagonism is to occur at ET A or ET B constrictor receptors and the ET B receptor‐mediated clearance of endothelin‐1 is blocked which potentiates the potency of endothelin‐1. This clearance mechanism, thus, joins other well‐known mechanisms of ET B ‐mediated endothelin‐1 release of thromboxane A 2 , prostacyclin, and nitric oxide that would either enhance or functionally antagonize ET A ‐ or ET B ‐mediated vasoconstriction …”