Further studies on the response of the guinea-pig isolated bronchus to endothelins and sarafotoxin S6b.

Endothelin-1 (ET-1), endothelin-3 (ET-3) and sarafotoxin S6b (SRFTX) produced a concentration-dependent contraction of the guinea-pig isolated bronchus. In untreated preparations, SRFTX was about 10 times more potent than ET-1 or ET-3 and produced a greater maximal effect. Mechanical removal of the bronchial epithelium (rubbing) or the addition of indomethacin (5 microM) increased the potency of all peptides, ET-3 being enhanced more than ET-1 or SRFTX. Further, the activity of ET-3 was enhanced by a mixture of peptidase inhibitors (thiorphan, captopril, bestatin, 1 microM each). When the three potentiating factors were combined (rubbed bronchi in presence of indomethacin and peptidase inhibitors), the following order of potency was found, ET-3 congruent to SRTFX greater than ET-1. For comparison, the activity of the three peptides was also studied in the rubbed rat isolated aorta in the presence of indomethacin and peptidase inhibitors and the following rank order of potency was found: ET-1 greater than SRFTX greater than ET-3. When the activity of the peptides was compared in these two preparations, ET-1 was 4 times more potent in the aorta than in the bronchus, while SRFTX and ET-3 were 8.7 and 133 times more potent in the bronchus than the aorta, respectively. These findings indicate that, in the guinea-pig bronchus, the contractile activity of these peptides is attenuated by the concomitant production of epithelium-derived relaxant factor(s), prostanoid production via the cyclooxygenase pathway and, possibly, enzymatic inactivation of added peptides. Further, the existence of multiple receptors mediating the contractile response to these peptides is suggested.