Repeated administration of ET(B) receptor agonist, IRL-1620, produces tachyphylaxis only to its hypotensive effect

IRL-1620, a highly selective ET(B) receptor agonist, is presently in a phase I clinical trial (NCT00613691) in the United States for patients with recurrent or progressive carcinoma. The effect of acute repeated administration of IRL-1620 on the development of tachyphylaxis to changes in blood pressure, heart rate and blood flow (renal and cerebral) has not been studied. The present studies were conducted in urethane anesthetized rats to determine the cardiovascular effects of acute repeated intravenous administration of IRL-1620. In order to determine the tachyphylactic effect, each dose of IRL-1620 was administered at 0, 60, and 120min. It was found that IRL-1620 did not significantly affect heart rate. IRL-1620 produced a transient fall in blood pressure. A fall in mean arterial pressure (MAP) of 35.47% with 1.6microg/kg, 38.87% with 5.0microg/kg and 28.04% with 15.0microg/kg dose of IRL-1620 was observed. Repeated administration of a low dose (1.6microg/kg, i.v.) of IRL-1620 produced a fall in MAP but no tachyphylaxis was observed. However, repeated administration of IRL-1620 (5.0microg/kg, i.v.) produced a fall in MAP of 40.12%, 29.15%, and 21.61% with the first, second and third injections, respectively. IRL-1620 produced a consistent decrease in renal blood flow and increase in cerebral blood flow without any evidence of tachyphylaxis. Pretreatment with ET(A) antagonist BMS187824 (5mg/kg, i.v.), followed by three doses of 5microg/kg IRL-1620 at 60min intervals eliminated the development of tachyphylaxis to the transient hypotension, confirming the involvement of the ET(A) receptor in tachyphylactic development. The findings indicate development of tachyphylaxis to IRL-1620 only to the fall in blood pressure when given repeatedly at mid-high doses, while the decrease in renal and increase in cerebral blood flow were not affected with regards to tachyphylactic development.