irl-1620 and Hypotension

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.

Topics: Animals; Antineoplastic Agents; Blood Circulation; Blood Pressure; Cerebrovascular Circulation; Endothelins; Heart Rate; Hypotension; Male; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Renal Circulation; Tachyphylaxis

1. This study attempts to investigate if endogenous nitric oxide (NO) can modulate the eicosanoid-releasing properties of intravenously administered endothelin-1 (ET-1) in the pulmonary and circulatory systems in the guinea-pig. 2. The nitric oxide synthase blocker N(omega)-nitro-L-arginine methyl ester (L-NAME; 300 microM; 30 min infusion) potentiated, in an L-arginine sensitive fashion, the release of thromboxane A2 (TxA2) stimulated by ET-1, the selective ET(B) receptor agonist IRL 1620 (Suc-[Glu9,Ala11,15]-ET-1(8-21)) or bradykinin (BK) (5, 50 and 50 nM, respectively, 3 min infusion) in guinea-pig isolated and perfused lungs. 3. In anaesthetized and ventilated guinea-pigs intravenous injection of ET-1 (0.1-1.0 nmol kg(-1)), IRL 1620 (0.2-1.6 nmol kg(-1)), BK (1.0-10.0 nmol kg(-1)) or U 46619 (0.2-5.7 nmol kg(-1)) each induced dose-dependent increases in pulmonary insufflation pressure (PIP). Pretreatment with L-NAME (5 mg kg(-1)) did not change basal PIP, but increased, in L-arginine sensitive manner, the magnitude of the PIP increases (in both amplitude and duration) triggered by each of the peptides (at 0.25, 0.4 and 1.0 nmol kg(-1), respectively), without modifying bronchoconstriction caused by U 46619 (0.57 nmol kg(-1)). 4. The increases in PIP induced by ET-1, IRL 1620 (0.25 and 0.4 nmol kg(-1), respectively) or U 46619 (0.57 nmol kg(-1)) were accompanied by rapid and transient increases of mean arterial blood pressure (MAP). Pretreatment with L-NAME (5 mg kg(-1); i.v. raised basal MAP persistently and, under this condition, subsequent administration of ET-1 or IRL 1620, but not of U-46619, induced hypotensive responses which were prevented by pretreatment with the cyclo-oxygenase inhibitor indomethacin. 5. Thus, endogenous NO appears to modulate ET-1-induced bronchoconstriction and pressor effects in the guinea-pig by limiting the peptide's ability to induce, possibly via ET(B) receptors, the release of TxA2 in the lungs and of vasodilatory prostanoids in the systemic circulation. Furthermore, it would seem that these eicosanoid-dependent actions of ET-1 in the pulmonary system and on systemic arterial resistance in this species are physiologically dissociated.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Resistance; Animals; Antihypertensive Agents; Arginine; Blood Pressure; Bradykinin; Bronchoconstriction; Cyclooxygenase Inhibitors; Drug Synergism; Eicosanoids; Endothelin-1; Endothelins; Enzyme Inhibitors; Female; Guinea Pigs; Hypotension; In Vitro Techniques; Indomethacin; Lung; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oligopeptides; Peptide Fragments; Perfusion; Piperidines; Thromboxane A2; Vasoconstrictor Agents