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Vasoactive Responses of U46619, PGF2 , Latanoprost, and Travoprost

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Vasoactive Responses of U46619, PGF2 , Latanoprost, and Travoprost Vasoactive Responses of U46619, PGF2␣, Latanoprost, and Travoprost in Isolated Porcine Ciliary Arteries Ineta Vysniauskiene, Reto Allemann, Josef Flammer, and Ivan O. Haefliger PURPOSE. To compare the vasoactive properties of the prosta- these responses can be modulated by SQ 29548 (TP-receptor noids U46619 (thromboxane A2 analogue), prostaglandin F2␣ antagonist) or AL-8810 (FP-receptor antagonist). (PGF2␣), latanoprost free acid, and travoprost free acid in isolated porcine ciliary arteries. METHODS. In a myograph system (isometric force measure- MATERIAL AND METHODS ment), quiescent vessels were exposed (cumulatively) to U46619, PGF , latanoprost, or travoprost (0.1 nM–0.1 mM). 2␣ Vessels Preparation Experiments were also conducted in the presence of SQ 29548 (TP-receptor antagonist; 3–10 ␮M) or AL-8810 (FP-receptor Porcine eyes were obtained from an abattoir immediately after death. antagonist; 3–30 ␮M). Contractions were expressed as the In cold modified Krebs-Ringer solution (NaCl 118 mM, KCl 4.7 mM, percentage of 100 mM potassium chloride-induced contrac- CaCl2 2.5 mM, K2PO4 1.2 mM, MgSO4 1.2 mM, NaHCO3 25 mM, tions. glucose 11.1 mM, and EDTA 0.026 mM), ciliary arteries were dissected 5 ␮ RESULTS. In quiescent vessels, contractions (concentration–re- and cut into 2-mm segments. In an organ chamber, two 45- m Ϯ tungsten wires were passed through the vessel’s lumen and attached to sponse curves) induced by (0.1 mM) PGF2␣ (87.9% 3.5%), U46619 (66.7% Ϯ 4.1%), and latanoprost (62.9% Ϯ 3.6%) were a force transducer for isometric force measurements (Myo-Interface; JP more pronounced (P Յ 0.001) than those induced by tra- Trading, Aarhus, Denmark). Vessels were left in place for 30 minutes in voprost (23.0% Ϯ 4.4%). Concentration–response curves for modified Krebs-Ringer solution (95% O2,5%CO2, 37°C) before being stretched in a stepwise manner and exposed between stretch steps to PGF2␣, latanoprost, and travoprost were preceded by a smaller contraction peak (0.1 ␮M) that was higher (P Յ 0.05) for 100 mM potassium chloride (KCl) until the optimum passive tension Ϯ Ϯ was reached (i.e., Ͻ10% variation of KCl-induced contractions be- travoprost (24.4% 2.8%) than for PGF2␣ (12.9% 4.6%), but not different (P ϭ 0.58) from latanoprost (22.0% Ϯ 3.0%). The tween two different stretch steps).6 To assess the functional integrity of the endothelium, vessels were precontracted with 0.1 ␮M U46619 50% maximal contraction (PD50: negative log M concentration) of U46619 (Ϫ8.05 Ϯ 0.13) was lower (P Յ 0.001) than those and then exposed to bradykinin. The endothelial function was consid- Ϫ Ϯ Ϫ Ϯ ered to be preserved if bradykinin (100 nM–1 ␮M) evoked at least 80% of latanoprost ( 5.65 0.10), PGF2␣ ( 5.49 0.14), and travoprost (Ϫ5.12 Ϯ 0.52). Contractions were inhibited (P Յ relaxation.7 Vessels were then washed out with modified Krebs-Ringer 0.05–0.001) either by SQ 29548 or AL-8810. solution before any of the following experimental protocols were conducted. CONCLUSIONS. In isolated porcine ciliary arteries, all prostanoids tested induced contractions. Among them, travoprost ap- peared to be the least potent and U46619 the most efficient. Experimental Protocols (Invest Ophthalmol Vis Sci. 2006;47:295–298) DOI:10.1167/ iovs.05-0760 In a first set of experiments, quiescent ciliary arteries were exposed cumulatively, to increasing concentrations (0.1 nM–0.1 mM) of U46619, PGF2␣, latanoprost, or travoprost. In a second set of experi- he thromboxane A2 analogue U46619 and prostaglandin ments, quiescent vessels were first incubated for 30 minutes with 1 ␮ TF2␣ (PGF2␣) belong to the prostanoid family. U46619 is different concentrations (3–10 M) of SQ 29548 (TP-receptor antago- regarded as a thromboxane A-receptor (TP) agonist and PGF2␣ nist) and then exposed to increasing concentrations (0.1 nM–0.1 mM) 1 as a prostaglandin F-receptor (FP) agonist. U46619 and PGF2␣ of U46619, PGF2␣, latanoprost, or travoprost. In a third set of experi- are known to be strong vasoconstrictors, particularly in the ments, quiescent vessels were first incubated for 30 minutes with ocular circulation.2,3 different concentrations (3–30 ␮M) of AL-8810 (FP-receptor antago- Latanoprost and travoprost are potent ocular hypotensive nist) and then exposed to increasing concentrations (0.1 nM–0.1 mM) drugs that share some chemical structural similarities with of U46619, PGF2␣, latanoprost, or travoprost. Timed control experi- 4 PGF2␣. In the present study, we compared the vasoactive ments were conducted in parallel with only the vehicle solution. responses of U46619, PGF2␣, latanoprost, and travoprost in isolated porcine ciliary arteries and additionally assessed how Drugs and Statistical Analysis U46619, PGF2␣, latanoprost free acid, and travoprost free acid were From the Laboratory of Pharmacology and Physiology, University obtained from Cayman Chemicals (Ann Arbor, MI) and dissolved in Eye Clinic, Basel, Switzerland. pure ethanol (maximal final concentration in the organ chamber, Supported in part by Alcon Laboratories, Fort Worth, Texas. Յ1%). Bradykinin and SQ 29548 were purchased from Sigma-Aldrich Submitted for publication June 16, 2005; revised July 15, 2005; (Buchs, Switzerland). AL-8810 was provided by Alcon Laboratories accepted November 21, 2005. (Fort Worth, TX). Concentrations are expressed as final molar concen- Disclosure: I. Vysniauskiene, Alcon Laboratories (F); R. Alle- trations in the organ chambers. Contractions are given as percent of mann, Alcon Laboratories (F); J. Flammer, Alcon Laboratories (F); 100 mM KCl-induced maximal contraction. Results are provided as I.O. Haefliger, Alcon Laboratories (F) mean Ϯ SEM with n representing the number of vessels studied (one The publication costs of this article were defrayed in part by page vessel per eye). The concentration causing 50% of the maximal con- charge payment. This article must therefore be marked “advertise- ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. traction is expressed as a negative log M concentration (PD50). Statis- Corresponding author: Ivan O. Haefliger, Laboratory of Ocular tical comparisons were conducted with a one-way ANOVA multiple Pharmacology and Physiology, University Eye Clinic, Mittlere Strasse comparison followed by the Bonferroni test, with a two-tailed P Յ 0.05 91, PO Box, CH-4012 Basel, Switzerland. considered to be statistically significant. Investigative Ophthalmology & Visual Science, January 2006, Vol. 47, No. 1 Copyright © Association for Research in Vision and Ophthalmology 295 Downloaded from tvst.arvojournals.org on 09/28/2021 296 Vysniauskiene et al. IOVS, January 2006, Vol. 47, No. 1 RESULTS Effect of Prostanoids in Quiescent Vessels In quiescent vessels (Fig. 1), all prostanoids induced contrac- tions (concentration–response curve). At a 0.1 mM concentra- tion, U46619, PGF2␣, latanoprost free acid, and travoprost free acid evoked contractions that were significantly different from those in timed control experiments. Contractions induced by Ϯ Ϯ PGF2␣ (87.9% 3.5%), U46619 (66.7% 4.1%), and latano- prost (62.9% Ϯ 3.6%) were significantly (P Յ 0.001) more pronounced than those induced by travoprost (23.0% Ϯ 4.4%). Ϫ Ϯ Յ The PD50 of U46619 ( 8.05 0.13) was significantly (P Ϫ Ϯ 0.001) lower than that of latanoprost ( 5.65 0.10), PGF2␣ (Ϫ5.49 Ϯ 0.14), and travoprost (Ϫ5.12 Ϯ 0.52). It has to be noted that the concentration–response curves evoked by PGF2␣, latanoprost free acid, and travoprost free acid were preceded by a small peak contraction that occurred at a con- centration of 0.1 ␮M and that was significantly different from that in the timed control. This first peak contraction was Յ significantly (P 0.05) different for travoprost than for PGF2␣ but not significantly (P ϭ 0.58) different for latanoprost. FIGURE 1. Contracting effect of the prostanoids U46619, PGF2␣,la- tanoprost free acid (latanoprost), and travoprost free acid (travoprost) Effect of SQ 29548 on in quiescent isolated porcine ciliary arteries. Statistical comparisons Prostanoid-Induced Contractions were made versus timed control (control) and U46619 (§), PGF2␣ (‡), latanoprost (†), or travoprost (*), with a single, double, or triple symbol In the presence of different concentrations of SQ 29548 (TP- corresponding to P Յ 0.05, P Յ 0.01, or P Յ 0.001, respectively. receptor antagonist), the concentration-response curve of U46619 (TP-receptor agonist) was significantly (P Յ 0.001) shifted to the right, without any decrease in the maximal contraction observed, indicating that SQ 29548 is likely to act as a competitive inhibitor for U46619 (Fig. 2). In the presence FIGURE 2. Effect of the TP-receptor antagonist SQ 29548 on contractions induced by U46619, PGF2␣, latano- prost free acid (latanoprost), and travoprost free acid (travoprost) in quiescent isolated porcine ciliary ar- teries. Statistical comparisons were made between timed control (con- trol) and the effect of 3 ␮M (*) and 10 ␮M (†) SQ 29548 on the contraction induced by the prostanoids, with a single, double, or triple symbol cor- responding to P Յ 0.05, P Յ 0.01, or P Յ 0.001, respectively. Downloaded from tvst.arvojournals.org on 09/28/2021 IOVS, January 2006, Vol. 47, No. 1 Prostanoid-Induced Vasoconstriction 297 FIGURE 3. Effect of the FP-receptor antagonist AL-8810 on contractions induced by U46619, PGF2␣, latano- prost free acid (latanoprost), and travoprost free acid (travoprost) in quiescent isolated porcine ciliary ar- teries. Statistical comparisons were made between timed control (con- trol) and the effect of 3 ␮M(*), 10 ␮M (†), 20 ␮M (‡), and 30 ␮M (§) AL-8810 on the contraction induced by the prostanoids, with a single, double, or triple symbol correspond- ing to P Յ 0.05, P Յ 0.01, or P Յ 0.001, respectively.
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