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Effect of IQB-9302 on isolated rat aorta.
Report 99/1 pg. 3

Local anaesthetics are applied locally and block nerve conduction of sensory impulses from the periphery tothe central nervous system. They bind to a specific receptor inside the pore of the Na+ channel in the nerves,blocking the entry of that ion.
Most of the local anaesthetics produce vasodilation of small arteries as a side effect. This is the reason whythey are usually associated to a vasoconstrictor that also decreases the rate of absorption, thus minimizingtheir systemic toxicity.
IQB-9302 is a new drug derived from bupivacaine currently under pharmacological development. In thepresent report we describe its effects on isolated rat aorta: 1) Precontracted with 35 mM KCl2) Precontracted with 1 µM phenylephrine3) On basal tone.
In all cases IQB-9302 was compared with bupivacaine.
Effect of IQB-9302 on isolated rat aorta.
Report 99/1 pg. 4

1.- Jacketed organ baths with a capacity of 40 ml, kept at 37ºC.
2.- Constant temperature water baths with pumps to ensure the optimal
heat exchange.
3.- Data adquisition system. MacLab for Macintosh.
4.- Program Chart v3.5.1.
5.- IQB-9302.HCl batch nº 9454.001 from LEBSA. Bupivacaine.HCl, phenylephrine.HCl, carbachol,
phentolamine and nifedipine from Sigma, Madrid, Spain.
Krebs-bicarbonate solution of the following composition: NaCl 119 mM, KCl 4.7 mM, MgSO4 1.2 mM,
KPO4H2 1.2 mM, CaCl2 1.5 mM, NaHCO3 24.9 mM, glucose 10.9 mM, was used in all experiments. The
solution was continuously bubbled with 95% oxygen and 5% carbon dioxide.
Male Sprague-Dawley rats weighing 225-300 g from our animal room were used in all the experiments. The
animals were killed by asphyxiation in a gas chamber. The thoracic aorta as close as possible to the heart was
quickly removed and placed in a Petri dish containing Krebs-bicarbonate solution and the excess fat and
connective tissue were removed. Then, the aorta was cut into 3-5 mm-wide rings and two fine stainless steel
hooks were carefully introduced into the vessel's lumen. In all experiments the muscles were loaded with 1g
and subjected to a 1 h initial equilibration period to allow development of a stable basal tone.
Once the tissues were stabilized with an initial incubation period of 60 min, contractions were evoked by
adding to the organ bath either KCl so that the final concentration of K+ was 35 mM (uncorrected for
osmolarity) or phenylephrine 1 µM (final concentration). After peak contraction, carbachol 10 µM was added
to test the presence of functional endothelium. The preparations were washed twice with fresh Krebs-
bicarbonate buffer to allow its relaxation to basal tone and new additions of 35 mM K+ or 1 µM
phenylephrine were repeated to evoke a persistent contraction. Then, the drugs to be tested were added
cumulatively (0.1 - 100 µM). Finally, 1 µM nifedipine (in the preparations precontracted with 35 mM K+) or
1 µM phentolamine (in those precontracted with phenylephrine) were added to test the functionality of the
Effect of IQB-9302 on isolated rat aorta.
Report 99/1 pg. 5

In those experiments designed to test the effects of the drugs on basal tone, they were added in the samecumulative way after washing of preparations without further contractions.
Data of contraction in g in the absence (control) or in the presence of drugs were transferred to an Excel
worksheet and were transformed into percentage considering 100% the initial contraction, before addition of
the drugs. The data of all the experiments were included in the same Excel worksheet and mean + SEM was
calculated. Statistical analysis of means was performed with the program Statworks for Macintosh using
Student's t-test. The level of significance between means was taken at P<0.05.
Effect of IQB-9302 on isolated rat aorta.
Report 99/1 pg. 6

Fig.1 shows original traces of three different experiments Panels A and B show the effects of cumulativeconcentrations of IQB-9302 on isolated rat aorta precontracted with 35 mM K+. (A) or bupivacaine onisolated rat aorta precontracted with 1 µM phenylephrine (B) Only the highest concentration tested (10-4 M)induced a slight vasorelaxant response in both cases. At the end of the experiment, nifedipine 1 µM (A) orphentolamine 1 µM (B) were added to test the functionality of the preparations; panel (C) shows anexperiment in which carbachol 10 µM was added on the peak contraction evoked by 35 mM K+ to asses thepresence of functional endothelium (relaxation induced by NO liberation). After washing out the aorta twicewith fresh Krebs-bicarbonate, IQB-9302 was added in a cumulative way. Observe that the compound did notmodify the resting tension of the vessel; only at 10-4 M a slight increase was produced. Finally, after a newwash out, the preparation was challenged again with 35 mM K+ to test the functionality of the preparation.
Fig. 2 summarises the results of different experiments comparing the effects of IQB-9302 and bupivacaine onrat aorta precontracted with 35 mM K+.As can be seen, IQB-9302 exerted a small increase of the K+-inducedcontraction (14.8+6.3%) at the concentration of 10 µM. At 100 µM, both IQB-9302 and bupivacaine inducedstatistically significant relaxations of 26.6+6.4% and 22.1+7.7% respectively, with respect to the initialcontraction.
Fig.3 compares the effects of IQB-9302 and bupivacaine on the contraction evoked by 1 µM phenylephrine inrat aorta. A very small increase in the contraction can be noticed for bupivacaine at the concentration of 1 µM(5.4+2%). Again, both IQB-9302 and bupivacaine, at 100 µM, produced statistically significanta relaxationsof 21.9+4.2% and 21.8+4.7%, respectively, with respect to the initial contraction.
Fig. 4 shows the effects of IQB-9302 and bupivacaine on the basal tone of rat aorta preparations. As can beseen, only bupivacaine 100 µM induced a significant increase in the basal tone (1.39+0.6 g).IQB-9302 tendedto increase the basal tone at 10-4 M, but the difference was not statistically significant.
In all the cases, there were no significant diferences between the effect of IQB-9302 and bupivacaine.
Effect of IQB-9302 on isolated rat aorta.
Report 99/1 pg. 7

According to the results presented in this report, it seems that IQB-9302 is acting on the isolated rat aorta inthe same way as bupivacaine. Both drugs produced vasodilation only at concentrations as high as 100 µM.
These are concentrations that will never be reached sistemically, after local administration of IQB-9302. Theonly diference observed between both drugs in the present experiments, was the increase in the basal toneinduced by bup


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