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Table 1. Pharmacological properties of the new BK analoguesVasodepressor potency aAnalogue ED 20ED 50ED 90[μg/min] [μg/min][μg/min]Uterotonicpotency:% of activity ofcBK or pA 2I 0.57±0.28 8.49±3.03 13.57±4.88 25%II 4.37±1.99 336.95±132.14 b 855.93±339.66 b 2.4%III 1.67±0.39 94.21±33.48 238.44±85.12 0.4%IV 11.30±3.13 1041.71±310.00 b 2648.05±794.33 b 1%V 1.55±0.35 23.71±10.63 56.26±23.85 43%VI 6.02±1.50 364.06±87.29 b 722.20±374.92 b 0.5%VII 2.52±1.18 80.47±21.01 201.98±52.47 2.8%VIII 24.63±8.74 1896.96±883.13 b 4815.70±2258.54 b 3.8%IX 1.79±0.52 48.85±15.75 122.21±40.25 24.5%X 6.22±2.28 368.69±160.27 b 933.81±409.19 b 13.2%d0.43±0.03 3.19±0.33 52.60±10.59 pA 2 = 7.7±0.13a ED 20 , ED 50 and ED 90 represent doses of BK antagonist (μg/min) that inhibit thevasodepressor response to 250 ng of BK by 20, 50 and 90%, respectively; b Values ED 50or ED 90 extrapolated from the dose-response curve; c Agonistic activity was calculated aspercentage of the BK activity (set to 100%); antagonistic activity was calculated as pA 2(negative common logarithm of analogue concentration shifting the log dose-responsecurve for BK by a factor of 0.3 to the right: the calculations were made from the linearportions of the curves); d Stewart’s antagonisttogether with those of Stewart’s antagonist (used as a positive control) and some relatedpeptides are summarized in Table 1.In the rat blood pressure test compounds I-X displayed antagonistic activity, howeverthe dimension of this effect was variable, starting from very low potency (peptide IV andVIII), through moderate (peptide II, III, V, VI, VII and IX) and ending on the model one(peptide I). In the rat uterus test all the analogues turned out to be agonists. In case ofpeptide I, V, IX and X BK agonistic activity was reduced to 25%, 43%, 24% and 13%respectively. Compound II, VII and VIII exhibited very weak agonistic properties.Analogues III, IV and VI were practically inactive.Interestingly all the new compounds inhibited the vasodepressor response in the ratblood pressure test (antagonistic activity) and at the same time they caused the contractionof the uterine tissue in the rat uterus test (agonistic activity). This would support the idea ofthe presence of different types of BK receptor in the rat uterus and blood vessels. Although(up to the present) there is no evidence for more than one gene for B 2 receptor within asingle species and B 2 receptor gene knockout mouse has lost all responses to exogenousBK, alternative splicing of a single gene transcript cannot be ruled out. Thepharmacological discrepancies observed with BK and its antagonists may be explained bytheir interaction with orphan G-protein-coupled receptors for which ligands are not known(for example GPCR 100 [6]) or with B 2 receptor existing in one of the few possibleconformations that results in stimulating the specific intracellular effector. Undoubtedly,further studies are needed to confirm these hypotheses.AcknowledgmentsThis work was supported by the University of Gdańsk (DS/8453-4-0169-0).References1. Bhoola, K.D., Figueroa, C.D., Worthy, K. Pharmacol. Rev. 44, 1-78 (1992).2. Regoli, D., Barabe, J. Pharmacol. Rev. 32, 1-46 (1980).3. Prahl, A. J. Pept. Sci. 13, 206-210 (2007).4. Holton, P. Br. J. Pharmacol. 3, 328-334 (1948).5. Labudda, O., et al. Acta Biochim. Pol. 54, 193-197 (2007).6. Boels, K., Schaller, H.C. Br. J. Pharmacol. 140, 932-938 (2003).321