The Experts below are selected from a list of 201 Experts worldwide ranked by ideXlab platform
Richard H Alper - One of the best experts on this subject based on the ideXlab platform.
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serotonin 5 ht1b 1d agonist stimulated 35s gtpγs binding in rat and guinea pig striatal membranes
Brain Research, 1999Co-Authors: Amy L Mize, Richard H AlperAbstract:Abstract Serotonin (5-hydroxytryptamine; 5-HT) receptor ligands were used to assess agonist-stimulated [ 35 S]GTPγS binding in rat and guinea pig striatal membranes. The assay contained 45–60 μg protein, 300 μM GDP and 0.1 nM [ 35 S]GTPγS, incubated at 37°C for 20 min. The non-selective agonists 5-HT, 5-CT (5-carboxyamidotryptamine), and L-694,247, and the selective 5-HT 1B receptor agonist CP 93,129 produced concentration-dependent increases in [ 35 S]GTPγS binding in rat striatum, whereas the selective 5-HT 1A receptor agonist R(+)-8-OH-DPAT [R(+)-8-hydroxy-2-(di- n -propylamino)tetralin] was inactive. Cyanopindolol, a 5-HT 1A/1B receptor antagonist, completely blocked the effect of 5-HT. Methiothepin, yohimbine and Cyanopindolol also blocked 5-CT-stimulated [ 35 S]GTPγS binding with the following rank order of potency: Cyanopindolol ≥ methiothepin >>> yohimbine, consistent with rat 5-HT 1B receptor pharmacology. Neither Cyanopindolol nor methiothepin altered basal [ 35 S]GTPγS binding by themselves while yohimbine had weak partial agonist activity. Furthermore, Cyanopindolol shifted the 5-CT concentration-response curve rightward, increasing the EC 50 and decreasing the maximal response, but did not affect L-694,247-stimulated [ 35 S]GTPγS binding. The ability of Cyanopindolol or spiperone (a 5-HT 1A/1D receptor antagonist) to alter CP 93,129-stimulated [ 35 S]GTPγS binding was determined. Cyanopindolol produced a rightward shift in the CP 93,129 concentration-response curve, while spiperone had no affect. Finally, in guinea pig striatum and hippocampus, L-694,247 produced a concentration dependent increase in [ 35 S]GTPγS binding. In conclusion, these studies indicate that 5-HT 1B receptor function can be assessed using agonist-stimulated [ 35 S]GTPγS binding in rat striatal membranes using CP 93,129, 5-HT or 5-CT, but not L-694,247.
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Serotonin 5-HT(1B/1D) agonist-stimulated [(35)S]GTPgammaS binding in rat and guinea pig striatal membranes.
Brain research, 1999Co-Authors: Amy L Mize, Richard H AlperAbstract:Serotonin (5-hydroxytryptamine; 5-HT) receptor ligands were used to assess agonist-stimulated [(35)S]GTPgammaS binding in rat and guinea pig striatal membranes. The assay contained 45-60 microgram protein, 300 microM GDP and 0.1 nM [(35)S]GTPgammaS, incubated at 37 degrees C for 20 min. The non-selective agonists 5-HT, 5-CT (5-carboxyamidotryptamine), and L-694,247, and the selective 5-HT(1B) receptor agonist CP 93,129 produced concentration-dependent increases in [(35)S]GTPgammaS binding in rat striatum, whereas the selective 5-HT(1A) receptor agonist R(+)-8-OH-DPAT [R(+)-8-hydroxy-2-(di-n-propylamino)tetralin] was inactive. Cyanopindolol, a 5-HT(1A/1B) receptor antagonist, completely blocked the effect of 5-HT. Methiothepin, yohimbine and Cyanopindolol also blocked 5-CT-stimulated [(35)S]GTPgammaS binding with the following rank order of potency: Cyanopindolol >/= methiothepin >>> yohimbine, consistent with rat 5-HT(1B) receptor pharmacology. Neither Cyanopindolol nor methiothepin altered basal [(35)S]GTPgammaS binding by themselves while yohimbine had weak partial agonist activity. Furthermore, Cyanopindolol shifted the 5-CT concentration-response curve rightward, increasing the EC(50) and decreasing the maximal response, but did not affect L-694, 247-stimulated [(35)S]GTPgammaS binding. The ability of Cyanopindolol or spiperone (a 5-HT(1A/1D) receptor antagonist) to alter CP 93,129-stimulated [(35)S]GTPgammaS binding was determined. Cyanopindolol produced a rightward shift in the CP 93,129 concentration-response curve, while spiperone had no affect. Finally, in guinea pig striatum and hippocampus, L-694,247 produced a concentration dependent increase in [(35)S]GTPgammaS binding. In conclusion, these studies indicate that 5-HT(1B) receptor function can be assessed using agonist-stimulated [(35)S]GTPgammaS binding in rat striatal membranes using CP 93,129, 5-HT or 5-CT, but not L-694, 247.
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Serotonin 5-HT1B/1D agonist-stimulated [35S]GTPγS binding in rat and guinea pig striatal membranes
Brain Research, 1999Co-Authors: Amy L Mize, Richard H AlperAbstract:Abstract Serotonin (5-hydroxytryptamine; 5-HT) receptor ligands were used to assess agonist-stimulated [ 35 S]GTPγS binding in rat and guinea pig striatal membranes. The assay contained 45–60 μg protein, 300 μM GDP and 0.1 nM [ 35 S]GTPγS, incubated at 37°C for 20 min. The non-selective agonists 5-HT, 5-CT (5-carboxyamidotryptamine), and L-694,247, and the selective 5-HT 1B receptor agonist CP 93,129 produced concentration-dependent increases in [ 35 S]GTPγS binding in rat striatum, whereas the selective 5-HT 1A receptor agonist R(+)-8-OH-DPAT [R(+)-8-hydroxy-2-(di- n -propylamino)tetralin] was inactive. Cyanopindolol, a 5-HT 1A/1B receptor antagonist, completely blocked the effect of 5-HT. Methiothepin, yohimbine and Cyanopindolol also blocked 5-CT-stimulated [ 35 S]GTPγS binding with the following rank order of potency: Cyanopindolol ≥ methiothepin >>> yohimbine, consistent with rat 5-HT 1B receptor pharmacology. Neither Cyanopindolol nor methiothepin altered basal [ 35 S]GTPγS binding by themselves while yohimbine had weak partial agonist activity. Furthermore, Cyanopindolol shifted the 5-CT concentration-response curve rightward, increasing the EC 50 and decreasing the maximal response, but did not affect L-694,247-stimulated [ 35 S]GTPγS binding. The ability of Cyanopindolol or spiperone (a 5-HT 1A/1D receptor antagonist) to alter CP 93,129-stimulated [ 35 S]GTPγS binding was determined. Cyanopindolol produced a rightward shift in the CP 93,129 concentration-response curve, while spiperone had no affect. Finally, in guinea pig striatum and hippocampus, L-694,247 produced a concentration dependent increase in [ 35 S]GTPγS binding. In conclusion, these studies indicate that 5-HT 1B receptor function can be assessed using agonist-stimulated [ 35 S]GTPγS binding in rat striatal membranes using CP 93,129, 5-HT or 5-CT, but not L-694,247.
Amy L Mize - One of the best experts on this subject based on the ideXlab platform.
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serotonin 5 ht1b 1d agonist stimulated 35s gtpγs binding in rat and guinea pig striatal membranes
Brain Research, 1999Co-Authors: Amy L Mize, Richard H AlperAbstract:Abstract Serotonin (5-hydroxytryptamine; 5-HT) receptor ligands were used to assess agonist-stimulated [ 35 S]GTPγS binding in rat and guinea pig striatal membranes. The assay contained 45–60 μg protein, 300 μM GDP and 0.1 nM [ 35 S]GTPγS, incubated at 37°C for 20 min. The non-selective agonists 5-HT, 5-CT (5-carboxyamidotryptamine), and L-694,247, and the selective 5-HT 1B receptor agonist CP 93,129 produced concentration-dependent increases in [ 35 S]GTPγS binding in rat striatum, whereas the selective 5-HT 1A receptor agonist R(+)-8-OH-DPAT [R(+)-8-hydroxy-2-(di- n -propylamino)tetralin] was inactive. Cyanopindolol, a 5-HT 1A/1B receptor antagonist, completely blocked the effect of 5-HT. Methiothepin, yohimbine and Cyanopindolol also blocked 5-CT-stimulated [ 35 S]GTPγS binding with the following rank order of potency: Cyanopindolol ≥ methiothepin >>> yohimbine, consistent with rat 5-HT 1B receptor pharmacology. Neither Cyanopindolol nor methiothepin altered basal [ 35 S]GTPγS binding by themselves while yohimbine had weak partial agonist activity. Furthermore, Cyanopindolol shifted the 5-CT concentration-response curve rightward, increasing the EC 50 and decreasing the maximal response, but did not affect L-694,247-stimulated [ 35 S]GTPγS binding. The ability of Cyanopindolol or spiperone (a 5-HT 1A/1D receptor antagonist) to alter CP 93,129-stimulated [ 35 S]GTPγS binding was determined. Cyanopindolol produced a rightward shift in the CP 93,129 concentration-response curve, while spiperone had no affect. Finally, in guinea pig striatum and hippocampus, L-694,247 produced a concentration dependent increase in [ 35 S]GTPγS binding. In conclusion, these studies indicate that 5-HT 1B receptor function can be assessed using agonist-stimulated [ 35 S]GTPγS binding in rat striatal membranes using CP 93,129, 5-HT or 5-CT, but not L-694,247.
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Serotonin 5-HT(1B/1D) agonist-stimulated [(35)S]GTPgammaS binding in rat and guinea pig striatal membranes.
Brain research, 1999Co-Authors: Amy L Mize, Richard H AlperAbstract:Serotonin (5-hydroxytryptamine; 5-HT) receptor ligands were used to assess agonist-stimulated [(35)S]GTPgammaS binding in rat and guinea pig striatal membranes. The assay contained 45-60 microgram protein, 300 microM GDP and 0.1 nM [(35)S]GTPgammaS, incubated at 37 degrees C for 20 min. The non-selective agonists 5-HT, 5-CT (5-carboxyamidotryptamine), and L-694,247, and the selective 5-HT(1B) receptor agonist CP 93,129 produced concentration-dependent increases in [(35)S]GTPgammaS binding in rat striatum, whereas the selective 5-HT(1A) receptor agonist R(+)-8-OH-DPAT [R(+)-8-hydroxy-2-(di-n-propylamino)tetralin] was inactive. Cyanopindolol, a 5-HT(1A/1B) receptor antagonist, completely blocked the effect of 5-HT. Methiothepin, yohimbine and Cyanopindolol also blocked 5-CT-stimulated [(35)S]GTPgammaS binding with the following rank order of potency: Cyanopindolol >/= methiothepin >>> yohimbine, consistent with rat 5-HT(1B) receptor pharmacology. Neither Cyanopindolol nor methiothepin altered basal [(35)S]GTPgammaS binding by themselves while yohimbine had weak partial agonist activity. Furthermore, Cyanopindolol shifted the 5-CT concentration-response curve rightward, increasing the EC(50) and decreasing the maximal response, but did not affect L-694, 247-stimulated [(35)S]GTPgammaS binding. The ability of Cyanopindolol or spiperone (a 5-HT(1A/1D) receptor antagonist) to alter CP 93,129-stimulated [(35)S]GTPgammaS binding was determined. Cyanopindolol produced a rightward shift in the CP 93,129 concentration-response curve, while spiperone had no affect. Finally, in guinea pig striatum and hippocampus, L-694,247 produced a concentration dependent increase in [(35)S]GTPgammaS binding. In conclusion, these studies indicate that 5-HT(1B) receptor function can be assessed using agonist-stimulated [(35)S]GTPgammaS binding in rat striatal membranes using CP 93,129, 5-HT or 5-CT, but not L-694, 247.
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Serotonin 5-HT1B/1D agonist-stimulated [35S]GTPγS binding in rat and guinea pig striatal membranes
Brain Research, 1999Co-Authors: Amy L Mize, Richard H AlperAbstract:Abstract Serotonin (5-hydroxytryptamine; 5-HT) receptor ligands were used to assess agonist-stimulated [ 35 S]GTPγS binding in rat and guinea pig striatal membranes. The assay contained 45–60 μg protein, 300 μM GDP and 0.1 nM [ 35 S]GTPγS, incubated at 37°C for 20 min. The non-selective agonists 5-HT, 5-CT (5-carboxyamidotryptamine), and L-694,247, and the selective 5-HT 1B receptor agonist CP 93,129 produced concentration-dependent increases in [ 35 S]GTPγS binding in rat striatum, whereas the selective 5-HT 1A receptor agonist R(+)-8-OH-DPAT [R(+)-8-hydroxy-2-(di- n -propylamino)tetralin] was inactive. Cyanopindolol, a 5-HT 1A/1B receptor antagonist, completely blocked the effect of 5-HT. Methiothepin, yohimbine and Cyanopindolol also blocked 5-CT-stimulated [ 35 S]GTPγS binding with the following rank order of potency: Cyanopindolol ≥ methiothepin >>> yohimbine, consistent with rat 5-HT 1B receptor pharmacology. Neither Cyanopindolol nor methiothepin altered basal [ 35 S]GTPγS binding by themselves while yohimbine had weak partial agonist activity. Furthermore, Cyanopindolol shifted the 5-CT concentration-response curve rightward, increasing the EC 50 and decreasing the maximal response, but did not affect L-694,247-stimulated [ 35 S]GTPγS binding. The ability of Cyanopindolol or spiperone (a 5-HT 1A/1D receptor antagonist) to alter CP 93,129-stimulated [ 35 S]GTPγS binding was determined. Cyanopindolol produced a rightward shift in the CP 93,129 concentration-response curve, while spiperone had no affect. Finally, in guinea pig striatum and hippocampus, L-694,247 produced a concentration dependent increase in [ 35 S]GTPγS binding. In conclusion, these studies indicate that 5-HT 1B receptor function can be assessed using agonist-stimulated [ 35 S]GTPγS binding in rat striatal membranes using CP 93,129, 5-HT or 5-CT, but not L-694,247.
Lynette C. Daws - One of the best experts on this subject based on the ideXlab platform.
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5-HT1B receptor modulation of the serotonin transporter in vivo: studies using KO mice.
Neurochemistry international, 2013Co-Authors: Sylvia Montañez, Jaclyn L. Munn, W. Anthony Owens, Rebecca E. Horton, Lynette C. DawsAbstract:The serotonin transporter (SERT) controls the strength and duration of serotonergic neurotransmission by the high-affinity uptake of serotonin (5-HT) from extracellular fluid. SERT is a key target for many psychotherapeutic and abused drugs, therefore understanding how SERT activity and expression are regulated is of fundamental importance. A growing literature suggests that SERT activity is under regulatory control of the 5-HT1B autoreceptor. The present studies made use of mice with a constitutive reduction (5-HT1B+/-) or knockout of 5-HT1B receptors (5-HT1B-/-), as well as mice with a constitutive knockout of SERT (SERT-/-) to further explore the relationship between SERT activity and 5-HT1B receptor expression. High-speed chronoamperometry was used to measure clearance of 5-HT from CA3 region of hippocampus in vivo. Serotonin clearance rate, over a range of 5-HT concentrations, did not differ among 5-HT1B receptor genotypes, nor did [(3)H]cyanoimipramine binding to SERT in this brain region, suggesting that SERT activity is not affected by constitutive reduction or loss of 5-HT1B receptors; alternatively, it might be that other transport mechanisms for 5-HT compensate for loss of 5-HT1B receptors. Consistent with previous reports, we found that the 5-HT1B receptor antagonist, Cyanopindolol, inhibited 5-HT clearance in wild-type mice. However, this effect of Cyanopindolol was lost in 5-HT1B-/- mice and diminished in 5-HT1B+/- mice, indicating that the 5-HT1B receptor is necessary for Cyanopindolol to inhibit 5-HT clearance. Likewise, Cyanopindolol was without effect on 5-HT clearance in SERT-/- mice, demonstrating a requirement for the presence of both SERT and 5-HT1B receptors in order for Cyanopindolol to inhibit 5-HT clearance in CA3 region of hippocampus. Our findings are consistent with SERT being under the regulatory control of 5-HT1B autoreceptors. Future studies to identify signaling pathways involved may help elucidate novel therapeutic targets for the treatment of psychiatric disorders, particularly those linked to gene variants of the 5-HT1B receptor.
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5-HT(1B) receptor-mediated regulation of serotonin clearance in rat hippocampus in vivo
Journal of neurochemistry, 2002Co-Authors: Lynette C. Daws, Georgianna G. Gould, Susan D. Teicher, Greg A. Gerhardt, Alan FrazerAbstract:The 5-hydroxytryptamine (5-HT; serotonin) transporter (5-HTT) is important in terminating serotonergic neurotransmission and is a primary target for many psychotherapeutic drugs. Study of the regulation of 5-HTT activity is therefore important in understanding the control of serotonergic neurotransmission. Using high-speed chronoamperometry, we have demonstrated that local application of 5-HT(1B) antagonists into the CA3 region of the hippocampus prolongs the clearance of 5-HT from extracellular fluid (ECF). In the present study, we demonstrate that the 5-HT(1B) antagonist Cyanopindolol does not produce this effect by increasing release of endogenous 5-HT or by directly binding to the 5-HTT. Dose-response studies showed that the potency of Cyanopindolol to inhibit clearance of 5-HT was equivalent to that of the selective 5-HT reuptake inhibitor fluvoxamine. Local application of the 5-HT(1A) antagonist WAY 100635 did not alter 5-HT clearance, suggesting that the effect of Cyanopindolol to prolong clearance is not via a mechanism involving 5-HT(1A) receptors. Finally, the effect of low doses of Cyanopindolol and fluvoxamine to inhibit clearance of 5-HT from ECF was additive. These data are consistent with the hypothesis that activation of terminal 5-HT(1B) autoreceptors increases 5-HTT activity.
Peter C M Molenaar - One of the best experts on this subject based on the ideXlab platform.
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putative β4 adrenoceptors in rat ventricle mediate increases in contractile force and cell ca2 comparison with atrial receptors and relationship to 3h cgp 12177 binding
British Journal of Pharmacology, 1999Co-Authors: Doreen Sarsero, Peter C M Molenaar, Alberto J Kaumann, Nicholas S FreestoneAbstract:1 We identified putative beta(4)-adrenoceptors by radioligand binding, measured increases in ventricular contractile force by (-)-CGP 12177 and (+/-)-Cyanopindolol and demonstrated increased Ca2+ transients by (-)-CGP 12177 in rat cardiomyocytes. 2 (-)-[H-3]-CGP 12177 labelled 13-22 fmol mg(-1) protein ventricular beta(1), beta(2)-adrenoceptors (pK(D) similar to 9.0) and 50-90 fmol mg(-1) protein putative beta(4)-adrenoceptors (pK(D) similar to 7.3). The affinity values (PKi) for (beta(1),beta(2)-) and putative beta(4)-adrenoceptors, estimated from binding inhibition, were (-)-propranolol 8.4, 5.7; (-)-bupranolol 9.7, 5.8; (+/-)-Cyanopindolol 10.0,7.4. 3 In left ventricular papillary muscle, in the presence of 30 mu M 3-isobutyl-1-methylxanthine, (-)CGP 12177 and (+/-)-Cyanopindolol caused positive inotropic effects, (pEC(50) (-)-CGP 12177, 7.6; (+/-)-Cyanopindolol, 7.0) which were antagonized by (-)-bupranolol (pK(B) 6.7-7.0) and (-)-CGP 20712A (pK(B) 6.3-6.6). The cardiostimulant effects of(-)-CGP 12177 in papillary muscle, left and right atrium were antagonized by (+/-)-Cyanopindolol (pK(i), 7.0-7.4). 4 (-)-CGP 12177 (1 mu M) in the presence of 200 nM (-)-propranolol increased Ca2+ transient amplitude by 56% in atrial myocytes, but only caused a marginal increase in ventricular myocytes. In the presence of 1 mu M 3-isobutyl-1-methylxanthine and 200 nM (-)-propranolol, 1 mu M (-)-CGP 12177 caused a 73% increase in Ca2+ transient amplitude in ventricular myocytes. (-)-CGP 12177 elicited arrhythmic transients in some atrial and ventricular myocytes. 5 Probably by preventing cyclic AMP hydrolysis, 3-isobutyl-1-methylxanthine facilitates the inotropic function of ventricular putative beta(4)-adrenoceptors. suggesting coupling to G(s) protein-adenylyl cyclase. The receptor-mediated increases in contractile force are related to increases of Ca2+ in atrial and ventricular myocytes. The agreement of binding affinities of agonists with cardiostimulant potencies is consistent with mediation through putative beta(4)-adrenoceptors labelled with (-)-[H-3]-CGP 12177.
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Differences between the third cardiac β‐adrenoceptor and the colonic β3‐adrenoceptor in the rat
British journal of pharmacology, 1996Co-Authors: Alberto J Kaumann, Peter C M MolenaarAbstract:1. The heart of several species including man contains atypical beta-adrenoceptors, in addition to coexisting beta 1- and beta 2-adrenoceptors. We now asked the question whether or not the third cardiac beta-adrenoceptor is identical to the putative beta 3-adrenoceptor. We compared the properties of the third cardiac beta-adrenoceptor with those of beta 3-adrenoceptors in isolated tissues of the rat. To study the third cardiac beta-adrenoceptor we used spontaneously beating right atria, paced left atria and paced left ventricular papillary muscles. As a likely model for putative beta 3-adrenoceptors we studied atypical beta-adrenoceptors of the colonic longitudinal muscle precontracted with 30 mM KCl. We used beta 3-adrenoceptor-selective agonists, antagonists and non-conventional partial agonists (ie high-affinity blockers of both beta 1- and beta 2-adrenoceptors know to exert also stimulant effects through beta 3-adrenoceptors). 2. The non-conventional partial agonist (-)-CGP 12177 caused positive chronotropic effects in right atria (pD2 = 7.3) and positive inotropic effects in left atria (pD2 = 7.5). The stimulant effects of (-)-CGP 12177 were resistant to blockade by 200 nM-2 microM (-)-propranolol and 3 microM ICI 118551 (a beta 2-selective antagonist) but antagonized by 1 microM (-)-bupranolol (pKB = 6.4-6.8), 3 microM CGP 20712A (a beta 1-selective antagonist) (pKB = 6.3-6.4) and 6.6 microM SR 59230A (a beta 3-selective antagonist, pKB = 5.1-5.4). 3. The non-conventional partial agonist Cyanopindolol caused positive chronotropic effects in right atria (pD2 = 7.7) and positive inotropic effects in left atria (pD2 = 7.1). The stimulant effects of Cyanopindolol were resistant to blockade by 200 nM (-)-propranolol but antagonized by 1 microM (-)-bupranolol (pKB = 6.8-7.1). 4. Neither (-)-CGP 12177 nor Cyanopindolol caused stimulant effects in papillary muscles at concentrations between 0.2 nM and 20 microM. 5. In the presence of 200 nM (-)-propranolol the beta 3-adrenoceptor-selective agonists BRL 37344 (6 microM), SR 58611A (6 microM), ZD 2079 (60 microM) and CL 316243 (60 microM) did not cause stimulant effects or modify the potency and efficacy of the effects of (-)-CGP 12177 in right and left atria. The combination of 2 microM (-)-propranolol and 2 microM (-)-noradrenaline did not modify the chronotropic potency and efficacy of (-)-CGP 12177 compared to the potency and efficacy in the presence of 2 microM (-)-propranolol alone. 6. (-)-CGP 12177 relaxed the colon with a pD2 of 6.9 and a maximum effect of 55% compared to (-)-isoprenaline. The relaxant effects of (-)-CGP 12177 were resistant to blockade by 200 nM (-)-propranolol, 3 microM CGP 20712A, 3 microM ICI 118551 but blocked by 2 microM (-)-propranolol (pKB = 6.0), 1 microM (-)-bupranolol (pKB = 6.4) and 3 microM SR 59230A (pKB = 6.3). In the presence of 200 nM (-)-propranolol, (-)-CGP 12177 (20 microM) antagonized surmountably the relaxant effects of BRL 37344 (pKP = 7.3) (-)-noradrenaline (pKP = 7.0); and CL 316243 (pKP = 7.0). 7. Cyanopindolol in the presence of 200 nM (-)-propranolol relaxed the colon with a pD2 of 7.0 and a maximum effect of 40% compared to (-)-isoprenaline. As expected from a partial agonist, Cyanopindolol antagonized the relaxant effects of both BRL 37344 and CL 316243 with a pKP = 7.6 and (-)-noradrenaline with a pKP = 7.4. 8. The following beta 3-adrenoceptor-selective agonists were potent colonic relaxants (pD2 values between parentheses): BRL 37344 (9.1), ZD 2079 (7.0), CL 316243 (9.0) and SR 58611A (8.2). The relaxant effects of these agonists were only marginally affected by 200 nM (-)-propranolol, not blocked by 3 microM CGP 20712A or 3 microM ICI 118551, and blocked by SR 59230A 3 microM (pKB = 6.9-7.5), 1 microM (-)-bupranolol (pKB = 6.2-6.4) and 2 microM (-)-propranolol (pKB = 6.3-6.5). 9...
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Localization of (-)-[125I]Cyanopindolol binding in guinea-pig heart: characteristics of non-β-adrenoceptor related binding in cardiac pacemaker and conducting regions
Neuroscience letters, 1992Co-Authors: Peter C M Molenaar, Andrew R Kompa, Susan J. Roberts, Helen S. Pak, Roger J. SummersAbstract:Receptor autoradiography was used in guinea-pig heart to locate binding sites for the beta-adrenoceptor ligand (-)[125I]Cyanopindolol (CYP) resistant to blockade by the beta-adrenoceptor antagonist (-)-propranolol (1 microM). Highly localized binding was observed to regions closely associated with the sinoatrial node, atrioventricular node and bundle of His but was not observed on myocardial, pacemaker, conducting cells or adipose tissue. Free [125I] also bound to identical sites. Binding was enhanced in the presence of ascorbic acid but was completely inhibited by (-)-isoprenaline (100 microM), serotonin (5-HT) (10 microM) and phentolamine (10 microM).
Barbara Malinowska - One of the best experts on this subject based on the ideXlab platform.
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Potential involvement of a propranolol-insensitive atypical beta-adrenoceptor the vasodilator effect of Cyanopindolol in the human pulmonary artery.
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2006Co-Authors: Hanna Kozłowska, Eberhard Schlicker, Miroslaw Kozlowski, Marta Baranowska, Barbara MalinowskaAbstract:The aim of our study was to examine whether non beta(1)-/beta(2)-adrenoceptors participate in the relaxation of the human pulmonary artery. For this purpose the vasodilatory effect of the non-conventional partial beta-adrenoceptor agonist Cyanopindolol was examined. Cyanopindolol (1-300 microM), studied in the presence of the beta(1)-/beta(2)-adrenoceptor antagonist propranolol, relaxed the human pulmonary artery preconstricted with serotonin 1 microM in a concentration-dependent manner (maximally by about 80%). This effect was diminished by bupranolol 10 microM (an antagonist of beta(1)-beta(3)-adrenoceptors and the low affinity state of the beta(1)-adrenoceptor) and CGP 20712 10 microM (known to antagonize the low-affinity state of the beta(1)-adrenoceptor at high concentrations). In further experiments, the effect of beta-adrenoceptor ligands on the serotonin-induced vasoconstriction was examined. The concentration-response curve for serotonin was not affected by Cyanopindolol 30 microM, bupranolol 10 microM and CGP 20712 10 microM but shifted to the right by Cyanopindolol 100 and 300 microM; the serotonin 5-HT(2A) receptor antagonist ketanserin 0.3 microM abolished the maximum contraction elicited by serotonin. In conclusion, the present study reveals that the vasodilatory effect of Cyanopindolol in the human pulmonary artery consists of two components, i.e. activation of a propranolol-insensitive atypical beta-adrenoceptor and antagonism against 5-HT(2A) receptors.
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Positive inotropic and lusitropic effects mediated via the low‐affinity state of β1‐adrenoceptors in pithed rats
British journal of pharmacology, 2005Co-Authors: Agnieszka Zakrzeska, Eberhard Schlicker, Hanna Kozłowska, Grzegorz Kwolek, Barbara MalinowskaAbstract:Activation by CGP 12177 and Cyanopindolol of the human and rat low-affinity state of β1-adrenoceptors increases frequency and contractile force and hastens relaxation in isolated cardiac tissues, and probably relaxes isolated vessels. In order to identify the positive inotropic, positive lusitropic and vasodilator effects of both agonists also in vivo, we have determined their effects on the left ventricular systolic pressure (LVSP), the rate of intraventricular pressure rise (+dP dt−1max) and decline (−dP dt−1max), the diastolic blood pressure (DBP) and the mesenteric blood flow (MBF) in pithed and vagotomized rats. CGP 12177 (0.1–100 nmol kg−1) and Cyanopindolol (1–1000 nmol kg−1) dose-dependently enhanced all cardiac parameters. The nonselective β-adrenoceptor antagonist bupranolol 10 μmol kg−1 diminished the CGP 12177 (100 nmol kg−1)-stimulated increases in LVSP from 26.3±8.2 to 13.1±1.8 mmHg (P
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Ligands at β2-, β3-, and the low-affinity state of β1-adrenoceptors block the α1-adrenoceptor-mediated constriction in human pulmonary and rat mesenteric arteries
Journal of cardiovascular pharmacology, 2005Co-Authors: Hanna Kozłowska, Eberhard Schlicker, Miroslaw Kozlowski, Urszula Siedlecka, Jerzy Laudanski, Barbara MalinowskaAbstract:We examined whether the β 2 -adrenoceptor agonists fenoterol and salbutamol, the β 3 -adrenoceptor agonists CL 316243 and ZD 2079, and the agonists of the low-affinity state of β-adrenoceptors, Cyanopindolol and CGP 12177 block α 1 -adrenoceptors in that concentration range in which they relax the human pulmonary and rat mesenteric arteries preconstricted with phenylephrine 10 μM and I μM, respectively. For quantification of vasodilatation pEC 2 5 values and for the antagonism toward α 1 -adrenoceptors, pA 2 values were determined. We found that in the rat mesenteric artery, (I) the pEC 2 5 values of the p-adrenoceptor ligands resemble their respective pA 2 values (difference ≤ 0.9 log units), and (2) the order of potencies is the same for both parameters, ie, Cyanopindolol ∼ fenoterol > CGP 12177 > salbutamol > ZD 2079 > CL 316243. In the human pulmonary artery, (1) the pEC 2 5 values are slightly lower (by 0.6-1.3 log units) than their respective pA 2 values, and (2) the rank order of potencies is the same for both parameters. In conclusion, the present study suggests that ligands of β 2 -adrenoceptors and of non-pi-non-β 2 -adrenoceptors relax rat and human vessels preconstricted with phenylephrine or norepinephrine mainly through their α 1 -adrenolytic effects. Hence, for the investigation of the role of p-adrenoceptors in vessels, the constrictor agent should be chosen with great caution.
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Further evidence for differences between cardiac atypical β‐adrenoceptors and brown adipose tissue β3‐adrenoceptors in the pithed rat
British journal of pharmacology, 1997Co-Authors: Barbara Malinowska, Eberhard SchlickerAbstract:1. We have previously shown (Malinowska & Schlicker, 1996) that the atypical beta-adrenoceptor involved in the positive chronotropic effect of the so-called non-conventional partial beta-adrenoceptor agonists CGP 12177 and Cyanopindolol in the pithed rat possesses properties markedly different from those observed for beta3-adrenoceptors in the literature. In the present study, we have directly compared the pharmacological properties of the atypical cardiostimulant beta-adrenoceptor and of the beta3-adrenoceptor mediating the thermogenic response in the brown adipose tissue in pithed and vagotomized rats. 2. Heart rate was dose-dependently increased by CGP 12177 and Cyanopindolol by maximally 150 and 100 beats min(-1), yielding pED50 values of 8.0 and 7.3, respectively (pED50, -log10 of the dose in mol kg(-1) body weight i.v. causing the half-maximum effect), but not affected by the selective beta3-adrenoceptor agonist CL 316243 (pED50 > 6.0). 3. CGP 12177, Cyanopindolol and CL 316243 increased temperature in the brown adipose tissue by maximally 1 degree C (pED50 values 7.4, 6.3 and 8.6, respectively). 4. The beta1-adrenoceptor antagonist CGP 20712 10 micromol kg(-1), attenuated the cardiostimulatory effect of CGP 12177 and, at a still higher dose (30 micromol kg(-1)), also antagonized its thermogenic effect. The -log10 values of the doses causing a two fold shift of the dose-response curves (DRCs) of CGP 12177 to the right were 6.1 and 5.2, respectively, and were much lower than the corresponding value for the antagonism of CGP 20712 against the beta1-adrenoceptor-mediated positive chronotropic effect which was 8.6. 5. The cardiostimulant and the thermogenic effect of CGP 12177 were not affected by the beta2-adrenoceptor antagonist ICI 118551 10 micromol kg(-1). 6. The beta3-adrenoceptor antagonist SR 59230A (which, by itself, caused a beta1-adrenoceptor-mediated increase in heart rate and, for this reason, was studied after administration of a low dose of CGP 20712) attenuated the cardiostimulant and the thermogenic effect of CGP 12177 to a similar extent. The -log10 values of the doses causing two fold rightward shifts of the DRCs of CGP 12177 were 5.9 and 5.7, respectively. 7. The non-selective beta-adrenoceptor antagonist bupranolol diminished the cardiostimulant and thermogenic response to a very similar extent. The -log10 values causing two fold rightward shifts of the DRCs of CGP 12177 were 5.6 and 5.7, respectively, and were much lower than the corresponding values for the antagonism of bupranolol against the beta1-adrenoceptor-mediated positive chronotropic effect and the beta2-adrenoceptor-mediated decrease in diastolic blood pressure which were 7.6 and 8.3, respectively. 8. The rank order of agonistic potencies for the cardiostimulant effect (CGP 12177 > Cyanopindolol > CL 316243) differs from that for the thermogenic response in the brown adipose tissue (CL 316243 > CGP 12177 > Cyanopindolol); furthermore, there is a difference with respect to the rank orders of antagonistic potencies for cardiostimulation (CGP 20712 > or = SR 59230A > or = bupranolol > ICI 118551) and thermogenesis (SR 59230A = bupranolol > CGP 20712 > ICI 118551). 9. In conclusion, our study provides further evidence that the atypical cardiostimulant beta-adrenoceptors (causing an increase in heart rate) and beta3-adrenoceptors are pharmacologically different.
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mediation of the positive chronotropic effect of cgp 12177 and Cyanopindolol in the pithed rat by atypical β adrenoceptors different from β3 adrenoceptors
British Journal of Pharmacology, 1996Co-Authors: Barbara Malinowska, Eberhard SchlickerAbstract:1. The influence of beta 1-, beta 2-, and beta 3-adrenoceptor agonists and of CGP 12177 and Cyanopindolol on heart rate and diastolic blood pressure was studied in the pithed rat. 2. The beta 1-adrenoceptor agonist, prenalterol, increased heart rate and the beta 2-adrenoceptor agonist, fenoterol, caused a fall in blood pressure. The effect of prenalterol was antagonized by the beta 1-adrenoceptor antagonist, CGP 20712 0.1 mumol kg-1 and the action of fenoterol was attenuated by the beta 2-adrenoceptor antagonist, ICI 118551 0.1 mumol kg-1. Both effects were markedly diminished by the non-selective beta-adrenoceptor antagonist, bupranolol 0.1 mumol kg-1. 3. The non-selective beta-adrenoceptor agonist, isoprenaline, three beta 3-agonists as well as CGP 12177 and Cyanopindolol elicited a positive chronotropic effect, exhibiting the following pED delta 60 values (negative log values of the doses increasing heart rate by 60 beats min-1): isoprenaline 10.4, CGP 12177 8.3, Cyanopindolol 7.2, BRL 37344 6.9, ZD 2079 5.2 and CL 316243 < 5. 4. CGP 20712 0.1 mumol kg-1, given together with ICI 118551 0.1 mumol kg-1, markedly attenuated the positive chronotropic effect of isoprenaline, BRL 37344, ZD 2079 and CL 316243 without affecting the increase in heart rate produced by CGP 12177 and Cyanopindolol. 5. The positive chronotropic effect of CGP 12177 and Cyanopindolol was attenuated by CGP 20712, 1 and 10 mumol kg-1 and bupranolol, 10 mumol kg-1 but was not affected by ICI 118551, 10 mumol kg-1. The effect of CGP 12177 was also not changed by BRL 37344 1 mumol kg-1, ZD 2079 10 mumol kg-1, CL 316243 10 mumol kg-1, the alpha 1-adrenoceptor antagonist, prazosin 1 mumol kg-1 and the 5-hydroxytryptamine 5-HT2A receptor antagonist, ketanserin 3 mumol kg-1. 6. CGP 12177 0.002 mumol kg-1 and Cyanopindolol 0.003 mumol kg-1 shifted to the right the dose-response curve of prenalterol for its positive chronotropic effect. The -log values of the doses causing a twofold shift to the right were 9.6 and 9.5, respectively. 7. Isoprenaline 0.00001-0.001 mumol kg-1, BRL 37344 0.01-1 mumol kg-1 and CGP 12177 0.1 mumol kg-1 caused a fall in diastolic blood pressure which was markedly attenuated by combined administration of CGP 20712 and ICI 118551, 0.1 mumol kg-1 each. 8. CGP 12177 0.01 and 0.1 mumol kg-1 and Cyanopindolol 1 mumol kg-1 elicited an increase in diastolic blood pressure. CGP 20712, ICI 118551, bupranolol and, in the case of CGP 12177, also BRL 37344, ZD 2079, CL 316243, prazosin and ketanserin did not influence this effect. 9. In conclusion, the positive chronotropic effect of CGP 12177 and Cyanopindolol is not mediated via beta 1-, beta 2-, beta 3-, alpha 1-adrenoceptors or 5-HT2A receptors. This effect may involve atypical beta-adrenoceptors, similar or identical to those described by Kaumann (1989) in isolated heart preparations.
