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Richard Bond

TitleProfessor
InstitutionUniversity of Houston
DepartmentPharmacological & Pharmaceutic
Address4800 Calhoun Rd
Houston TX 77004
Phone713-743-1210
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    Collapse Research 
    Collapse research activities and funding
    R29GM054805     (BOND, RICHARD AGUSTIN)Sep 30, 1997 - Sep 28, 2002
    NIH/NIGMS
    REVISING RECEPTOR THEORY FOR G PROTEIN-COUPLED RECEPTORS
    Role: Principal Investigator

    R01AI079236     (BOND, RICHARD AGUSTIN)Sep 1, 2009 - Apr 14, 2012
    NIH/NIAID
    Mechanisms of beta-blocker induced improvements in asthma
    Role: Principal Investigator

    R56AI079236     (BOND, RICHARD AGUSTIN)Apr 15, 2012 - Sep 30, 2014
    NIH/NIAID
    Mechanisms of Beta-blocker Induced Improvements in Asthma
    Role: Principal Investigator

    R01AI110007     (WALKER, JULIA K L)Jun 18, 2014 - May 31, 2019
    NIH/NIAID
    Optimizing Beta-Adrenoceptor Signaling Bias in Asthma
    Role: Co-Principal Investigator

    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    1. Joshi R, Valdez D, Kim H, Eikenburg DC, Knoll BJ, Bond RA. Effects of ß-blockers on house dust mite-driven murine models pre- and post-development of an asthma phenotype. Pulm Pharmacol Ther. 2017 Oct; 46:30-40. PMID: 28729042.
      View in: PubMed
    2. Forkuo GS, Kim H, Thanawala VJ, Al-Sawalha N, Valdez D, Joshi R, Parra S, Pera T, Gonnella PA, Knoll BJ, Walker JK, Penn RB, Bond RA. Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by ß2-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase-Knockout Mice. Am J Respir Cell Mol Biol. 2016 Aug; 55(2):234-42. PMID: 26909542; PMCID: PMC4979368 [Available on 08/01/17].
    3. Bond RA, Thanawala VJ, Parra S, Leff P. Differences in asthma study models and the effectiveness of ß2 -adrenoceptor ligands: response to Lipworth et al. Br J Pharmacol. 2016 Jan; 173(1):250-1. PMID: 26687674; PMCID: PMC4813386 [Available on 01/01/17].
    4. Knight JM, Mak G, Shaw J, Porter P, McDermott C, Roberts L, You R, Yuan X, Millien VO, Qian Y, Song LZ, Frazier V, Kim C, Kim JJ, Bond RA, Milner JD, Zhang Y, Mandal PK, Luong A, Kheradmand F, McMurray JS, Corry DB. Long-Acting Beta Agonists Enhance Allergic Airway Disease. PLoS One. 2015; 10(11):e0142212. PMID: 26605551; PMCID: PMC4659681.
    5. Thanawala VJ, Valdez DJ, Joshi R, Forkuo GS, Parra S, Knoll BJ, Bouvier M, Leff P, Bond RA. ß-Blockers have differential effects on the murine asthma phenotype. Br J Pharmacol. 2015 Oct; 172(20):4833-46. PMID: 26211486; PMCID: PMC4621987 [Available on 10/01/16].
    6. Al-Sawalha N, Pokkunuri I, Omoluabi O, Kim H, Thanawala VJ, Hernandez A, Bond RA, Knoll BJ. Epinephrine Activation of the ß2-Adrenoceptor Is Required for IL-13-Induced Mucin Production in Human Bronchial Epithelial Cells. PLoS One. 2015; 10(7):e0132559. PMID: 26161982; PMCID: PMC4498766.
    7. Curtis MJ, Bond RA, Spina D, Ahluwalia A, Alexander SP, Giembycz MA, Gilchrist A, Hoyer D, Insel PA, Izzo AA, Lawrence AJ, MacEwan DJ, Moon LD, Wonnacott S, Weston AH, McGrath JC. Experimental design and analysis and their reporting: new guidance for publication in BJP. Br J Pharmacol. 2015 Jul; 172(14):3461-71. PMID: 26114403; PMCID: PMC4507152.
    8. Michel MC, Seifert R, Bond RA. Dynamic bias and its implications for GPCR drug discovery. Nat Rev Drug Discov. 2014 Nov; 13(11):869. PMID: 25323926.
      View in: PubMed
    9. Geng C, Rajapakshe K, Shah SS, Shou J, Eedunuri VK, Foley C, Fiskus W, Rajendran M, Chew SA, Zimmermann M, Bond R, He B, Coarfa C, Mitsiades N. Androgen receptor is the key transcriptional mediator of the tumor suppressor SPOP in prostate cancer. Cancer Res. 2014 Oct 01; 74(19):5631-43. PMID: 25274033; PMCID: PMC4209379.
    10. Thanawala VJ, Forkuo GS, Stallaert W, Leff P, Bouvier M, Bond R. Ligand bias prevents class equality among beta-blockers. Curr Opin Pharmacol. 2014 Jun; 16:50-7. PMID: 24681351; PMCID: PMC4065631.
    11. Bond RA. The intrinsic bias of generalizations. Am J Respir Crit Care Med. 2014 Feb 01; 189(3):359. PMID: 24484333; PMCID: PMC3977730.
    12. Penn RB, Bond RA, Walker JK. GPCRs and arrestins in airways: implications for asthma. Handb Exp Pharmacol. 2014; 219:387-403. PMID: 24292841; PMCID: PMC4429126.
    13. Forkuo GS, Thanawala VJ, Al-Sawalha N, Bond RA, Walker JK. Reply: Adverse effects of long-acting beta-agonists on airway hyperresponsiveness. Am J Respir Cell Mol Biol. 2013 Sep; 49(3):502. PMID: 23991664; PMCID: PMC3824060.
    14. Vollert C, Forkuo GS, Bond RA, Eriksen JL. Chronic treatment with DCPCX, an adenosine A(1) antagonist, worsens long-term memory. Neurosci Lett. 2013 Aug 26; 548:296-300. PMID: 23748072; PMCID: PMC3722854.
    15. Geng C, He B, Xu L, Barbieri CE, Eedunuri VK, Chew SA, Zimmermann M, Bond R, Shou J, Li C, Blattner M, Lonard DM, Demichelis F, Coarfa C, Rubin MA, Zhou P, O'Malley BW, Mitsiades N. Prostate cancer-associated mutations in speckle-type POZ protein (SPOP) regulate steroid receptor coactivator 3 protein turnover. Proc Natl Acad Sci U S A. 2013 Apr 23; 110(17):6997-7002. PMID: 23559371; PMCID: PMC3637757.
    16. Thanawala VJ, Forkuo GS, Al-Sawalha N, Azzegagh Z, Nguyen LP, Eriksen JL, Tuvim MJ, Lowder TW, Dickey BF, Knoll BJ, Walker JK, Bond RA. ß2-Adrenoceptor agonists are required for development of the asthma phenotype in a murine model. Am J Respir Cell Mol Biol. 2013 Feb; 48(2):220-9. PMID: 23204390; PMCID: PMC3604060.
    17. Kim SJ, Zhang H, Khaliulin I, Choisy SC, Bond R, Lin H, El Haou S, Milnes JT, Hancox JC, Suleiman MS, James AF. Activation of glibenclamide-sensitive ATP-sensitive K+ channels during ß-adrenergically induced metabolic stress produces a substrate for atrial tachyarrhythmia. Circ Arrhythm Electrophysiol. 2012 Dec; 5(6):1184-92. PMID: 23159416.
      View in: PubMed
    18. Nguyen LP, Singh B, Okulate AA, Alfaro VY, Tuvim MJ, Dickey BF, Bond RA. Complementary anti-inflammatory effects of a ß-blocker and a corticosteroid in an asthma model. Naunyn Schmiedebergs Arch Pharmacol. 2012 Feb; 385(2):203-10. PMID: 21964666.
      View in: PubMed
    19. Bond RA, Giles H. For the love of paradox: from neurobiology to pharmacology. Behav Pharmacol. 2011 Sep; 22(5-6):385-9. PMID: 21712710; PMCID: PMC3155657.
    20. Walker JK, Penn RB, Hanania NA, Dickey BF, Bond RA. New perspectives regarding ß(2) -adrenoceptor ligands in the treatment of asthma. Br J Pharmacol. 2011 May; 163(1):18-28. PMID: 21175591; PMCID: PMC3085865.
    21. Bond RA, Spina D. Special issue of BJP on respiratory pharmacology. Br J Pharmacol. 2011 May; 163(1):1-3. PMID: 21470199; PMCID: PMC3085863.
    22. Michel MC, Harding SE, Bond RA. Are there functional ß3-adrenoceptors in the human heart? Br J Pharmacol. 2011 Feb; 162(4):817-22. PMID: 20735409; PMCID: PMC3042193.
    23. Peng H, Bond RA, Knoll BJ. The effects of acute and chronic nadolol treatment on ß2AR signaling in HEK293 cells. Naunyn Schmiedebergs Arch Pharmacol. 2011 Feb; 383(2):209-16. PMID: 21225244.
      View in: PubMed
    24. Charlton SJ, Bond RA. BJP issue on drug discovery. Br J Pharmacol. 2010 Nov; 161(6):1201-2. PMID: 20977464; PMCID: PMC3000644.
    25. Hanania NA, Mannava B, Franklin AE, Lipworth BJ, Williamson PA, Garner WJ, Dickey BF, Bond RA. Response to salbutamol in patients with mild asthma treated with nadolol. Eur Respir J. 2010 Oct; 36(4):963-5. PMID: 20889466.
      View in: PubMed
    26. McGrath JC, Bond RA. Sir James Black (1924-2010). Br J Pharmacol. 2010 Jul; 160 Suppl 1:S2. PMID: 20590647; PMCID: PMC2947408.
    27. Dickey BF, Walker JK, Hanania NA, Bond RA. beta-Adrenoceptor inverse agonists in asthma. Curr Opin Pharmacol. 2010 Jun; 10(3):254-9. PMID: 20399707; PMCID: PMC2905467.
    28. Hanania NA, Dickey BF, Bond RA. Clinical implications of the intrinsic efficacy of beta-adrenoceptor drugs in asthma: full, partial and inverse agonism. Curr Opin Pulm Med. 2010 Jan; 16(1):1-5. PMID: 19887938; PMCID: PMC2855430.
    29. Nguyen LP, Lin R, Parra S, Omoluabi O, Hanania NA, Tuvim MJ, Knoll BJ, Dickey BF, Bond RA. Beta2-adrenoceptor signaling is required for the development of an asthma phenotype in a murine model. Proc Natl Acad Sci U S A. 2009 Feb 17; 106(7):2435-40. PMID: 19171883; PMCID: PMC2650174.
    30. Nguyen LP, Omoluabi O, Parra S, Frieske JM, Clement C, Ammar-Aouchiche Z, Ho SB, Ehre C, Kesimer M, Knoll BJ, Tuvim MJ, Dickey BF, Bond RA. Chronic exposure to beta-blockers attenuates inflammation and mucin content in a murine asthma model. Am J Respir Cell Mol Biol. 2008 Mar; 38(3):256-62. PMID: 18096872; PMCID: PMC2258446.
    31. Hanania NA, Singh S, El-Wali R, Flashner M, Franklin AE, Garner WJ, Dickey BF, Parra S, Ruoss S, Shardonofsky F, O'Connor BJ, Page C, Bond RA. The safety and effects of the beta-blocker, nadolol, in mild asthma: an open-label pilot study. Pulm Pharmacol Ther. 2008; 21(1):134-41. PMID: 17703976; PMCID: PMC2254137.
    32. Lin R, Peng H, Nguyen LP, Dudekula NB, Shardonofsky F, Knoll BJ, Parra S, Bond RA. Changes in beta 2-adrenoceptor and other signaling proteins produced by chronic administration of 'beta-blockers' in a murine asthma model. Pulm Pharmacol Ther. 2008; 21(1):115-24. PMID: 17689122; PMCID: PMC2775056.
    33. Bond RA, Spina D, Parra S, Page CP. Getting to the heart of asthma: can "beta blockers" be useful to treat asthma? Pharmacol Ther. 2007 Sep; 115(3):360-74. PMID: 17681610.
      View in: PubMed
    34. Chapman RW, Minnicozzi M, Celly CS, Phillips JE, Kung TT, Hipkin RW, Fan X, Rindgen D, Deno G, Bond R, Gonsiorek W, Billah MM, Fine JS, Hey JA. A novel, orally active CXCR1/2 receptor antagonist, Sch527123, inhibits neutrophil recruitment, mucus production, and goblet cell hyperplasia in animal models of pulmonary inflammation. J Pharmacol Exp Ther. 2007 Aug; 322(2):486-93. PMID: 17496165.
      View in: PubMed
    35. Parra S, Bond RA. Inverse agonism: from curiosity to accepted dogma, but is it clinically relevant? Curr Opin Pharmacol. 2007 Apr; 7(2):146-50. PMID: 17284360.
      View in: PubMed
    36. Dudekula N, Arora V, Callaerts-Vegh Z, Bond RA. The temporal hormesis of drug therapies. Dose Response. 2006 May 01; 3(3):414-24. PMID: 18648614; PMCID: PMC2475944.
    37. Bond RA, Ijzerman AP. Recent developments in constitutive receptor activity and inverse agonism, and their potential for GPCR drug discovery. Trends Pharmacol Sci. 2006 Feb; 27(2):92-6. PMID: 16406086.
      View in: PubMed
    38. Bond RA. A proposal for a national program reporting beneficial drug responses, analogous to the existing program to detect adverse drug responses. Med Hypotheses. 2006; 66(1):10-3. PMID: 16198061.
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    39. Webb A, Bond R, McLean P, Uppal R, Benjamin N, Ahluwalia A. Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc Natl Acad Sci U S A. 2004 Sep 14; 101(37):13683-8. PMID: 15347817; PMCID: PMC518813.
    40. Xiao RP, Zhu W, Zheng M, Chakir K, Bond R, Lakatta EG, Cheng H. Subtype-specific beta-adrenoceptor signaling pathways in the heart and their potential clinical implications. Trends Pharmacol Sci. 2004 Jul; 25(7):358-65. PMID: 15219978.
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    41. Callaerts-Vegh Z, Evans KL, Dudekula N, Cuba D, Knoll BJ, Callaerts PF, Giles H, Shardonofsky FR, Bond RA. Effects of acute and chronic administration of beta-adrenoceptor ligands on airway function in a murine model of asthma. Proc Natl Acad Sci U S A. 2004 Apr 06; 101(14):4948-53. PMID: 15069206; PMCID: PMC387354.
    42. Xiao RP, Zhang SJ, Chakir K, Avdonin P, Zhu W, Bond RA, Balke CW, Lakatta EG, Cheng H. Enhanced G(i) signaling selectively negates beta2-adrenergic receptor (AR)--but not beta1-AR-mediated positive inotropic effect in myocytes from failing rat hearts. Circulation. 2003 Sep 30; 108(13):1633-9. PMID: 12975249.
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    43. Flesch M, Höper A, Dell'Italia L, Evans K, Bond R, Peshock R, Diwan A, Brinsa TA, Wei CC, Sivasubramanian N, Spinale FG, Mann DL. Activation and functional significance of the renin-angiotensin system in mice with cardiac restricted overexpression of tumor necrosis factor. Circulation. 2003 Aug 05; 108(5):598-604. PMID: 12874189.
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    44. Callaerts-Vegh Z, Evans KL, Shipley GL, Davies PJ, Cuba DL, Gurji HA, Giles H, Bond RA. Effects of different beta adrenoceptor ligands in mice with permanent occlusion of the left anterior descending coronary artery. Br J Pharmacol. 2003 Apr; 138(8):1505-16. PMID: 12721106; PMCID: PMC1573808.
    45. Evans KL, Bond RA, Corry DB, Shardonofsky FR. Frequency dependence of respiratory system mechanics during induced constriction in a murine model of asthma. J Appl Physiol (1985). 2003 Jan; 94(1):245-52. PMID: 12486022.
      View in: PubMed
    46. Bond RA. Can intellectualism stifle scientific discovery? Nat Rev Drug Discov. 2002 Oct; 1(10):825-9. PMID: 12360260.
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    47. Liu X, Callaerts-Vegh Z, Evans KL, Bond RA. Chronic infusion of beta-adrenoceptor antagonist and inverse agonists decreases elevated protein kinase A activity in transgenic mice with cardiac-specific overexpression of human beta 2-adrenoceptor. J Cardiovasc Pharmacol. 2002 Sep; 40(3):448-55. PMID: 12198331.
      View in: PubMed
    48. Bond RA. Is paradoxical pharmacology a strategy worth pursuing? Trends Pharmacol Sci. 2001 Jun; 22(6):273-6. PMID: 11395153.
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    49. Franceschini D, Orr-Urtreger A, Yu W, Mackey LY, Bond RA, Armstrong D, Patrick JW, Beaudet AL, De Biasi M. Altered baroreflex responses in alpha7 deficient mice. Behav Brain Res. 2000 Aug; 113(1-2):3-10. PMID: 10942027.
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    50. Nagaraja S, Iyer S, Liu X, Eichberg J, Bond RA. Treatment with inverse agonists enhances baseline atrial contractility in transgenic mice with chronic beta2-adrenoceptor activation. Br J Pharmacol. 1999 Jul; 127(5):1099-104. PMID: 10455254; PMCID: PMC1566118.
    51. Clarke WP, Bond RA. The elusive nature of intrinsic efficacy. Trends Pharmacol Sci. 1998 Jul; 19(7):270-6. PMID: 9703760.
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    52. Milligan G, Bond RA. Inverse agonism and the regulation of receptor number. Trends Pharmacol Sci. 1997 Dec; 18(12):468-74. PMID: 9458695.
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    53. Gürdal H, Bond RA, Johnson MD, Friedman E, Onaran HO. An efficacy-dependent effect of cardiac overexpression of beta2-adrenoceptor on ligand affinity in transgenic mice. Mol Pharmacol. 1997 Aug; 52(2):187-94. PMID: 9271340.
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    54. Bond RA. Do recent operational studies indicate that a single state model is no longer applicable to G protein-coupled receptors? Ann N Y Acad Sci. 1997 May 30; 812:92-7. PMID: 9186724.
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    55. Samama P, Bond RA, Rockman HA, Milano CA, Lefkowitz RJ. Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice. Proc Natl Acad Sci U S A. 1997 Jan 07; 94(1):137-41. PMID: 8990174; PMCID: PMC19258.
    56. Jaber M, Koch WJ, Rockman H, Smith B, Bond RA, Sulik KK, Ross J, Lefkowitz RJ, Caron MG, Giros B. Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function. Proc Natl Acad Sci U S A. 1996 Nov 12; 93(23):12974-9. PMID: 8917529; PMCID: PMC24031.
    57. Bond RA, Lefkowitz RJ. The third beta is not the charm. J Clin Invest. 1996 Jul 15; 98(2):241. PMID: 8755628; PMCID: PMC507421.
    58. Bond RA, Girdlestone D. Romancing receptor research at Verona classification meeting. Trends Pharmacol Sci. 1996 Mar; 17(3):85-9. PMID: 8936341.
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    59. Nagao T, Nakashima M, Smart FW, Bond RA, Morrison KJ, Vanhoutte PM. Potentiation of endothelium-dependent hyperpolarization to serotonin by dietary intake of NC 020, a defined fish oil, in the porcine coronary artery. J Cardiovasc Pharmacol. 1995 Nov; 26(5):679-81. PMID: 8637179.
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    60. Koch WJ, Rockman HA, Samama P, Hamilton RA, Bond RA, Milano CA, Lefkowitz RJ. Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor. Science. 1995 Jun 02; 268(5215):1350-3. PMID: 7761854.
      View in: PubMed
    61. Bond RA, Leff P, Johnson TD, Milano CA, Rockman HA, McMinn TR, Apparsundaram S, Hyek MF, Kenakin TP, Allen LF, et al. Physiological effects of inverse agonists in transgenic mice with myocardial overexpression of the beta 2-adrenoceptor. Nature. 1995 Mar 16; 374(6519):272-6. PMID: 7885448.
      View in: PubMed
    62. Milano CA, Allen LF, Dolber PC, Johnson TD, Rockman HA, Bond RA, Lefkowitz RJ. Marked enhancement in myocardial function resulting from overexpression of a human beta-adrenergic receptor gene. J Thorac Cardiovasc Surg. 1995 Feb; 109(2):236-41. PMID: 7853876.
      View in: PubMed
    63. Milligan G, Bond RA, Lee M. Inverse agonism: pharmacological curiosity or potential therapeutic strategy? Trends Pharmacol Sci. 1995 Jan; 16(1):10-3. PMID: 7732597.
      View in: PubMed
    64. Hieble JP, Bond RA. New directions in adrenoceptor pharmacology. Trends Pharmacol Sci. 1994 Nov; 15(11):397-9. PMID: 7855898.
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    65. Milano CA, Dolber PC, Rockman HA, Bond RA, Venable ME, Allen LF, Lefkowitz RJ. Myocardial expression of a constitutively active alpha 1B-adrenergic receptor in transgenic mice induces cardiac hypertrophy. Proc Natl Acad Sci U S A. 1994 Oct 11; 91(21):10109-13. PMID: 7937846; PMCID: PMC44967.
    66. Milano CA, Allen LF, Rockman HA, Dolber PC, McMinn TR, Chien KR, Johnson TD, Bond RA, Lefkowitz RJ. Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor. Science. 1994 Apr 22; 264(5158):582-6. PMID: 8160017.
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    67. Boulanger CM, Hughes H, Bond RA, Rafla E, Vanhoutte PM. Effects of S9977 on adrenergic neurotransmission. Gen Pharmacol. 1993 Mar; 24(2):429-34. PMID: 8387054.
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    68. Schini VB, Bond R, Gao Y, Illiano S, Junquero DC, Mombouli JV, Nagao T, Smart F, Vanhoutte PM. The sydnonimine C87-3754 evokes endothelium-independent relaxations and prevents endothelium-dependent contractions in blood vessels of the dog. J Cardiovasc Pharmacol. 1993; 22 Suppl 7:S10-6. PMID: 7504762.
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    69. Bond RA, Vanhoutte PM. Interaction of tertatolol at the "atypical" or beta 3-adrenoceptor in guinea-pig ileum. Gen Pharmacol. 1992 Mar; 23(2):171-6. PMID: 1353468.
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    70. Gao YS, Nagao T, Bond RA, Janssens WJ, Vanhoutte PM. Nebivolol induces endothelium-dependent relaxations of canine coronary arteries. J Cardiovasc Pharmacol. 1991 Jun; 17(6):964-9. PMID: 1714022.
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    71. Blue DR, Bond RA, Adham N, Delmendo R, Michel AD, Eglen RM, Whiting RL, Clarke DE. Antagonist characterization of atypical beta adrenoceptors in guinea pig ileum: blockade by alprenolol and dihydroalprenolol. J Pharmacol Exp Ther. 1990 Mar; 252(3):1034-42. PMID: 1969469.
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    72. Bond RA, Clarke DE. Agonist and antagonist characterization of a putative adrenoceptor with distinct pharmacological properties from the alpha- and beta-subtypes. Br J Pharmacol. 1988 Nov; 95(3):723-34. PMID: 2905184; PMCID: PMC1854239.
    73. Bond RA, Clarke DE. A response to isoprenaline unrelated to alpha- and beta-adrenoceptor agonism. Br J Pharmacol. 1987 Jul; 91(3):683-6. PMID: 2886175; PMCID: PMC1853534.
    74. Bond RA, Charlton KG, Clarke DE. Evidence for a receptor mediated action of norepinephrine distinct from alpha- and beta-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol. 1986 Nov; 334(3):261-6. PMID: 2880303.
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    75. Charlton KG, Bond RA, Clarke DE. An inhibitory prejunctional 5-HT1-like receptor in the isolated perfused rat kidney. Apparent distinction from the 5-HT1A, 5-HT1B and 5-HT1C subtypes. Naunyn Schmiedebergs Arch Pharmacol. 1986 Jan; 332(1):8-15. PMID: 3951568.
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