Desensitization and resensitization of β1- and putative β4-adrenoceptor mediated responses occur in parallel in a rat model of cardiac failure

Andrew R. Kompa, Roger J. Summers

Research output: Contribution to journalArticleResearchpeer-review

Abstract

1. Cardiostimulant effects of the non-conventional partial agonist, CGP 12177A, are mediated by a receptor distinct from the β 3 -adrenoceptor and termed the putative β 4 -adrenoceptor. Using a rat model of cardiac failure, induced by myocardial infarction (MI), we compared the desensitization and resensitization of responses to CGP 12177A with those to isoprenaline and RO 363 in left (LA) and right atria (RA). We also examined the ability of β-adrenoceptor antagonists to block responses to CGP 12177A. 2. MI reduced the maximum inotropic response to isoprenaline by 48% (sham 4.1 ± 0.6 mN, n = 10; MI 2.1 ± 0.4 mN, n = 8, P < 0.02), RO 363 by 61% (sham 4.2 ± 0.5 mN, n = 10 MI 1.8 ± 0.3 mN, n = 8, P < 0.005) and CGP 12177A by 49% (sham 1.4 ± 0.1 mN, n = 5; MI 0.7 ± 0.2 mN, n = 7 P < 0.O5 in electrically stimulated LA. MI also reduced the sensitivity to isoprenaline (pEC 50 : sham 8.79 ± 0.08, n = 10, MI 8.30 ± 0.10, n = 8; P = 0.001) and RO 363 (pEC 50 : sham 8.69 ± 0.07, n = 10; MI 8.33 ± 0.10, n = 8; P < 0.01). The maximum chronotropic responses to isoprenaline, RO 363 and CGP 12177A in RA were unaffected. 3. Pertussis toxin treatment (10 μg kg -1 , i.p.) restored the maximum inotropic response and sensitivity to isoprenaline (sham 3.5 ± 0.5 mN. n = 9; MI 3.2 ± 0.6 mN, n = 11, P = 0.702) and CGP 12177A (sham 1.6 ± 0.3 mN, n = 6; MI 1.9 ± 0.4 mN, n = 7, P = 0.537) in MI animals to levels similar to those in the sham group. 4. CGP 20712A (pK(B): LA 6.7 ± 0.2, n = 6; RA 7.1 ± 0.1, n = 4), ICI 118,551 (pK(B): LA 6.4 ± 0.1, n = 5; RA 6.3 ± 0.1, n = 6), propranolol (PK(B): LA 6.6 ± 0.1, n = 5; RA 6.8 ± 0.1, n = 6) and bupranolol (pK(B): LA 7.2 ± 0.1, n = 6; RA 7.7 ± 0.1, n = 8), showed moderate affinity for the putative β 4 -adrenoceptor. 5. Desensitization after MI and resensitization (after pertussis toxin treatment) to isoprenaline and CGP 12177A therefore occur in parallel, suggesting that the β 1 - and putative β 4 -adrenoceptor use the same signalling pathway. Antagonist affinity studies confirmed that drugs acting at β 1 -adrenoceptors also interact with putative β 4 -adrenoceptors with approximately 100 times lower affinity. We suggest that CGP 12177A produces its cardiac effects by interacting with a low affinity state of the β 1 -adrenoreceptor.

Original languageEnglish
Pages (from-to)1399-1406
Number of pages8
JournalBritish Journal of Pharmacology
Volume128
Issue number7
DOIs
Publication statusPublished - 1 Jan 1999

Keywords

  • Cardiac failure
  • CGP12177A
  • Isoprenaline
  • Pertussis toxin
  • Putative β -adrenoceptor
  • Rat atrium
  • RO 363
  • β -adrenoceptor

Cite this

@article{a86de8a6b83a4b558cff1fa789d55848,
title = "Desensitization and resensitization of β1- and putative β4-adrenoceptor mediated responses occur in parallel in a rat model of cardiac failure",
abstract = "1. Cardiostimulant effects of the non-conventional partial agonist, CGP 12177A, are mediated by a receptor distinct from the β 3 -adrenoceptor and termed the putative β 4 -adrenoceptor. Using a rat model of cardiac failure, induced by myocardial infarction (MI), we compared the desensitization and resensitization of responses to CGP 12177A with those to isoprenaline and RO 363 in left (LA) and right atria (RA). We also examined the ability of β-adrenoceptor antagonists to block responses to CGP 12177A. 2. MI reduced the maximum inotropic response to isoprenaline by 48{\%} (sham 4.1 ± 0.6 mN, n = 10; MI 2.1 ± 0.4 mN, n = 8, P < 0.02), RO 363 by 61{\%} (sham 4.2 ± 0.5 mN, n = 10 MI 1.8 ± 0.3 mN, n = 8, P < 0.005) and CGP 12177A by 49{\%} (sham 1.4 ± 0.1 mN, n = 5; MI 0.7 ± 0.2 mN, n = 7 P < 0.O5 in electrically stimulated LA. MI also reduced the sensitivity to isoprenaline (pEC 50 : sham 8.79 ± 0.08, n = 10, MI 8.30 ± 0.10, n = 8; P = 0.001) and RO 363 (pEC 50 : sham 8.69 ± 0.07, n = 10; MI 8.33 ± 0.10, n = 8; P < 0.01). The maximum chronotropic responses to isoprenaline, RO 363 and CGP 12177A in RA were unaffected. 3. Pertussis toxin treatment (10 μg kg -1 , i.p.) restored the maximum inotropic response and sensitivity to isoprenaline (sham 3.5 ± 0.5 mN. n = 9; MI 3.2 ± 0.6 mN, n = 11, P = 0.702) and CGP 12177A (sham 1.6 ± 0.3 mN, n = 6; MI 1.9 ± 0.4 mN, n = 7, P = 0.537) in MI animals to levels similar to those in the sham group. 4. CGP 20712A (pK(B): LA 6.7 ± 0.2, n = 6; RA 7.1 ± 0.1, n = 4), ICI 118,551 (pK(B): LA 6.4 ± 0.1, n = 5; RA 6.3 ± 0.1, n = 6), propranolol (PK(B): LA 6.6 ± 0.1, n = 5; RA 6.8 ± 0.1, n = 6) and bupranolol (pK(B): LA 7.2 ± 0.1, n = 6; RA 7.7 ± 0.1, n = 8), showed moderate affinity for the putative β 4 -adrenoceptor. 5. Desensitization after MI and resensitization (after pertussis toxin treatment) to isoprenaline and CGP 12177A therefore occur in parallel, suggesting that the β 1 - and putative β 4 -adrenoceptor use the same signalling pathway. Antagonist affinity studies confirmed that drugs acting at β 1 -adrenoceptors also interact with putative β 4 -adrenoceptors with approximately 100 times lower affinity. We suggest that CGP 12177A produces its cardiac effects by interacting with a low affinity state of the β 1 -adrenoreceptor.",
keywords = "Cardiac failure, CGP12177A, Isoprenaline, Pertussis toxin, Putative β -adrenoceptor, Rat atrium, RO 363, β -adrenoceptor",
author = "Kompa, {Andrew R.} and Summers, {Roger J.}",
year = "1999",
month = "1",
day = "1",
doi = "10.1038/sj.bjp.0702920",
language = "English",
volume = "128",
pages = "1399--1406",
journal = "British Journal of Pharmacology",
issn = "1476-5381",
publisher = "Wiley-Blackwell",
number = "7",

}

Desensitization and resensitization of β1- and putative β4-adrenoceptor mediated responses occur in parallel in a rat model of cardiac failure. / Kompa, Andrew R.; Summers, Roger J.

In: British Journal of Pharmacology, Vol. 128, No. 7, 01.01.1999, p. 1399-1406.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Desensitization and resensitization of β1- and putative β4-adrenoceptor mediated responses occur in parallel in a rat model of cardiac failure

AU - Kompa, Andrew R.

AU - Summers, Roger J.

PY - 1999/1/1

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N2 - 1. Cardiostimulant effects of the non-conventional partial agonist, CGP 12177A, are mediated by a receptor distinct from the β 3 -adrenoceptor and termed the putative β 4 -adrenoceptor. Using a rat model of cardiac failure, induced by myocardial infarction (MI), we compared the desensitization and resensitization of responses to CGP 12177A with those to isoprenaline and RO 363 in left (LA) and right atria (RA). We also examined the ability of β-adrenoceptor antagonists to block responses to CGP 12177A. 2. MI reduced the maximum inotropic response to isoprenaline by 48% (sham 4.1 ± 0.6 mN, n = 10; MI 2.1 ± 0.4 mN, n = 8, P < 0.02), RO 363 by 61% (sham 4.2 ± 0.5 mN, n = 10 MI 1.8 ± 0.3 mN, n = 8, P < 0.005) and CGP 12177A by 49% (sham 1.4 ± 0.1 mN, n = 5; MI 0.7 ± 0.2 mN, n = 7 P < 0.O5 in electrically stimulated LA. MI also reduced the sensitivity to isoprenaline (pEC 50 : sham 8.79 ± 0.08, n = 10, MI 8.30 ± 0.10, n = 8; P = 0.001) and RO 363 (pEC 50 : sham 8.69 ± 0.07, n = 10; MI 8.33 ± 0.10, n = 8; P < 0.01). The maximum chronotropic responses to isoprenaline, RO 363 and CGP 12177A in RA were unaffected. 3. Pertussis toxin treatment (10 μg kg -1 , i.p.) restored the maximum inotropic response and sensitivity to isoprenaline (sham 3.5 ± 0.5 mN. n = 9; MI 3.2 ± 0.6 mN, n = 11, P = 0.702) and CGP 12177A (sham 1.6 ± 0.3 mN, n = 6; MI 1.9 ± 0.4 mN, n = 7, P = 0.537) in MI animals to levels similar to those in the sham group. 4. CGP 20712A (pK(B): LA 6.7 ± 0.2, n = 6; RA 7.1 ± 0.1, n = 4), ICI 118,551 (pK(B): LA 6.4 ± 0.1, n = 5; RA 6.3 ± 0.1, n = 6), propranolol (PK(B): LA 6.6 ± 0.1, n = 5; RA 6.8 ± 0.1, n = 6) and bupranolol (pK(B): LA 7.2 ± 0.1, n = 6; RA 7.7 ± 0.1, n = 8), showed moderate affinity for the putative β 4 -adrenoceptor. 5. Desensitization after MI and resensitization (after pertussis toxin treatment) to isoprenaline and CGP 12177A therefore occur in parallel, suggesting that the β 1 - and putative β 4 -adrenoceptor use the same signalling pathway. Antagonist affinity studies confirmed that drugs acting at β 1 -adrenoceptors also interact with putative β 4 -adrenoceptors with approximately 100 times lower affinity. We suggest that CGP 12177A produces its cardiac effects by interacting with a low affinity state of the β 1 -adrenoreceptor.

AB - 1. Cardiostimulant effects of the non-conventional partial agonist, CGP 12177A, are mediated by a receptor distinct from the β 3 -adrenoceptor and termed the putative β 4 -adrenoceptor. Using a rat model of cardiac failure, induced by myocardial infarction (MI), we compared the desensitization and resensitization of responses to CGP 12177A with those to isoprenaline and RO 363 in left (LA) and right atria (RA). We also examined the ability of β-adrenoceptor antagonists to block responses to CGP 12177A. 2. MI reduced the maximum inotropic response to isoprenaline by 48% (sham 4.1 ± 0.6 mN, n = 10; MI 2.1 ± 0.4 mN, n = 8, P < 0.02), RO 363 by 61% (sham 4.2 ± 0.5 mN, n = 10 MI 1.8 ± 0.3 mN, n = 8, P < 0.005) and CGP 12177A by 49% (sham 1.4 ± 0.1 mN, n = 5; MI 0.7 ± 0.2 mN, n = 7 P < 0.O5 in electrically stimulated LA. MI also reduced the sensitivity to isoprenaline (pEC 50 : sham 8.79 ± 0.08, n = 10, MI 8.30 ± 0.10, n = 8; P = 0.001) and RO 363 (pEC 50 : sham 8.69 ± 0.07, n = 10; MI 8.33 ± 0.10, n = 8; P < 0.01). The maximum chronotropic responses to isoprenaline, RO 363 and CGP 12177A in RA were unaffected. 3. Pertussis toxin treatment (10 μg kg -1 , i.p.) restored the maximum inotropic response and sensitivity to isoprenaline (sham 3.5 ± 0.5 mN. n = 9; MI 3.2 ± 0.6 mN, n = 11, P = 0.702) and CGP 12177A (sham 1.6 ± 0.3 mN, n = 6; MI 1.9 ± 0.4 mN, n = 7, P = 0.537) in MI animals to levels similar to those in the sham group. 4. CGP 20712A (pK(B): LA 6.7 ± 0.2, n = 6; RA 7.1 ± 0.1, n = 4), ICI 118,551 (pK(B): LA 6.4 ± 0.1, n = 5; RA 6.3 ± 0.1, n = 6), propranolol (PK(B): LA 6.6 ± 0.1, n = 5; RA 6.8 ± 0.1, n = 6) and bupranolol (pK(B): LA 7.2 ± 0.1, n = 6; RA 7.7 ± 0.1, n = 8), showed moderate affinity for the putative β 4 -adrenoceptor. 5. Desensitization after MI and resensitization (after pertussis toxin treatment) to isoprenaline and CGP 12177A therefore occur in parallel, suggesting that the β 1 - and putative β 4 -adrenoceptor use the same signalling pathway. Antagonist affinity studies confirmed that drugs acting at β 1 -adrenoceptors also interact with putative β 4 -adrenoceptors with approximately 100 times lower affinity. We suggest that CGP 12177A produces its cardiac effects by interacting with a low affinity state of the β 1 -adrenoreceptor.

KW - Cardiac failure

KW - CGP12177A

KW - Isoprenaline

KW - Pertussis toxin

KW - Putative β -adrenoceptor

KW - Rat atrium

KW - RO 363

KW - β -adrenoceptor

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U2 - 10.1038/sj.bjp.0702920

DO - 10.1038/sj.bjp.0702920

M3 - Article

VL - 128

SP - 1399

EP - 1406

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 1476-5381

IS - 7

ER -