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PROPOSAL FOR THE INTERACTION OF NON‐CONVENTIONAL PARTIAL AGONISTS AND CATECHOLAMINES WITH THE ‘PUTATIVE (β‐ADRENOCEPTOR’ IN MAMMALIAN HEART
Author(s) -
Molenaar Peter,
Sarsero Doreen,
Kaumann Alberto J.
Publication year - 1997
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.1997.tb02107.x
Subject(s) - partial agonist , agonist , chronotropic , intrinsic activity , isoprenaline , receptor , chemistry , endocrinology , medicine , antagonist , pharmacology , biology , heart rate , stimulation , blood pressure
SUMMARY 1. Evidence for a ‘putative β‐adrenoceptor’ originated over 20 years ago when cardiostimulant effects were observed to non‐conventional partial agonists. These agonists were originally described as β 1 ‐ and β 2 ‐adrenoceptor antagonists; however, they cause cardiostimulant effects at much higher concentrations than those required to block β 2 ‐ and β 2 ‐adrenoceptors. Cardiostimulant effects of non‐conventional partial agonists have been observed in mouse, rat, guinea‐pig, cat, ferret and human heart tissues. 2. The receptor is expressed in several heart regions, including the sinoatrial node, atrium and ventricle. 3. The receptor is resistant to blockade by most antagonists that possess high affinity for β 1 ‐ and β 2 ‐adrenoceptors, but is blocked with moderate affinity by (–)‐bupranolol and CGP20712A. 4. The receptor is pharmacologically distinct from the β 3 ‐adrenoceptor. Micromolar concentrations of β 3 ‐adrenoceptor agonists have no agonist or blocking activity. The receptor is also resistant to blockade by a β3‐adrenoceptor‐selective antagonist. 5. The receptor mediates increases in cAMP levels and cAMP‐dependent protein kinase (PK) A activity in cardiac tissues. Phosphodiesterase inhibition potentiates the positive chronotropic and inotropic effects of non‐conventional partial agonists. 6. The receptor mediates hastening of atrial and ventricular relaxation, which is consistent with involvement of a cAMP‐dependent pathway. 7. The non‐conventional partial agonist (–)–[ 3 H]–CGP 12177A labels the cardiac putative β 4 ‐adrenoceptor. Non‐conventional partial agonists compete for binding with affinities that are closely similar to their agonist potencies. Catecholamines compete for binding in a stereoselective manner with a rank order of affinity of (–)—R0363> (–)—isoprenaline > (–)—noradrenaline > (–)—adrenaline >> (+)—isoprenaline, suggesting that catecholamines can interact with the receptor. 8. The putative β 4 ‐adrenoceptor appears to be coupled to the G s ‐adenylyl cyclase system, which could serve as a guide to its future cloning. Activation of the receptor may plausibly improve diastolic function but could also mediate arrhythmias.