PROPOSAL FOR THE INTERACTION OF NON‐CONVENTIONAL PARTIAL AGONISTS AND CATECHOLAMINES WITH THE 'PUTATIVE (β‐ADRENOCEPTOR'IN …
P Molenaar, D Sarsero… - Clinical and experimental …, 1997 - Wiley Online Library
P Molenaar, D Sarsero, AJ Kaumann
Clinical and experimental pharmacology and physiology, 1997•Wiley Online LibraryEvidence 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 β1‐and β2‐adrenoceptor antagonists; however, they cause cardiostimulant
effects at much higher concentrations than those required to block β2‐and β2‐
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 …
effects were observed to non‐conventional partial agonists. These agonists were originally
described as β1‐and β2‐adrenoceptor antagonists; however, they cause cardiostimulant
effects at much higher concentrations than those required to block β2‐and β2‐
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 …
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 β1‐ and β2‐adrenoceptor antagonists; however, they cause cardiostimulant effects at much higher concentrations than those required to block β2‐ and β2‐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 β1‐ and β2‐adrenoceptors, but is blocked with moderate affinity by (–)‐bupranolol and CGP20712A.
4. The receptor is pharmacologically distinct from the β3‐adrenoceptor. Micromolar concentrations of β3‐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 (–)–[3H]–CGP 12177A labels the cardiac putative β4‐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 β4‐adrenoceptor appears to be coupled to the Gs‐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.
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