Regional differences of β1- and β2-adrenoceptor-mediated functions in feline heart
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The effects of (−)-adrenaline and (−)-noradrenaline were studied on isolated preparations of kitten heart. To define the contribution of β1-adrenoceptors (β1AR) and β2-adrenoceptors (β2AR) we used as tools the highly β1AR-selective antagonist CGP 20,712 A and non-linear analysis of antagonism. The β2AR-mediated responses to the catecholamines, disclosed by CGP 20,712 A, were verified by blockade with the β2AR-selective ICI 118,551. The relative density and contribution of β1AR and β2AR to (−)-adrenaline- and (−)-noradrenaline-induced adenylyl cyclase stimulation was also estimated in right ventricular membranes.
In the sinoatrial pacemaker (−)-adrenaline caused positive chronotropic effects through both β1AR and β2AR while (−)-noradrenaline does so predominantly through β1AR. During β1AR blockade (−)-adrenaline did cause the same maximum effects through β2AR as (−)-noradrenaline did through β1AR.
In left atria (−)-adrenaline caused positive inotropic effects predominantly through β1AR. CGP 20,712A also uncovered a β2AR component at high (−)-adrenaline concentrations comprising one third of the maximum β1AR-mediated response.
Receptor binding assays revealed that 80% of right ventricular βAR wereβ1AR and 20% β2AR. Consistent with this finding, around 80% of the adenylyl cyclase stimulation by both (−)-noradrenaline and (−)-adrenaline was mediated through β1AR, around 20% through β2AR. The positive inotropic effects of (−)-noradrenaline appeared to be nearly exclusively mediated through β1AR in right ventricular papillary muscles. were quite variable with regard to β1AR and β2AR in right ventricular papillary muscles. Although β1AR-mediated effects are predominant in many muscles with only a small contribution of β2AR, in some muscles β2AR mediated around 50% of the maximum effect elicited through β1AR. In 3 out of 17 muscles β2AR mediated the same maximum effect of (−)-adrenaline as β1AR.
On occasion, we found marked βAR heterogeneity amongst two muscles from the same right ventricle. One muscle only exhibited β1AR-mediated effects of (−)-adrenaline whereas in the other muscle maximal effects could be elicited through β2AR.
CGP 20,712 A had the same affinity for β1AR (pKB = 9.6) and β2AR (pKB = 5.4) in all 3 heart regions studied, suggesting identical affinities of the corresponding receptors. The pronounced tissue differences in the function of β1AR and β2AR appear therefore due to marked differences in receptor density or receptor coupling.
Surprisingly, pronounced β2AR-mediated inotropic effects of (−)-adrenaline in right ventricular papillary muscles showed prolonged relaxation times; furthermore, the time to peak force was not shortened. These observations are inconsistent with an involvement of cyclic AMP. In contrast, β1AR-mediated effects of both (−)-noradrenaline and (−)-adrenaline shortened time to peak force, as expected from an involvement of cyclic AMP.
We suggest that feline ventricular β2AR mediate an inotropic effect of (−)-adrenaline that does not involve cyclic AMP. This effect may be due to the direct opening of calcium channels by Gs protein reported by Yatani et al. (1987).
Key wordsKitten heart β1- and β2-adrenoceptors (−)-Adrenaline (−)-Noradrenaline CGP 20,712 A
- β2 AR
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