Similar localisation of α1- and β-adrenoceptors in rabbit heart in relation to sympathetic nerve endings
Introduction
Activation of the myocardial α1-adrenoceptors separately from the β-adrenoceptors will elicit a positive inotropic response in mammalian tissue (for reviews, e.g., Scholz, 1980, Brückner et al., 1985, Osnes et al., 1985, Benfey, 1993, Fedida, 1993, Terzic et al., 1993), and this activation contributes to the final inotropic response elicited by noradrenaline, as shown in the rat and rabbit heart Skomedal et al., 1988, Skomedal et al., 1990.
It has been shown that the α1-adrenoceptor population is located geometrically more distantly from the sympathetic nerve terminals than the β-adrenoceptors in rat papillary muscles (Dybvik et al., 1995), which supports the prominent role of the β1-adrenoceptor system in rat myocardium (Skomedal et al., 1988). Earlier studies showed that in rabbit myocardium the α1-adrenoceptor population is activated by lower concentrations of noradrenaline than the β-adrenoceptor population (Aass et al., 1983), which is in contrast to the situation in rat myocardium Skomedal and Osnes, 1983, Dybvik et al., 1995. A prazosin sensitive inotropic response elicited by noradrenaline in rabbit myocardium was potentiated by cocaine (Skomedal et al., 1990). Studies by others Verity, 1971, Ebner and Waud, 1978 showed that the potentiating effect of neuronal uptake blockade by cocaine is inversely influenced by the average distance between the receptor population and the nerve terminals. Thus, this agent could be used to estimate the location of the adrenoceptor populations relative to the sympathetic nerve terminals. This experimental approach, as reviewed by Stene-Larsen (1981), was previously used to study this relation of cardiac α1- and β-adrenoceptors in rats (Dybvik et al., 1995).
The different functional role of the two receptor systems may be reflected in their relative location in relation to the sympathetic nerve terminals in the myocardium (Dybvik et al., 1995). In rabbit myocardium, little is known about the localisation of the α1-adrenoceptor population in relation to the sympathetic nerve terminals and to the β-adrenoceptor population. The purpose of the present study was to investigate this relative adrenoceptor location by studying the potentiating effect of neuronal uptake blockade upon the inotropic and lusitropic responses to noradrenaline when stimulating the two adrenoceptor systems separately. As noradrenaline is the only substrate for neuronal uptake (in contrast to isoprenaline, phenylephrine and adrenaline) Iversen, 1967, Iversen, 1973 this agonist was used in the present experiments.
Our experiments revealed parallel shifts of the various dose–response curves by neuronal uptake blockade indicating that in rabbit papillary muscles the major parts of both the α1- and β-adrenoceptors population are located near or in the sympathetic synaptic clefts.
Section snippets
Isolated papillary muscles
Rabbit papillary muscles (less than 1 mm in diameter), were isolated as described earlier for rat papillary muscles with minor modifications (Skomedal et al., 1980). Hearts were isolated from male rabbits weighing 2.0–3.0 kg and anaesthetized with pentobarbital (about 50 mg/kg). During coronary perfusion with the buffer mentioned below, right ventricular papillary muscles were excised and mounted in an organ bath with a physiological salt solution containing the following (mmol/l): NaCl 118.3,
Effects of neuronal uptake blockade by cocaine on adrenoceptor stimulation by noradrenaline
Cumulative dose–response curves for the inotropic and the lusitropic responses to noradrenaline in the presence of hydrocortisone and in the presence of timolol (10−6 mol/l) or prazosin (10−7 mol/l), as well as without adrenoceptor blockade Fig. 1, Fig. 2 were examined in the absence and presence of cocaine (3×10−5 mol/l).
Discussion
The present study shows that neuronal uptake blockade by cocaine potentiated the α1- and β-adrenoceptors mediated inotropic and lusitropic responses to noradrenaline to a similar degree and in a way indicating that at least the major parts of both adrenoceptor populations are located near or within the synaptic clefts of the sympathetic nerve terminals. Thus, both the α1- and β-adrenoceptor populations seem to be located with a similar average distance from the nerve endings.
The dose–response
Acknowledgements
We thank Ms. Anne Sjetnan and Ms. Iwona Schiander for excellent technical assistance. The work was supported by The Norwegian Research Council, The Norwegian Council on Cardiovascular Diseases and by EU Biomed 2 Concerted Action.
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