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α1-Adrenoceptors of rat myocardium: Comparison of agonist binding and positive inotropic response

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Summary

Binding of agonists to al-adrenoceptors labelled by 3H-prazosin was investigated in membranes of rat myocardium and compared to the inotropic response elicited by α1-adrenoceptor activation on isolated right ventricles.

  1. 1.

    At 30°C the full agonists, adrenaline and phenylephrine, displaced 3H-prazosin with a shallow inhibition curve. The data are compatible with the assumption that 32% of the binding sites were in a state of high affinity for the agonist adrenaline (KI 85 nmol/l) and 68% in a low affinity state (KI I738 nmol/l). GTP transformed all binding sites into the low affinity form suggesting that at least some of the cardiac α1-adrenoceptors are coupled to N-proteins.

  2. 2.

    At 0°C most of the binding sites (86%) were in a state of high affinity for agonists (KI for adrenaline: 91 nmol/l).

  3. 3.

    For several partial agonists and antagonists (cirazoline, methoxamine, indanidine (Sgd 101-75), oxymetazoline and phentolamine) no such distinct temperature- and GTP-shifts could be demonstrated suggesting a different kind of interaction with al-binding sites.

  4. 4.

    When temperature was changed during incubation with adrenaline, a rise of temperature (from 0°C to 30°C) converted high affinity sites into the low affinity form, whereas a decrease in temperature (from 30°C to 0°C) failed to induce the high affinity state for agonists. Short term incubation (0.5 min) with adrenaline at 30°C resulted in significantly lower IC50 values as compared to equilibrium conditions at the same temperature.

  5. 5.

    Occupancy of al-adrenoceptor binding sites with adrenaline at O°C but not at 30°C rather closely paralleled the concentration-response curve for the α1-mediated increase in ontractile force.

  6. 6.

    Irreversible blockade of α1-adrenoceptors with phenoxybenzamine decreased the maximum inotropic response but only slightly affected pD2 values for the α1-stimulant effect of adrenaline.

Our binding experiments suggest that myocardial α1-adrenoceptors can exist in states of different affinity for agonists. Some agonists like adrenaline and phenylephrine seem to induce a temperature-dependent change in the conformation of the receptor which may represent a rapid form of desensitization. Since no appreciable receptor reserve was detected it is hypothesized that the high affinity state which can be measured at 0°C under equilibrium conditions may be relevant to the initiation of the functional response.

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Authors and Affiliations

  1. Pharmakologisches Institut des Universitätsklinikums Essen, Hufelandstrasse 55, D-4300, Essen 1, Germany

    Gerhard Groß, Gertraud Hanft & Christian-U. Rugevics

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  1. Gerhard Groß
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  2. Gertraud Hanft
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  3. Christian-U. Rugevics
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Groß, G., Hanft, G. & Rugevics, CU. α1-Adrenoceptors of rat myocardium: Comparison of agonist binding and positive inotropic response. Naunyn-Schmiedeberg's Arch Pharmacol 338, 582–588 (1988). https://doi.org/10.1007/BF00179334

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