DIBENAMINE BLOCKADE IN STRIPS OF RABBIT AORTA AND ITS USE IN DIFFERENTIATING RECEPTORS

¹ Department of Pharmacology, Washington University School of Medicine, St. Louis, Mo.

1. The contractile responses of strips of rabbit aorta to a variety of stimulating drugs can be blocked by pre-treating the strips with Dibenamine. With regard to susceptibility to blockade, the drugs tested fall in the following order: sympathomimetic amines (epinephrine, norepinephrine and isopropylarterenol) 5-hydroxytryptamine > histamine > acetylcholine.

2. The presence of a very high concentration of a given stimulating drug during exposure of strips to Dibenamine partially or completely protects against blockade of that drug. Such "self-protection" is considered strong evidence that Dibenamine exerts its blocking action by reacting in an essentially irreversible manner with the free receptors with which the stimulating drugs combine in activating contraction.

3. Among the three sympathomimetic amines tested there is also "cross-protection" agamst Dibenamine blockade. However, there is no cross-protection between them and histamine or acetyicholine or 5-hydroxytryptamine, or between any two of the last three drugs. This indicates that the aortic smooth muscle has specific sets of contraction receptors for the sympathornimetic amines, for histamine, for acetylcholine, and for 5-hydroxytryptamine.

4. After Dibenamine blockade of the contracting effect of epinephrine and norepinephrine, these drugs produce relaxation of aortic strips. The maximal relaxing effect of these drugs after Dibenamine is about 10 to 15 per cent as great as their maximal contracting effect before Dibenamine, and is equal to the maximal relaxing effect of isopropylarterenol, either before or after Dibenamine. Experimental evidence is presented indicating that these three drugs react with the same relaxation receptors and that these are not inactivated by Dibenamine. Qualitative and quantitative differences in the effects of these drugs both before and after Dibenamine blockade have been explained on the basis of differences in their affinities for both contraction and relaxation receptors.

5. Experimental evidence is also presented which indicates that contraction and relaxation receptors for sympathomimetic amines exist in the same individual cells of aortic smooth muscle.

6. Dibenamine blockade of contraction of aortic strips by stimulating drugs appears to be essentially irreversible for periods up to two hours following exposure to Dibenamine. However, prolonged post-exposure testing in the case of epinephrine has demonstrated that the blockade is actually very slowly reversible. A possible mechanism for this very slow reversibility based on the regeneration of free receptors for epinephrine has been proposed.

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