SOME FACTORS DETERMINING THE RESPONSE OF RABBIT AORTIC STRIPS TO dl-NOREPINEPHRINE-7-H³ HYDROCHLORIDE AND THE INFLUENCE OF COCAINE, GUANETHIDINE AND METHYLPHENIDATE ON THESE FACTORS

¹ Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont

Some factors determining the contractile response of rabbit aortic strips to norepinephrine have been studied. Norepinephrine is taken up and bound as increasing, linear functions of time from concentrations of 2 x 10^-8 M and 10-⁷ M norepinephrine. After the first 5 to 10 min of exposure the difference between the curve for total uptake and the curve for bound norepinephrine remains constant with time. This difference represents the diffusible fraction of the total uptake. The norepinephrine component of the diffusible fraction also does not change with time over a 30-min period; neither does the magnitude of contraction. The contractile response is an increasing, linear function of the diffusible norepinephrine over the steep part of the concentration-action curve, i.e., from 2 x 10^-8 M to 10^-7 M norepinephrine. Likewise, the response is an increasing, linear function of the rate of binding of norepinephrine over this concentration range. Cocaine produces a concentration-dependent reduction in total uptake, binding rate and in diffusible norepinephrine. Approximately 30% reduction in binding rate can be produced with cocaine, guanethidine and methylphenidate without an increase in response. In the range of 30 to 70% reduction in binding rate, the response to norepinephrine is an increasing function of the percent reduction in binding produced by these drugs. Cocaine and guanethidine can produce considerable additional increase in response without additional reduction in binding. A simple mathematical model is described which relates increase in response, reduction in binding rate and local low concentrations of norepinephrine at binding sites. The curves generated by this model which relate percent increase in response to percent reduction in binding rate do not closely resemble experimental curves relating these two parameters. It is concluded that decrease in the binding rate of norepinephrine may not be an important determinant of the supersensitivity produced by cocaine, guanethidine and methylphenidate in rabbit aortic strips. It is suggested that these drugs have an action in the smooth muscle cells which may account in large part for supersensitivity.

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