External Ca-independent release of norepinephrine by sympathomimetics and its role in negative feedback modulation

The release of [3H]norepinephrine from isolated mouse vas deferens has been measured. 1-Phenylephrine and 1-norepinephrine significantly enhanced the spontaneous release of radioactivity. As shown by a combination of HPLC and scintillation spectrometry, the release of total radioactivity in response to 1-phenylephrine or 1-norepinephrine consisted mainly of [3H]norepinephrine. Evidence has been obtained that the release of endogenous norepinephrine by exogenous norepinephrine and 1-phenylephrine is independent of the external Ca2+ concentration. The released endogenous norepinephrine in turn inhibits the release of norepinephrine in response to electrical field stimulation. In the presence of yohimbine, the enhancement of spontaneous release due to 1-phenylephrine (or to 1-norepinephrine) was not affected, whereas there was a significant superimposed release of [3H]norepinephrine in response to field stimulation, indicating that the inhibition of stimulation-induced norepinephrine release is an alpha 2-adrenoceptor-mediated process. An important consequence of these findings is to question previous interpretations that the effects of administration of 1-norepinephrine or 1-phenylephrine are due exclusively to their direct effects on the effector cells. The Ca-independent release of endogenous norepinephrine might partly initiate their pharmacological responses. It is concluded that this Ca-independent release is of functional importance, since norepinephrine may accumulate in a concentration sufficient to modulate the release of norepinephrine from varicosities in response to electrical stimulation.