Presynaptic regulation of cardiac norepinephrine release in ischemia

In myocardial ischemia presynaptic regulation of norepinephrine release may be altered either by ischemic effects on presynaptic receptor signaling or by ischemia-evoked accumulation of endogenous agonists. Because presynaptic receptors are targets of several drugs, such alterations may have pharmacotherapeutic implications. We investigated the effect of brief ischemic periods on presynaptic regulation of norepinephrine release by α₂-adrenoceptors, β₁-adrenoceptors, adenosine A₁-, angiotensin AT₁-, and bradykinin B₂-receptors in isolated perfused rat hearts. Exocytotic norepinephrine release was evoked by electrical field stimulation. Paired stimulations were performed to compare the pharmacologic intervention (S₂) with the release under baseline conditions (S₁), and the effects of receptor agonists and antagonists were compared under nonischemic and stop-flow conditions. In summary, during brief myocardial ischemia, presynaptic modulation of norepinephrine release is differentially regulated. Autoinhibitory α₂-adrenoceptors lose their activity, whereas stimulatory β₂-adrenoceptors are sensitized. Inhibitory adenosine A₁-receptors gain importance during ischemia owing to endogenous adenosine formation. Bradykinin- and angiotensinmediated stimulation of norepinephrine release is not affected under ischemic conditions.