Contrasting effects of presynaptic ␣2-adrenergic autoinhibition and pharmacologic augmentation of presynaptic inhibition on sympathetic heart rate control. synaptic ␣ 2-adrenergic receptors are known to exert feedback inhibition on norepinephrine release from the sympathetic nerve terminals. To elucidate the dynamic characteristics of the inhibition, we stimulated the right cardiac sympathetic nerve according to a binary white noise signal while measuring heart rate (HR) in anesthetized rabbits

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... (n ϭ 6). We estimated the transfer function from cardiac sympathetic nerve stimulation to HR and the corresponding step response of HR, with and without the blockade of presynaptic inhibition by yohimbine (1 mg/kg followed by 0.1 mg ⅐ kg Ϫ1 ⅐ h Ϫ1 iv). We also examined the effect of the ␣2-adrenergic receptor agonist clonidine (0.3 and 1.5 mg ⅐ kg Ϫ1 ⅐ h Ϫ1 iv) in different rabbits (n ϭ 5). Yohimbine increased the maximum step response (from 7.2 Ϯ 0.8 to 12.2 Ϯ 1.7 beats/min, means Ϯ SE, P Ͻ 0.05) without significantly affecting the initial slope (0.93 Ϯ 0.23 vs. 0.94 Ϯ 0.22 beats ⅐ min Ϫ1 ⅐ s Ϫ1 ). Higher dose but not lower dose clonidine significantly decreased the maximum step response (from 6.3 Ϯ 0.8 to 6.8 Ϯ 1.0 and 2.8 Ϯ 0.5 beats/min, P Ͻ 0.05) and also reduced the initial slope (from 0.56 Ϯ 0.07 to 0.51 Ϯ 0.04 and 0.22 Ϯ 0.06 beats ⅐ min Ϫ1 ⅐ s Ϫ1 , P Ͻ 0.05). Our findings indicate that presynaptic ␣2-adrenergic autoinhibition limits the maximum response without significantly compromising the rapidity of effector response. In contrast, pharmacologic augmentation of the presynaptic inhibition not only attenuates the maximum response but also results in a sluggish effector response. systems analysis; transfer function; ␣-adrenergic blockade; rabbits PRESYNAPTIC ␣ 2 -ADRENERGIC receptors play an important role in regulating neurotransmitter release in the central and peripheral nervous systems. The concept that neurotransmitter release is modulated by presynaptic autoreceptors was proposed in the 1970s (19, 20, 25, 31-33, 37, 38). Langer (18) first demonstrated that an ␣-adrenergic antagonist phentolamine, at a concentration below that required to produce its negative chronotropic effect, increases the magnitude of heart rate (HR) response to sympathetic nerve stimulation. Since then, a number of in vivo and in vitro studies have been conducted to characterize the negative feedback regulation of norepinephrine (NE) release via the presynaptic ␣ 2 -adrenergic receptors located on the sympathetic nerve terminals (1, 6, 9, 11, 17, 24, 26, 27a, 29, 30, 34, 35). However, the dynamic nature of the presynaptic ␣ 2 -adrenergic inhibition in sympathetic HR control remains to be quantified. Because we focus on the effector response to sympathetic nerve stimulation, the term "presynaptic" may be interpreted as "prejunctional" throughout this paper to describe more specifically the NE kinetics at the neuroeffector junction. We first schematize our hypothesis on the possible modes of operations of the presynaptic inhibition. With reference to Fig. 1 , the solid and dotted lines indicate the HR responses with and without the presynaptic inhibition, respectively. Figure 1A represents a "limiter-like" operation of the presynaptic inhibition in which the steady-state response is attenuated, while the initial slope of the response is unchanged. Figure 1B represents an "attenuator-like" operation in which the steady-state response is attenuated, while the initial slope of the response is also reduced in proportion to the attenuation of the steady-state response. Since the rapid effector response is one of the important hallmarks of neural regulation compared with humoral regulation, determining which of the two operations likely occurs would contribute to the physiological understanding of the presynaptic inhibition. The words "limiter-like" and "attenuator-like" in this paper are used in the specific senses described above. To answer which of the two operations likely occurs in the presynaptic inhibition, we examined the HR response to dynamic sympathetic nerve stimulation, with or without blocking the ␣ 2 -adrenergic receptors in anesthetized rabbits. Because the HR response is mainly mediated by the postsynaptic ␤ 1 -adrenergic receptors, the administration of an ␣ 2 -adrenergic receptor antagonist does not eliminate the HR response to sympathetic nerve stimulation. We also examined the effects of pharmacologic augmentation of the ␣ 2 -adrenergic receptors on the HR response to dynamic sympathetic nerve stimulation. The results of the present study indicated that the presynaptic ␣ 2 -adrenergic autoinhibition is a limiter-like operation. In contrast, the pharmacologic