Figure 1.

Suggested localization of the inhibitory effect of 3,4-DAP on K_V in pre- and postganglionic parasympathetic and sympathetic neurons involved in the regulation of HR. By inhibiting K_V, 3,4-DAP will induce Ach release from preganglionic parasympathetic and sympathetic nerve endings as well as in postganglionic parasympathetic nerve terminals, and also induce norepinephrine (NE) release from postganglionic sympathetic nerve endings. The inhibitors used to localize the effect of 3,4-DAP, i.e., the Ach synthesis inhibitor hemicholinium-3, the mAchR and nAchR blockers atropine and hexamethonium, respectively, reserpine which depletes sympathetic nerve endings of NE, and the βAR antagonist nadolol, which block sympathetic control of HR, are indicated in capital letters next to site of action. When effect of one drug involved more than one step in the response chain or involved both the parasympathetic and sympathetic chains, drugs were combined to identify the site of 3,4-DAP action. Through the effect on HR, the results showed that Ach release from preganglionic vagal nerves was blunted by augmented 3,4-DAP-sensitive hyperpolarizing K_V activity in SHR (indicated in upper gray box), thus preventing activation of the postganglionic neuron and vagal inhibition of HR (indicated in lower gray box). Presynaptic K_V in the parasympathetic ganglia therefore functioned as a bottleneck in vagal transmission in SHR. These ganglia are likely to be located in superficial fat tissue close to the sinoatrial node. Blunted arrows indicate the inhibitory effect of presynaptic K_V on transmitter release.