Angiotensin II activates a nitric-oxide-driven inhibitory feedback in the rat paraventricular nucleus.
The hypothalamic paraventricular nucleus (PVN) has been shown to play major obligatory roles in autonomic and neuroendocrine regulation. Angiotensin II (ANG) acts as a neurotransmitter regulating the excitability of magnocellular neurons in this nucleus. We report here that ANG also activates a nitric-oxide-mediated negative feedback loop in the PVN that acts to regulate the functional output of magnocellular neurons. Thus in addition to its depolarizing actions on magnocellular neurons, ANG application results in an increase in the frequency of inhibitory postsynaptic potentials in a population of these neurons without effect on the amplitude of these events. ANG was also without significant effect on the mean frequency or amplitude of mini synaptic currents analyzed in voltage-clamp experiments. This increase in inhibitory input after ANG can be abolished by the nitric oxide synthase inhibitor Nomega-nitro-l-arginine methylester, demonstrating a requisite role for nitric oxide in the activation of this pathway. The depolarization of magnocellular neurons that show increased inhibitory postsynaptic potential (IPSP) frequency in response to ANG is significantly smaller than that observed in neurons in which IPSPs frequency was unaffected (3.2 +/- 1.1 vs. 8.0 +/- 0.5 mV, P < 0.05). Correspondingly, after nitric oxide synthase inhibition, the depolarizing effects of ANG on magnocellular neurons are augmented (2.0 +/- 0.7 vs. 6.7 +/- 0.7 mV, P < 0.05). The depolarization was also enhanced in the presence of the GABAergic antagonist bicuculline (1.9 +/- 1.2 vs. 11.9 +/- 2.3, P < 0.001). These data demonstrate that there exists within the PVN an intrinsic negative feedback loop that modulates neuronal excitability in response to peptidergic excitation.
Latchford
Kevin J
KJ
Department of Physiology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
Ferguson
Alastair V
AV
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000502:physiology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009433:Neural Inhibition / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D009569:Nitric Oxide; D019331:NG-Nitroarginine Methyl Ester