ANG II-induced excitation of paraventricular nucleus magnocellular neurons: a role for glutamate interneurons.

The hypothalamic paraventricular nucleus (PVN) plays a critical role in cardiovascular and neuroendocrine regulation. ANG II (ANG) acts throughout the periphery in the maintenance of fluid-electrolyte homeostasis and has also been demonstrated to act as a neurotransmitter in PVN exerting considerable influence on neuronal excitability in this nucleus. The mechanisms underlying the ANG-mediated excitation of PVN magnocellular neurons have yet to be determined. We have used whole cell patch-clamp techniques in hypothalamic slices to examine the effects of ANG on magnocellular neurons. Application of ANG resulted in a depolarization of magnocellular neurons, a response that was abolished in TTX, suggesting an indirect mechanism of action. Interestingly, ANG also increased the frequency of excitatory postsynaptic potentials/currents in magnocellular neurons, an effect that was abolished after application of the glutamate antagonist kynurenic acid. ANG was without effect on the amplitude of excitatory postsynaptic currents, suggesting a presynaptic action on an excitatory interneuron within PVN. The ANG-induced depolarization was shown to be sensitive to kynurenic acid, revealing the requisite role of glutamate in mediating the ANG-induced excitation of magnocellular neurons. These observations indicate that the ANGergic excitation of magnocellular PVN neurons are dependent on an increase in glutamatergic input and thus highlight the importance of a glutamate interneuron in mediating the effects of this neurotransmitter.

Slowly inactivating potassium conductance (I(D)): a potential target for stroke therapy.

BACKGROUND AND PURPOSE: Excessive accumulation of extracellular glutamate results in the death of most, but not all, neurons in the central nervous system. Understanding the unique properties of cells that can withstand this excitotoxic challenge may identify specific targets for novel stroke therapies. METHODS: A combination of in vivo methods for analysis of excitotoxic cell death after activation of N-methyl-D-aspartate (NMDA) receptors and in vitro patch-clamp analysis of specific conductances in hypothalamic slices and dissociated cells has been used to assess the roles of specific potassium conductances in delayed cell death after NMDA receptor activation. RESULTS: We report that a specific D-type potassium conductance (I(D)), necessary for the rapid repolarization of the membrane after a strong depolarization, serves such a protective purpose in magnocellular neurons of the paraventricular nucleus. Manipulations that inhibit this current (4-aminopyridine or angiotensin II) increase neuronal excitability and augment cell death after NMDA receptor activation. In addition, this protection is not observed in magnocellular neurons of spontaneously hypertensive rats, and intriguingly it can be reestablished by blocking angiotensin II receptors in these animals. CONCLUSIONS: These observations provide a persuasive experimental explanation for the unexpected finding that therapeutic treatments for hypertension that block central as well as peripheral angiotensin type 1 receptors reduce the severity and occurrence of stroke.

Hormonal and neurotransmitter roles for angiotensin in the regulation of central autonomic function.

In this review we present the case for both hormonal and neurotransmitter actions of angiotensin II (ANG) in the control of neuronal excitability in a simple neural pathway involved in central autonomic regulation. We will present both single-cell and whole-animal data highlighting hormonal roles for ANG in controlling the excitability of subfornical organ (SFO) neurons. More controversially we will also present the case for a neurotransmitter role for ANG in SFO neurons in controlling the excitability of identified neurons in the paraventricular nucleus (PVN) of the hypothalamus. In this review we highlight the similarities between the actions of ANG on these two populations of neurons in an attempt to emphasize that whether we call such actions "hormonal" or "neurotransmitter" is largely semantic. In fact such definitions only refer to the method of delivery of the chemical messenger, in this case ANG, to its cellular site of action, in this case the AT1 receptor. We also described in this review some novel concepts that may underlie synthesis, metabolic processing, and co-transmitter actions of ANG in this pathway. We hope that such suggestions may lead ultimately to the development of broader guiding principles to enhance our understanding of the multiplicity of physiological uses for single chemical messengers.

Local circuitry regulates the excitability of rat neurohypophysial neurones.

The importance of angiotensin II (AII) and glutamate has long since been recognized in neuroendocrine regulation. However, the mechanisms by which AII and glutamate modulate the excitability of the paraventricular nucleus (PVN) have largely remained a mystery until recently. It is now apparent that AII and glutamate are potent stimulators of both magnocellular and parvocellular neurones in the rat PVN. While glutamate, the predominant excitatory neurotransmitter in the CNS, ubiquitously excites PVN neurones, AII appears to mediate excitability of the PVN by both direct and indirect mechanisms. Interestingly, both of these neurotransmitters, upon exciting the PVN, activate an inhibitory feedback system, which is capable of diminishing the initial stimulus. Physiologically, this moderates the output signals from the PVN, and probably also regulates neuropeptide release from the neurohypophysis. The importance of this negative-feedback loop is evident in the pathophysiological implications of a disruption in the system. Evidence suggests that a breakdown in this system may be responsible in part for the onset and maintenance of both congestive heart failure and hypertension. Future studies will continue to characterize both the actions of glutamate and AII in the PVN, and to further elucidate the mechanisms which control the excitability of the PVN.