Voltage-Dependent Calcium Currents Are Enhanced in Nucleus of the Solitary Tract Neurons Isolated From Renal Wrap Hypertensive Rats

Abstract

Abstract-The nucleus of the solitary tract (NTS) is the central site of termination of baroreceptor afferents. We hypothesize that changes occur in voltage-gated calcium channels (VGCCs) within NTS neurons as a consequence of hypertension. Whole-cell patch-clamp recordings were obtained from adult normotensive (109Ϯ2 mm Hg; nϭ6 from 6 sham-operated and 31 nonsurgically treated) and hypertensive (158Ϯ6 mm Hg; nϭ24) rats. In some experiments, 4-(4-[dihexadecylamino]styryl)-N-methylpyridinium iodide was applied to the aortic nerve to visualize NTS neurons receiving baroreceptor synaptic contacts. Ba 2ϩ currents (500 ms; Ϫ80 mV prepotential; 500 ms voltage steps in 5-mV increments to ϩ15mV) peaked between Ϫ20 and Ϫ10 mV and were blocked by 100 m of Cd 2ϩ . Peak VGCCs were not different comparing non-4-(4-[dihexadecylamino]styryl)-N-methylpyridinium iodide-labeled and 4-(4-[dihexadecylamino]styryl)-N-methylpyridinium iodide-labeled NTS neurons in hypertensive and normotensive rats. The peak VGCC was significantly greater in cells from hypertensive compared with normotensive rats for both non-DiA-labeled (Pϭ0.02) and DiA-labeled (Pϭ0.04) neurons. To separate high-voltage activated (HVA) and low-voltage activated (LVA) components of VGCCs, voltage ramps (Ϫ110 mV to ϩ30 mV over 50 ms) were applied from a holding potential of Ϫ60 mV (LVA channels inactivated) and a holding potential of Ϫ100 mV (both LVA and HVA currents activated). HVA currents were subtracted from HVAϩLVA currents to yield the LVA current. Peak LVA currents were not different between hypertensive (8.9Ϯ0.8 pA/pF) and normotensive (7.8Ϯ0.6 pA/pF) groups of NTS neurons (Pϭ0.27). These results demonstrate that 4 weeks of renal wrap hypertension induce an increase in Ca T he arterial baroreceptor reflex plays an indispensable role in integrated cardiovascular regulation. Baroreceptors are stretch receptors located in systemic arteries, and they transmit information to the central nervous system regarding the level of blood pressure. The central nervous system integrates this information and initiates changes in heart rate and peripheral resistance in an attempt to maintain blood pressure within normal limits. The first central synapse of the baroreflex arc is in the medullary nucleus of the solitary tract (NTS); therefore, NTS neurons play a key role in cardiovascular regulation.We have reported previously that ligand-gated and voltagegated ion channels in NTS neurons receiving arterial baroreceptor afferent inputs undergo adaptive changes in chronic hypertension. In renal wrap hypertension, NTS neuronal sensitivity to activation of ␥-aminobutyric acid type A receptors is reduced, 1,2 whereas sensitivity to activation of ␥-aminobutyric acid type B receptors is enhanced. 1 Voltagegated, transient outward potassium currents are reduced in NTS neurons in chronic renal wrap hypertension. 3 These alterations are viewed as adaptations in response to hypertension and could modify baroreflex regulation of sympathetic nerve discharge and heart rate in hypertension. 4...

COX-1-derived PGE2and PGE2type 1 receptors are vital for angiotensin II-induced formation of reactive oxygen species and Ca2+influx in the subfornical organ

“…The SFO (11,14), PGE 2 /EP 1 R signaling (6,7,21), ROS (6,66,68), and voltage-gated Ca 2ϩ channels (37,52,70) have each been independently proposed as important mediators in the regulation of hypertension. Here we provide the first in vitro evidence that all of these factors are transductionally linked in ANG II-mediated signaling in the SFO.…”

“…It is well established that ANG II-mediated signals activate NADPH oxidase, leading to accumulation of ROS in the brain that are functionally coupled with hypertensive responses (67). This ANG II-mediated overproduction of ROS is also associated with the activation of voltage-gated L-type Ca 2ϩ channels in central neurons (52,57,58,70) and other cell types (2,55,62). Activation of L-type Ca 2ϩ channels is critical to neurotransmission and long-term potentiation (LTP) in the central nervous system (60,64).…”

Plasticity in glutamatergic NTS neurotransmission

“…Although in these studies it is difficult to differentiate the presynaptic and postsynaptic locus of such changes, Mifflin’s laboratory has demonstrated several postsynaptic alterations. For instance, in isolated NTS cells receiving aortic depressor nerve input, hypertension (induced as above) reduced transient A- type potassium currents (Belugin and Mifflin, 2005) and increased high voltage-activated calcium currents (Tolstykh et al, 2007). The functional role of these ion channel alterations on synaptic transmission and the reflex as a whole in hypertensive rats remains an intriguing question.…”

Plasticity of GABAergic Mechanisms Within the Nucleus of the Solitary Tract in Hypertension

“…The in vitro analysis of NTS neuronal responses to activation of GABA A receptors found no difference in the dose-response relationship of neurons receiving aortic nerve inputs and neurons not receiving aortic nerve inputs, although the sample size was small14. Similarly, changes in transient outward potassium currents37 and high-threshold voltage-gated calcium channels46 did not differ comparing NTS neurons that received aortic nerve inputs to those that did not receive aortic nerve inputs.…”

“…Hypertension also induces enhanced current flow through high-voltage activated, but not low-voltage activated, Ca 2+ channels in NTS neurons that receive baroreceptor afferent inputs27. There is a link between enhanced calcium influx and reduced GABA A receptor function.…”