Rostral Ventrolateral Medulla Neurons of Neonatal Wistar-Kyoto and Spontaneously Hypertensive Rats

Abstract—We compared the electrophysiological properties of neurons in the rostral ventrolateral medulla (RVLM) of neonatal Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), and responses to angiotensin II and its type 1 receptor antagonist candesartan. Using the whole-cell patch-clamp technique, we examined the characteristics of RVLM neurons in brainstem–spinal cord preparations with a preserved sympathetic neuronal network. The baseline membrane potential of irregularly firing neurons was less negative (−50.1±0.6 versus −52.0±0.6 mV) and the firing rate was faster (3.0±0.2 versus 2.0±0.2 Hz) in SHR (n=56) than in WKY (n=38). Superfusion with angiotensin II (6 &mgr;mol/L) significantly depolarized the RVLM bulbospinal neurons in SHR (5.4±1.1 mV, n=15) but not in WKY. In contrast, candesartan (0.12 &mgr;mol/L) induced a significant membrane hyperpolarization (−3.7±0.4 mV; n=14) and a decrease in the firing rate in RVLM bulbospinal neurons of SHR but not of WKY. These results suggest that endogenously generated angiotensin II binds to type 1 receptors on RVLM bulbospinal neurons, thus tonically contributing to a higher membrane potential and a faster firing rate in SHR. The electrophysiological properties of RVLM neurons and their responses to angiotensin II and candesartan differ between neonatal WKY and SHR. These differences in RVLM neurons suggest a mechanism that possibly leads to elevation in blood pressure.

[1]  J. C. Smith,et al.  Microenvironment of respiratory neurons in the in vitro brainstem‐spinal cord of neonatal rats. , 1993, The Journal of physiology.

[2]  J. Chalmers,et al.  Brainstem and bulbospinal neurotransmitter systems in the control of blood pressure. , 1991, Journal of hypertension.

[3]  M. Miyazaki,et al.  Quantitative localization of angiotensin II receptor subtypes in spontaneously hypertensive rats. , 1994, Blood pressure. Supplement.

[4]  T. Saruta,et al.  Improvement in baroreflex function by an oral angiotensin receptor antagonist in rats with myocardial infarction. , 1997, Hypertension.

[5]  R. M. Lee,et al.  Blood pressure and heart rate development in young spontaneously hypertensive rats. , 1998, American journal of physiology. Heart and circulatory physiology.

[6]  D. Ballantyne,et al.  Chemosensitive medullary neurones in the brainstem‐‐spinal cord preparation of the neonatal rat. , 1996, The Journal of physiology.

[7]  D. Averill,et al.  Effect of angiotensin II in ventrolateral medulla of spontaneously hypertensive rats. , 1991, The American journal of physiology.

[8]  N. Schork,et al.  Hyperkinetic borderline hypertension in Tecumseh, Michigan , 1991, Journal of hypertension.

[9]  P. Guyenet Role of the ventral medulla oblongata in blood pressure regulation , 1990 .

[10]  M. Fujishima,et al.  Effects of chronic oral treatment with imidapril and TCV-116 on the responsiveness to angiotensin II in ventrolateral medulla of SHR. , 1999, Journal of hypertension.

[11]  T. Ogihara,et al.  Central Amino Acids Mediate Cardiovascular Response to Angiotensin II in the Rat , 1998, Brain Research Bulletin.

[12]  T. Wong,et al.  Responses of cardiovascular neurons in the rostral ventrolateral medulla of the normotensive Wistar Kyoto and spontaneously hypertensive rats to iontophoretic application of angiotensin II , 1991, Brain Research.

[13]  T. Saruta,et al.  Effects of antihypertensive agents on baroreceptor function in early hypertensive rats. , 1994, Hypertension.

[14]  Motohisa Osaka,et al.  Potentiated Sympathetic Nervous and Renin-Angiotensin Systems Reduce Nonlinear Correlation Between Sympathetic Activity and Blood Pressure in Conscious Spontaneously Hypertensive Rats , 2002, Circulation.

[15]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[16]  K. Kubo,et al.  Candesartan (CV-11974) dissociates slowly from the angiotensin AT1 receptor. , 1997, European journal of pharmacology.

[17]  G. Dibona,et al.  Sodium Intake Influences Hemodynamic and Neural Responses to Angiotensin Receptor Blockade in Rostral Ventrolateral Medulla , 2001, Hypertension.

[18]  G. Paxinos,et al.  Mapping of angiotensin II receptor subtype heterogeneity in rat brain , 1992, The Journal of comparative neurology.

[19]  R. Dampney,et al.  Functional organization of central pathways regulating the cardiovascular system. , 1994, Physiological reviews.

[20]  D. Averill,et al.  Losartan, nonpeptide angiotensin II-type 1 (AT1) receptor antagonist, attenuates pressor and sympathoexcitatory responses evoked by angiotensin II andL-glutamate in rostral ventrolateral medulla , 1994, Brain Research.

[21]  T. Saruta,et al.  Baroreflex control of renal sympathetic nerve activity is potentiated at early phase of two-kidney, one-clip Goldblatt hypertension in conscious rabbits. , 1990, Circulation research.

[22]  Y. W. Li,et al.  Angiotensin II decreases a resting K+ conductance in rat bulbospinal neurons of the C1 area. , 1996, Circulation research.

[23]  Tom E. C. Smith,et al.  Reconceptualizing Support Systems for Persons with Challenging Behaviors , 1994, Psychological reports.

[24]  T. Wong,et al.  Electrophysiological properties of neurons in the rostral ventrolateral medulla of normotensive and spontaneously hypertensive rats , 1991, Brain Research.

[25]  S. Takai,et al.  Inhibition of the angiotensin II Type 1 receptor by TCV-116: quantitation by in vitro autoradiography. , 1999, Japanese journal of pharmacology.

[26]  I. Homma,et al.  Whole cell recordings from respiratory neurons in the medulla of brainstem-spinal cord preparations isolated from newborn rats , 1992, Pflügers Archiv.

[27]  A. Allen Blockade of angiotensin AT1-receptors in the rostral ventrolateral medulla of spontaneously hypertensive rats reduces blood pressure and sympathetic nerve discharge , 2001, Journal of the renin-angiotensin-aldosterone system : JRAAS.

[28]  E A Anderson,et al.  Elevated Sympathetic Nerve Activity in Borderline Hypertensive Humans Evidence From Direct Intraneural Recordings , 1989, Hypertension.

[29]  K. Hoe,et al.  Chronic peripheral administration of the angiotensin II AT1 receptor antagonist Candesartan blocks brain AT1 receptors , 2000, Brain Research.

[30]  R. Dampney,et al.  Tonic cardiovascular effects of angiotensin II in the ventrolateral medulla. , 1990, Hypertension.

[31]  T. Saruta,et al.  Three types of putative presympathetic neurons in the rostral ventrolateral medulla studied with rat brainstem–spinal cord preparation , 2000, Autonomic Neuroscience.

[32]  D. Lu,et al.  Increased angiotensin II type-1 receptor gene expression in neuronal cultures from spontaneously hypertensive rats. , 1993, Endocrinology.