Stimulation Of Afferent Renal Nerves Research Articles

Input from afferent renal nerves is involved in progression of hypertensive heart failure through central vasopressin-mediated sympathoexcitation

Introduction: Paraventricular nucleus of hypothalamus (PVN), a control center of sympathetic outflow, receives the input from afferent renal nerves. Although acute stimulation of afferent renal nerves increases central sympathetic outflow, it remains unclear if the renal afferents contribute to progression of heart failure. Acute stimulation of afferent renal nerves was reported to increase plasma vasopressin concentration. In addition, central dendritic release of vasopressin by activation of vasopressin-expressing neurons located in the PVN may cause sympathoexcitation via stimulation of neighboring presympathetic neurons in the PVN. Therefore, we hypothesized that the chronic input from afferent renal nerves contributes to sympathoexcitation and hypertensive cardiac dysfunction along with activation of vasopressin-expressing neurons and presympathetic neurons in the PVN. Methods: Male Dahl salt-sensitive rats were fed low salt diet (LS) or 8% high salt diet from 6 weeks of age, and the high salt-fed rats were allocated to selective afferent renal denervation (HS-ARDN) or sham surgery (HS-Sham) at 9 weeks. The effect of ARDN on central sympathetic regulation was investigated at 12 weeks (pre-heart failure phase). In another cohort, its effect on cardiac phenotypes was evaluated at 16 weeks (heart failure phase). Results: At 12 weeks, plasma norepinephrine level was increased in HS-Sham compared to LS and was attenuated by ARDN (LS 188.7±16.5 pg/ml, HS-Sham 563.8±82.7 pg/ml, HS-ARDN 327.4±50.2 pg/ml; n=15, 12, 14; p<0.05). The c-Fos expression, a marker of neuronal activity, in presympathetic neurons in the PVN was also increased in HS-Sham and attenuated in HS-ARDN, which was in parallel with the c-Fos expression in vasopressin-expressing neurons in the PVN. At 16 weeks, the decrease of left ventricular (LV) fractional shortening (HS-Sham 25.9±1.7 % vs LS 46.7±0.6 %, n=9, 9; p<0.01) was improved in HS-ARDN (42.2±1.2 %, n=7; p<0.01 vs HS-Sham). LV weight and lung weight were significantly increased in HS-Sham compared to LS (LV weight/body weight: 4.39±0.19 mg/g vs 2.53±0.03 mg/g; lung weight/body weight: 5.29±0.37 mg/g vs 3.55±0.05 mg/g; p<0.05), and these changes were attenuated in HS-ARDN (LV weight/body weight: 3.73±0.14 mg/g; lung weight/body weight: 4.17±0.11 mg/g; p<0.05 vs HS-Sham). Histological LV fibrosis and fibrosis marker expression, such as connective tissue growth factor, in LV were significantly attenuated in HS-ARDN compared to HS-Sham. ARDN did not significantly impact the high salt-induced blood pressure elevation in both cohorts. Conclusion: The input from afferent renal nerves contributes to cardiac dysfunction, probably via the central vasopressin-mediated sympathoexcitation even without blood pressure changes in hypertensive heart failure model. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Contribution of afferent renal nerve signals to acute and chronic blood pressure regulation in stroke-prone spontaneously hypertensive rats.

The activation of sympathetic nervous system plays a critical role in the development of hypertension. The input from afferent renal nerves may affect central sympathetic outflow; however, its contribution to the development of hypertension remains unclear. We investigated the role of afferent renal nerves in acute and chronic blood pressure regulation using normotensive Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Acute chemical stimulation of afferent renal nerves elicited larger increases in blood pressure and renal sympathetic nerve activity in young 9-week-old SHRSP compared to WKY. Selective afferent renal denervation (ARDN) and conventional total renal denervation (TRDN) ablating both afferent and efferent nerves in young SHRSP revealed that only TRDN, but not ARDN, chronically attenuated blood pressure elevation. ARDN did not affect plasma renin activity or plasma angiotensin II levels, whereas TRDN decreased both. Neither TRDN nor ARDN affected central sympathetic outflow and systemic sympathetic activity determined by neuronal activity in the parvocellular region of hypothalamic paraventricular nucleus and rostral ventrolateral medulla and by plasma and urinary norepinephrine levels, respectively. Renal injury was not apparent in young SHRSP compared with WKY, suggesting that renal afferent input might not be activated in young SHRSP. In conclusion, the chronic input from afferent renal nerves does not contribute to the development of hypertension in SHRSP despite the increased blood pressure response to the acute stimulation of afferent renal nerves. Efferent renal nerves may be involved in the development of hypertension via activation of the renin-angiotensin system in SHRSP.

Afferent renal nerve input is involved in blood pressure elevation through activation of angiotensin receptor type 1 in hypothalamic paraventricular nucleus in stroke‐prone spontaneously hypertensive rats

BackgroundRenal nerves contain both sympathetic efferent fibers and sensory afferent fibers. Activation of efferent renal nerves increases renin release and renal sodium reabsorption, causing hypertension. However, previous studies suggested that the contribution of afferent renal nerves to blood pressure (BP) regulation may differ among the animal models of hypertension. Activation of brain renin‐angiotensin system, specifically angiotensin receptor type 1 (AT1R), in hypothalamic paraventricular nucleus (PVN), which receives afferent renal input, is crucially involved in BP elevation. Therefore, the aim of this study was to examine whether the afferent renal input contributes to BP elevation through AT1R activation in the PVN in stroke‐prone spontaneously hypertensive rats (SHRSP).MethodsIn chronic experiment, total renal denervation (TRDN), selective afferent renal denervation (ARDN), or sham surgery was performed in male SHRSP at 10 weeks of age, which is the developing phase of hypertension. ARDN was produced by wrapping renal artery and vein with capsaicin‐soaked gauze. Systolic BP was measured by tail‐cuff method at baseline and 2 and 6 days after surgery. In acute experiment, we evaluated the effect of AT1R blockade with losartan in the PVN on pressor response to afferent renal nerve stimulation by intrapelvic infusion of 10 μM capsaicin under anesthesia in male Wistar‐Kyoto rats (WKY) and SHRSP at 10 weeks of age.ResultsSystolic BP was sequentially increased at day 2 and day 6 in sham‐operated SHRSP ([n=4], baseline, 188.3±9.2 mmHg; day 2, 192.1±8.1 mmHg; day 6, 201.1±3.9 mmHg). In both ARDN‐SHRSP and TRDN‐SHRSP, systolic BP was decreased from baseline at day 2 after surgery (ARDN [n=4], baseline, 187.3±10.3 mmHg; day 2, 170.5±5.2 mmHg; p=0.085; TRDN [n=4], baseline, 186.4±5.9 mmHg; day2 145.1±4.2 mmHg; p=0.003), and the decrease in systolic BP was smaller in ARDN‐SHRSP than in TRDN‐SHRSP (ARDN, −16.7±13.2 mmHg; TRDN, ‐ 41.4±10.0 mmHg; p=0.03). Although systolic BP was increased at day 6 compared to day 2 in ARDN‐SHRSP and TRDN‐SHRSP (ARDN, 197.8±14.9 mmHg; TRDN, 185.8±19.3 mmHg), the BP change from baseline to day 6 was smaller in ARDN‐SHRSP and TRDN‐SHRSP compared with sham‐operated SHRSP. We validated TRDN and ARDN by immunohistochemistry and western blotting: in the renal pelvis, both CGRP and tyrosine hydroxylase (a marker for afferent and efferent renal nerves, respectively) were abolished in TRDN‐SHRSP, and CGRP was selectively abolished in ARDN‐SHRSP. In acute experiment, BP elevation induced by afferent renal nerve stimulation was greater in SHRSP than in WKY (Δmean BP, SHRSP [n=4],12.2±4.1 mmHg; WKY [n=4], 6.6±5.4 mmHg; p=0.07). Prior microinjection of losartan into the PVN attenuated the pressor response to afferent renal nerve stimulation in SHRSP (Δmean BP, 1.1±4.4 mmHg, p=0.04 vs before losartan), but not in WKY (Δmean BP, 3.2±6.7 mmHg, p>0.10 vs before losartan).ConclusionNot only efferent renal nerve activation but afferent renal nerve input contributes to development of hypertension in SHRSP. The AT1R activation in the PVN may be involved in its mechanism.

Abstract 082: Intrarenal Nacl Boli Cause Longlasting Inhibition of Renal Sympathetic Nerve Activity (RSNA)

Afferent renal nerve fibers from the kidney likely counterregulate salt sensitive blood pressure increases by decreasing renal sympathetic nerve activity. We recently reported on a long-lasting tonic sympatho-inhibition due to intrarenal afferent renal nerve stimulation eliciting a TRPV1 dependent neuro-humoral pathway. We wanted to test the hypothesis that sodium influences this afferent sympatho-depressory mechanism. Groups of anesthetized SD rats (n=8) were equipped with femoral catheters (blood pressure (BP) & heart rate (HR) recording, drug application), a renal arterial catheter for intrarenal administration (IRA) of high salt (10 % NaCl, 10 μl) or Capsaicin (CAP 3.3, 6.6, 10, 33*10-7 M, 10 μl) and a bipolar electrode for RSNA recordings; eventually an intravenous (iv) bolus of the NK1-receptor blocker RP67580 (10*10-3M, 15 μl) was given. Cultured dorsal root ganglion neurons (Th11-L2) of rats with renal afferents were investigated in current clamp mode to assess action potential generation or in voltage clamp mode to investigate inward currents during 10 sec superperfusion to 4.5 % NaCl or equiosmotic mannitol. solution Results are given in mean±SEM. IRA high salt and IRA CAP decreased RSNA from baseline 4.1±0.6 μV*sec to 2.2±0.8 μV*sec (10% NaCl, p<0.05) and 3.9±0.5 μV*sec to 0.9±0.2 μV*sec (CAP, p<0.01). Suppressed RSNA in high salt groups and CAP could be unmasked by systemic (i.v.) administration of the NK1-blocker (2.7±1.8 μV*sec to 5.8±2.2 μV*sec; p<0.05 (10% NaCl); 1.0±0.2 μV*sec to 6.1±1.5 μV*sec; p<0.01 (CAP)). Cultured renal neurons exhibited production of action potentials (3.5±0.8*, from baseline, p<0.05) and increased sustained inward currents from baseline during exposure to NaCl 4.5 % (-10708.8±3546.5 pA*, from baseline, p<0.05). No responses to equiosmolar mannitol. Increased intrarenal sodium concentrations might induce long-lasting sympatho-depression via a neuro-humoral TRPV1 dependent and tachykinin mediated afferent nerve pathway from the kidney. Impairment of this sympatho-depressory mechanism could be involved in salt sensitive hypertension.

Intrarenal High Salt Administration Causes Tonic Inhibition of Renal Sympathetic Nerve Activity (RSNA)

Afferent renal nerve fibers from the kidney likely counterregulate salt sensitive blood pressure increases by decreasing renal sympathetic nerve activity. We recently reported on a long‐lasting tonic sympatho‐inhibition due to intrarenal afferent renal nerve stimulation eliciting a TRPV1 dependent neuro‐humoral pathway. We wanted to test the hypothesis that sodium influences this afferent sympatho‐depressory mechanism.Groups of anesthetized SD rats (n=8) were equipped with femoral catheters (blood pressure (BP) & heart rate (HR) recording, drug application), a renal arterial catheter for intrarenal administration (IRA) of high salt (10 % NaCl, 10 μl) or Capsaicin (CAP 3.3, 6.6, 10, 33*10–7 M, 10 μl) and a bipolar electrode for RSNA recordings; eventually an intravenous (iv) bolus of the NK1‐receptor blocker RP67580 (10*10–3M, 15 μl) was given. Cultured dorsal root ganglion neurons (Th11‐L2) of rats with renal afferents were investigated in current clamp mode to assess action potential generation or in voltage clamp mode to investigate inward currents during 10 sec exposure to 4.5 % NaCl or equi‐osmotic 20% mannitol. Results are given in mean±SEM.IRA high salt and IRA CAP decreased RSNA from baseline 4.1±0.6 μV*sec to 2.2±0.8 μV*sec (10% NaCl, p<0.05) and 3.9±0.5 μV*sec to 0.9±0.2 μV*sec (CAP, p<0.01). Suppressed RSNA in high salt groups and CAP could be unmasked by systemic (i.v.) administration of the NK1‐blocker (2.7±1.8 μV*sec to 5.8±2.2 μV*sec; p<0.05 (10% NaCl); 1.0±0.2 μV*sec to 6.1±1.5 μV*sec; p<0.01 (CAP)). Cultured renal neurons exhibited production of action potentials (3.5±0.8*, from baseline, p<0.05) and increased sustained inward currents from baseline during exposure to NaCl 4.5 % (−10708.8±3546.5 pA*, from baseline, p<0.05). No responses to mannitol 20%.Increased intrarenal sodium concentrations might induce long‐lasting sympatho‐depression via a neuro‐humoral TRPV1 dependent and tachykinin mediated afferent nerve pathway from the kidney. Impairment of this sympatho‐depressory mechanism could be involved in salt sensitive hypertension.Support or Funding InformationDFG Deutsche Forschungsgemeinschaft VE 104/4‐1This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Integration of renal sensory afferents at the level of the paraventricular nucleus dictating sympathetic outflow

The sympathetic nervous system has been identified as a major contributor to the pathophysiology of chronic heart failure (CHF) and other diseases such as hypertension and diabetes, both in experimental animal models and patients. The kidneys have a dense afferent sensory innervation positioning it to be the origin of multimodal input to the central nervous system. Afferent renal nerve (ARN) signals are centrally integrated, and their activation results in a general increase in sympathetic tone, which is directed toward the kidneys as well as other peripheral organs innervated by the sympathetic nerves. In the central nervous system, stimulation of ARN increases the neuronal discharge frequency and neuronal activity in the paraventricular nucleus (PVN) of the hypothalamus. The activity of the neurons in the PVN is attenuated during iontophoretic application of glutamate receptor blocker, AP5. An enhanced afferent renal input to the PVN may be critically involved in dictating sympathoexcitation in CHF. Furthermore, renal denervation abrogates the enhanced neuronal activity within the PVN in rats with CHF, thereby possibly contributing to the reduction in sympathetic tone. Renal denervation also restores the decreased endogenous levels of neuronal nitric oxide synthase (nNOS) in the PVN of rats with CHF. Overall, these data demonstrate that sensory information originating in the kidney excites pre-autonomic sympathetic neurons within the PVN and this "renal-PVN afferent pathway" may contribute to elevated sympathetic nerve activity in hyper-sympathetic disease conditions such as CHF and hypertension.

Renal Denervation Improves Exaggerated Sympathoexcitation in Rats With Heart Failure: A Role for Neuronal Nitric Oxide Synthase in the Paraventricular Nucleus.

Renal denervation (RDN) has been postulated to reduce sympathetic drive during heart failure (HF), but the central mechanisms are not completely understood. The purpose of the present study was to assess the contribution of neuronal nitric oxide synthase (nNOS) within the paraventricular nucleus (PVN) in modulating sympathetic outflow in rats with HF that underwent RDN. HF was induced in rats by ligation of the left coronary artery. Four weeks after surgery, bilateral RDN was performed. Rats with HF had an increase in FosB-positive cells in the PVN with a concomitant increase in urinary excretion of norepinephrine, and both of these parameters were ameliorated after RDN. nNOS-positive cells immunostaining, diaphorase staining, and nNOS protein expression were significantly decreased in the PVN of HF rats, findings that were ameliorated by RDN. Microinjection of nNOS inhibitor N(G)-monomethyl l-arginine into the PVN resulted in a blunted increase in lumbar sympathetic nerve activity (11±2% versus 24±2%) in HF than in sham group. This response was normalized after RDN. Stimulation of afferent renal nerves produced a greater activation of PVN neurons in rats with HF. Afferent renal nerve stimulation elicited a greater increase in lumbar sympathetic nerve activity in rats with HF than in sham rats (45±5% versus 22±2%). These results suggest that intact renal nerves contribute to the reduction of nNOS in the PVN, resulting in the activation of the neurons in the PVN of rats with HF. RDN restores nNOS and thus attenuates the sympathoexcitation commonly observed in HF.

Activation of afferent renal nerves modulates RVLM-projecting PVN neurons.

Renal denervation for the treatment of hypertension has proven to be successful; however, the underlying mechanism/s are not entirely clear. To determine if preautonomic neurons in the paraventricular nucleus (PVN) respond to afferent renal nerve (ARN) stimulation, extracellular single-unit recording was used to investigate the contribution of the rostral ventrolateral medulla (RVLM)-projecting PVN (PVN-RVLM) neurons to the response elicited during stimulation of ARN. In 109 spontaneously active neurons recorded in the PVN of anesthetized rats, 25 units were antidromically activated from the RVLM. Among these PVN-RVLM neurons, 84% (21/25) were activated by ARN stimulation. The baseline discharge rate was significantly higher in these neurons than those PVN-RVLM neurons not activated by ARN stimulation (16%, 4/25). The responsiveness of these neurons to baroreflex activation induced by phenylephrine and activation of cardiac sympathetic afferent reflex (CSAR) was also examined. Almost all of the PVN neurons that responded to ARN stimulation were sensitive to baroreflex (95%) and CSAR (100%). The discharge characteristics for nonevoked neurons (not activated by RVLM antidromic stimulation) showed that 23% of these PVN neurons responded to ARN stimulation. All the PVN neurons that responded to ARN stimulation were activated by N-methyl-D-aspartate, and these responses were attenuated by the glutamate receptor blocker AP5. These experiments demonstrated that sensory information originating in the kidney is integrated at the level of preautonomic neurons within the PVN, providing a novel mechanistic insight for use of renal denervation in the modulation of sympathetic outflow in disease states such as hypertension and heart failure.

Different responses of arterial blood pressure to electrical stimulation of the renal artery in patients with resistant hypertension

SIMPLICITY-HTN 3 revealed several limitations of renal denervation (RDN) for the treatment of resistant hypertension [ [1] Bhatt D.L. Kandzari D.E. O'Neill W.W. D'Agostino R. Flack J.M. Katzen B.T. Leon M.B. Liu M. Mauri L. Negoita M. Cohen S.A. Oparil S. Rocha-Singh K. Townsend R.R. Bakris G.L. SYMPLICITY HTN-3 Investigators: a controlled trial of renal denervation for resistant hypertension. N. Engl. J. Med. 2014; 370: 1393-1401 Crossref PubMed Scopus (1566) Google Scholar ]. One of the main limitations is that the current RDN technique lacks a measurable endpoint. Recently, electrical stimulation of the renal nerves through the ablation catheter introduced in the renal artery before and after RDN was proposed as a promising method in this journal [ 2 Hilbert S. Kosiuk J. Hindricks G. Bollmann A. Blood pressure and autonomic responses to electrical stimulation of the renal arterial nerves before and after ablation of the renal artery. Int. J. Cardiol. 2014; 177: 669-671 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar , 3 Hao Y. Lu Z. Renal denervation: should we still hang in there?. Int. J. Cardiol. 2014; 176: 1255-1256 Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar ]. These reports showed that the effect of intra-renal artery electrical stimulation on renal nerves, especially the afferent sensory nerve, before and after ablation, was useful as RDN endpoint. However, the afferent sensory nerve on the lateral side of renal artery might include not only afferent excitatory sympathetic nerve fibers but also inhibitory sympathetic nerve fibers [ [4] Stella A. Weaver L. Golin R. Genovesi S. Zanchetti A. Cardiovascular effects of afferent renal nerve stimulation. Clin. Exp. Hypertens. A. 1987; 9: 97-111 Crossref PubMed Scopus (12) Google Scholar ]. In this report, we present two patients with resistant hypertension who showed opposite arterial blood pressure responses to electrical stimulation before and after RDN.

A novel method of selective ablation of afferent renal nerves by periaxonal application of capsaicin.

Renal denervation has been shown to lower arterial pressure in some hypertensive patients, yet it remains unclear whether this is due to ablation of afferent or efferent renal nerves. To investigate the role of afferent renal nerves in arterial pressure regulation, previous studies have used methods that disrupt both renal and nonrenal afferent signaling. The present study was conducted to develop and validate a technique for selective ablation of afferent renal nerves that does not disrupt other afferent pathways. To do this, we adapted a technique for sensory denervation of the adrenal gland by topical application of capsaicin and tested the hypothesis that exposure of the renal nerves to capsaicin (renal-CAP) causes ablation of afferent but not efferent renal nerves. Renal-CAP had no effect on renal content of the efferent nerve markers tyrosine hydroxylase and norepinephrine; however, the afferent nerve marker, calcitonin gene-related peptide was largely depleted from the kidney 10 days after intervention, but returned to roughly half of control levels by 7 wk postintervention. Moreover, renal-CAP abolished the cardiovascular responses to acute pharmacological stimulation of afferent renal nerves. Renal-CAP rats showed normal weight gain, as well as cardiovascular and fluid balance regulation during dietary sodium loading. To some extent, renal-CAP did blunt the bradycardic response and increase the dipsogenic response to increased salt intake. Lastly, renal-CAP significantly attenuated the development of deoxycorticosterone acetate-salt hypertension. These results demonstrate that renal-CAP effectively causes selective ablation of afferent renal nerves in rats.

Central projections of sodium‐sensitive afferent renal nerves in rats (687.3)

Renal denervation is reported to treat resistant essential hypertension. Many suggest that afferent renal nerves (ARN) are responsible for the full expression of hypertension. We hypothesized that osmosensitive ARN activate sites in the CNS that contribute to hypertension by evoking excessive sympathetic nerve activity. To determine the central projections, a dual lumen cannula was implanted through the left ureter into the renal pelvis of the rat. Several days later, renal pelvic afferents were bathed with different concentrations of NaCl (20, 308 and 500 mEq/L) using a push‐pull perfusion for 2 hrs while recording arterial pressure in conscious rats. Activation of CNS sites was identified using immunohistochemical detection of c‐Fos protein and compared to controls (no infusion or denervation). Many sites were dose‐dependently stimulated in response to intrarenal infusion of NaCl. These included the nucleus tractus solitarius, area postrema, parabrachial nucleus, paraventricular hypothalamus, and other areas. The results indicate that stimulation of osmosensitive ARN leads to activation of central autonomic sites involved in the regulation of sympathetic outflow. Thus, this work identifies likely sites mediating ARN‐induced sympathoexcitation contributing to the pathogenesis of hypertension.Grant Funding Source: Supported by USPHS HL25449 (ADL) and DA017371 (MMK).

Afferent renal nerve stimulation excites RVLM projecting PVN neurons in rats

Recently renal denervation in hypertensive patients has proven to be very successful, however the underlying mechanism is not entirely clear. To determine if pre‐autonomic neurons in the paraventricular nucleus of the hypothalamus (PVN) are responsive to afferent renal nerve stimulation (ARN‐Sti), extracellular recording was used to investigate the contribution of the rostral ventrolateral medulla (RVLM) projecting PVN (PVN‐RVLM) neurons to ARN‐Sti. We also examined if these same neurons were responsive to baroreflex (BR) (i.v. injection of phenylephrine), or cardiac sympathetic afferent reflex (CSAR) (epicardial bradykinin). In 109 spontaneously active neurons recorded in the PVN of anesthetized rats, 25 units were antidromically activated from the RVLM. Among units classified as RVLM projecting PVN neurons, 84% (21/25) were activated by ARN‐Sti and the baseline discharge rate was significantly higher in them compared to those that were not activated by ARN‐Sti (16%, 4/25). In addition, almost all of neurons sensitive to ARN‐Sti were sensitive to BR (95%) and CSAR (100%). Among the non‐evoked neurons (not responding to stimulated from the RVLM) in the PVN, 23% respond to ARN‐Sti while 77% did not; most of the ARN sensitive neurons (83%) were responsive to baroreflex stimulation. Non of the non‐evoked neurons respond to CSAR. These results demonstrate that sensory information originating in kidney is integrated at the level pre‐autonomic neurons within the PVN, providing a novel mechanistic insight for use of renal denervation in modulation of sympathetic outflow in disease states such as hypertension and heart failure. Supported by NIH 62222.

Blood Pressure and Autonomic Responses to Electrical Stimulation of the Renal Arterial Nerves Before and After Ablation of the Renal Artery

Radiofrequency (RF) catheter ablation of the renal artery is therapeutic in patients with drug-refractory essential hypertension. This study was designed to examine the role of the renal autonomic nerves and of RF application from inside the renal artery in the regulation of blood pressure (BP). An open irrigation catheter was inserted into either the left or right renal artery in 8 dogs. RF current (17 ± 2 watts) was delivered to one renal artery. Electrical autonomic nerve stimulation was applied to each renal artery before and after RF ablation. BP, heart rate, indices of heart rate variability, and serum catecholamines were analyzed. Before RF ablation, electrical autonomic nerve stimulation of either renal artery increased BP from 150 ± 16/92 ± 15 to 173 ± 21/105 ± 16 mm Hg. After RF ablation, BP increased similarly when the nonablated renal artery was electrically stimulated, although the rise in BP was attenuated when the ablated renal artery was stimulated. Serum catecholamines and sympathetic nerve indices of heart rate variability increased when electrical autonomic nerve stimulation was applied before RF ablation and to the nonablated renal artery after RF ablation, although it changed minimally when the ablated renal artery was stimulated, suggesting interconnectivity between afferent renal nerve stimulation and systemic sympathetic activity. Renal artery angiogram showed no apparent injury after RF ablation. In conclusion, electrical stimulation of the renal arterial autonomic nerves increases BP via an increase in central sympathetic nervous activity. This response might be used to determine the target ablation site and end point of renal artery RF ablation.

Afferent renal inputs to paraventricular nucleus vasopressin and oxytocin neurosecretory neurons

Extracellular single-unit recording experiments were done in pentobarbital sodium-anesthetized rats to investigate the effects of electrical stimulation of afferent renal nerves (ARN) and renal vein (RVO) or artery (RAO) occlusion on the discharge rate of putative arginine vasopressin (AVP) and oxytocin (Oxy) neurons in the paraventricular nucleus of the hypothalamus (PVH). PVH neurons antidromically activated by electrical stimulation of the neurohypophysis were classified as either AVP or Oxy secreting on the basis of their spontaneous discharge patterns and response to activation of arterial baroreceptors. Ninety-eight putative neurosecretory neurons in the PVH were tested for their response to electrical stimulation of ARN: 44 were classified as putative AVP and 54 as putative Oxy neurons. Of the 44 AVP neurons, 52% were excited, 7% were inhibited, and 41% were nonresponsive to ARN stimulation. Of the 54 Oxy neurons, 43% were excited, 6% inhibited, and 51% were not affected by ARN. An additional 45 neurosecretory neurons (29 AVP and 16 Oxy neurons) were tested for their responses to RVO and/or RAO. RVO inhibited 42% of the putative AVP neurons and 13% of the putative Oxy neurons. On the other hand, RAO excited 33% of the AVP and 9% of the Oxy neurons. No AVP or Oxy neurons were found to be excited by RVO or inhibited by RAO. These data indicate that sensory information originating in renal receptors alters the activity of AVP and Oxy neurons in the PVH and suggest that these renal receptors contribute to the hypothalamic control of AVP and Oxy release into the circulation.

Afferent renal inputs onto subfornical organ neurons responsive to angiotensin II.

Experiments were done in pentobarbital sodium-anesthetized rats to investigate the effect of electrical stimulation of afferent renal nerves (ARN) on the discharge rate of subfornical organ (SFO) neurons that responded to changes in plasma levels of angiotensin II (ANG II) and projected directly to the paraventricular nucleus of the hypothalamus (PVH). Extracellular recordings were made from 76 histologically verified single neurons in the SFO that were excited by intracarotid infusions of ANG II. Of these units, 54.8% (23 of 42) responded with excitation to ARN stimulation (mean onset latency, 125 +/- 35 ms). None of the SFO units excited by plasma ANG II were found to be inhibited by ARN stimulation. An additional 34 units in the SFO that were excited by plasma ANG II were also antidromically activated by stimulation of the PVH. Of these neurons, 17.8% (6 of 34) were also excited by stimulation of ARN. The results indicate that inputs from ARN converge onto SFO neurons that alter their discharge rate during changes in plasma concentration of ANG II and project directly to the PVH. These data suggest that ARN may play an important role in body fluid balance and circulatory regulation by modulating the activity of SFO neurons that function in the detection of blood-borne signals resulting from the decrease in extracellular fluid volume and arterial pressure and that influence the activity of hypothalamic nuclei that contain neurosecretory neurons.

Fos induction in central structures after afferent renal nerve stimulation

Experiments were done in the conscious and unrestrained rat to identify central structures activated by electrical stimulation of afferent renal nerves (ARN) using the immunohistochemical detection of Fos-like proteins. Fos-labelled neurons were found in a number of forebrain and brainstem structures bilaterally, but with a contralateral predominance. Additionally, Fos-labelled neurons were found in the lower thoracolumbar spinal cord predominantly ipsilateral to the side of ARN stimulation. Within the forebrain, neurons containing Fos-like immunoreactivity after ARN stimulation were primarily found along the outer edge of the rostral organum vasculosum of the laminae terminalis, in the medial regions of the subfornical organ, in the median preoptic nucleus, in the ventral subdivision of the bed nucleus of the stria terminalis, along the lateral part of the central nucleus of the amygdala, throughout the deeper layers of the dysgranular insular cortex, in the parvocellular component of the paraventricular nucleus of the hypothalamus (PVH), and in the paraventricular nucleus of the thalamus. Additionally, a smaller number of Fos-labelled neurons was observed in the supraoptic nucleus, in the magnocellular component of the PVH and along the lateral border of the arcuate nucleus. Within the brainstem, Fos-labelled neurons were found predominantly in the commissural and medial subnuclei of the nucleus of the solitary tract and in the external subnucleus of the lateral parabrachial nucleus. A smaller number were observed near the caudal pole of the locus coeruleus, and scattered throughout the ventrolateral medullary and pontine reticular formation in the regions known to contain the A1, C1 and A5 catecholamine cell groups. The final area observed to contain Fos-labelled neurons in the central nervous system was the thoracolumbar spinal cord (T9–L1) which contained cells in laminae I–V of the dorsal horn ipsilateral to side of stimulation and in the intermediolateral cell column at the same levels bilaterally, but with an ipsilateral predominance. Few, if any Fos-labelled neurons were observed in the same structures of control animals in which the ARN were stimulated, but the renal nerves proximal to the site of stimulation were transected, or in the sham operated animals. These data indicate that ARN information originating in renal receptors is conveyed to a number of central areas known to be involved in the regulation of body fluid balance and arterial pressure, and suggest that this afferent information is an important component of central mechanisms regulating these homeostatic functions. © 1997 Elsevier Science B.V. All rights reserved.

Effect of moderately increased intrapelvic pressure on renal tissue pressure and vasopressin release in rabbits.

Electrical stimulation of afferent renal nerves and activation of intrarenal receptors increases plasma vasopressin concentration, but the role of afferent renal nerves in the control of vasopressin secretion is not clear. Recently, we reported that activation of renal mechanoreceptors stimulates the release of vasopressin. However, intrapelvic pressure was increased to 50 mmHg, and this increase is above the normal physiological range. Therefore, in the present study, we investigated the effect of moderately increased intrapelvic pressure on plasma vasopressin concentration in anesthetized rabbits. First, we measured renal tissue pressure while intrapelvic pressure was increased stepwise in 10-mmHg increments. Basal renal tissue pressure was 17 +/- 2 mmHg. Renal tissue pressure increased only when intrapelvic pressure was higher than the basal tissue pressure of each animal. Usually, increases in intrapelvic pressure less than 20 mmHg did not increase renal tissue pressure. This finding suggests that only increases in intrapelvic pressure more than 20 mmHg can activate renal mechanoreceptors. Based on this finding, the effects of moderate increases in intrapelvic pressure (15 and 30 mmHg) were studied. With a 15-mmHg increase in intrapelvic pressure, plasma vasopressin concentration did not change significantly. However, when intrapelvic pressure was increased to 30 mmHg, plasma vasopressin concentration increased from 5.6 +/- 1.4 to 9.5 +/- 2.8 pg/ml at 5 min (p < 0.05) and to 8.8 +/- 2.0 pg/ml at 10 min (p < 0.05). Plasma renin activity and mean arterial pressure also increased when intrapelvic pressure was increased to 30 mmHg. We conclude that moderate increases in intrapelvic pressure stimulate vasopressin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of intrarenal bradykinin infusion on vasopressin release in rabbits.

Electrical stimulation of afferent renal nerves and activation of renal mechanoreceptors increase plasma vasopressin concentrations. In the present study, the effect of renal chemoreceptor activation on plasma vasopressin concentration was investigated in anesthetized rabbits. Renal chemoreceptors were activated with intrarenal infusions of bradykinin. With intrarenal infusion of bradykinin at 136 ng/min, plasma vasopressin concentration increased from 4.5 +/- 1.5 to 26.8 +/- 14.2 pg/ml at 5 minutes (p less than 0.01), whereas with infusion at 1,360 ng/min, plasma vasopressin increased from 5.9 +/- 2.0 to 54.4 +/- 16.4 pg/ml at 5 minutes (p less than 0.01). There was no significant change in plasma vasopressin during intravenous infusion of bradykinin at 136 ng/min. Infusion at 1,360 ng/min increased plasma vasopressin from 2.7 +/- 0.5 to 14.8 +/- 6.4 pg/ml (p less than 0.01), but this increase was significantly less than that produced by intrarenal infusion of the same dose of bradykinin. Similar effects on plasma vasopressin were observed during paired intrarenal and intravenous infusions of bradykinin at 136 ng/min. Renal denervation markedly reduced the vasopressin responses to intrarenal infusion of bradykinin at 136 ng/min (2.8 +/- 0.5 to 4.0 +/- 0.7 pg/ml, p less than 0.01) and 1,360 ng/min (3.2 +/- 0.7 to 7.8 +/- 1.8 pg/ml, p less than 0.05). These results indicate that bradykinin stimulates vasopressin release by an intrarenal action and suggest that this action is mediated by afferent renal nerves.

Medial medullary contribution to tonic descending inhibition of visceral input

In the present study, we sought to define the extent and source of tonic descending modulation of spinal neurons receiving visceral input from the afferent renal nerve (ARN). Spinal gray neurons responding to stimulation of the ARN in 64 chloralose-anesthetized rats were located primarily in laminae IV and V (70%), with fewer neurons located in laminae I and VII. ARN stimulation excited 76 and inhibited 8 neurons. Analysis of response latencies demonstrated that responses were due to activation of A delta- and/or C-fiber afferents. Reversible spinalization with cervical cold block (2-5 degrees C) affected activity in most neurons excited by ARN stimulation without affecting inhibited neurons. Cervical cold block increased the spontaneous activity of (disinhibited) the majority of neurons (54 of 76 neurons) and disfacilitated the spontaneous activity of 14 neurons. The evoked response to ARN stimulation was disinhibited by cold block in 51% and disfacilitated in 17% of the neurons, and there was a good correlation between neurons with disinhibited spontaneous activity and those with disinhibited evoked activity. Microinjections of muscimol (0.5-1 nmol) into the rostral medial medulla affected spontaneous and ARN-evoked activities similarly to cold block in 14 of 15 neurons, although the responses to muscimol were usually smaller in magnitude. We conclude that ARN input is modulated supraspinally and that the nucleus raphe magnus and adjacent neuropil contain neurons that contribute to tonic supraspinal inhibition of renal input in the rat.

Activation of renal mechanoreceptors increases vasopressin release in rabbits

Electrical stimulation of afferent renal nerves increases plasma vasopressin (AVP) concentration, but the role of these nerves in the control of AVP release is not known. The aim of the present study was to investigate the effect of activation of renal mechanoreceptors and chemoreceptors on plasma AVP concentration in anesthetized rabbits. Intrapelvic pressure was increased to activate renal mechanoreceptors, and the renal pelvis was perfused with 1.0 M NaCl, 0.1 M KCl, and 1.0 M mannitol solutions to activate R2 chemoreceptors. With increased pelvic pressure, plasma AVP concentration increased from 12.4 +/- 3.8 to 36.2 +/- 16.1 pg/ml at 5 min and to 37.4 +/- 16.1 pg/ml at 10 min (P less than 0.01). Plasma renin activity increased from 15.7 +/- 4.0 to 22.1 +/- 3.3 ng.ml-1.2 h-1 (P less than 0.05), but blood pressure and heart rate did not change significantly. Similar increases in plasma AVP concentration occurred during perfusion of the renal pelvis with 1.0 M NaCl (17.6 +/- 8.1 to 53.7 +/- 24.0 pg/ml), 0.1 M KCl (9.2 +/- 2.1 to 39.7 +/- 17.3 pg/ml), and 1.0 M mannitol (27.5 +/- 10.9 to 77.5 +/- 30.8 pg/ml) solutions. However, because pelvic pressure increased by 40-50 mmHg during the perfusions, the experiments were repeated with use of a different perfusion method in which pelvic pressure increased by less than 5 mmHg. Under these conditions, plasma AVP concentration did not change significantly during perfusion with any of the solutions. To determine whether the mechanoreceptor-induced increase in AVP release is mediated by the renal nerves, pelvic pressure was increased in another group of rabbits after renal denervation.(ABSTRACT TRUNCATED AT 250 WORDS)