Impaired responsiveness of renal mechanosensory nerves in heart failure: role of endogenous angiotensin

Increasing renal pelvic pressure results in PGE(2)-mediated release of substance P. Substance P increases afferent renal nerve activity (ARNA), which leads to a reflex increase in urinary sodium excretion (U(Na)V). Endogenous ANG II modulates the responsiveness of renal mechanosensory nerves. The ARNA and U(Na)V responses are suppressed by low- and enhanced by high-sodium diet. We examined whether the ARNA responses are altered in rats with congestive heart failure (CHF), a condition characterized by increased ANG II and sodium retention. The ARNA responses to increasing renal pelvic pressure 相似文献   

Differential effects of endothelin on activation of renal mechanosensory nerves: stimulatory in high-sodium diet and inhibitory in low-sodium diet

Activation of renal mechanosensory nerves is enhanced by high and suppressed by low sodium dietary intake. Afferent renal denervation results in salt-sensitive hypertension, suggesting that activation of the afferent renal nerves contributes to water and sodium balance. Another model of salt-sensitive hypertension is the endothelin B receptor (ETBR)-deficient rat. ET and its receptors are present in sensory nerves. Therefore, we examined whether ET receptor blockade altered the responsiveness of the renal sensory nerves. In anesthetized rats fed high-sodium diet, renal pelvic administration of the ETBR antagonist BQ-788 reduced the afferent renal nerve activity (ARNA) response to increasing renal pelvic pressure 7.5 mmHg from 26+/-3 to 9+/-3% and the PGE2-mediated renal pelvic release of substance P from 9+/-1 to 3+/-1 pg/min. Conversely, in rats fed low-sodium diet, renal pelvic administration of the ETAR antagonist BQ-123 enhanced the ARNA response to increased renal pelvic pressure from 9+/-2 to 23+/-6% and the PGE2-mediated renal pelvic release of substance P from 0+/-0 to 6+/-1 pg/min. Adding the ETAR antagonist to ETBR-blocked renal pelvises restored the responsiveness of renal sensory nerves in rats fed a high-sodium diet. Adding the ETBR antagonist to ETAR-blocked pelvises suppressed the responsiveness of the renal sensory nerves in rats fed a low-sodium diet. In conclusion, activation of ETBR and ETAR contributes to the enhanced and suppressed responsiveness of renal sensory nerves in conditions of high- and low-sodium dietary intake, respectively. Impaired renorenal reflexes may contribute to the salt-sensitive hypertension in the ETBR-deficient rat.     

Dietary sodium modulates the interaction between efferent and afferent renal nerve activity by altering activation of α2-adrenoceptors on renal sensory nerves

Activation of efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), which then reflexively decreases ERSNA via activation of the renorenal reflexes to maintain low ERSNA. The ERSNA-ARNA interaction is mediated by norepinephrine (NE) that increases and decreases ARNA by activation of renal α(1)-and α(2)-adrenoceptors (AR), respectively. The ERSNA-induced increases in ARNA are suppressed during a low-sodium (2,470 ± 770% s) and enhanced during a high-sodium diet (5,670 ± 1,260% s). We examined the role of α(2)-AR in modulating the responsiveness of renal sensory nerves during low- and high-sodium diets. Immunohistochemical analysis suggested the presence of α(2A)-AR and α(2C)-AR subtypes on renal sensory nerves. During the low-sodium diet, renal pelvic administration of the α(2)-AR antagonist rauwolscine or the AT1 receptor antagonist losartan alone failed to alter the ARNA responses to reflex increases in ERSNA. Likewise, renal pelvic release of substance P produced by 250 pM NE (from 8.0 ± 1.3 to 8.5 ± 1.6 pg/min) was not affected by rauwolscine or losartan alone. However, rauwolscine+losartan enhanced the ARNA responses to reflex increases in ERSNA (4,680 ± 1,240%·s), and renal pelvic release of substance P by 250 pM NE, from 8.3 ± 0.6 to 14.2 ± 0.8 pg/min. During a high-sodium diet, rauwolscine had no effect on the ARNA response to reflex increases in ERSNA or renal pelvic release of substance P produced by NE. Losartan was not examined because of low endogenous ANG II levels in renal pelvic tissue during a high-sodium diet. Increased activation of α(2)-AR contributes to the reduced interaction between ERSNA and ARNA during low-sodium intake, whereas no/minimal activation of α(2)-AR contributes to the enhanced ERSNA-ARNA interaction under conditions of high sodium intake.     

Renal sympathetic nerve activity modulates afferent renal nerve activity by PGE2-dependent activation of alpha1- and alpha2-adrenoceptors on renal sensory nerve fibers

Increasing efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA). To test whether the ERSNA-induced increases in ARNA involved norepinephrine activating alpha-adrenoceptors on the renal sensory nerves, we examined the effects of renal pelvic administration of the alpha(1)- and alpha(2)-adrenoceptor antagonists prazosin and rauwolscine on the ARNA responses to reflex increases in ERSNA (placing the rat's tail in 49 degrees C water) and renal pelvic perfusion with norepinephrine in anesthetized rats. Hot tail increased ERSNA and ARNA, 6,930 +/- 900 and 4,870 +/- 670%.s (area under the curve ARNA vs. time). Renal pelvic perfusion with norepinephrine increased ARNA 1,870 +/- 210%.s. Immunohistochemical studies showed that the sympathetic and sensory nerves were closely related in the pelvic wall. Renal pelvic perfusion with prazosin blocked and rauwolscine enhanced the ARNA responses to reflex increases in ERSNA and norepinephrine. Studies in a denervated renal pelvic wall preparation showed that norepinephrine increased substance P release, from 8 +/- 1 to 16 +/- 1 pg/min, and PGE(2) release, from 77 +/- 11 to 161 +/- 23 pg/min, suggesting a role for PGE(2) in the norepinephrine-induced activation of renal sensory nerves. Prazosin and indomethacin reduced and rauwolscine enhanced the norepinephrine-induced increases in substance P and PGE(2). PGE(2) enhanced the norepinephrine-induced activation of renal sensory nerves by stimulation of EP4 receptors. Interaction between ERSNA and ARNA is modulated by norepinephrine, which increases and decreases the activation of the renal sensory nerves by stimulating alpha(1)- and alpha(2)-adrenoceptors, respectively, on the renal pelvic sensory nerve fibers. Norepinephrine-induced activation of the sensory nerves is dependent on renal pelvic synthesis/release of PGE(2).     

Role of renal nerves in development of hypertension in DOCA-salt model in rats: a telemetric approach

Centrally mediated hyperactivity of the autonomic nervous system contributes to DOCA hypertension; however, the targeted peripheral vascular bed(s) remain unclear. We propose that if renal sympathetic activity is a factor in the development of DOCA-salt hypertension, then renal denervation (RDNX) should attenuate the hypertensive response. In protocol 1, uninephrectomized RDNX (n = 9) and sham-denervated (n = 6) Sprague-Dawley rats were allowed free access to 0.9% NaCl solution and 0.1% NaCl diet. Mean arterial pressure (MAP) and heart rate were telemetrically recorded for 4 days before and 36 days after DOCA (100 mg/rat) implantation; sodium and water balances were recorded daily. Protocol 2 was similar except that saline intake in sham rats (n = 7) was matched to that observed in RDNX rats of protocol 1 for 30 days; for the last 10 days, the rats were allowed free access to saline. Before DOCA in protocol 1, MAP was lower (P < 0.05) in RDNX rats (99 +/- 1 mmHg) compared with sham rats (111 +/- 3 mmHg); however, heart rate and sodium and water balances were similar between groups. RDNX attenuated the MAP response to DOCA by approximately 50% (DeltaMAP = 22 +/- 3 mmHg, where Delta is change in MAP) when compared with sham rats (DeltaMAP = 38 +/- 6). RDNX rats consumed significantly less saline than sham rats, and cumulative sodium and water balances were reduced by 33% and 23%, respectively. In protocol 2, a similar pattern in MAP elevation was observed in RDNX and saline-restricted, sham-denervated rats even when saline restriction was removed. These results indicate that the renal sympathetic nerves are important in hypertension development but that other factors are also involved.     

Baroreflex regulation of renal sympathetic nerve activity and heart rate in renal wrap hypertensive rats

Despite its usefulness as a nongenetic model of hypertension, little information is available regarding baroreflex function in the Grollman, renal wrap model of hypertension in the rat. Baroreflex regulation of renal sympathetic nerve activity (RSNA) and heart rate (HR) were studied in male, Sprague-Dawley rats hypertensive (HT) for 1 or 4-6 wk after unilateral nephrectomy and figure-8 ligature around the remaining kidney or normotensive (NT) after sham surgery. Rats were anesthetized with Inactin and RSNA, and HR was recorded during intravenous infusions of sodium nitroprusside or phenylephrine to lower or raise mean arterial pressure (MAP). Response curves were analyzed using a logistic sigmoid function. In 1- and 4-wk HT rats the midpoints of RSNA and HR reflex curves were shifted to the right (P < 0.05). Comparing NT to 1- or 4-wk HT rats, the gain of RSNA-MAP curves was no different; however, gain was reduced in the HR-MAP curves at both 1 and 4 wk in HT rats (P < 0.05). In anesthetized rats the HR range was small; therefore, MAP and HR were measured in conscious rats during intravenous injections of three doses of phenylephrine and three doses of sodium nitroprusside. Linear regressions revealed a reduced slope in both 1- and 4-wk HT rats compared with NT rats (P < 0.05). The results indicate that baroreflex curves are shifted to the right, to higher pressures, in hypertension. After 1-4 wk of hypertension the gain of baroreflex regulation of RSNA is not altered; however, the gain of HR regulation is reduced.     

Cardiac sympathetic afferent stimulation impairs baroreflex control of renal sympathetic nerve activity in rats

It is well known that cardiac sympathetic afferent reflexes contribute to increases in sympathetic outflow and that sympathetic activity can antagonize arterial baroreflex function. In this study, we tested the hypothesis that in normal rats, chemical and electrical stimulation of cardiac sympathetic afferents results in a decrease in the arterial baroreflex function by increasing sympathetic nerve activity. Under alpha-chloralose (40 mg/kg) and urethane (800 mg/kg i.p.) anesthesia, renal sympathetic nerve activity, mean arterial pressure, and heart rate were recorded. The arterial baroreceptor reflex was evaluated by infusion of nitroglycerin (25 microg i.v.) and phenylephrine (10 microg i.v.). Left ventricular epicardial application of capsaicin (0.4 microg in 2 microl) blunted arterial baroreflex function by 46% (maximum slope 3.5 +/- 0.3 to 1.9 +/- 0.2%/mmHg, P < 0.01). When the central end of the left cardiac sympathetic nerve was electrically stimulated (7 V, 1 ms, 20 Hz), the sensitivity of the arterial baroreflex was similarly decreased by 42% (maximum slope 3.2 +/- 0.3 to 1.9 +/- 0.4%/mmHg; P < 0.05). Pretreatment with intracerebroventricular injection of losartan (500 nmol in 1 microl of artificial cerebrospinal fluid) completely prevented the impairment of arterial baroreflex function induced by electrical stimulation of the central end of the left cardiac sympathetic nerve (maximum slope 3.6 +/- 0.4 to 3.1 +/- 0.5%/mmHg). These results suggest that the both chemical and electrical stimulation of the cardiac sympathetic afferents reduces arterial baroreflex sensitivity and the impairment of arterial baroreflex function induced by cardiac sympathetic afferent stimulation is mediated by central angiotensin type 1 receptors.     

Glucocorticoids act in the dorsal hindbrain to modulate baroreflex control of heart rate

Systemic corticosterone (Cort) modulates arterial baroreflex control of both heart rate and renal sympathetic nerve activity. Because baroreceptor afferents terminate in the dorsal hindbrain (DHB), an area with dense corticosteroid receptor expression, we tested the hypothesis that prolonged activation of DHB Cort receptors increases the midpoint and reduces the gain of arterial baroreflex control of heart rate in conscious rats. Small (3-4 mg) pellets of Cort (DHB Cort) or Silastic (DHB Sham) were placed on the surface of the DHB, or Cort was administered systemically by placing a Cort pellet on the surface of the dura (Dura Cort). Baroreflex control of heart rate was determined in conscious male Sprague Dawley rats on each of 4 days after initiation of treatment. Plots of arterial pressure vs. heart rate were analyzed using a four-parameter logistic function. After 3 days of treatment, the arterial pressure midpoint for baroreflex control of heart rate was increased in DHB Cort rats (123 +/- 2 mmHg) relative to both DHB Sham (108 +/- 3 mmHg) and Dura Cort rats (109 +/- 2 mmHg, P < 0.05). On day 4, baseline arterial pressure was greater in DHB Cort (112 +/- 2 mmHg) compared with DHB Sham (105 +/- 2 mmHg) and Dura Cort animals (106 +/- 2 mmHg, P < 0.05), and the arterial pressure midpoint was significantly greater than mean arterial pressure in the DHB Cort group only. Also on day 4, maximum baroreflex gain was reduced in DHB Cort (2.72 +/- 0.12 beats x min(-1) x mmHg(-1)) relative to DHB Sham and Dura Cort rats (3.51 +/- 0.28 and 3.37 +/- 0.27 beats x min(-1) x mmHg(-1), P < 0.05). We conclude that Cort acts in the DHB to increase the midpoint and reduce the gain of the heart rate baroreflex function.     

Effect of renal medullary H2O2 on salt-induced hypertension and renal injury

Dahl salt-sensitive (SS) and consomic, salt-resistant SS-13(BN) rats possess substantial differences in blood pressure salt-sensitivity even with highly similar genetic backgrounds. The present study examined whether increased oxidative stress, particularly H2O2, in the renal medulla of SS rats contributes to these differences. Blood pressure was measured using femoral arterial catheters in three groups of rats: 1) 12-wk-old SS and consomic SS-13(BN) rats fed a 0.4% NaCl diet, 2) SS rats fed a 4% NaCl diet and chronically infused with saline or catalase (6.9 microg x kg(-1) x min(-1)) directly into the renal medulla, and 3) SS-13(BN) fed high salt (4%) and infused with saline or H2O2 (347 nmol x kg(-1) x min(-1)) into the renal medullary interstitium. After chronic blood pressure measurements, renal medullary interstitial H2O2 concentration ([H2O2]) was collected by microdialysis and analyzed with Amplex red. Blood pressure and [H2O2] were both significantly higher in SS (126 +/- 3 mmHg and 145 +/- 17 nM, respectively) vs. SS-13(BN) rats (116 +/- 2 mmHg and 56 +/- 14 nM) fed a 0.4% diet. Renal interstitial catalase infusion significantly decreased [H2O2] (96 +/- 41 vs. 297 +/- 52 nM) and attenuated the hypertension (146 +/- 2 mmHg catalase vs. 163 +/- 4 mmHg saline) in SS rats after 5 days of high salt (4%). H2O2 infused into the renal medulla of consomic SS-13(BN) fed high salt (4%) for 7 days accentuated the salt sensitivity (145 +/- 2 mmHg H2O2 vs. 134 +/- 1 mmHg saline). [H2O2] was also increased in the treated group (83 +/- 1 nM H2O2 vs. 44 +/- 9 nM saline). These data show that medullary production of H2O2 may contribute to salt-induced hypertension in SS rats and that chromosome 13 of the Brown Norway contains gene(s) that protect against renal medullary oxidant stress.     

Aging and baroreflex control of RSNA and heart rate in rats

Aging is associated with altered autonomic control of cardiovascular function, but baroreflex function in animal models of aging remains controversial. In this study, pressor and depressor agent-induced reflex bradycardia and tachycardia were attenuated in conscious old (24 mo) rats [57 and 59% of responses in young (10 wk) Wistar rats, respectively]. The intrinsic heart rate (HR, 339 +/- 5 vs. 410 +/- 10 beats/min) was reduced in aged animals, but no intergroup differences in resting mean arterial blood pressure (MAP, 112 +/- 3 vs. 113 +/- 5 mmHg) or HR (344 +/- 9 vs. 347 +/- 9 beats/min) existed between old and young rats, respectively. The aged group also exhibited a depressed (49%) parasympathetic contribution to the resting HR value (vagal effect) but preserved sympathetic function after intravenous methylatropine and propranolol. An implantable electrode revealed tonic renal sympathetic nerve activity (RSNA) was similar between groups. However, old rats showed impaired baroreflex control of HR and RSNA after intravenous nitroprusside (-0.63 +/- 0. 18 vs. -1.84 +/- 0.4 bars x cycle(-1) x mmHg(-1) x s(-1)). Therefore, aging in rats is associated with 1) preserved baseline MAP, HR, and RSNA, 2) impaired baroreflex control of HR and RSNA, and 3) altered autonomic control of resting HR.     

ET(A) receptor blockade prevents renal dysfunction in salt-sensitive hypertension induced by sensory denervation

To test the hypothesis that activation of the endothelin type A (ET(A)) receptor contributes to decreased renal excretory function and increased blood pressure in sensory nerve-degenerated rats fed a high-salt diet, neonatal Wistar rats were given vehicle or capsaicin (CAP, 50 mg/kg s.c.) on the first and second day of life. After being weaned, vehicle or CAP-treated rats were fed a normal (NS, 0.5%) or a high- (HS, 4%) sodium diet for 2 wk with or without ABT-627 (5 mg x kg(-1) x day(-1), a selective ET(A) receptor antagonist). Systolic blood pressure increased in CAP-treated rats fed a HS diet (CAP-HS) compared with vehicle-treated rats fed a HS diet (CON-HS, 145 +/- 7 vs. 89 +/- 5 mmHg, P < 0.05). Creatinine clearance and fractional sodium excretion (FE(Na)) decreased in CAP-HS rats compared with CON-HS rats (creatinine clearance, 0.54 +/- 0.05 vs. 0.81 +/- 0.09 ml x min(-1) x 100 g body wt(-1); FE(Na), 8.68 +/- 0.99 vs. 12.53 +/- 1.47%, respectively; P < 0.05). Water and sodium balance increased in CAP-HS rats compared with CON-HS (water balance, 20.2 +/- 1.5 vs. 15.5 +/- 1.9 ml/day; sodium balance, 11.9 +/- 3.1 vs. 2.4 +/- 0.3 meq/day, respectively; P < 0.05). The endothelin (ET)-1 levels in plasma and isolated glomeruli increased by about twofold in CAP-HS rats compared with CON-HS rats (P < 0.05). ABT-627 prevented the decrease in creatinine clearance and FE(Na), the increase in water and sodium balance, and the increase in blood pressure in CAP-HS rats (P < 0.05). Therefore, the blockade of the ET(A) receptor ameliorates the impairment of renal excretory function and prevents the elevation in blood pressure in salt-sensitive hypertension induced by degeneration of sensory nerves, indicating that the activation of the ET(A) receptor impairs renal function and contributes to the development of a salt-induced increase in blood pressure in this model.     

Baroreflex control of lumbar and renal sympathetic nerve activity in conscious rats

This study compared the baroreflex control of lumbar and renal sympathetic nerve activity (SNA) in conscious rats. Arterial pressure (AP) and lumbar and renal SNA were simultaneously recorded in six freely behaving rats. Pharmacological estimates of lumbar and renal sympathetic baroreflex sensitivity (BRS) were obtained by means of the sequential intravenous administration of sodium nitroprusside and phenylephrine. Sympathetic BRS was significantly (P < 0.05) lower for lumbar [3.0 +/- 0.4 normalized units (NU)/mmHg] than for renal (7.6 +/- 0.6 NU/mmHg) SNA. During a 219-min baseline period, spontaneous lumbar and renal BRS were continuously assessed by computing the gain of the transfer function relating AP and SNA at heart rate frequency over consecutive 61.4-s periods. The transfer gain was considered only when coherence between AP and SNA significantly differed from zero, which was verified in 99 +/- 1 and 96 +/- 3% of cases for lumbar and renal SNA, respectively. When averaged over the entire baseline period, spontaneous BRS was significantly (P < 0.05) lower for lumbar (1.3 +/- 0.2 NU/mmHg) than for renal (2.3 +/- 0.3 NU/mmHg) SNA. For both SNAs, spontaneous BRS showed marked fluctuations (variation coefficients were 26 +/- 2 and 28 +/- 2% for lumbar and renal SNA, respectively). These fluctuations were positively correlated in five of six rats (R = 0.44 +/- 0.06; n = 204 +/- 8; P < 0.0001). We conclude that in conscious rats, the baroreflex control of lumbar and renal SNA shows quantitative differences but is modulated in a mostly coordinated way.     

Role of the renal nerves in blood pressure in male and female SHR

Female spontaneously hypertensive rats (SHR) have lower blood pressures than males. The renin-angiotensin system plays an important role in the sexual dimorphism of blood pressure in SHR. The sympathetic nervous system can stimulate renin release, and, therefore, the present study was performed to determine whether the renal sympathetic nerves play a role in the sexual dimorphism of blood pressure in SHR. Male and female SHR underwent bilateral kidney denervation or sham surgery, and, 2 wk later, mean arterial pressure (MAP) and pulse interval were recorded, and baroreflex sensitivity (BRS) was measured by the sequence technique. Left ventricle index (LVI) was also calculated. MAP was higher in sham-operated males than females (182 +/- 5 vs. 169 +/- 4 mmHg; P < 0.01), but, despite the higher MAP in males, LVI was significantly greater in female rats. BRS was not different between sham-operated male and female SHR. Following bilateral renal denervation, MAP was decreased by a similar percentage (8-10%) in males (169 +/- 2 mmHg) and females (152 +/- 3 mmHg), whereas LVI was reduced only in female SHR. BRS was not altered by renal denervation in either sex. These data indicate that renal nerves play a role in the control of blood pressure in SHR independent of sex, but do not play a role in mediating the sex differences in blood pressure.     

Combined prenatal and postnatal protein restriction influences adult kidney structure, function, and arterial pressure

The effects of prenatal protein restriction on adult renal and cardiovascular function have been studied in considerable detail. However, little is known about the effects of life-long protein restriction, a common condition in the developing world. Therefore, we determined in rats the effects of combined pre- and postnatal protein restriction on adult arterial pressure and renal function and responses to increased dietary sodium. Nephron number was also determined. Male Sprague-Dawley rats were born to mothers fed a low [8% (wt/wt), LP] or normal [20% (wt/wt), NP] isocaloric protein diet throughout pregnancy and maintained on these diets after birth. At postnatal day 135, nephron number, mean arterial pressure (MAP), and renal function were determined. A high-NaCl [8.0% (wt/wt), high-salt] diet was fed to a subset of rats from weaning. MAP was less in LP than in NP rats (120 +/- 2 vs. 128 +/- 2 mmHg, P < 0.05) and was not significantly altered by increased salt intake. Nephron number was 31% less in LP than in NP rats (P < 0.001). The volume of individual glomeruli was also less in LP than in NP rats, as were calculated effective renal plasma flow and glomerular filtration rate. Glomerular filtration rate, but not effective renal plasma flow, appeared to be increased by high salt intake, particularly in LP rats. In conclusion, protein restriction induced a severe nephron deficit, but MAP was lower, rather than higher, in protein-restricted than in control rats in adulthood. These findings indicate that the postnatal environment plays a key role in determining the outcomes of developmental programming.     

Glucocorticoids modulate baroreflex control of renal sympathetic nerve activity

Experiments were performed to determine the effects of glucocorticoids on arterial baroreceptor reflex control of renal sympathetic nerve activity (RSNA). Intravenous infusions of phenylephrine and nitroprusside were used to produce graded changes in arterial pressure (AP) in Inactin-anesthetized male Sprague-Dawley rats. Baroreflex control of RSNA was determined during a baseline period and 2 and 3 h after administration of the glucocorticoid type II receptor antagonist Mifepristone (30 mg/kg sc) or vehicle (oil). Corticosterone (cort) treatment (100 mg cort pellet sc for 2-3 wk) increased baseline AP from 115 +/- 2 to 128 +/- 1 mmHg. Cort treatment also decreased the gain coefficient and increased the midpoint of the baroreflex curve. Treatment of cort rats with Mifepristone decreased AP within 2 h and increased the gain coefficient and decreased the midpoint of the baroreflex function curve back toward values measured in control rats. Mifepristone altered the baroreflex function curve even when AP was maintained at baseline levels. Therefore, these data demonstrate for the first time that glucocorticoids can modulate baroreflex control of RSNA by a mechanism that is, in part, independent of changes in AP.     

PGE(2) increases release of substance P from renal sensory nerves by activating the cAMP-PKA transduction cascade

Increasing renal pelvic pressure increases afferent renal nerve activity (ARNA) by a PGE(2)-mediated release of substance P (SP) from renal pelvic nerves. The role of cAMP activation in the PGE(2)-mediated release of SP was studied by examining the effects of the adenylyl cyclase (AC) activator forskolin and AC inhibitor dideoxyadenosine (DDA). Forskolin enhanced the bradykinin-mediated release of SP from an isolated rat renal pelvic wall preparation, from 7.3 +/- 1.3 to 15.6 +/- 3.0 pg/min. PGE(2) at a subthreshold concentration for SP release mimicked the effects of forskolin. The EP(2) receptor agonist butaprost, 15 microM, and PGE(2), 0.14 microM, produced similar increases in SP release, from 5.8 +/- 0.8 to 17.0 +/- 2.3 pg/min and from 8.0 +/- 1.3 to 21.6 +/- 2.7 pg/min. DDA blocked the SP release produced by butaprost and PGE(2). The PGE(2)-induced release of SP was also blocked by the PKA inhibitors PKI(14-22) and H-89. Studies in anesthetized rats showed that renal pelvic administration of butaprost, 10 microM, and PGE(2), 0.14 microM, resulted in similar ARNA responses, 1,520 +/- 390 and 1,170 +/- 270%. s (area under the curve of ARNA vs. time) that were blocked by DDA. Likewise, the ARNA response to increased renal pelvic pressure, 7,180 +/- 710%. s, was blocked by DDA. In conclusion, PGE(2) activates the cAMP-PKA pathway leading to a release of SP and activation of renal pelvic mechanosensory nerve fibers.     

Analysis of afferent,central, and efferent components of the baroreceptor reflex in mice

Studies of genetically modified mice provide a powerful approach to investigate consequences of altered gene expression in physiological and pathological states. The goal of the present study was to characterize afferent, central, and efferent components of the baroreceptor reflex in anesthetized Webster 4 mice. Baroreflex and baroreceptor afferent functions were characterized by measuring changes in renal sympathetic nerve activity (RSNA) and aortic depressor nerve activity (ADNA) in response to nitroprusside- and phenylephrine-induced changes in arterial pressure. The data were fit to a sigmoidal logistic function curve. Baroreflex diastolic pressure threshold (P(th)), the pressure at 50% inhibition of RSNA (P(mid)), and baroreflex gain (maximum slope) averaged 74 +/- 5 mmHg, 101 +/- 3 mmHg, and 2.30 +/- 0.54%/mmHg, respectively (n = 6). The P(th), P(mid), and gain for the diastolic pressure-ADNA relation (baroreceptor afferents) were similar to that observed for the overall reflex averaging 79 +/- 9 mmHg, 101 +/- 4 mmHg, and 2.92 +/- 0.53%/mmHg, respectively (n = 5). The central nervous system mediation of the baroreflex and the chronotropic responsiveness of the heart to vagal efferent activity were independently assessed by recording responses to electrical stimulation of the left ADN and the peripheral end of the right vagus nerve, respectively. Both ADN and vagal efferent stimulation induced frequency-dependent decreases in heart rate and arterial pressure. The heart rate response to ADN stimulation was nearly abolished in mice anesthetized with pentobarbital sodium (n = 4) compared with mice anesthetized with ketamine-acepromazine (n = 4), whereas the response to vagal efferent stimulation was equivalent under both types of anesthesia. Application of these techniques to studies of genetically manipulated mice can be used to identify molecular mechanisms of baroreflex function and to localize altered function to afferent, central, or efferent sites.     

Independent modification of baroreceptor and exercise pressor reflex function by nitric oxide in nucleus tractus solitarius

It has been suggested that nitric oxide (NO) is a key modulator of both baroreceptor and exercise pressor reflex afferent signals processed within the nucleus tractus solitarius (NTS). However, studies investigating the independent effects of NO within the NTS on the function of each reflex have produced inconsistent results. To address these concerns, the effects of microdialyzing 10 mM L-arginine, an NO precursor, and 20 mM N(G)-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, into the NTS on baroreceptor and exercise pressor reflex function were examined in 17 anesthetized cats. Arterial baroreflex regulation of heart rate was quantified using vasoactive drugs to induce acute changes in mean arterial pressure (MAP). To activate the exercise pressor reflex, static hindlimb contractions were induced by electrical stimulation of spinal ventral roots. To isolate the exercise pressor reflex, contractions were repeated after barodenervation. The gain coefficient of the arterial cardiac baroreflex was significantly different from control (-0.24 +/- 0.04 beats.min(-1).mmHg(-1)) after the dialysis of L-arginine (-0.18 +/- 0.02 beats.min(-1).mmHg(-1)) and L-NAME (-0.29 +/- 0.02 beats.min(-1).mmHg(-1)). In barodenervated animals, the peak MAP response to activation of the exercise pressor reflex (change in MAP from baseline, 39 +/- 7 mmHg) was significantly attenuated by the dialysis of L-arginine (change in MAP from baseline, 29 +/- 6 mmHg). The results demonstrate that NO within the NTS can independently modulate both the arterial cardiac baroreflex and the exercise pressor reflex. Collectively, these findings provide a neuroanatomical and chemical basis for the regulation of baroreflex and exercise pressor reflex function within the central nervous system.     

Sympathetic-renal interaction in chronic arterial pressure control

The effects of neonatal sympathectomy of donors or recipients on posttransplantation arterial pressure were investigated in spontaneously hypertensive rats (SHR) by renal transplantation experiments. Conscious mean arterial pressure (MAP) and renal vascular resistance were 136 +/- 1 mmHg and 15.5 +/- 1.2 mmHg x ml(-1) x min x g in sympathectomized SHR (n = 8) vs. 158 +/- 4 mmHg (P < 0.001) and 20.8 +/- 1.1 mmHg x ml(-1) x min x g (P < 0.05) in controls (n = 10). Seven weeks after transplantation of a kidney from neonatally sympathectomized SHR donors, MAP in SHR recipients (n = 10) was 20 mmHg lower than in controls transplanted with a kidney from hydralazine-treated SHR (n = 10) (P < 0.05) associated with reduced sodium sensitivity of MAP. Neonatal sympathectomy also lowered MAP in F1-hybrids (F1H; SHR x Wistar-Kyoto rats). Within 6 wk after transplantation, renal grafts from untreated SHR increased MAP by 20 mmHg in sympathectomized F1H (n = 10) and by 35 mmHg in sham-treated F1H (n = 8) (P < 0.05). Neonatal sympathectomy induces chronic changes in SHR kidney function leading to a MAP reduction even when extrarenal sympathetic tone is restored. Generalized reduction in sympathetic tone resets the kidney-fluid system to reduced MAP and blunts the extent of arterial pressure rise induced by an SHR kidney graft.     

Role of neuronal nitric oxide synthase in mediating renal hemodynamic changes during pregnancy

Renal plasma flow (RPF) and glomerular filtration rate (GFR) are markedly increased during pregnancy. We recently reported that the renal hemodynamic changes observed during pregnancy in rats are associated with enhanced renal protein expression of neuronal nitric oxide synthase (nNOS). The purpose of this study was to determine the role of nNOS in mediating renal hemodynamic changes observed during pregnancy. To achieve this goal, we examined the effects of the nNOS inhibitor 7-nitroindazole (7-NI) on kidney function in normal conscious, chronically instrumented virgin (n = 6) and pregnant rats (n = 9) at day 16 of gestation. Infusion of 7-NI had no effect on RPF (4.7 +/- 0.7 vs. 4.8 +/- 0.9 ml/min), GFR (2.2 +/- 0.2 vs. 2.5 +/- 0.4 ml/min), or mean arterial pressure (MAP; 127 +/- 7 vs. 129 +/- 10 mmHg) in virgin rats. In contrast, 7-NI infused into pregnant rats decreased RPF (8.9 +/- 1.6 vs. 6.5 +/- 1.4 ml/min) and GFR (4.4 +/- 0.7 vs. 3.3 +/- 0.7 ml/min) while having no effect on MAP (123 +/- 4 vs. 123 +/- 3 mmHg). In summary, inhibition of nNOS in pregnant rats at midgestation results in significant decreases in RPF and GFR. nNOS inhibition in virgin rats had no effect on renal hemodynamics. These data suggest that nNOS may play a role in mediating the renal hemodynamic changes that occur during pregnancy.