Renal denervation chronically lowers arterial pressure independent of dietary sodium intake in normal rats

The present study was designed to test the hypothesis that renal nerves chronically modulate arterial pressure (AP) under basal conditions and during changes in dietary salt intake. To test this hypothesis, continuous telemetric recording of AP in intact (sham) and renal denervated (RDNX) Sprague-Dawley rats was performed and the effect of increasing and decreasing dietary salt intake on AP was determined. In protocol 1, 24-h AP, sodium, and water balances were measured in RDNX (n = 11) and sham (n = 9) rats during 5 days of normal (0.4% NaCl) and 10 days of high (4.0% NaCl) salt intake, followed by a 3-day recovery period (0.4% NaCl). Protocol 2 was similar with the exception that salt intake was decreased to 0.04% NaCl for 10 days after the 5-day period of normal salt (0.04% NaCl) intake (RDNX; n = 6, sham; n = 5). In protocol 1, AP was lower in RDNX (91 +/- 1 mmHg) compared with sham (101 +/- 2 mmHg) rats during the 5-day 0.4% NaCl control period. During the 10 days of high salt intake, AP increased <5 mmHg in both groups so that the difference between sham and RDNX rats remained constant. In protocol 2, AP was also lower in RDNX (93 +/- 2 mmHg) compared with sham (105 +/- 4 mmHg) rats during the 5-day 0.4% NaCl control period, and AP did not change in response to 10 days of a low-salt diet in either group. Overall, there were no between-group differences in sodium or water balance in either protocol. We conclude that renal nerves support basal levels of AP, irrespective of dietary sodium intake in normal rats.     

Sodium homeostasis in transplanted rats with a spontaneously hypertensive rat kidney

Recipients of a kidney from spontaneously hypertensive rats (SHR) but not from normotensive Wistar-Kyoto rats (WKY) develop posttransplantation hypertension. To investigate whether renal sodium retention precedes the development of posttransplantation hypertension in recipients of an SHR kidney on a standard sodium diet (0.6% NaCl), we transplanted SHR and WKY kidneys to SHR x WKY F1 hybrids, measured daily sodium balances during the first 12 days after removal of both native kidneys, and recorded mean arterial pressure (MAP) after 8 wk. Recipients of an SHR kidney (n = 12) retained more sodium than recipients of a WKY kidney (n = 12) (7.3 +/- 10 vs. 4.0 +/- 0.7 mmol, P < 0.05). MAP was 144 +/- 6 mmHg in recipients of an SHR kidney and 106 +/- 5 mmHg in recipients of a WKY kidney (P < 0.01). Modest sodium restriction (0.2% NaCl) in a further group of recipients of an SHR kidney (n = 10) did not prevent posttransplantation hypertension (MAP, 142 +/- 4 mmHg). Urinary endothelin and urodilatin excretion rates were similar in recipients of an SHR and a WKY kidney. Transient excess sodium retention after renal transplantation may contribute to posttransplantation hypertension in recipients of an SHR kidney.     

ANG II-induced hypertension and the role of the area postrema during normal and increased dietary salt

It has been shown that the area postrema (AP) plays a role in the development of certain types of chronic angiotensin II (ANG II)-induced hypertension in the rat but is not of great importance in the salt sensitivity of arterial pressure. It has recently been proposed, however, that elevated sodium levels may exacerbate the hypertensive effects of ANG II, which by itself dramatically affects salt sensitivity, by acting at sodium-sensing neurons in certain circumventricular organs of the brain. Thus the interactions of ANG II, sodium, and the central nervous system remain to be fully understood. The purpose of this study was to examine the role of the AP in ANG II-induced hypertension during periods of normal and elevated dietary salt. We hypothesized that an intact AP was necessary for the full development of hypertension under chronic ANG II infusion and that its role would be pronounced during periods of increased dietary sodium. To test this, male Sprague-Dawley rats underwent ablation of the area postrema (APx, n = 6) or sham operation (sham, n = 6). After 3 wk of recovery, rats were instrumented with radiotelemetry transducers for constant blood pressure and heart rate monitoring and venous catheters for vehicle infusion. After a 3-day control period of 0.9% saline infusion (7 ml/day) and 0.4% dietary sodium, a 10-day period of ANG II infusion (10 ng.kg(-1).min(-1)) was begun, immediately followed by a second 10-day period during which rats were fed a 4.0% sodium diet. By day 6 of ANG II infusion, mean arterial pressure (MAP) in APx rats had increased to 139 +/- 4 mmHg, whereas MAP in sham rats had increased to 126 +/- 3 mmHg. This difference was found to be significant and continued through day 1 of the high-salt period, after which MAP of the two groups had risen to similar levels. On day 9 of high salt, MAP was again observed to be significantly higher (162 +/- 1 mmHg) in APx rats when compared with sham rats (147 +/- 4 mmHg.) These results do not support the hypothesis that the AP is necessary for the full development of ANG II-induced hypertension at normal or elevated levels of dietary sodium.     

Time course of synergistic interaction between DOCA and salt on blood pressure: roles of vasopressin and hepatic osmoreceptors

In DOCA-salt rats, the time course of the synergistic interaction between osmolality and DOCA to produce hypertension is unknown. Therefore, in rats 2 wk after implantation of subcutaneous silicone pellets containing DOCA (65 mg) or no drug (sham), we determined blood pressure (BP) and heart rate (HR) responses, using telemetric pressure transducers, during 2 wk of excess salt ingestion (1% NaCl in drinking water). BP was unaltered in sham rats after increased salt, but in DOCA rats BP increased within 4 h. The initial hypertension of 30-35 mmHg stabilized within 2 days, followed approximately 5 days later by a further increment of approximately 30 mmHg. HR first decreased during the dark phase; the second phase was linked to an abrupt increase in HR and BP variability and decreased HR variability. Pressor responses to acute intravenous hypertonic saline infusion were doubled in DOCA-treated rats via vasopressin and nonvasopressin mechanisms. Only in DOCA-treated rats, portal vein hypertonic saline infusion increased BP, which was prevented by V(1) vasopressin blockade. After 2 wk of DOCA-salt, oral ingestion of water rapidly decreased BP. Intraportal infusion of water did not lower BP in DOCA-salt rats, suggesting that hepatic osmoreceptors were not involved. In summary, the hypertension of DOCA-treated rats consuming excess salt exhibits multiple phases and can be rapidly reversed. Hypertonicity-induced vasopressin and nonvasopressin pressor mechanisms that are augmented by DOCA, and hepatic osmoreceptors may contribute to the initial developmental phase. With time, combined DOCA-salt induces marked changes in the regulation of the autonomic nervous system, which may favor hypertension development.     

Afferent renal denervation impairs baroreflex control of efferent renal sympathetic nerve activity

Increasing efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), which decreases ERSNA to prevent sodium retention. High-sodium diet enhances ARNA, suggesting an important role for ARNA in suppressing ERSNA during excess sodium intake. Mean arterial pressure (MAP) is elevated in afferent renal denervated by dorsal rhizotomy (DRX) rats fed high-sodium diet. We examined whether the increased MAP in DRX is due to impaired arterial baroreflex function. In DRX and sham DRX rats fed high-sodium diet, arterial baroreflex function was determined in conscious rats by intravenous nitroprusside and phenylephrine or calculation of transfer function gain from arterial pressure to ERSNA (spontaneous baroreflex sensitivity). Increasing MAP did not suppress ERSNA to the same extent in DRX as in sham DRX, -60 +/- 4 vs. -77 +/- 6%. Maximum gain, -4.22 +/- 0.45 vs. -6.04 +/- 0.90% DeltaERSNA/mmHg, and the maximum value of instantaneous gain, -4.19 +/- 0.45 vs. -6.04 +/- 0.81% DeltaERSNA/mmHg, were less in DRX than in sham DRX. Likewise, transfer function gain was lower in DRX than in sham DRX, 3.9 +/- 0.2 vs. 6.1 +/- 0.5 NU/mmHg. Air jet stress produced greater increases in ERSNA in DRX than in sham DRX, 35,000 +/- 4,900 vs. 20,900 +/- 3,410%.s (area under the curve). Likewise, the ERSNA responses to thermal cutaneous stimulation were greater in DRX than in sham DRX. These studies suggest impaired arterial baroreflex suppression of ERSNA in DRX fed high-sodium diet. There were no differences in arterial baroreflex function in DRX and sham DRX fed normal-sodium diet. Impaired arterial baroreflex function contributes to increased ERSNA, which would eventually lead to sodium retention and increased MAP in DRX rats fed high-sodium diet.     

Chronic infusion of angiotensin-(1-7) into the lateral ventricle of the brain attenuates hypertension in DOCA-salt rats

Angiotensin-(ANG)-(1-7) is known by its central and peripheral actions, which mainly oppose the deleterious effects induced by accumulation of ANG II during pathophysiological conditions. In the present study we evaluated whether a chronic increase in ANG-(1-7) levels in the brain would modify the progression of hypertension. After DOCA-salt hypertension was induced for seven days, Sprague-Dawley rats were subjected to 14 days of intracerebroventricular (ICV) infusion of ANG-(1-7) (200 ng/h, DOCA-A7) or 0.9% sterile saline. As expected, on the 21st day, DOCA rats presented increased mean arterial pressure (MAP) (≈40%), and impaired baroreflex control of heart rate (HR) and baroreflex renal sympathetic nerve activity (RSNA) in comparison with that in normotensive control rats (CTL). These changes were followed by an overactivity of the cardiac sympathetic tone and reduction of the cardiac parasympathetic tone, and exaggerated mRNA expression of collagen type I (≈9-fold) in the left ventricle. In contrast, DOCA rats treated with ANG-(1-7) ICV had an improvement of baroreflex control of HR, which was even higher than that in CTL, and a restoration of the baroreflex control of RSNA, the balance of cardiac autonomic tone, and normalized mRNA expression of collagen type I in the left ventricle. Furthermore, DOCA-A7 had MAP lowered significantly. These effects were not accompanied by significant circulating or cardiac changes in angiotensin levels. Taken together, our data show that chronic increase in ANG-(1-7) in the brain attenuates the development of DOCA-salt hypertension, highlighting the importance of this peptide in the brain for the treatment of cardiovascular diseases.     

Involvement of angiotensin-(1-7) in the hypothalamic hypotensive effect of captopril in sinoaortic denervated rats

The role of anterior hypothalamic angiotensin-(1-7) (Ang-(1-7)) on blood pressure regulation was studied in sinoaortic denervated (SAD) rats. Since angiotensin-converting enzyme inhibitors increase endogenous levels of Ang-(1-7), we addressed the involvement of Ang-(1-7) in the hypotensive effect induced by captopril in SAD rats. Wistar rats 7 days after SAD or sham operation (SO) were anaesthetized and the carotid artery was cannulated for monitoring mean arterial pressure (MAP). A needle was inserted into the anterior hypothalamus for drug administration. Intrahypothalamic administration of Ang-(1-7) (5 pmol) was without effect in SO rats but reduced MAP in SAD rats by 15.5+/-3.2 mm Hg and this effect was blocked by 250 pmol [D-Ala(7)]-Ang-(1-7), a Mas receptor antagonist. Angiotensin II (Ang II) induced an increase in MAP in both groups being the effect greater in SAD rats (DeltaMAP=15.8+/-1.4 mm Hg) than in SO rats (DeltaMAP=9.6+/-1.0 mm Hg). Ang-(1-7) partially abolished the pressor response caused by Ang II in SAD rats. Whilst the captopril intrahypothalamic injection did not affect MAP in SO animals, it significantly reduced MAP in SAD rats (DeltaMAP=-13.3+/-1.9 mm Hg). Either [D-Ala(7)]-Ang-(1-7) or an anti-Ang-(1-7) polyclonal antibody partially blocked the MAP reduction caused by captopril. In conclusion, whilst Ang-(1-7) does not contribute to hypothalamic blood pressure regulation in SO normotensive animals, in SAD rats the heptapeptide induces a reduction of blood pressure mediated by Mas receptor activation. Although Ang-(1-7) is not formed in enough amount in the AHA of SAD animals to exert cardiovascular effects in normal conditions, our results suggest that enhancement of hypothalamic Ang-(1-7) levels by administration of captopril is partially involved in the hypotensive effect of the ACE inhibitor.     

Increased reactive oxygen species contributes to kidney injury in mineralocorticoid hypertensive rats.

Hypertension is associated with increased reactive oxygen species (ROS). Renal ROS production and their effects on renal function have never been investigated in mineralocorticoid hypertensive rats. In this study we hypothesized that increased ROS production in kidneys from deoxycorticosterone (DOCA)-salt rats contributes to adverse renal morphological changes and impaired renal function in DOCA-salt hypertensive rats. We also determined whether ROS-induced renal injury was dependent on blood pressure. DOCA-salt hypertensive rats exhibited a marked increase in blood pressure, renal ROS production, glomerular and tubular lesions, and microalbuminuria compared to sham rats. Treatment of DOCA-salt hypertensive rats with apocynin for 28 days resulted in attenuation of systolic blood pressure and improvement of renal morphology. Renal superoxide level in DOCA-salt rats was 215% of sham-operated rats and it was significantly decreased to 140% with apocynin treatment. Urinary protein level was decreased from 27 +/- 3 mg/day in DOCA-salt hypertensive rats to 9 +/- 2 mg/day. 28 days of Vitamin E treatment also reduced renal injury in regard to urinary protein level and renal morphology but had no effect on blood pressure in DOCA-salt rats. Increased urinary 8-isoprostane, a marker for oxidative stress, in DOCA-salt hypertensive rats (55 +/- 8 ng/day) was diminished by vitamin E treatment (24 +/- 6 ng/day). These data suggest that renal injury characteristic of mineralocorticoid hypertension is associated with oxidative stress and is partly independent of blood pressure.     

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.     

Oxygen-conserving effects of apnea in exercising men.

We sought to determine whether apnea-induced cardiovascular responses resulted in a biologically significant temporary O(2) conservation during exercise. Nine healthy men performing steady-state leg exercise carried out repeated apnea (A) and rebreathing (R) maneuvers starting with residual volume +3.5 liters of air. Heart rate (HR), mean arterial pressure (MAP), and arterial O(2) saturation (Sa(O(2)); pulse oximetry) were recorded continuously. Responses (DeltaHR, DeltaMAP) were determined as differences between HR and MAP at baseline before the maneuver and the average of values recorded between 25 and 30 s into each maneuver. The rate of O(2) desaturation (DeltaSa(O(2))/Deltat) was determined during the same time interval. During apnea, DeltaSaO(2)/Deltat had a significant negative correlation to the amplitudes of DeltaHR and DeltaMAP (r(2) = 0.88, P < 0.001); i.e., individuals with the most prominent cardiovascular responses had the slowest DeltaSa(O(2))/Deltat. DeltaHR and DeltaMAP were much larger during A (-44 +/- 8 beats/min, +49 +/- 4 mmHg, respectively) than during R maneuver (+3 +/- 3 beats/min, +30 +/- 5 mmHg, respectively). DeltaSa(O(2))/Deltat during A and R maneuvers was -1.1 +/- 0.1 and -2.2 +/- 0.2% units/s, respectively, and nadir Sa(O(2)) values were 58 +/- 4 and 42 +/- 3% units, respectively. We conclude that bradycardia and hypertension during apnea are associated with a significant temporary O(2) conservation and that respiratory arrest, rather than the associated hypoxia, is essential for these responses.     

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.     

Immune suppression blocks sodium-sensitive hypertension following recovery from ischemic acute renal failure

The present study determined the effect of immune suppression with mycophenolate mofetil (MMF) on sodium-sensitive hypertension following recovery from ischemia reperfusion (I/R)-induced acute renal failure. Male Sprague-Dawley rats fed 0.4% NaCl chow were subjected to 40 min bilateral I/R or control sham surgery. After 35 days of recovery, when plasma creatinine levels had returned to normal, the rats were switched to 4.0% NaCl chow for 28 days and administered vehicle or MMF (20 mg.kg(-1).day(-1) ip). High-salt mean arterial pressure was significantly higher in I/R rats (144 +/- 16 mmHg) compared with vehicle-treated sham rats (122 +/- 2 mmHg). Treatment of I/R rats with MMF during the period of high salt intake prevented the salt-induced increase in arterial pressure (114 +/- 3 mmHg). Conscious creatinine clearance was lower in I/R rats (0.27 +/- 0.07 ml.min(-1).100 g body wt(-1)) compared with vehicle-treated sham rats (0.58 +/- 0.04 ml.min(-1).100 g body wt(-1)); MMF treatment prevented the decrease in creatinine clearance in I/R rats (0.64 +/- 0.07 ml.min(-1).100 g body wt(-1)). I/R injury also significantly increased glomerular tissue damage and increased the presence of ED-1 positive (macrophages) and S100A4 positive cells (fibroblasts) in the renal interstitium. The I/R rats treated with MMF exhibited a significant reduction in infiltrating macrophages and fibroblasts and decreased histological damage. The present data indicate that infiltrating immune cells mediate or participate in the development of sodium-sensitive hypertension and renal damage in rats apparently recovered from renal I/R injury.     

Mineralocorticoids upregulate arterial contraction to epidermal growth factor

The present studies test the hypothesis that contraction to EGF is dependent on mineralocorticoids and/or an elevation in systolic blood pressure (SBP). Endothelium-denuded thoracic aortas from sham normotensive, N(omega)-nitro-L-arginine (L-NNA) hypertensive, Wistar-Kyoto (WKY), and spontaneously hypertensive rats (SHR) were used in isolated tissue-bath experiments. Maximal contraction to epidermal growth factor [EGF; percentage of phenylephrine (PE; 10 umol/l)-induced contraction] was greater in strips from L-NNA (32 +/- 5%) and SHR (53 +/- 8%) rats compared with sham and WKY rats (17 +/- 1 and 12 +/- 4%, respectively). Wistar-Furth rats became only mildly hypertensive when given DOCA salt (134 +/- 6 mmHg) compared with Wistar rats (176 +/- 9 mmHg), but aortas from both strains had a similarly enhanced contraction to EGF (approximately 9 times the maximal contraction of sham aorta). Furthermore, in vitro incubation of aortas from Wistar and Wistar-Furth rats with aldosterone (10 nmol/l) increased EGF-receptor mRNA expression by >50%. These data indicate that arterial contraction to EGF may occur independent of hypertension and be stimulated by mineralocorticoids.     

Endothelin type A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia

We have reported that eucapnic intermittent hypoxia (E-IH) causes systemic hypertension, elevates plasma endothelin 1 (ET-1) levels, and augments vascular reactivity to ET-1 and that a nonspecific ET-1 receptor antagonist acutely lowers blood pressure in E-IH-exposed rats. However, the effect of chronic ET-1 receptor inhibition has not been evaluated, and the ET receptor subtype mediating the vascular effects has not been established. We hypothesized that E-IH causes systemic hypertension through the increased ET-1 activation of vascular ET type A (ET(A)) receptors. We found that mean arterial pressure (MAP) increased after 14 days of 7 h/day E-IH exposure (109 +/- 2 to 137 +/- 4 mmHg; P < 0.005) but did not change in sham-exposed rats. The ET(A) receptor antagonist BQ-123 (10 to 1,000 nmol/kg iv) acutely decreased MAP dose dependently in conscious E-IH but not sham rats, and continuous infusion of BQ-123 (100 nmol.kg(-1).day(-1) sc for 14 days) prevented E-IH-induced increases in MAP. ET-1-induced constriction was augmented in small mesenteric arteries from rats exposed 14 days to E-IH compared with those from sham rats. Constriction was blocked by the ET(A) receptor antagonist BQ-123 (10 microM) but not by the ET type B (ET(B)) receptor antagonist BQ-788 (100 microM). ET(A) receptor mRNA content was greater in renal medulla and coronary arteries from E-IH rats. ET(B) receptor mRNA was not different in any tissues examined, whereas ET-1 mRNA was increased in the heart and in the renal medulla. Thus augmented ET-1-dependent vasoconstriction via vascular ET(A) receptors appears to elevate blood pressure in E-IH-exposed rats.     

Role of intrarenal alpha(2)-adrenoceptors in the renal responses to xylazine in rats

This study examined the contribution of intrarenal alpha(2)-adrenoceptor mechanisms to the enhanced urine flow rate (V) and urinary sodium excretion (U(Na)V) responses in ketamine-xylazine-anesthetized rats. Ten minutes after left renal artery (LRA) injection, the alpha(2)-adrenoceptor antagonist yohimbine (5 microg) significantly decreased V from 58 +/- 8 to 35 +/- 7 microl. min(-1). g kidney wt(-1) and U(Na)V from 2.8 +/- 0.4 to 2.1 +/- 0.4 microeq. min(-1). g kidney wt(-1) without altering right kidney function. The renal effects of the LRA injection of yohimbine were completely abolished in chronic bilaterally renal-denervated (RDNX) rats. In RDNX rats, a higher LRA dose of yohimbine (15 microg) significantly reduced left and right kidney V, with no effects on U(Na)V. In separate bladder-catheterized rats, yohimbine (0.5 mg/kg), 20 min after intravenous injection, significantly decreased V from 63 +/- 9 to 13 +/- 2 microl. min(-1). g kidney wt(-1 )and U(Na)V from 4.5 +/- 0.5 to 1.1 +/- 0.1 microeq. min(-1). g kidney wt(-1). In RDNX rats, this dose of yohimbine reduced V and U(Na)V, but the magnitude was blunted compared with intact rats. In contrast, 0.1 mg/kg iv yohimbine significantly reduced V and U(Na)V to similar magnitudes in intact and RDNX groups. Together, these findings indicate that intravenous xylazine acts by renal nerve-dependent and -independent mechanisms to enhance renal excretory function in ketamine-anesthetized rats. Because the effects of the LRA dose of yohimbine were abolished in renal-denervated animals, it appears that xylazine has a direct renal action to augment the renal excretion of water and sodium via a presynaptic alpha(2)-adrenoceptor pathway that inhibits the release of neurotransmitters from renal sympathetic nerve terminals.     

Baroreflexes prevent neurally induced sodium retention in angiotensin hypertension

Recent studies indicate that renal sympathetic nerve activity is chronically suppressed during ANG II hypertension. To determine whether cardiopulmonary reflexes and/or arterial baroreflexes mediate this chronic renal sympathoinhibition, experiments were conducted in conscious dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into hemibladders to allow separate 24-h urine collection from denervated (Den) and innervated (Inn) kidneys. Dogs were studied 1) intact, 2) after thoracic vagal stripping to eliminate afferents from cardiopulmonary and aortic receptors [cardiopulmonary denervation (CPD)], and 3) after subsequent denervation of the carotid sinuses to achieve CPD plus complete sinoaortic denervation (CPD + SAD). After control measurements, ANG II was infused for 5 days at a rate of 5 ng. kg(-1). min(-1). In the intact state, 24-h control values for mean arterial pressure (MAP) and the ratio for urinary sodium excretion from Den and Inn kidneys (Den/Inn) were 98 +/- 4 mmHg and 1.04 +/- 0.04, respectively. ANG II caused sodium retention and a sustained increase in MAP of 30-35 mmHg. Throughout ANG II infusion, there was a greater rate of sodium excretion from Inn vs. Den kidneys (day 5 Den/Inn sodium = 0.51 +/- 0.05), indicating chronic suppression of renal sympathetic nerve activity. CPD and CPD + SAD had little or no influence on baseline values for either MAP or the Den/Inn sodium, nor did they alter the severity of ANG II hypertension. However, CPD totally abolished the fall in the Den/Inn sodium in response to ANG II. Furthermore, after CPD + SAD, there was a lower, rather than a higher, rate of sodium excretion from Inn vs. Den kidneys during ANG II infusion (day 5 Den/Inn sodium = 2.02 +/- 0.14). These data suggest that cardiac and/or arterial baroreflexes chronically inhibit renal sympathetic nerve activity during ANG II hypertension and that in the absence of these reflexes, ANG II has sustained renal sympathoexcitatory effects.     

Contribution of the subfornical organ to angiotensin II-induced hypertension

Previous studies clearly demonstrated acute actions of angiotensin II (ANG II) at one of the central circumventricular organs, the subfornical organ (SFO), but studies demonstrating a role for the SFO in the chronic actions of ANG II remain uncertain. The purpose of this study was to examine the role of the SFO in the chronic hypertensive phase of ANG II-induced hypertension. We hypothesized that the SFO is necessary for the full hypertensive response observed during the chronic phase of ANG II-induced hypertension. To test this hypothesis, male Sprague-Dawley rats were subjected to sham operation (sham rats) or electrolytic lesion of the SFO (SFOx rats). After 1 wk, the rats were instrumented with venous catheters and radiotelemetric transducers for intravenous administration of ANG II and measurement of blood pressure and heart rate, respectively. Rats were then allowed 1 wk for recovery. After 3 days of saline control infusion (7 ml of 0.9% NaCl/day), sham and SFOx rats were infused with ANG II at 10 ng.kg(-1).min(-1) i.v. for 10 consecutive days and then allowed to recover for 3 days. A 0.4% NaCl diet and distilled water were provided ad libitum. At day 5 of ANG II infusion, mean arterial pressure increased 11.7 +/- 3.0 mmHg in sham rats (n = 9) but increased only 3.7 +/- 1.4 mmHg in SFOx rats (n = 9). This trend continued through day 10 of ANG II treatment. These results support the hypothesis that the SFO is necessary for the full hypertensive response to chronic ANG II administration.     

ETA receptor-mediated role of endothelin in the kidney of doca-salt hypertensive rats

Renal effects of FR139317, an endothelin ET_A receptor antagonist, were examined using anesthetized normotensive and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. The intravenous bolus injection of FR139317 (10 mg/kg) produced a slight decrease in mean blood pressure (MAP; −13%) in the control rats and this hypotension was accompanied by a moderate renal vasodilation (renal vascular resistance: RVR; −12%). In the DOCA-salt hypertensive rat, FR139317 had a more pronounced hypotensive effect (MAP; −26%) accompanied by a potent renal vasodilation (RVR; −33%). FR 139317 significantly increased renal blood flow only in the DOCAsalt rats. In contrast, FR139317 produced a significant decrease in urine flow and urinary sodium excretion only in control rats. Northern blot analysis revealed that the renal prepro endothelin-1 (ET-1) mRNA level was significantly increased in DOCA-salt hypertensive rats. Thus, it seems likely that endogenous ET-1 is responsible for the maintenance of DOCA-salt-induced hypertension. We also suggest that at least in part, ET-1 and £ta receptors are involved in renal hemodynamic abnormalities in DOCA-salt-induced hypertension. The augmentation of renal ET-1 production may possibly have a function in the development and maintenance of DOCA-salt-induced hypertension.     

Angiotensin II hypertension is attenuated in interleukin-6 knockout mice

Plasma levels of IL-6 correlate with high blood pressure under many circumstances, and ANG II has been shown to stimulate IL-6 production from various cell types. This study tested the role of IL-6 in mediating the hypertension caused by high-dose ANG II and a high-salt diet. Male C57BL6 and IL-6 knockout (IL-6 KO) mice were implanted with biotelemetry devices and placed in metabolic cages to measure mean arterial pressure (MAP), heart rate (HR), sodium balance, and urinary albumin excretion. Baseline MAP during the control period averaged 114 +/- 1 and 109 +/- 1 mmHg for wild-type (WT) and IL-6 KO mice, respectively, and did not change significantly when the mice were placed on a high-salt diet (HS; 4% NaCl). ANG II (90 ng/min sc) caused a rapid increase in MAP in both groups, to 141 +/- 9 and 141 +/- 4 in WT and KO mice, respectively, on day 2. MAP plateaued at this level in KO mice (134 +/- 2 mmHg on day 14 of ANG II) but began to increase further in WT mice by day 4, reaching an average of 160 +/- 4 mmHg from days 10 to 14 of ANG II. Urinary albumin excretion on day 4 of ANG II was not different between groups (9.18 +/- 4.34 and 8.53 +/- 2.85 microg/2 days for WT and KO mice). By day 14, albumin excretion was nearly fourfold greater in WT mice, but MAP dropped rapidly back to control levels in both groups when the ANG II was stopped after 14 days. Thus the approximately 30 mmHg greater ANG II hypertension in the WT mice suggests that IL-6 contributes significantly to ANG II-salt hypertension. In addition, the early separation in MAP, the albumin excretion data, and the rapid, post-ANG II recovery of MAP suggest an IL-6-dependent mechanism that is independent of renal injury.     

Morphological and biochemical characterization of remodeling in aorta and vena cava of DOCA-salt hypertensive rats

Arterial remodeling occurs in response to mechanical and neurohumoral stimuli. We hypothesized that veins, which are not exposed to higher pressures in hypertension, would demonstrate less active remodeling than arteries. We assessed remodeling with two standard measures of arterial remodeling: vessel morphometry and the expression/function of matrix metalloproteinases (MMPs). Thoracic aorta and vena cava from sham normotensive and DOCA-salt hypertensive rats (110 +/- 4 and 188 +/- 8 mmHg systolic blood pressure, respectively) were used. Wall thickness was increased in DOCA-salt vs. sham aorta (301 +/- 23 vs. 218 +/- 14 mum, P < 0.05), as was medial area, but neither measure was altered in the vena cava. The aorta and vena cava expressed the gelatinases MMP-2, MMP-9, transmembrane proteinase MT1-MMP, and tissue inhibitor of metalloproteinase-2 (TIMP-2). Immunohistochemically, MMP-2 localized to smooth muscle in the aorta and densely in endothelium/smooth muscle of the vena cava. Western and zymographic analyses verified that MMP-2 was active in all vessels and less active in the vena cava than aorta. In hypertension, MMP-2 expression and activity in the aorta were increased (59.1 +/- 3.7 and 74.5 +/- 6.1 units in sham and DOCA, respectively, P < 0.05); similar elevations were not observed in the vena cava. MMP-9 was weakly expressed in all vessels. MT1-MMP was expressed by the aorta and vena cava and elevated in the vena cava from DOCA-salt rats. TIMP-2 expression was significantly increased in the aorta of DOCA rats compared with sham but was barely detectable in the vena cava of sham or DOCA-salt hypertensive rats. These findings suggest that large veins may not undergo vascular remodeling in DOCA-salt hypertension.