Evidence in volume-dependent hypertension for an augmenting factor for norepinephrine overflow from sympathetic nerve endings

It has been reported that salt loading induces a blood pressure rise in rats whose renal mass has been reduced. We examined the involvement of the peripheral sympathetic nervous system in the pathogenesis of hypertension in subtotally nephrectomized and salt-loaded rats. Male Wistar rats (200-240 g) underwent subtotal nephrectomy (removal of 70-80% of the renal mass). After surgery, 1% saline was given ad libitum as drinking water in the experimental group (E), while tap water was given to the controls (C). On the 10th day after nephrectomy, blood pressure was determined, and plasma samples were collected. Deproteinized plasma samples were diluted with Ringer-Locke solution (1/40 v/v), and were perfused into isolated mesenteric artery-intestinal loop preparations of normotensive male Wistar rats. Pressor responses and norepinephrine overflow induced by electrical nerve stimulation, and the pressor responses to exogenous norepinephrine were assessed before and after the addition of deproteinized plasma to the perfusate. Systolic blood pressure was significantly elevated in the experimental group (E: 150 +/- 5 mmHg, C: 109 +/- 4 mmHg, p less than 0.01). When deproteinized plasma from the experimental group was perfused, pressor responses to electrical nerve stimulation were significantly increased (E: 167.2 +/- 13.7%, C: 91.1 +/- 6.4%; p less than 0.01), as was norepinephrine overflow (E: 117.3 +/- 6.4%, C: 90.7 +/- 5.9%; p less than 0.05), while responses to exogenous norepinephrine were only slightly augmented compared with the control group (E: 120.0 +/- 2.7%, C: 105.5 +/- 9.0%; n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)     

The contribution of systemic hypertension to progression of chronic renal failure in the rat remnant kidney: effect of treatment with an angiotensin converting enzyme inhibitor or a calcium inhibitor

In order to establish if pharmacological treatment of systemic hypertension modifies the course of progressive renal failure, we studied the effects of an angiotensin converting enzyme inhibitor and a calcium antagonist, on the renal structure and function in the remnant kidney model of chronic renal failure in the rat. Progressive renal failure was induced in adult female Sprague Dawley rats (SDR) by surgical removal of the right kidney, and segmental infarction of seven-eighths of the left kidney. Following subtotal nephrectomy, plasma creatinine rose from 65 +/- 16 mumol/l to 173 +/- 19 mumol/l (P less than 0.001) over a period of 6 weeks, systolic blood pressure (SBP) rose from 121 +/- 2 mmHg to 176 +/- 7 mmHg (P less than 0.001) and urinary protein excretion from 0.6 +/- 0.2 to 84 +/- 22 mg/24 h (P less than 0.001). Glomerular mesangial expansion was present after 2 weeks, then progressed, in association with the development of glomerular sclerosis, which became prominent after 6 weeks. Rats were treated with enalapril (5 mg/kg per day) or felodipine (30 mg/kg per day) from 1 week after subtotal nephrectomy, and their course compared with that of untreated rats. Systemic SBP decreased to a similar degree by both drug treatments. Six weeks after surgery, plasma creatinine concentration was lower in the enalapril-treated group (110 +/- 8 mumol/l, P less than 0.05) than in the felodipine-treated group (153 +/- 23 mumol/l). The latter group showed similar plasma creatinine concentrations to those of the untreated rats (173 +/- 19 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for increased renal norepinephrine overflow during sodium restriction in humans

To investigate the differentiated pattern of efferent sympathetic nerve activity by means of analyzing norepinephrine kinetics in response to sodium restriction, cardiorenal sympathetic activity during rest and mental stress was studied in 12 subjects (33.3 +/- 2.6 years old, SEM) exposed to a low and a normal sodium diet; 5-40 mmol and 160-200 mmol/24 hours, respectively (crossover design). Organ norepinephrine release was calculated from organ plasma flow, arteriovenous plasma concentration gradient across the organ and the organ's fractional extraction of radiolabeled norepinephrine. Body weight and urinary sodium/24 hr fell significantly and urinary potassium/24 hr and both supine and standing blood pressure remained unchanged. Total norepinephrine release to plasma and norepinephrine plasma clearance were similar in both phases (approximately 460 ng/min and 1.90 l/min, respectively). A 138% increase in renal norepinephrine overflow was observed during sodium restriction (from 112 to 267 ng/min, p less than 0.025), which was due to elevated renal vein norepinephrine (434 versus 290 pg/ml, p less than 0.01) because renal plasma flow and renal norepinephrine extraction were unaltered. Similarly, sodium restriction caused a 168% elevation of renal renin secretion (p less than 0.05). Resting cardiac norepinephrine spillover and cardiac norepinephrine reuptake were unchanged between the two salt phases. Total and cardiac norepinephrine release, supine blood pressure, and heart rate increased to about the same extent in response to mental testing regardless of salt phase. In conclusion, sodium restriction induced a differential and physiological increase in resting renal sympathetic nervous activity, leaving cardiac norepinephrine overflow unchanged. Cardiac norepinephrine uptake was normal, which further supports the concept of a true increase of efferent renal nerve activity.     

Sympathetic nervous system activity and the thermic effect of feeding in man

Animal studies have demonstrated an important role for the sympathetic nervous system in food-induced increases in energy expenditure. Despite studies in man showing a rise in plasma norepinephrine after a meal, no relationship has previously been demonstrated between the increment in plasma norepinephrine and the increase in energy expenditure. Because changes in plasma norepinephrine may not always accurately reflect alterations in sympathetic nervous system activity, we investigated the effects of an 800-kcal high-carbohydrate meal on both plasma norepinephrine kinetics and energy expenditure as well as their relationship to each other. A post-cibum increase in both energy expenditure (0.18 +/- 0.09 kcal/min, P less than 0.001) and plasma norepinephrine concentration (44 +/- 39 pg/ml, P less than 0.05) was noted but again no relationship between the two parameters was found. In contrast, the increment in norepinephrine appearance rate after the meal (0.11 +/- 0.09 microgram/min, P less than 0.001) was significantly correlated to the increment in energy expenditure (r = 0.57, n = 20, P less than 0.01). No change was noted in norepinephrine clearance rate after the meal. It is concluded that sympathetic nervous system induced increases in energy expenditure may account for at least part of the thermogenesis that occurs after a high-carbohydrate meal. It is postulated that individual variability in this sympathetic nervous system induced component of the thermic effect of feeding may account for some of the differences in energy expenditure noted between obese or elderly subjects and normal weight young controls after a meal.     

Elevated insulin, norepinephrine, and neuropeptide Y in hypertension

To investigate the relationship between insulin and sympathetic activity, plasma norepinephrine, neuropeptide Y, serum glucose and insulin concentrations were measured in ten age-, weight-, and sex-matched normotensive and untreated hypertensive subjects at fasting and 2 h following ingestion of a 75 g oral glucose dose. Hypertensives had higher fasting serum insulin (27 +/- 6 v 12 +/- 2 microU/mL; P = .02) and plasma norepinephrine (356 +/- 38 v 235 +/- 35 pg/mL; P = .03) concentrations than normotensives. Glucose load increased serum insulin (P less than .001) and plasma norepinephrine concentrations (P = .001) in both groups and hypertensives had still higher postglucose insulin (P = .003) and norepinephrine levels (P = .003) than normotensives. Fasting neuropeptide Y was higher in hypertensives than in normotensives (P = .03) and correlated with age in both groups (r = 0.7; r = 0.77). Postglucose serum insulin correlated positively with plasma norepinephrine (r = 0.75; P = .013) in normotensives, but these parameters correlated negatively in hypertensives (r = -0.7; P = .036). We hypothesize that elevated plasma norepinephrine and neuropeptide Y levels reflect an increased level of sympathetic nervous activity in hypertensives, which in turn may be responsible for the abnormal relationship between plasma NE and insulin levels.     

Effect of inhibition of prostaglandin synthesis on sympathetic nervous system function in man.

The effect of inhibition of prostaglandin synthesis by indomethacin on the function of the peripheral sympathetic nervous system was studied in eight normotensive subjects. Sympathetic nervous function was assessed by measurement of plasma norepinephrine, alpha-adrenergic receptor sites on platelet membranes, and urinary excretion of epinephrine and norepinephrine. Treatment with indomethacin for 7 days resulted in significant decreases in basal plasma norepinephrine from 134 +/- 7 to 99 +/- 6 (SEM) pg/ml (P less than 0.01), a 26% decrease. Posturally stimulated norepinephrine concentrations (337 +/- 14 pg/ml in control studies) were 255 +/- 18 pg/ml (P less than 0.02), 25% lower, with indomethacin. Plasma norepinephrine after 5-min compression of hand grip (468 +/- 47 pg/ml in control) was 331 +/- 30 pg/ml (P less than 0.005), 29% lower, with indomethacin. The number of platelet alpha-adrenergic receptor sites did not change with indomethacin, nor did prostaglandin E1-stimulated cAMP production by platelet membranes. In addition, indomethacin produced no change in urinary excretion of norepinephrine or epinephrine. It is suggested that inhibition of prostaglandin synthesis may lead, via baroreceptor feedback, to a decrease in plasma norepinephrine concentration.     

Neurohumoral mechanisms and left ventricular hypertrophy: effects of hygienic therapy

To determine the effects of hygienic (non-drug) therapy on blood pressure (BP) control and its relationship to sympathetic tone and left ventricular mass (LVM) in primary hypertension, plasma norepinephrine (NE) and renin activity (PRA), LVM, and nutritional and behavioral status were assessed in 76 borderline to mild hypertensives. Pretherapy plasma NE was related to diastolic blood pressure (DBP) and PRA (r = 0.24, P less than .05 and r = 0.37, P less than .01, respectively). Plasma NE of high renin patients (221 +/- 52) (mean +/- SD) was greater than that of normal renin patients (159 +/- 61, ng/l, P less than .01). LVM was related to systolic blood pressure (SBP) (P less than .001), DBP (P less than .01) and urinary sodium (P less than .05), and inversely related to PRA (P less than .01). Septal wall thickness was related to hostility (r = 0.42, P less than .05). After seven weeks of hygienic therapy, DBP was reduced by 6 mmHg (P less than .01). The change in SBP was related to baseline plasma NE (P less than .05) and inversely related to LVM (P less than .05). These results suggest that raised sympathetic tone may be a pathogenic factor in primary hypertension and that hygienic therapy lowers BP more effectively in patients with raised sympathetic tone and low LVM.     

Total and renal sympathetic nervous system activity in alcoholic cirrhosis

Basal sympathetic nervous system activity was assessed in 8 unmedicated patients with alcoholic cirrhosis using a previously developed radiotracer method for measuring total and renal noradrenaline release to, and clearance from, plasma. Compared to the control group total noradrenaline clearance was significantly increased in the patients with advanced alcoholic cirrhosis (Pugh grade C) [1.89 +/- 0.13 vs 1.51 +/- 0.11 l/min, P less than 0.05) indicating that endogenous plasma noradrenaline levels underestimate total sympathetic nervous system activity in these patients. Renal noradrenaline clearance was similar to controls independent of the severity of the liver disease. Both total and renal noradrenaline release were significantly increased in the patients with cirrhosis. The ratio of renal to total noradrenaline release was similar in cirrhotic (26 +/- 7%) and control (23 +/- 5%) groups. Increased arterial plasma adrenaline levels, indicative of adrenal medullary stimulation, were also evident in the patients with cirrhosis and correlated significantly with total noradrenaline spillover (r = 0.732, P less than 0.05). These results strongly suggest that in patients with cirrhosis, rather than a preferential increase in renal sympathetic tone, the increase is part of a pattern of generalized sympathoadrenomedullary activation. Although renal renin secretion was significantly increased in the cirrhotic group no correlation with renal noradrenaline release was seen (r = 0.199), raising the possibility that in cirrhosis renal sympathetic tone is not a major determinant of renal renin secretion. Finally, renal noradrenaline release did not correlate with renal blood or plasma flow but an influence of the sympathetic nervous system on renal function was suggested by the correlation observed between total noradrenaline spillover and impaired salt (r = -0.683, P less than 0.05) and water excretion (r = -0.702, P less than 0.05) demonstrated in the cirrhotic patients.     

Failure of plasma norepinephrine to consistently reflect sympathetic activity in humans

To determine whether venous plasma norepinephrine concentrations consistently reflect changes in sympathetic nervous activity, the influence of mental arithmetic, static handgrip, and submaximal bicycle exercise on intra-arterial blood pressure, heart rate, and plasma norepinephrine was studied in 51 subjects with untreated essential hypertension (mean age, 46 years; range, 16-69 years). At rest, plasma norepinephrine was unrelated to age or blood pressure. Mental arithmetic increased mean arterial pressure from 108 +/- 18 to 127 +/- 18 mm Hg (mean +/- S.D.; p less than 0.001) and heart rate from 69 +/- 7 to 93 +/- 13 beats/min (p less than 0.001) but not plasma norepinephrine (547 +/- 297 to 518 +/- 250 pg/ml). Isometric exercise raised mean arterial pressure from 115 +/- 18 to 148 +/- 21 mm Hg (p less than 0.001) and heart rate from 76 +/- 9 to 95 +/- 13 beats/min (p less than 0.001) but not plasma norepinephrine (683 +/- 253 to 741 +/- 253 pg/ml). Bicycle exercise increased mean arterial pressure from 114 +/- 20 to 146 +/- 26 mm Hg (p less than 0.001), heart rate from 77 +/- 9 to 128 +/- 19 beats/min (p less than 0.001), and plasma norepinephrine from 645 +/- 228 to 1151 +/- 462 pg/ml (p less than 0.001). Both the maximum mean arterial pressure and the peak heart rate attained during bicycle exercise were related to the exercise plasma norepinephrine level (r = 0.33, p less than 0.02 and r = 0.28, p less than 0.03, respectively). Increases in plasma norepinephrine with exercise were not greater in older or more hypertensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired renorenal reflexes in two-kidney, one clip hypertensive rats

In normotensive rats, stimulation of renal mechanoreceptors by an increase in ureteral pressure results in a contralateral inhibitory renorenal reflex response with contralateral natriuresis. Similar effects are produced by stimulation of renal chemoreceptors by renal pelvic perfusion with 0.9 M NaCl. However, in spontaneously hypertensive rats the renorenal reflex responses to renal mechanoreceptor and chemoreceptor stimulation are impaired. The present study was performed to examine whether the renorenal reflexes were altered in two-kidney, one clip hypertensive rats, a model of hypertension in which it has been suggested that the afferent renal nerves contribute to the enhanced peripheral sympathetic nervous activity. A 0.2 mm silver clip was placed around one renal artery 4 weeks before the study. At the time of study, mean arterial pressure was 156 +/- 4 mm Hg. Renal mechanoreceptor and chemoreceptor stimulation of either the nonclipped or clipped kidney failed to affect ipsilateral afferent renal nerve activity, contralateral efferent renal nerve activity, and contralateral urine flow rate and urinary sodium excretion. Renal denervation of the nonclipped kidney increased ipsilateral urinary sodium excretion from 0.65 +/- 0.13 to 1.50 +/- 0.42 mumol/min/g and decreased contralateral urinary sodium excretion from 0.18 +/- 0.03 to 0.13 +/- 0.03 mumol/min/g (p less than 0.05). Thus, denervation of the nonclipped kidney resulted in a similar contralateral excitatory renorenal reflex response as in normotensive rats. However, denervation of the clipped kidney increased both ipsilateral and contralateral urinary sodium excretion, from 0.14 +/- 0.04 to 0.27 +/- 0.5 mumol/min/g and from 1.29 +/- 0.33 to 2.09 +/- 0.59 mumol/min/g (p less than 0.01), respectively. Taken together these data suggest that the lack of inhibitory renorenal reflexes from the clipped kidney may enhance efferent sympathetic nervous activity and thereby contribute to the hypertension in two-kidney, one clip hypertensive rats.     

Exercise-induced secretion of atrial natriuretic factor and its relation to hemodynamic and sympathetic stimulation in untreated essential hypertension.

This study evaluates the release of atrial natriuretic factor (ANF) during maximal exercise in 7 patients with untreated moderate to severe hypertension with invasive monitoring of hemodynamic characteristics in relation to sympathetic activity. Peripheral venous ANF (fmol/ml) was determined at rest and maximal exercise producing a respiratory exchange ratio of 1.14 +/- 0.10. In 5 of 7 patients, simultaneous right ventricular and peripheral venous ANF samples could be obtained to assess exercise myocardial secretion of ANF. With exercise, mean blood pressure increased from 150 +/- 26 to 192 +/- 29 mm Hg (p less than 0.001), pulmonary wedge pressure increased from 7 +/- 3 to 18 +/- 10 mm Hg (p less than 0.05) and ANF increased from 11.7 +/- 8.2 to 25.7 +/- 15.9 (p less than 0.02). This ANF response correlated weakly with pulmonary wedge pressure (r = 0.497, p = not significant), since patients without an increase in pulmonary wedge pressure had no increase in ANF. However, changes in pulmonary wedge pressure and plasma norepinephrine during exercise were inversely correlated (r = -0.811, p less than 0.02), with the greatest increase in norepinephrine occurring with a minimal increase in pulmonary wedge pressure. Similarly, ANF and plasma norepinephrine were inversely correlated during exercise (r = -0.869, p less than 0.05). A significant increase in right ventricular ANF indicated myocardial secretion. Plasma ANF therefore increased because of active myocardial production during exercise in patients with moderate to severe hypertension. These findings further suggest a directionally opposing relation between ANF release resulting from increased atrial tension and sympathetic nervous system influence on cardiac performance during exercise.     

Plasma norepinephrine and dietary sodium intake in normal subjects and patients with essential hypertension

To evaluate the relationship between sodium intake and the activity of the sympathetic nervous system in patients with essential hypertension, plasma catecholamine levels were measured in 49 essential hypertensive patients and 38 age-matched normal subjects under regular-, high-, and low-sodium diets (mean 24-hour sodium excretions; 116 +/- 8, 267 +/- 29, 31 +/- 7 mEq/day, respectively). The levels of plasma norepinephrine were significantly (p less than 0.01) higher in hypertensive patients than in normal subjects. However, they were significantly reduced by high-sodium intake and increased by low-sodium intake in both patients and controls. The percent decrease and change in the absolute plasma norepinephrine levels from low- to high-sodium states were greater in normal subjects than in the hypertensive patients. The results are interpreted as indicating that an abnormal relationship exists between sodium intake and the activity of sympathetic nervous system in patients with essential hypertension.     

Dietary sodium and potassium-induced transient changes in blood pressure and catecholamine excretion in the Sprague-Dawley rat

When Sprague-Dawley derived rats were changed from a chow type diet to a moderately high sodium diet, rapid transient changes in blood pressure (BP) and catecholamine excretion were observed. After 1 dietary week, BP increased from 122 +/- .1 mm Hg to approximately 145 mm Hg (p less than 0.001), and there was a concomitant 20% reduction in urinary norepinephrine (UNEV) and epinephrine (UEV) excretion (p less than 0.05). Heart rates were reduced (p less than 0.05). These data suggest that sodium-induced increases in BP were initially associated with suppressed sympathetic nervous system activity. During dietary Weeks 2 and 3, some animals had a persistent moderate elevation in BP (BP less than or equal to 150 mm Hg), while others developed more severe increases. UNEV in moderately hypertensive animals returned to control levels during this period; but UEV and heart rates remained suppressed. UNEV in severely hypertensive animals exceeded (13% +/- 3%, p less than 0.05) that of controls. This increase coincided with their most severe hypertension (171 +/- 1 mm Hg, p less than 0.001). UE values and heart rate data indicate that systemic adrenergic tone was likely suppressed at this time and that the increased UNEV was renal in origin. By dietary Week 4, the BP of severely hypertensive animals had begun to fall, and indices of sympathetic nervous system tone were indistinguishable among all groups. Inclusion of a dietary potassium supplement ameliorated the development of hypertension only in those animals that became severely hypertensive, and appeared to prevent the early suppression of indices of sympathetic activity.     

Alpha 1-adrenergic blockade and cardiovascular pressor responses in essential hypertension

The effects of selective alpha 1-adrenergic blockade with terazosin on blood pressure and cardiovascular pressor responsiveness were assessed in 17 subjects with mild to moderate essential hypertension (mean age, 48 +/- 2 [SEM] years). As compared with a 2-week placebo period, 8 weeks of terazosin treatment (mean dose, 10.5 +/- 1.7 mg/day) caused a fall of supine (from 153/103 +/- 3/2 to 143/96 +/- 4/2 mm Hg; p less than 0.025) and upright (from 145/106 +/- 4/2 to 131/94 +/- 5/3 mm Hg; p less than 0.01) arterial pressure; a marked blunting of cardiovascular pressor responsiveness to norepinephrine, as judged from the pressor dose (from 73 +/- 9 to 2156 +/- 496 ng/kg/min; p less than 0.02) and from the rightward shift (p less than 0.01) of the plasma concentration-blood pressure response curve; and a slight increase in plasma norepinephrine concentration (from 37.7 +/- 3.3 to 52.2 +/- 7.8 ng/dl; p less than 0.01). Heart rate, body weight, exchangeable sodium, blood volume, and norepinephrine plasma clearance; plasma epinephrine, renin, angiotensin II, and aldosterone levels; the relationships between angiotensin II-induced increases in arterial pressure or plasma aldosterone and the concomitant increments of plasma angiotensin II; and heart rate responsiveness to isoproterenol did not change significantly after terazosin treatment. These findings suggest that the fall of arterial pressure induced by selective alpha 1-adrenergic blockade in subjects with essential hypertension is associated with, and probably explained by, inhibition of alpha 1-mediated, noradrenergic-dependent vasoconstriction. alpha 1-Adrenergic receptor antagonism did not modify body sodium concentration, the adrenomedullary component of the sympathetic nervous system, angiotensin II levels, or beta-adrenergic dependent mechanisms.     

Furosemide enhancement of experimental gentamicin nephrotoxicity: comparison of functional and morphological changes with activities of urinary enzymes.

Dogs were given gentamicin (10 mg/kg) intramuscularly every 8 hr for 10 days. Levels of serum creatinine rose by day 6 (0.91 +/- 0.08 vs. 0.75 +/- 0.02 mg/dl for controls, P less than 0.05) and of blood urea nitrogen by day 8 (24.3 +/- 4.80 vs. 16.1 +/- 0.90 mg/dl for controls, P less than 0.05). Gentamicin nephrotoxicity occurred earlier and was more marked when furosemide (2 mg/kg) was added: the level of serum creatinine by day 6 was 1.62 +/- 0.25 mg/dl (P less than 0.05), and the level of blood urea nitrogen by day 8 was 181 +/- 23.5 mg/dl (P less than 0.01). Elevations in the activities of the urinary enzymes beta-glucuronidase, N-acetyl-beta-glucosaminidase, and muramidase preceded rises in levels of serum creatinine and blood urea nitrogen. Examination of serial percutaneous renal biopsy specimens showed that gentamicin administration was associated with hyaline droplet degeneration, lysosomal changes, and, later, cell necrosis (primarily of the proximal tubules). Changes in renal morphology were more severe and occurred earlier when furosemide was administered concomitantly. In summary, furosemide enhanced gentamicin nephrotoxicity. Enzymuria was an early sign of gentamicin nephrotoxicity.     

Adaptive myocardial hypertrophy in the renal ablation model

We have previously reported downregulation of the vascular alpha 1-receptor in the 5/6 renal ablation model. In this investigation we have examined the adaptive response of the heart following 5/6 renal ablation. Renal ablated and sham rats were maintained under identical conditions for 6 weeks. Despite the presence of systemic hypertension in renal ablated rats (185 +/- 10 mm Hg, P less than .01), heart weight did not differ from sham. [125I] +/- CYP binding was performed and myocardial norepinephrine (NE) content determined to evaluate myocardial sympathetic neuroeffector mechanisms. Scatchard analysis and 1-isoproterenol competition curves did not reveal a difference in the binding properties of the myocardial beta-receptor. No difference in myocardial NE was found in renal ablated and sham rats. Unexpectedly, 1-isoproterenol stimulation of adenylate cyclase was impaired in renal ablated rats (32.6 +/- 6 v 58.6 +/- 5 pmol/mg/min, P less than .01) and the dose response curve shifted to the right. We conclude that despite systemic hypertension an adaptive hypertrophic response was not present in hearts of renal ablated rats; myocardial sympathetic neuroeffector mechanisms are not altered in this model; and impaired stimulation of adenylate cyclase appears to be the result of a post-receptor defect.     

Paraventricular nucleus lesions attenuate the development of hypertension in DOCA/salt-treated rats

To determine whether paraventricular nucleus (PVN) can play a role in the hypertension in DOCA/salt-treated rats, DOCA/salt hypertension was produced in PVN lesions and sham-operated rats. In lesioned rats, the development of hypertension was significantly attenuated (day 7: 132 +/- 3 v 157 +/- 5 mm Hg, P less than 0.01; day 14: 132 +/- 3 v 157 +/- 5 mm Hg, P less than 0.01; day 21: 189 +/- 2 v 224 +2- 6 mm Hg, P less than 0.01). Lesions lowered systolic blood pressure in even control rats. Mean blood pressure (mBP) from awake free moving rats was also significantly lower in lesioned DOCA/salt-treated rats than those of sham-operated DOCA/salt-treated rats (155 +/- 14 mm Hg v 193 +/- 13, P less than 0.01), while mBP was not different between lesioned and sham-operated control rats. The reduction of mBP by hexamethonium injections was significantly larger in sham-operated DOCA/salt-treated rats than those of lesioned DOCA/salt rats. (-53 +/- 3% v -45 +/- 2, P less than 0.05). Plasma norepinephrine and epinephrine were significantly elevated in DOCA/salt-treated rats, however, PVN lesions inhibited significantly those elevations. 1-Deaminopenicillamine, 4-valine, 8-D-arginine Vasopressin (dPVDAVP) injections did not affect BP and heart rate in all rats. Body weight, water intake, urine volume, urine Na, K, and vasopressin excretion, and urine osmorality were not altered by lesions. These findings suggest that PVN contributes to development of hypertension in DOCA/salt-treated rats with sympathetic nervous activations.     

Plasma norepinephrine and dopamine-beta-hydroxylase activity in chronic renal failure.

To evaluate the activity of the sympathetic nervous system in chronic renal failure, plasma norepinephrine (NE) and dopamine-beta-hydroxylase (DBH) activity were measured by a radioenzymatic assay and a photometric assay respectively. The level of plasma NE was significantly higher in 14 patients with hemodialysis than in healthy individuals (p less than 0.001). The level of plasma NE fell significantly in 6 patients with hemodialysis receiving 0.30-0.45 mg/day of clonidine hydrochloride (a depressor of the sympathetic outflow from the central nervous system) (p less than 0.05). Systolic blood pressure was correlated with the level of plasma NE in patients with hemodialysis who were not receiving clonidine. They had high level of plasma NE and low level of plasma DBH activity. Therefore, this findings suggest that high level of plasma NE in chronic renal failure is caused not only by decreased urinary excretion, but also by increased overflow from the sympathetic nervous clefts.     

Renal kallikrein excretion in cirrhotics with ascites: relationship to renal hemodynamics

To investigate if the renal kallikrein-kinin system may be involved in the homeostasis of renal perfusion in cirrhosis, urinary kallikrein activity was measured in 11 normal subjects, 31 cirrhotics with ascites and preserved renal plasma flow (548.2 +/- 32.2 ml per min) and glomerular filtration rate (85.8 +/- 3.4 ml per min), and 18 cirrhotics with functional renal failure (renal plasma flow: 229.9 +/- 23.4 ml per min; glomerular filtration rate: 34.9 +/- 3.3 ml per min). Plasma renin activity, plasma norepinephrine concentration and the urinary excretion of prostaglandin E2 were also measured in these subjects. Cirrhotics without renal failure showed a significantly higher renin (4.9 +/- 1.1 ng per ml per hr), norepinephrine (458.2 +/- 50.4 pg per ml), urinary kallikrein (15.4 +/- 1.8 pkat per min) and urinary prostaglandin E2 (0.52 +/- 0.08 ng per min) than did normal subjects (1.08 +/- 0.1 ng per ml per hr, 218.1 +/- 18.2 pg per ml; 8.4 +/- 1.4 pkat per min and 0.24 +/- 0.02 ng per min, respectively). Cirrhotics with renal failure showed a significantly higher renin (16.1 +/- 3.4 ng per ml per hr) and norepinephrine (739.4 +/- 79.2 pg per ml), and a significantly lower urinary kallikrein (5.2 +/- 0.6 pkat per min) and urinary prostaglandin E2 (0.15 +/- 0.02 ng per min) than did normal subjects and cirrhotics without renal failure. Glomerular filtration rate correlated (p less than 0.001) with urinary kallikrein (r = 0.53), urinary prostaglandin E2 (r = 0.55), plasma renin (r = -0.41) and norepinephrine (r = -0.44).(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of sodium in hypertensive cardiac hypertrophy

Cardiac hypertrophy in systemic hypertension may not result simply from increased afterload. Previous studies indicate that factors other than blood pressure may influence cardiac hypertrophy. We evaluated the effects of dietary sodium restriction in two-kidney one-clip renal hypertensive rats. After the renal artery had been clipped, the rats received a normal diet until hypertension was established; thereafter, a sodium-deficient diet was instituted in one group. Clipped rats on a regular diet had significantly higher systolic blood pressures than sham-operated controls (205 +/- 9 vs. 129 +/- 1 mm Hg, respectively). Sodium restriction did not reverse hypertension (190 +/- 8 mm Hg), but led to a significant reduction of relative heart weight compared to rats on the normal diet (2.94 +/- 0.24 vs. 3.86 +/- 0.23 mg/g, respectively; P less than 0.01). The hypertrophied hearts of animals on the regular diet showed depressed tissue catecholamines (significant only for norepinephrine); sodium restriction resulted in a restoration to normal levels. Thus, we demonstrated a dissociation of blood pressure and cardiac hypertrophy in the two-kidney one-clip model, similar to previous findings in other models. Our results support the concept that factors other than blood pressure contribute to cardiac hypertrophy. Dietary sodium intake appears to be one such factor. In addition, a possible role of the sympathetic nervous system is suggested.