The birth, death and resurrection of avoidance: a reconceptualization of a troubled paradigm.

Research on avoidance conditioning began in the late 1930s as a way to use laboratory experiments to better understand uncontrollable fear and anxiety. Avoidance was initially conceived of as a two-factor learning process in which fear is first acquired through Pavlovian aversive conditioning (so-called fear conditioning), and then behaviors that reduce the fear aroused by the Pavlovian conditioned stimulus are reinforced through instrumental conditioning. Over the years, criticisms of both the avoidance paradigm and the two-factor fear theory arose. By the mid-1980s, avoidance had fallen out of favor as an experimental model relevant to fear and anxiety. However, recent progress in understanding the neural basis of Pavlovian conditioning has stimulated a new wave of research on avoidance. This new work has fostered new insights into contributions of not only Pavlovian and instrumental learning but also habit learning, to avoidance, and has suggested that the reinforcing event underlying the instrumental phase should be conceived in terms of cellular and molecular events in specific circuits rather than in terms of vague notions of fear reduction. In our approach, defensive reactions (freezing), actions (avoidance) and habits (habitual avoidance) are viewed as being controlled by unique circuits that operate nonconsciously in the control of behavior, and that are distinct from the circuits that give rise to conscious feelings of fear and anxiety. These refinements, we suggest, overcome older criticisms, justifying the value of the new wave of research on avoidance, and offering a fresh perspective on the clinical implications of this work.

HMG-CoA reductase inhibitors and the kidney.

During the last two decades, numerous studies have demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) diminish the risk of cardiovascular morbidity and mortality. Although these studies have focused primarily on the ability of statins to lower circulating levels of low-density lipoprotein cholesterol, more recent research has shown that statins may protect the vasculature via pleiotropic effects not directly related to lipid lowering. These include adjustments in cell-signaling pathways that play a role in atherogenesis and that affect the expression of inflammatory elements, curtail oxidative stress, and enhance endothelial function. More recently, researchers have begun to explore whether these agents exert similar beneficial effects in renal parenchymal and renovascular disease. This review examines the available evidence that dyslipidemia may augment the inflammatory reaction of cytokines in patients with renal disease and that statins may improve renal dysfunction by altering the response of the kidney to dyslipidemia, even in persons with end-stage renal disease on dialysis or with renal transplantation. In this context, some data suggest that statin-mediated alterations in inflammatory responses and endothelial function may reduce proteinuria and the rate of progression of kidney disease.

Effect of renal injury-induced neurogenic hypertension on NO synthase, caveolin-1, AKt, calmodulin and soluble guanylate cyclase expressions in the kidney.

Single injection of a small quantity of phenol into the cortex of one kidney in rats results in development of persistent hypertension (HTN) which is thought to be mediated by activation of renal afferent and efferent sympathetic pathways and sodium retention. Nitric oxide (NO) plays a major role in regulation of renal vascular resistance, tubular Na(+) reabsorption, pressure natriuresis, and thereby systemic arterial pressure. The present study was performed to test the hypothesis that chronic renal injury-induced HTN may be associated with dysregulation of NO system in the kidney. Accordingly, urinary NO metabolite (NO(x)) and cGMP excretions as well as renal cortical tissue (right kidney) expressions of NO synthase (NOS) isoforms [endothelial, neuronal, and inducible NOS, respectively (eNOS, nNOS, and iNOS)], NOS-regulatory factors (Caveolin-1, phospho-AKt, and calmodulin), and second-messenger system (soluble guanylate cyclase [sGC] and phosphodiesterase-5 [PDE-5]) were determined in male Sprague-Dawley rats 4 wk after injection of phenol (50 mul of 10% phenol) or saline into the lower pole of left kidney. The phenol-injected group exhibited a significant elevation of arterial pressure, marked reductions of urinary NO(x) and cGMP excretions, downregulations of renal tissue nNOS, eNOS, Phospho-eNOS, iNOS, and alpha chain of sGC. However, renal tissue AKt, phospho-AKT, Calmodulin, and PDE-5 proteins were unchanged in the phenol-injected animals. In conclusion, renal injury in this model results in significant downregulations of NOS isoforms and sGC and consequent reductions of NO production and cGMP generation by the kidney, events that may contribute to maintenance of HTN in this model.

Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease.

Experimental evidence suggests that aldosterone contributes to progressive kidney disease. Angiotensin-converting enzyme inhibitors and angiotensin type 1 receptor antagonists suppress the renin-angiotensin system but they do not effectively reduce plasma aldosterone. Hence, administration of aldosterone receptor antagonists may provide additional renal protection. In the present prospective randomized open-label study, we evaluated the effects of spironolactone (25 mg/day for 1 year) on proteinuria and estimated glomerular filtration rate in 83 patients with chronic kidney disease already treated with angiotensin-converting enzyme inhibitors and/or angiotensin type 1 receptor antagonists. Eighty-two patients were treated with angiotensin-converting enzyme inhibitors and/or angiotensin type 1 receptor antagonists alone and served as controls. After 1 year of therapy, proteinuria decreased from 2.1+/-0.08 to 0.89+/-0.06 g/g creatinine (P<0.001) in patients treated with spironolactone, but it did not change in control patients. Baseline aldosterone levels were significantly correlated with proteinuria (r=0.76, P<0.0001), and predicted the degree of reduction in proteinuria with spironolactone (r=0.42, P<0.0002). Baseline estimated glomerular filtration rate was similar in patients treated with spironolactone and controls (62.4+/-2.4 and 62.2+/-2.1 ml/min/1.73 m(2), respectively). After 1 month of therapy with spironolactone, estimated glomerular filtration rate decreased more in patients treated with spironolactone than in controls. However, by the end of 1 year the monthly rate of decrease in estimated glomerular filtration rate from baseline was lower in patients treated with spironolactone than in controls (0.323+/-0.044 vs 0.474+/-0.037 ml/min/1.73 m(2), P<0.01). Spironolactone caused a significant rise in serum potassium levels (from 4.2+/-0.04 at baseline to 5.0+/-0.05 mEq/l after 12 months of treatment, P<0.001). In conclusion, this study has shown that spironolactone may reduce proteinuria and retard renal progression in chronic kidney disease patients.

Hypertension in renal parenchymal disease: why is it so resistant to treatment?

The association between hypertension and chronic renal disease is well known. The pathogenesis of hypertension in patients with chronic kidney disease (CKD) is complex and multifactorial, which may explain why it is resistant to treatment. The traditional paradigm is that hypertension in CKD is due either to an excess of intravascular volume (volume dependent) or to excessive activation of the renin-angiotensin system in relation to the state of sodium/volume balance (renin-dependent hypertension). This review focuses on the importance of less established mechanisms, such as increased activity of the sympathetic nervous system, increased endothelin production, decreased availability of endothelium-derived vasodilators and structural changes of the arteries, renal ischemia, and sleep apnea.

Silent ischemia is more prevalent among hypertensive patients with microalbuminuria and salt sensitivity.

Some patients with essential hypertension manifest greater than normal urinary albumin excretion (UAE). Salt-sensitive hypertensives also manifest greater UAE compared to salt-resistant individuals. Although the significance of these associations is not well established, several lines of evidence suggest that microalbuminuria and/or salt sensitivity may be associated with greater prevalence of cardiovascular risks and events. In this study, we have evaluated by ergometric exercise 42 subjects with microalbuminuria and 42 matched individuals with normal UAE. All these subjects also underwent a standardized protocol to determine blood pressure sensitivity to a high salt intake. Patients with microalbuminuria displayed greater levels of ambulatory blood pressure and a greater rise in systolic blood pressure during exercise compared to patients with normal UAE (33.1 +/- 1.56 vs 26.4 +/- 1.7 mmHg, P < 0.001). Seven hypertensive patients with microalbuminuria developed ST segment depression during exercise compared to only one subject with normal UAE. Salt-sensitive patients manifested greater UAE than salt-resistant subjects (58 and 14 mg, 24 h, P < 0.001) and greater prevalence of silent ischemia (6 vs 2) than salt-resistant individuals. In conclusion, these studies have shown that hypertensive individuals with microalbuminuria and/or salt sensitivity manifest an increased prevalence of silent ischemia.

Omapatrilat versus lisinopril: efficacy and neurohormonal profile in salt-sensitive hypertensive patients.

Omapatrilat, a vasopeptidase inhibitor, simultaneously inhibits neutral endopeptidase and ACE. The efficacy and hormonal profile of omapatrilat and lisinopril were compared in salt-sensitive hypertensive patients. On enrollment, antihypertensive medications were withdrawn, and patients received a single-blind placebo. On day 15, salt-sensitivity determinations were made. Salt-sensitive hypertensive patients returned within 5 to 10 days for baseline evaluations of ambulatory diastolic blood pressure, ambulatory systolic blood pressure, and atrial natriuretic peptide. Salt-sensitive hypertensive patients were randomized to receive double-blind omapatrilat (n=28) or lisinopril (n=33) at initial doses of 10 mg for 1 week, increasing to 40 and 20 mg, respectively, for an additional 3 weeks. Ambulatory blood pressure and urinary atrial natriuretic peptide were assessed at study termination. Both omapatrilat and lisinopril significantly reduced mean 24-hour ambulatory diastolic and systolic blood pressures; however, omapatrilat produced significantly greater reductions in mean 24-hour ambulatory diastolic blood pressure (P=0.008), ambulatory systolic blood pressure (P=0.004), and ambulatory mean arterial pressure (P=0.005) compared with values from lisinopril. Both drugs potently inhibited ACE over 24 hours. Omapatrilat significantly (P<0.001) increased urinary excretion of atrial natriuretic peptide over 0- to 24-hour (3.8-fold) and 12- to 24-hour (2-fold) intervals; lisinopril produced no change. Omapatrilat significantly (P<0.001) increased urinary excretion of cGMP over the 0- to 24- and 4- to 8-hour intervals compared with that from lisinopril. Neither drug had a diuretic, natriuretic, or kaliuretic effect. In conclusion, in salt-sensitive hypertensive patients, omapatrilat demonstrated the hormonal profile of a vasopeptidase inhibitor and lowered ambulatory diastolic and systolic blood pressures more than lisinopril.

Interleukin-1beta and neurogenic control of blood pressure in normal rats and rats with chronic renal failure.

Increased sympathetic nervous system (SNS) activity plays a role in the genesis of hypertension in rats with chronic renal failure (CRF). The rise in central SNS activity is mitigated by increased local expression of neuronal nitric oxide synthase (NOS) mRNA and NO(2)/NO(3) production. Because interleukin (IL)-1beta may activate nitric oxide in the brain, we have tested the hypothesis that IL-1beta may modulate the activity of the SNS via regulation of the local expression of neuronal NOS (nNOS) in the brain of CRF and control rats. To this end, we first found that administration of IL-1beta in the lateral ventricle of control and CRF rats decreased blood pressure and norepinephrine (NE) secretion from the posterior hypothalamus (PH) and increased NOS mRNA expression. Second, we observed that an acute or chronic injection of an IL-1beta-specific antibody in the lateral ventricle raised blood pressure and NE secretion from the PH and decreased NOS mRNA abundance in the PH of control and CRF rats. Finally, we measured the IL-1beta mRNA abundance in the PH, locus coeruleus, and paraventricular nuclei of CRF and control rats by RT-PCR and found it to be greater in CRF rats than in control rats. In conclusion, these studies have shown that IL-1beta modulates the activity of the SNS in the central nervous system and that this modulation is mediated by increased local expression of nNOS mRNA.

The kidney and the neurogenic control of blood pressure in renal disease.

Hypertension is very common in patients with chronic renal failure (CRF) and it contributes to morbidity and mortality as well as to the progression of renal disease. Several mechanisms may play a role in the pathogenesis of hypertension in CRF, but the best known are sodium retention and activation of the renin-angiotensin-aldosterone system. More recently, evidence has accumulated to support a role for increased sympathetic nervous system (SNS) activity in the genesis of hypertension associated with CRF. Our laboratory findings indicate that specific renal injuries, caused by 5/6 nephrectomy and/or phenol injection in the kidney, activate renal afferent pathways that connect with integrative structures in the brain involved in the regulation of SNS activity and blood pressure. This results in a rise in blood pressure sustained by noradrenergic mechanisms. Our laboratory has also shown that the rise in central SNS activity is mitigated by increased local expression of nitric oxide synthase (NOS)-mRNA and nitric oxide (NO) production, and by upregulation of interleukin-1beta.

Neurogenic factors and hypertension in renal disease.

Hypertension in chronic renal failure (CRF) is very common and contributes to morbidity and mortality and to the progression of renal disease. The pathogenesis of hypertension in CRF has been attributed mostly to sodium retention and to activation of the renin-angiotensin-aldosterone system. More recently an abundance of evidence has accumulated to support a role for increased sympathetic nervous system (SNS) activity in the genesis of hypertension associated with CRF. Evidence from our laboratory has also demonstrated that the rise in central SNS activity is mitigated by increased local expression of nitric oxide synthase (NOS)-mRNA and nitric oxide (NO) production, and that the upregulation of NO production in the brain is mediated by IL-1beta.

Losartan reduces sympathetic nerve outflow from the brain of rats with chronic renal failure.

Sympathetic nervous system (SNS) activity, measured by norepinephrine (NE) turnover rate, was greater in the posterior hypothalamic (PH) nuclei, the paraventricular nuclei (PVN), and the locus coeruleus (LC) of 5/6 nephrectomised (CRF) rats than of control rats. NE secretion from the PH was also greater in CRF than in control rats. These findings demonstrate that SNS activity plays an important role in the genesis of hypertension associated with CRF. The increase in central SNS activity was mitigated by increased local expression of nitric oxide synthase (NOS)-mRNA and nitric oxide (NOx) production. Because angiotensin II may stimulate the central SNS, we tested the hypothesis that losartan, a specific angiotensin II AT(1)-receptor antagonist, may lower blood pressure (BP), at least in part, by central noradrenergic inhibition. To this end, we studied two groups of CRF rats. One group received losartan (10 mg/kg body weight) in drinking water between the 3rd and 4th week after nephrectomy, the second group received drinking water without losartan. SNS activity was measured by NE secretion from the PH using the microdialysis technique. NOS-mRNA gene expression was also measured by RT-PCR in the PH, PVN, and LC of CRF and control rats. Losartan reduced systolic BP from 184+/-3.7 to 152+/-3.1 mmHg and NE secretion from the PH from 340+/-9.7 to 247+/-4.8 pg/ml. CRF rats treated with losartan manifested a significant (p<0.01) increase in the expression of nNOS-mRNA in the PH (from 84+/-1.2 to 99+/-2.6), the PVN (from 44+/-1.5 to 63+/-2.1), and the LC (from 59+/-6.7 to 76+/-2.1). CRF rats also manifested a significant increase (p<0.01) in the expression of IL-1beta the PH (from 41.6+/-2.8 to 54.3+/-1.4), PVN (from 44+/-1.9 to 54+/-1.5), and LC (from 35.5+/-1.6 to 53.5+/-1.9). In conclusion, these studies suggest that the antihypertensive action of losartan in CRF rats may be mediated, at least in part, by inhibition of central SNS outflow. The studies also suggest that the inhibitory action of losartan on the SNS may be mediated by activation of IL-1beta, which, in turn, stimulates nNOS, an important modulator of central SNS activity.

Microalbuminuria in essential hypertension: significance, pathophysiology, and therapeutic implications.

Some patients with essential hypertension manifest greater than normal urinary albumin excretion (UAE). The significance of this association, which is the object of this review, is not well established. Hypertensive patients with microalbuminuria manifest greater levels of blood pressure, particularly at night, and higher serum levels of cholesterol, triglycerides, and uric acid than patients with normal UAE. Levels of high-density lipoprotein cholesterol, on the other hand, were lower in patients with microalbuminuria than in those with normal UAE. Patients with microalbuminuria manifested greater incidence of insulin resistance and thicker carotid arteries than patients with normal UAE. After a follow-up of 7 years, we observed that 12 cardiovascular events occurred among 54 (21.3%) patients with microalbuminuria and only two such events among 87 patients with normal UAE (P < 0.0002). Stepwise logistic regression analysis showed that UAE, cholesterol level, and diastolic blood pressure were independent predictors of the cardiovascular outcome. Rate of creatinine clearance from patients with microalbuminuria decreased more than that from those with normal UAE. In conclusion, these studies suggest that hypertensive individuals with microalbuminuria manifest a variety of biochemical and hormonal derangements with pathogenic potential, which results in hypertensive patients having a greater incidence of cardiovascular events and a greater decline in renal function than patients with normal UAE.

Association between hyperlipidemia and microalbuminuria in essential hypertension.

BACKGROUND: Some patients with essential hypertension manifest greater than normal urinary albumin excretion (UAE). A few retrospective studies have suggested that there is an association between microalbuminuria and cardiovascular risk. The reasons for this association are not well established, and they are the object of this review. RESULTS: We found that hypertensive patients with microalbuminuria manifest greater levels of blood pressure, particularly at night. Serum levels of cholesterol, triglycerides, and uric acid in patients with microalbuminuria were higher than levels in those with normal UAE, whereas levels of high-density lipoprotein cholesterol in patients with microalbuminuria were lower than levels in patients with normal UAE. Patients with microalbuminuria manifest a greater incidence of insulin resistance, and thicker carotid arteries. After a follow-up of seven years we observed that 12 cardiovascular events occurred among 54 (21.3%) patients with microalbuminuria, and only two such events among 87 patients with normal UAE (P < 0.0002). Stepwise logistical regression analysis showed that UAE, cholesterol level and diastolic blood pressure were independent predictors of the cardiovascular outcome. The rate of clearance of creatinine from patients with microalbuminuria decreased more than did that from those with normal urinary albumin excretion. CONCLUSIONS: These studies suggest that hypertensive individuals with microalbuminuria manifest a variety of biochemical and hormonal derangements with pathogenic potential, which result in greater incidence of cardiovascular events and a greater decline in renal function than do patients with normal UAE.

Diagnosis and evaluation of secondary hypertension.

Although patients with secondary hypertension comprise only a small percentage of those with elevated blood pressure, this subgroup should not be ignored. In many cases, correcting the cause of secondary hypertension can lead to a cure, thus avoiding the need for long-term medical therapy, with its attendant risks and economic toll. Moreover, effective treatment of secondary hypertension can prevent chronic complications, such as left ventricular hypertrophy and coronary artery disease, which markedly increase morbidity and mortality. Nearly all forms of secondary hypertension are related to decreased renal function and/or derangement of hormonal balance or secretion. If hypertension is secondary to chronic renal failure of any etiology, it can be recognized from biochemical assays for blood urea nitrogen and creatinine.

Microalbuminuria predicts cardiovascular events and renal insufficiency in patients with essential hypertension.

BACKGROUND: Some patients with essential hypertension manifest greater than normal urinary excretion of albumin (UAE). Authors of a few retrospective studies have suggested that there is an association between microalbuminuria and cardiovascular risk. OBJECTIVE: To evaluate whether microalbuminuria is associated with a greater than normal risk of cardiovascular and renal events. METHODS: We performed a retrospective cohort analysis of 141 hypertensive individuals followed up for approximately 7 years. Hypertensive patients were defined as having microalbuminuria if the baseline average UAE of three urine collections was in the range 30-300 mg/24 h. RESULTS: Fifty-four patients had microalbuminuria and 87 had normal UAE. At baseline, the two groups were similar for age, weight, blood pressure, and rate of clearance of creatinine. Serum levels of cholesterol, triglycerides, and uric acid in patients with microalbuminuria were higher than levels in those with normal UAE, whereas levels of high-density lipoprotein cholesterol in patients with microalbuminuria were lower than levels in patient with normal UAE. During follow-up, 12 cardiovascular events occurred among the 54 (21.3%) patients with microalbuminuria and only two such events among the 87 patients with normal UAE (P < 0.0002). Stepwise logistic regression analysis showed that UAE (P = 0.003), cholesterol level (P = 0.047) and diastolic blood pressure (P = 0.03) were independent predictors of the cardiovascular outcome. Rate of clearance of creatinine from patients with microalbuminuria decreased more than did that from those with normal UAE (decrease of 12.1 +/- 2.77 versus 7.1 +/- 0.88 ml/min, P < 0.03). CONCLUSIONS: This study suggests that hypertensive individuals with microalbuminuria manifest a greater incidence of cardiovascular events and a greater decline in renal function than do patients with normal UAE.

A limited renal injury may cause a permanent form of neurogenic hypertension.

Previously, we have shown that an acute injury to the kidney produced by an intrarenal injection of phenol causes an immediate increase in blood pressure and in norepinephrine (NE) secretion from the posterior hypothalamus. The studies suggest that in this model afferent impulses from the kidney to central integrative structures in the brain may be responsible for the increase in blood pressure. To further evaluate whether a renal injury caused by the intrarenal injection of phenol leads to a permanent elevation of blood pressure and whether this is mediated by increased sympathetic nervous system activity, we examined the chronic effects (4 weeks) of an intrarenal injection of 50 microL of 10% phenol on blood pressure and NE secretion from the posterior hypothalamus. Systolic blood pressure increased from 128 +/- 2.1 to 176 +/- 1.5 mm Hg (P < .01) 4 weeks after receiving the intrarenal injection of phenol, but it did not change in rats that received the vehicle (128 +/- 2.4 and 135 +/- 1.7 mm Hg) and in rats that were subjected to renal denervation (127 +/- 3.4 and 124 +/- 1.0 mm Hg). The secretion of NE from the posterior hypothalamic nuclei was greater (P < .01) in rats that received phenol (253 +/- 9.6 pg/mL) than in controls (158 +/- 8.6 pg/mL) and denervated rats (170 +/- 2.1 pg/mL). These studies have shown that a limited injury to one kidney may cause a permanent elevation of blood pressure and this is associated with increased sympathetic nervous system activity.

Dietary salt intake, blood pressure and the kidney in hypertensive patients with non-insulin dependent diabetes mellitus.

The mechanisms responsible for hypertension in NIDDM patients are only partially understood. Increased sensitivity to dietary salt intake and to vasoconstrictor hormones are among the mechanisms proposed. We have studied 19 hypertensive NIDDM patients 7 salt-sensitive and 12 salt-resistant while they were ingesting a diet with 20 mEq/day of Na+ for 9 days and while they were ingesting a diet containing 250 mEq/day of Na+ for 14 days. During the last 4 days of each dietary regimen, they received 60 mg/day of slow-release nifedipine. Blood pressure response to increasing doses of norepinephrine and angiotensin II was studied at the end of each of the four phases of the study. High salt intake increased blood pressure and decreased heart rate in these patients. High salt intake also increased the vascular response to norepinephrine but not to angiotensin II in NIDDM hypertensive subjects. Glomerular filtration rate and renal blood flow were not different during the low and high salt diets. There were no differences in the blood pressure response to norepinephrine or angiotensin II, nor in renal hemodynamic changes among salt-sensitive and salt-resistant NIDDM patients. Nifedipine decreased blood pressure equally in salt-sensitive and salt-resistant hypertensive patients and during the high and the low salt intake. Nifedipine increased renal blood flow, both in salt-sensitive and in salt-resistant individuals, but the differences did not reach statistical significance. Nifedipine decreased the blood pressure response to both norepinephrine and angiotensin II. The studies indicate that an increased reactivity to the pressor action of norepinephrine may contribute to the maintenance of hypertension in NIDDM hypertensive subjects and high salt intake may aggravate the pressor responsiveness to norepinephrine in these patients. Nifedipine is an effective antihypertensive drug in NIDDM patients and its action may be in part related to a decrease in pressor response to norepinephrine and angiotensin II.

Effect of L-arginine on systemic and renal haemodynamics in salt-sensitive patients with essential hypertension.

In response to a high sodium (Na+) intake, salt-sensitive patients with hypertension retain more Na+ and manifest a greater rise in arterial pressure than salt-resistant patients. Because there is limited information regarding the role of nitric oxide (NO) in salt-sensitivity we examined the effects of L-arginine (500 mg/kg, i.v. for 30 min) on mean arterial pressure and renal haemodynamics in 21 hypertensive and five normotensive African-Americans. At the end of L-arginine infusion mean arterial pressure fell more in salt-sensitive (-11.5 +/- 2.5) than in salt-resistant (-3.7 +/- 1.5 mm Hg) and control subjects (-3.2 +/- 3.8 mm Hg). At the end of L-arginine infusion effective renal plasma flow (ERPF) increased more (P < 0.05) in controls (+108 +/- 13.9 ml/min/1.73 m2) than in salt-resistant (+55 +/- 16.0 ml/min/1.73 m2) and salt-sensitive patients (+22 +/- 21.5 ml/min/1.73 m2). This study has shown that salt-sensitive African-Americans manifest different systemic and renal haemodynamic responses to L-arginine than salt-resistant patients and controls. The fall in mean blood pressure following L-arginine was greater in salt-sensitive than in salt-resistant patients and controls, whereas the increase in ERPF was reduced in salt-sensitive compared to salt-resistant and normal subjects. The data are in keeping with the notion that a defect in NO production may participate to the genesis of blood pressure sensitivity to salt.