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OBJECTIVES Our aim was to assess the importance of the sympathetic nervous system as assessed by urinary catecholamine measurement in the aetiology of essential hypertension and the importance of antihypertensive therapy in the excretion of urinary catecholamines. METHODS Twenty-four-hour urinary catecholamine measurement was performed in 1925 patients who were referred for treatment of hypertension and grouped according to the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure classification: of the 655 untreated patients, 59 were normotensive individuals (SBP < 140 and DBP < 90 mmHg), n = 219 stage 1 (SBP 140-159 or DBP 90-99 mmHg), n = 236 stage 2 (SBP 160-179 or DBP 100-109 mmHg) and n = 141 stage 3 (SBP ≥ 180 or DBP ≥ 110 mmHg). RESULTS There was a statistically significant positive relationship between 24-h urinary norepinephrine excretion and the severity of hypertension, such that the higher the blood pressure the higher the urinary norepinephrine excretion (mean ± standard error of mean): normotensive group, 221 ± 13 nmol/24 h; stage 1, 254 ± 8 nmol/24 h; stage 2, 263 ± 7 nmol/24 h and stage 3, 296 ± 12 nmol/24 h (P

To determine the effects of potassium supplementation on endothelial function, cardiovascular risk factors, and bone turnover and to compare potassium chloride with potassium bicarbonate, we carried out a 12-week randomized, double-blind, placebo-controlled crossover trial in 42 individuals with untreated mildly raised blood pressure. Urinary potassium was 77±16, 122±25, and 125±27 mmol/24 hours after 4 weeks on placebo, potassium chloride, and potassium bicarbonate, respectively. There were no significant differences in office blood pressure among the 3 treatment periods, and only 24-hour and daytime systolic blood pressures were slightly lower with potassium chloride. Compared with placebo, both potassium chloride and potassium bicarbonate significantly improved endothelial function as measured by brachial artery flow-mediated dilatation, increased arterial compliance as assessed by carotid-femoral pulse wave velocity, decreased left ventricular mass, and improved left ventricular diastolic function. There was no significant difference between the 2 potassium salts in these measurements. The study also showed that potassium chloride reduced 24-hour urinary albumin and albumin:creatinine ratio, and potassium bicarbonate decreased 24-hour urinary calcium, calcium:creatinine ratio, and plasma C-terminal cross-linking telopeptide of type 1 collagen significantly. These results demonstrated that an increase in potassium intake had beneficial effects on the cardiovascular system, and potassium bicarbonate may improve bone health. Importantly, these effects were found in individuals who already had a relatively low-salt and high-potassium intake.

A reduction in salt intake lowers blood pressure. However, most previous trials were in whites with few in blacks and Asians. Salt reduction may also reduce other cardiovascular risk factors (eg, urinary albumin excretion, arterial stiffness). However, few well-controlled trials have studied these effects. We carried out a randomized double-blind crossover trial of salt restriction with slow sodium or placebo, each for 6 weeks, in 71 whites, 69 blacks, and 29 Asians with untreated mildly raised blood pressure. From slow sodium to placebo, urinary sodium was reduced from 165±58 (±SD) to 110±49 mmol/24 hours (9.7 to 6.5 g/d salt). With this reduction in salt intake, there was a significant decrease in blood pressure from 146±13/91±8 to 141±12/88±9 mm Hg ( P P P P

It has been suggested that inappropriate stimulation of the renin-angiotensin system (RAS) is responsible for the increase in blood pressure that occurs in autosomal-dominant polycystic kidney disease (ADPKD) before the development of renal failure. However, the interpretation of previous studies in ADPKD patients is confounded by inadequate matching with control populations for blood pressure and renal function, or failure to control the sodium intake of participants.A double-blind, placebo-controlled study of two different sodium intakes (350 and 50 mmol/day for 5 days) in a group of 11 hypertensive ADPKD patients and eight matched control subjects with essential hypertension. In addition, blood pressure and hormonal responses were measured after the administration of the angiotensin-converting enzyme inhibitor enalapril for 3 days.Blood pressure and hormonal responses of the RAS after a reduction in sodium intake and after the administration of enalapril were identical in ADPKD patients and controls.Activation of the classic circulating RAS is no greater in hypertensive ADPKD patients than in individuals with essential hypertension.

High blood pressure and proteinuria are the major risk factors for cardiovascular and renal disease. In black individuals, there is an increased risk of hypertension, stroke, heart failure, and kidney disease. There are no controlled studies of the effects of reducing salt intake on blood pressure and urine protein excretion in black individuals. Therefore, the aim of our study was to determine the effects of modest salt restriction on blood pressure and urine protein excretion in nondiabetic black hypertensive subjects. The study was randomized, double blind, and placebo controlled. After run-in periods on their usual diet and on reduced salt, participants continued to restrict their salt intake and then received either slow sodium tablets, designed to bring their salt intake back to normal, or placebo tablets for 4 weeks in a randomized, double-blind, crossover study. In the 40 who completed the study, urinary sodium excretion fell on slow sodium to placebo from 169±73 to 89±52 mmol per 24 hours ( P P P

Many randomized trials have shown that a reduction in salt intake lowers blood pressure in hypertensive individuals. However, few have looked at the effects according to hypertension category. A recent analysis of the third and fourth National Health and Nutrition Examination Survey suggests that salt intake may not be related to blood pressure in isolated systolic or combined hypertension. To look at this further, we reanalyzed the data of our previous salt reduction trials. Hypertensive individuals were studied in randomized double-blind crossover studies: 1 month of usual salt intake compared with 1 month of reduced salt intake. In isolated systolic hypertension (n=24), blood pressure was reduced from 166±19/86±7 to 156±20/85±7 mm Hg (systolic P P =0.459) with a reduction in urinary sodium from 175±51 to 87±38 mmol per 24-hour period (10.3 to 5.1 g per day of salt). In combined hypertension (n=88), blood pressure was reduced from 161±16/100±9 to 154±17/96±9 mm Hg ( P

Randomized trials have shown that increasing potassium intake lowers blood pressure. However, most previous trials used potassium chloride, whereas potassium in fruits and vegetables is not a chloride salt. It is unclear whether a nonchloride salt of potassium has a greater or lesser effect on blood pressure compared with potassium chloride. We performed a randomized crossover trial comparing potassium chloride with potassium citrate (96 mmol/d, each for 1 week) in 14 hypertensive individuals. At baseline, blood pressure was 15116/937 mm Hg with a 24-hour urinary potassium of 8124 mmol. During the randomized crossover part of the study, blood pressure was 14012/ 887 mm Hg with potassium chloride (24-hour urinary potassium: 16436 mmol) and 13812/886 mm Hg with potassium citrate (24-hour urinary potassium: 16033 mmol). These blood pressures were significantly lower compared with that at baseline; however, there was no significant difference in blood pressure between potassium chloride and potassium citrate, mean difference (95% confidence interval): 1.6 (2.3 to 5.6) mm Hg for systolic and 0.6 (2.4 to 3.7) mm Hg for diastolic. Our results, in conjunction with the evidence from many previous trials that potassium chloride has a significant blood pressure-lowering effect, suggest that potassium citrate has a similar effect on blood pressure as potassium chloride. These results support other evidence for an increase in potassium intake and indicate that potassium does not need to be given in the form of chloride to lower blood pressure. Increasing the consumption of foods high in potassium is likely to have the same effect on blood pressure as potassium chloride. (Hypertension. 2005; 45:571-574.)

Two studies were performed to determine the quantitative relationship between salt intake and urinary volume (U v ) in humans. In study 1, 104 untreated hypertensives were studied on the fifth day of a high- and a low-salt diet. The 24-hour U v was 2.2 L (urinary sodium [U Na ] 277 mmol) on the high-salt diet and decreased to 1.3 L ( P Na 20.8 mmol) on the low-salt diet. The reduction in 24-hour U v was significantly related to the decrease in 24-hour U Na ( P v by 367 mL. In study 2, 634 untreated hypertensives were studied on their usual diet. There was a significant relationship between 24-hour U v and U Na ( P v by 454 mL. The International Study of Salt and Blood Pressure (INTERSALT) of 1731 hypertensives and 8343 normotensives on their usual diet showed that 24-hour U v was significantly related to U Na ( P v by 379 and 399 mL in hypertensives and normotensives, respectively. These findings document the important effect that salt intake has on U v . The recommended reduction in salt intake in the general population is from 10 to 5 g/d. This would reduce fluid intake in the population by ≈350 mL/d per person. This would have a large impact on the sales of soft drinks, mineral water, and beer.

Abstract —We recently showed that rarefaction of skin capillaries in the dorsum of the fingers of patients with essential hypertension is due to the structural (anatomic) absence of capillaries rather than functional nonperfusion. It is not known whether this rarefaction is primary (ie, antedates the onset of hypertension) or secondary (ie, as a consequence of sustained and prolonged elevation of blood pressure [BP]). The aim of the present investigation was to study skin capillary density in a group of patients with mild borderline hypertension to assess whether rarefaction antedates the onset of sustained elevation of BP. The study group included 18 patients with mild borderline hypertension (mean supine BP, 136/83 mm Hg), 32 normotensive controls (mean BP, 126/77 mm Hg), and 45 patients with established essential hypertension (mean BP, 156/98 mm Hg). The skin of the dorsum of the fingers was examined by intravital capillary videomicroscopy before and after venous congestion at 60 mm Hg for 2 minutes. Patients with borderline essential hypertension had the lowest resting capillary density when compared with normotensive controls and patients with established hypertension. Maximal capillary density with venous congestion in the borderline group remained the lowest. The study confirmed that patients with borderline essential hypertension have skin capillary densities that are equally low as or even lower than patients with established hypertension. Both groups had significantly lower capillary densities than normal controls. One explanation for the results is that capillary rarefaction may be due to an early structural abnormality in essential hypertension.

Abstract —A reduction in the density of capillaries (rarefaction) is known to occur in many tissues in patients with essential hypertension. This rarefaction may play a role in increasing peripheral resistance. However, the mechanism underlying this capillary rarefaction is not understood. The aim of this study was to assess the extent of structural versus functional capillary rarefaction in the skin of dorsum of fingers in essential hypertension. The capillary microcirculation was examined with video microscopy before and after maximizing the number of perfused capillaries by venous congestion. The study group comprised 17 patients with essential hypertension (mean supine blood pressure, 155/96 mm Hg) and 17 closely matched normotensive controls (mean blood pressure, 127/77 mm Hg). We used intravital video microscopy with an epi-illuminated microscope to examine the skin of the dorsum of left middle phalanx before and after venous congestion at 60 mm Hg for 2 minutes. A significantly lower mean capillary density occurred at baseline in hypertensive subjects versus normotensive subjects. With venous occlusion, capillary density increased significantly in both groups; however, maximal capillary density remained significantly lower in the hypertensive subjects than in the normotensive subjects. The study strongly suggests that much of the reduction in capillary density in the hypertensive subjects is caused by structural (anatomic) absence of capillaries rather than functional nonperfusion.

Abstract The combination of an angiotensin-converting enzyme inhibitor and a calcium antagonist has a synergistic effect in patients with more severe hypertension. However, when this combination fails to control blood pressure, it is not clear which drug is then additive. The aim of this work was to study in a double-blind, randomized, crossover design the effect on blood pressure of the addition of either a thiazide diuretic (bendrofluazide, 5 mg once daily) or a β-blocker (atenolol, 100 mg once daily) or placebo each for a month in hypertensive patients who are not adequately controlled on the combined treatment of amlodipine 5 mg once daily and lisinopril 5 mg twice daily. Eighteen patients with a supine diastolic pressure of more than 90 mm Hg after at least 1 month on the combined treatment of amlodipine and lisinopril were enrolled in the study. The results show that in patients whose blood pressures are not controlled by the combination of amlodipine and lisinopril, the addition of bendrofluazide 5 mg once daily causes a significant fall in blood pressure compared with placebo and a significantly greater fall than 100 mg atenolol once daily.

We have shown previously that the combination of captopril and nifedipine was effective at peak response but was very short acting. We therefore decided to study the longer-acting angiotensin converting enzyme inhibitor lisinopril and the long-acting calcium antagonist amlodipine, each alone and in combination, in a double-blind, randomized crossover study in which blood pressures were measured at peak and trough. This study provided the opportunity to investigate what parameters in these patients might possibly predict the fall in blood pressure with the individual drugs and with the combination.Fifteen patients with essential hypertension (eight male, 10 Caucasian; mean age 53 years) were studied. After 1 month observation on no treatment they were entered into a single-blind run-in of placebo given once a day for 1 month. Patients were then allocated randomly to amlodipine (5 mg once a day), lisinopril (10 mg once a day) or their combination (once a day) for 1 month in a double-blind crossover study. All patients were studied on their usual diet and no dietary advice was given. Blood pressure was measured by semi-automatic ultrasound sphygmomanometer both 24 h and 6 h (trough and peak) after the last dose.During the crossover part of the study there was a significant additional blood pressure-lowering effect (at trough) of the combination compared with either amlodipine or lisinopril alone. Similar results were observed for the blood pressures at peak. The fall in blood pressure with lisinopril was related to baseline plasma renin activity, whereas when amlodipine was given, either alone or in combination, the fall in blood pressure was independent of baseline renin activity. The Blacks (n = 5) appeared not to respond as well to lisinopril as the Caucasians (n = 10). Finally, the blood pressure response to amlodipine tended to be associated with the severity of hypertension.The results of the present study indicate that: amlodipine and lisinopril in combination have a marked additional effect on blood pressure compared with either given as a monotherapy; their potentiation of action is long-acting; Black patients tend not to respond to the monotherapy with lisinopril as well as Caucasian patients, although they respond similarly to the combination; the response to amlodipine tends to be greater the higher the initial blood pressure; and, finally, the response to lisinopril is greater the higher the plasma renin activity.

Priapism is a debilitating disease for which there is at present no clinically accepted pharmacologic intervention. It has been estimated that priapism lasting more than 24 hours in patients is associated with a 44–90% rate of erectile dysfunction (ED). In this investigation we determined in two animal models of priapism (opiorpin-induced priapism in the rat and priapism in a mouse model of sickle cell disease) if there is evidence for an increase in markers of oxidative stress in corporal tissue. In both animal models we demonstrate that priapism results in increased levels of lipid peroxidation, glutathione S-transferase activity, and oxidatively damaged proteins in corporal tissue. Using Western blot analysis we demonstrated there is up regulation of the ubiquitination ligase proteins, Nedd-4 and Mdm-2, and the lysososomal autophage protein, LC3. The anti-apoptotic protein, Bcl-2, was also up regulated. Overall, we demonstrate that priapism is associated with increased oxidative stress in corporal tissue and the activation of protein degradation pathways. Since oxidative stress is known to mediate the development of ED resulting from several etiologies (for example ED resulting from diabetes and aging) we suggest that damage to erectile tissue resulting from priapism might be prevented by treatments targeting oxidative stress.

Basal atrial natriuretic peptide levels and the response to exogenous atrial natriuretic peptide are influenced by dietary sodium intake. In view of interest in the therapeutic potential of elevating plasma atrial natriuretic peptide by inhibition of neutral endopeptidase 24.11, we studied the renal and hormonal effects of 200 mg of the oral endopeptidase 24.11 inhibitor candoxatril in eight patients with untreated essential hypertension on high sodium (350 mmol/day) and low sodium (10 mmol/day) diets. With endopeptidase 24.11 inhibition, plasma atrial natriuretic peptide increased more than twofold on low and high sodium diets (p less than 0.05). Plasma N-terminal pro-atrial natriuretic peptide increased on the high sodium intake but was unaffected by candoxatril. Urinary sodium excretion increased threefold on the low sodium and sixfold on the high sodium diet (p less than 0.05). The absolute increase in urinary sodium excretion during the 24 hours after treatment compared with placebo was 18 +/- 8 mmol on the low sodium and 98 +/- 34 mmol on the high sodium diet (p less than 0.05). Plasma renin activity was suppressed by treatment on the low but not on the high sodium diet (p less than 0.05). Blood pressure did not change in the 6 hours after a single dose of candoxatril. These findings show that sodium intake is a major determinant of the response to endopeptidase 24.11 inhibition. The lack of effect on N-terminal pro-atrial natriuretic peptide suggests that candoxatril does not influence cardiac secretion of atrial natriuretic peptide or catabolism of N-terminal pro-atrial natriuretic peptide, and the latter does not appear to play a role in the response to candoxatril.

When the function of the renin system is inhibited, blood pressure becomes more dependent on changes in sodium and water balance. Diuretics alone and sodium restriction alone are additive to converting enzyme inhibitor therapy. However, it is not known if these two ways of reducing sodium balance are additive in the presence of established converting enzyme inhibition. We therefore performed a double-blind crossover study of the effects of moderate sodium restriction in 21 patients with essential hypertension who were already being treated with the combination of a converting enzyme inhibitor and a diuretic. After 1 month of captopril (50 mg twice daily) and hydrochlorothiazide (25 mg once daily) therapy, with their usual sodium intake, average supine blood pressure was 147/96 +/- 5/3 (SEM) mm Hg 2 hours after treatment. Patients then reduced their sodium intake to around 80-100 mmol/day for the remainder of the study. After 2 weeks of sodium restriction, they entered a double-blind, randomized, crossover study of Slow Sodium (100 mmol sodium/day) compared with Slow Sodium placebo, while continuing sodium restriction and the above treatment. During the double-blind study, after 1 month of treatment with captopril (50 mg twice daily), hydrochlorothiazide (25 mg once daily), and Slow Sodium placebo, supine blood pressure 2 hours after treatment was 138/88 +/- 4/2 mm Hg (24-hour urinary sodium 104 +/- 11 mmol). After 1 month of captopril (50 mg twice daily), hydrochlorothiazide (25 mg once daily), and Slow Sodium tablets, supine blood pressure 2 hours after treatment was 147/91 +/- 5/2 mm Hg (p less than 0.05; 24-hour urinary sodium 195 +/- 14 mmol).(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract A moderate reduction in salt intake lowers blood pressure in individuals with hypertension and improves blood pressure control in those taking a converting enzyme inhibitor. However, it is unclear how effective reduction of salt intake is compared with addition of other drugs, in particular, thiazide diuretics. We directly compared the separate effects on blood pressure of reducing sodium intake or adding a thiazide diuretic in the presence of a converting enzyme inhibitor in a double-blind, randomized, crossover study. We studied 11 subjects with essential hypertension who had been taking 25 mg captopril twice daily for at least 1 month. In the double-blind study, after 1 month of captopril alone, supine blood pressure was 151±5/95±4 (SEM) mm Hg. With the addition of 25 mg hydrochlorothiazide once daily for 1 month, blood pressure fell to 137±5/87±3 mm Hg. When a moderate reduction in salt intake (from 206±26 to 109±20 mmol urinary sodium/24 h) was added to captopril for 1 month, blood pressure was reduced by a similar amount (to 137±4/90±3 mm Hg). Plasma potassium fell during the diuretic treatment (3.9±0.1 to 3.7±0.1 mmol/L, P

1373 INFLUENCE OF ESTRADIOL ON THE SPHINGOSINE-1PHOSPHATE (S1P) SIGNALING PATHWAY IN THE VAGINA Sarah Collins, Rowena Chua, Nirmala Kanika, Moses Tar, Katherine Sandhu, Arnold Melman, Michael E DiSanto*. Bronx, NY. INTRODUCTION AND OBJECTIVE: The vaginal walls help to maintain the bladder in its correct anatomical position preventing pelvic organ prolapse with vaginal smooth muscle (SM) content/tone suggested to play a role. The bioactive lipid S1P is emerging as a master regulator of SM phenotype. S1P interacts with three G-protein-coupled receptors termed S1P1, S1P2 and S1P3 which activate a myriad of signal transduction pathways including the RhoA/Rho-kinase pathway. S1P is present in serum at levels (~1 μM) consistent with SM contraction. The goal of this study was to determine if 1) the major components of the S1P pathway exist in the vagina, 2) regional differences exist in the S1P pathway between distal and proximal vagina, 3) the S1P synthesis pathway is hormonally regulated and 4) S1P serum levels can be used as a noninvasive biomarker of vaginal SM phenotype. METHODS: Vaginal tissue from 6 normal 12 wk female Sprague Dawley rats was divided into the distal one-third and proximal two-thirds and used for regional expression studies. In addition, 3 groups of 8 rats each (sham-operated or bilateral ovariectomy (OVX) for 6 weeks followed by placebo or estradiol (E) pellet for 4 weeks) were generated