Candoxatril, an orally active neutral endopeptidase inhibitor, raises plasma atrial natriuretic factor and is natriuretic in essential hypertension.

OBJECTIVE: Candoxatril (UK79,300) is an orally available inhibitor of the neutral endopeptidase (E.C.3.4.24.11) which degrades atrial natriuretic factor (ANF). This study was designed to establish initial safety and efficacy data in essential hypertension for this novel class of drug. DESIGN: A prospective, double-blind, placebo-controlled, single-dose comparison of candoxatril with placebo in a crossover manner. Three doses of candoxatril (10, 50 and 200 mg) were used, with four subjects at each dose level. SETTING: The Medical Research Council Blood Pressure Unit, Western Infirmary, Glasgow, UK (a hospital clinical research unit). PATIENTS: Twelve patients with untreated essential hypertension. Diastolic blood pressure was greater than 95 mmHg on three separate occasions before entry to the study. INTERVENTION: Candoxatril or matching placebo was administered orally in the fasting state. Serial measurements of urinary volume and electrolyte excretion were taken (on each hour, urine volume was replaced with an equivalent volume of water by mouth). Blood pressure and heart rate were recorded for 12 h after drug administration and serial blood samples were taken for measurement of plasma ANF and neurohormone concentrations. MAIN OUTCOME MEASURES: Urine volume and electrolyte concentration; blood pressure; heart rate; plasma atrial natriuretic factor. RESULTS: Plasma ANF concentrations rose significantly in all patients within 2 h of candoxatril administration compared with placebo although peak and integrated ANF levels were similar at all three doses. A significant natriuresis was only seen after 200 mg candoxatril, with a greater cumulative urine sodium excretion over 12 h compared with placebo; this was associated with a greater diuresis over 12 h compared with placebo. After a single oral dose of candoxatril, blood pressure and heart rate remained unchanged. CONCLUSIONS: Candoxatril in a single dose caused no adverse effects in essential hypertension. The drug caused a rise in basal ANF levels at all doses, but natriuresis was only seen with the highest dose used. No change in blood pressure was recorded after acute dosing, and the results of chronic studies with this compound are awaited. Oral inhibitors of ANF degradation may have therapeutic potential in cardiovascular disorders.     

Inhibition of the metabolism of atrial natriuretic factor causes diuresis and natriuresis in chronic heart failure

Atrial natriuretic factor (ANF) is a peptide hormone secreted by the heart that is degraded in vivo by endopeptidase 24:11 (atriopeptidase). UK 69,578 is a novel atriopeptidase inhibitor that raises plasma levels of ANF in animals and normal volunteers, with associated diuresis and natriuresis. This study examines the effects of UK 69,578 in patients with mild heart failure. UK 69,578 was administered as an intravenous infusion over 20 min in a placebo-controlled, cross-over study to six patients with stable (NYHA Class 2) chronic heart failure. The atriopeptidase inhibitor was well tolerated and no side effects were encountered. Mean baseline plasma ANF was elevated at 88 pg/mL (normal less than 50), and increased 2- to 5-fold after UK 69,578 administration. Plasma ANF did not change significantly following placebo. There was a marked diuresis after UK 69,578 compared to placebo. Urinary sodium excretion doubled for 4 to 6 h, but there was no significant rise in potassium excretion. There was no increase in plasma active renin concentration during the study period. Noninvasive hemodynamic monitoring revealed no significant changes in heart rate, systemic arterial blood pressure, or echocardiographic left ventricular dimensions. However, invasive measurements using a Swan-Ganz catheter demonstrated falls in mean right atrial and pulmonary artery wedge pressures after UK 69,578. There was no change in cardiac output. Thus, inhibition of endopeptidase 24:11 by UK 69,578 results in significant elevation of plasma ANF, with associated diuresis, natriuresis and venodilatation. The compound was well tolerated in these patients with mild chronic heart failure.     

Thermal hydrotherapy improves quality of life and hemodynamic function in patients with chronic heart failure

Background

Chronic heart failure is characterized by increased peripheral vascular resistance and reduced peripheral perfusion due to adrenergic and renin angiotensin activation and impaired endothelial function. Recent studies have shown that nonpharmacological peripheral vasodilation with thermal therapy by means of warm-water baths and sauna has beneficial effects in chronic heart failure. European hydrotherapy (according to Kneipp) additionally uses short cold water stimuli, which lead to prolonged vasodilation and adaptive responses. Studies on the efficacy of hydrotherapy in chronic heart failure are lacking.

Methods

We studied 15 patients (5 men, 10 women, mean (± SD) age 64.3 ± 1.8 years) with mild chronic heart failure (NYHA functional class II to III, ejection fraction 30%-40%). Patients were randomly assigned to 6 weeks of intensive home-based hydrotherapy or 6 weeks restriction in a crossover intervention trial. Quality of life and heart-failure-related symptoms were assessed by means of a validated questionnaire (PLC). Graded bicycle exercise test with incremental workloads (0, 50, 75, 100 watts) was performed at the end of each treatment period. The hydrotherapeutic program consisted of a structured combination of daily home-based external warm- and cold-water applications.

Results

Baseline characteristics were balanced between the groups. With hydrotherapy, a significant (P ≤ .05) improvement in 3 of 6 dimensions of quality of life (mood, physical capacity, enjoyment) and a significant reduction in heart-failure-related symptoms was found. Heart rates at rest and at 50-Watt workload were significantly reduced by hydrotherapy; blood pressure decreased nonsignificantly at rest and during exercise. The hydrotherapeutic treatment was well accepted and no relevant adverse effects were observed.

Conclusions

A home-based hydrotherapeutic thermal treatment program improves quality of life, heart-failure-related symptoms and heart rate response to exercise in patients with mild chronic heart failure. The results of this investigation suggest a beneficial adaptive response to repeated brief cold stimuli in addition to enhanced peripheral perfusion due to thermal hydrotherapy in patients with chronic heart failure.     

Atrial natriuretic factor improves renal function and lowers systolic blood pressure in renal allograft recipients treated with cyclosporin A.

OBJECTIVE: Atrial natriuretic factor (ANF) has several properties which suggest that it may ameliorate cyclosporin A nephrotoxicity. We therefore investigated the response to a pharmacological dose of ANF in renal transplant recipients treated with cyclosporin A. DESIGN: A single-blind randomized crossover design comparing the renal and haemodynamic effects of D-glucose (placebo) with ANF. METHODS: Seven patients with stable renal function following renal transplantation were studied under maximal water diuresis. Glomerular filtration rate and effective renal plasma flow were estimated from clearances of inulin and para-aminohippurate, respectively. RESULTS: Plasma ANF levels increased significantly in association with increased diuresis and natriuresis. Glomerular filtration rate was unchanged after placebo but increased significantly after ANF fusion. Likewise, effective renal plasma flow increased significantly with ANF infusion. There was a significant fall in systolic blood pressure, with no apparent change in heart rate and diastolic blood pressure. CONCLUSIONS: These results suggest that ANF may have beneficial effects in protecting against cyclosporin A-induced nephrotoxicity and hypertension.     

Diuresis pattern,plasma vasopressin and blood pressure in healthy elderly persons with nocturia and nocturnal polyuria

BACKGROUND: Nocturia, a common symptom in the elderly, is often caused by increased urine production at night. METHODS: The present study comprised 17 men and six women aged 68.1 +/- 4.7 (mean +/- SD) years with nocturia (> or = 2 nocturnal voids) and nocturnal polyuria (nocturnal urinary output of > or = 0.9 mL min(-1)). A physical examination, measurements of recumbent blood pressure after a 15-minute rest, plasma AVP assay at noon and midnight, and urine collection performed during a 24-hour period. RESULTS: The daytime urine output was 1358 +/- 664 mL, and the nocturnal urine output 796 +/- 312 mL. The AVP level was lower at midnight than at noon in 17 persons, and higher at midnight in six persons. Blood pressure was 142.0 +/- 15.7/87.4 +/- 9.1 mmHg. Systolic (but not diastolic) blood pressure increased with decreasing nocturnal plasma AVP. Increasing nocturnal diuresis rate (r2= 0.26; p < 0.01) but not plasma AVP was associated with increasing systolic blood pressure. CONCLUSION: In elderly persons with nocturia and nocturnal polyuria, the plasma AVP is low and does not rise nocturnally. The systolic blood pressure is increased with increasing diuresis but unaffected by plasma AVP.     

Comparative Vascular and Renal Excretory Effects of Atrial Natriuretic Factor,Sodium Nitroprusside and 8-BR-cGMP in Spontaneously Hypertensive Rats

ANF (99–126) (1 μg/kg/min x 30 min iv) lowered BP from 198±3 to 140±4 mmHg (P<.05; N=7), in association with marked diuresis (372.2±33.9 vs 48.2±11.5 μ/kg/min in the control) and natriuresis (62.7±6.4 vs 6.6±1.7 μEq/kg/min) in anesthetized SHR. Concomitantly, great increases in plasma cGMP levels and urinary cGMP excretion occurred. Elevation in plasma cGMP due to ANF persisted in SHR with bilateral nephrectomy. SNP (4 μg/kg/min x 30 min iv) decreased BP from 192±3 to 158±5 mmHg (P<.05; N=7). In contrast to ANF, this occurred without significant changes in urine and sodium excretion; alterations in plasma and urinary cGMP were also absent. Furthermore, 8-Br-cGMP (0.3 mg/kg/min x 30 min iv) also lowered BP from 164±9 to 129±7 mmHg (P<.05; N=6) in the absence of diuresis (8.5±1.3 vs 19.8±4.1 μl/kg/min). Intravenous infusion of 8-Br-cAMP at the same rate did not affect BP and produced a modest but significant increase in sodium and water excretion. Our results indicate that the renal excretory responses to exogenous cGMP or SNP differ from those to ANF. The findings are consistent with a mediating role of cGMP in the vascular but not the renal effects of ANF, since at equally effective hypotensive doses both SNP and 8-Br-cGMP failed to register any significant renal excretory effects.     

心包积液穿刺引流对心钠素释放的影响

目的探讨心包穿刺放液引起的心包腔内压、心房压变化与心房扩张,对心钠素（ＡＮＦ）释放的影响。方法对６例大量心包积液患者进行心包置管引流,记录引流前后的心包腔压力及尿量的变化,测定心包积液与血浆ＡＮＦ浓度。其中一例做血流动力学监测。结果心包穿刺放液前血浆ＡＮＦ低于正常水平,心包液ＡＮＦ高于血浆水平（Ｐ＜０．０５）,放液后心包压、右房压下降,血浆ＡＮＦ反向升高（Ｐ＜０．０５）,２４小时尿量增加,心包液ＡＮＦ明显下降,且低于血浆水平。结论心包积液穿刺放液刺激血浆ＡＮＦ的释放,产生利尿作用。ＡＮＦ的释放依赖于心房的扩张,而不是心房压的升高。心包具有分泌ＡＮＦ功能,其分泌量随心包腔内压增高而增加。     

Involvement of Endogenous Dopamine and Da-1 Receptors in the Renal Effects of Atrial Natriuretic Factor in Rats

The precise mechanism of the diuretic and natriuretic effects of Atrial Natriuretic Factor (ANF) is still unclear. The present study was undertaken with the aim of elucidating the mechanism of interaction between ANF, dopamine (DA) and DA receptors in the renal effects of ANF in rats. In pentobarbital anesthetized rats, ANF infusion (10 µg/kg/hour) produced marked diuresis and natriuresis which was accompanied by significant hypotension, bradycardia and also a modest increase in glomerular filtration rate However, there was no accompanying increase in urinary DA excretion during ANF infusion. Pretreatment with SCH 23390, a selective DA-1 receptor antagonist caused significant attenuation of the diuretic and natriuretic effects of ANF whereas the hemodynamic changes produced by ANF were still evident in SCH 23390 treated animals. Plasma ANF levels were elevated to the same magnitude in both the control and SCH 23390 treated groups. Pretreatment with carbidopa, a dopa decarboxylase inhibitor also significantly blunted the diuretic and natriuretic effects of ANF. The antagonism of the ANF-induced diuresis and natriuresis by SCH 23390 and carbidopa was comparable in magnitude. These results suggest that endogenous DA, via activation of DA-1 receptors plays a permissive role in the renal effects of ANF, perhaps by enhancing tubular responsiveness to ANF. However, there does not appear to be a stimulatory effect of ANF on renal DA production or release.     

Total sympathetic activity and atrial natriuretic factor levels in VVI and DDD pacing with different atrioventricular delays during daily activity and exercise.

The purpose of the study was to assess at rest and during exercise total sympathetic activity, as expressed by plasma cyclic AMP (cAMP) blood levels and sinus node activity (SNA), as well as atrial natriuretic factor (ANF) blood levels in VVI and DDD pacing with long and short atrioventricular delays in DDD paced patients suffering from complete heart block. Clinical parameters, such as exercise time, and arterial blood pressure (ABP) were also taken into consideration. Thirteen patients (six males, mean age 65 +/- 2 years), were examined randomly in VVI and DDD pacing with 100 and 150 ms atrioventricular delays (AVD). Plasma cAMP and ANF were measured at rest, at peak exercise and 15 and 30 min after the test. The cAMP at rest remained unchanged whatever the pacing mode or the AVD, but 30 min after exercise, the cAMP levels were statistically lower in DDD pacing with short AVD (100 ms) than in DDD with long AVD (150 ms) or VVI pacing (cAMP DDD/100 ms: 16 +/- 0.8 pmol.ml-1, cAMP DDD/150 ms: 20 +/- 2 pmol.ml-1, P < 0.01, cAMP VVI: 29 pmol.ml-1, P < 0.001). ANF plasma levels at rest were significantly higher in VVI pacing than in DDD modes, with either long or short AVD (ANF DDD/100 ms: 93 +/- 10 pg.ml-1, ANF DDD/150 ms: 100 +/- 13 pg.ml-1, ANF VVI: 150 +/- 16 pg.ml-1, P < 0.001, P < 0.03 respectively compared to VVI).(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased release of the N-terminus of the atrial natriuretic factor prohormone with increasing absolute atmospheres of pressure in a hyperbaric chamber and reversal with oxygen therapy

Increasing atmospheres of absolute pressure (ATA) on the cardiopulmonary system results in a marked diuresis. The present investigation was designed to determine if the diuresis observed with increasing ATA is associated with increased release of the N-terminus of the atrial natriuretic factor (ANF) prohormone that contains two potent diuresis-producing hormones consisting of amino acids (aa) 1-30 (pro ANF 1-30; long-acting sodium stimulator) and aa 31-67 (pro ANF 31-67; vessel dilator) of this 126 aa prohormone. Seven healthy volunteers (mean age, 31 years) had the circulating concentration of the N-terminus of the ANF prohormone evaluated at 1, 2, and 3 ATA in a monoplace hyperbaric chamber by two specific and sensitive radioimmunoassays that immunologically recognize (1) the whole 98 aa N-terminus and (2) the midportion of the N-terminus consistent with aa 31-67 (pro ANF 31-67). With increasing ATA from 1 (sea level) to 2 (equivalent to 33 feet of sea water), the circulating concentrations of both the whole N-terminus and pro ANF 31-67 increased threefold. At 3 ATA (66 feet of sea water), their circulating concentrations increased sixfold over their concentrations, at 1 ATA. With the addition of 100 percent O2 while at 3 and 2 ATA, the circulating concentrations of both the whole N-terminus and pro ANF 31-67 immediately decreased to their prehyperbaric ATA levels and remained there with further decompression to 1 ATA and removal of O2 supplementation. The increased circulating concentration of the N-terminus of the ANF prohormone containing two peptides with potent diuretic effects during increasing atmospheres of absolute pressure may help to explain the diuresis that has been observed with increasing ATA.     

Effect of sinorphan, an endopeptidase inhibitor on severe congestive cardiac insufficiency]

Sinorphan is a powerful inhibitor of enkephalinases or endopeptidases 24-11, enzymes implicated in the degradation of the atrial natriuretic factor (ANF). In healthy volunteers, it increases plasma concentrations of endogenic ANF and increases diuresis and natriuresis. In order to study the tolerance and biological effects of pharmacological increase of plasma concentrations of endogenic ANF in severe congestive cardiac failure, 12 patients (in functional Classes III or IV of the NYHA classification) were given a single oral dose of 10, 20 or 40 mg of Sinorphan. Sinorphan was clinically well tolerated. The diastolic blood pressure decreased slightly (- 10 +/- 9 mmHg) but significantly (p less than 0.05). Systolic blood pressure and heart rate were unchanged. Despite spontaneously high plasma ANF concentrations (on average 15 times higher than normal subjects), Sinorphan induced an additional increase of 80 to 100% of plasma ANF concentration compared to the initial values (p less than 0.01) with no dose-dependent response for the dosages used. The inhibition of plasma endopeptidase activity attained 47% at the 30th minute. Urinary cyclic GMP excretion increased by 30% at the second hour (p less than 0.05). In addition, a statistically non significant tendency to increase diuresis and natriuresis was observed. These results show that Sinorphan increases plasma ANF concentrations by inhibition of its degradation in severe congestive cardiac failure and that this increase seems to be associated with potentially beneficial biological changes. The concept of endopeptidase inhibition should constitute a new therapeutic approach in cardiac failure, a situation in which the ANF seems to exert a favourable effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal and vascular effects of atrial natriuretic factor during cardiopulmonary bypass.

STUDY OBJECTIVE: To evaluate renal and vasodilator effects of synthetic atrial natriuretic factor (ANF) in patients undergoing cardiopulmonary bypass (CPB) with special reference to the applicability of ANF as a diuretic and natriuretic. DESIGN: The study consisted of two parts. The first 15 consecutive patients in a university hospital received a pharmacologically effective bolus dose of 100 micrograms ANF, as demonstrated previously in other studies, or placebo. After analysis of the bolus data (see "Results" section below), the 12 subsequent patients were administered ANF 50 micrograms as a constant 30-min infusion at a rate of 1.67 micrograms/min or placebo. PATIENTS: The patients were scheduled for elective coronary artery bypass grafting operation. There was no evidence of congestive heart failure in any patient, and no one had an endocrine or renal disorder. INTERVENTIONS: After achievement of hypothermia (29 to 30 degrees C of rectal temperature) during CPB, a bolus dose of ANF 100 micrograms was given or an infusion of ANF 1.67 micrograms/min for 30 min, ie, a total dose of 50 micrograms was started. The control patients received placebo correspondingly. Intravenous fluids were administered according to a predetermined scheme. MEASUREMENTS AND MAIN RESULTS: For the pharmacologic effects of ANF urine volume, urinary sodium excretion and mean arterial pressure (MAP) were measured. Only three of the eight patients receiving the bolus dose of ANF had a diuretic and natriuretic response to the drug, and the responses were significantly related (r = 0.91, p less than 0.05 and r = 0.98, p less than 0.001, respectively) to the prevailing MAP at the time of the bolus administration. The bolus dose of ANF decreased MAP significantly (p less than 0.001 vs placebo) from 65 +/- 6 (mean +/- SEM) to 55 +/- 6 mm Hg within 5 min. The infusion of ANF did not affect MAP, but it increased urine output (16.1 +/- 5.0 ml/min, when the data obtained during the 30-min infusion and a 30-min period after the infusion were combined) and urinary sodium excretion (1,651 +/- 514 microEq/min) significantly (p less than 0.05 and p less than 0.01, respectively) as compared with the corresponding values of 3.3 +/- 1.1 ml/min and 386 +/- 141 microEq/min after placebo. CONCLUSIONS: Prevailing arterial pressure is an important determinant of the diuretic and natriuretic activity of synthetic ANF in patients undergoing CPB. A low-dose infusion of ANF (50 micrograms within 30 min) provides diuresis and natriuresis without significant changes in MAP in these patients.     

Prolonged Low Dose Infusion of Atrial Natriuretic Factor in Essential Hypertension

The C-terminal fragment of atrial natriuretic factor (ANF) was infused intravenously at 0.5 pmol/kg/min during 12 hours in 6 patients with mild to moderate essential hypertension, and in 6 normotensive volunteers, all recumbent and well hydrated, under a daily intake of 200 and 120 mmoles of sodium and potassium, respectively. Plasma C-terminal ANF tended to increase during ANF and to decrease during vehicle infusions. Plasma concentrations of the N-terminal fragment of ANF decreased by 20 to 40% (p < 0.05) during ANF and remained unchanged following vehicle infusion, suggesting that exogenous ANF reduces endogenous ANF secretion. ANF increased significantly plasma cyclic guanosine monophosphate (p < 0.01) from 3.1 ± 0.4 to 4.3 ± 0.8 and from 2.8 ± 0.4 to 5.1 ± 0.5 nmol/L in controls and patients respectively. ANF reduced systolic diastolic blood pressure during the last 8 hours of the infusion, by about 5% (p = 0.055) in patients, but did not alter blood pressure in controls. Sodium excretion during ANF increased 42% vs vehicle (p < 0.05), in the patients group and remained unchanged in controls. Hematocrit levels increased significantly in both groups with ANF infusion. We conclude that a prolonged infusion of ANF at a physiological rate causes a modest increase in plasma cyclic guanosine monophosphate, hemoconcentration, and reduces endogenous ANF secretion. It also stimulates diuresis and natriuresis and slightly reduces systolic blood pressure in patients with essential hypertension.     

A randomized and controlled trial of hydrotherapy in rheumatoid arthritis

Objective . The aim of this study was to evaluate the therapeutic effects of hydrotherapy which combines elements of warm water immersion and exercise. It was predicted that hydrotherapy would result in a greater therapeutic benefit than either of these components separately. Method . One hundred thirty-nine patients with chronic rheumatoid arthritis were randomly assigned to hydrotherapy, seated immersion, land exercise, or progressive relaxation. Patients attended 30-minute sessions twice weekly for 4 weeks. Physical and psychological measures were completed before and after intervention, and at a 3-month followup. Results . All patients improved physically and emotionally, as assessed by the Arthritis Impact Measurement Scales 2 questionnaire. Belief that pain was controlled by chance happenings decreased, signifying improvement. In addition, hydrotherapy patients showed significantly greater improvement in joint tenderness and in knee range of movement (women only). At followup, hydrotherapy patients maintained the improvement in emotional and psychological state. Conclusions . Although all patients experienced some benefit, hydrotherapy produced the greatest improvements. This study, therefore, provides some justification for the continued use of hydrotherapy.     

Glomerular and vascular atrial natriuretic factor receptors in cardiomyopathic hamsters: correlation with the peptide biological effects

STUDY OBJECTIVE--The aim was to study glomerular and vascular atrial natriuretic factor (ANF) receptors and their relationship with the post-receptor effects of the peptide in experimental heart failure. DESIGN--Binding sites ANF were studied in renal glomerular and mesenteric artery membranes. The natriuretic and relaxing effects of ANF were evaluated in the intact animal and in noradrenaline precontracted aortic strips respectively. Plasma and tissue ANF levels were also assessed. EXPERIMENTAL MATERIAL--The study was performed on cardiomyopathic (UM-X7.1) hamsters (n = 15) with a moderate degree of heart failure. Age matched Golden Syriam hamsters (n = 15) were used as controls. MEASUREMENTS AND MAIN RESULTS--Cardiomyopathic hamsters presented lower blood pressure, body weight, and plasma Na+, and higher heart weight than normal hamsters. Plasma ANF (1-98) and (99-126) levels and ventricular ANF content were higher in cardiomyopathic hamster than in controls. ANF and frusemide decreased blood pressure, and increased diuresis and natriuresis in normal hamsters. The blood pressure reduction by ANF in cardiomyopathic hamsters was approximately of the same magnitude as in normal hamsters but their renal response was blunted. The blood pressure lowering effect of frusemide was similar in both cardiomyopathic and normal hamsters, but the diuretic and natriuretic responses were greatly reduced in the former. Glomerular ANF receptor density was higher and receptor affinity was lower in cardiomyopathic hamsters than in controls. Noradrenaline precontracted vascular strips from cardiomyopathic hamster were more sensitive to the relaxant effect of ANF than those from controls. No differences in either density or affinity of vascular receptor were observed. CONCLUSIONS--The results suggest that the renal hyporesponsiveness of cardiomyopathic hamsters to ANF is not due to a down regulation of glomerular ANF receptors. The fact that the natriuretic response to frusemide is also blunted suggest the involvement of other factors.     

Hemodynamic and Renal Effects of Atrial Natriuretic Factor (99-126) in Volume Expanded Sheep

ABSTRACT

The renal and hemodynamic effects of atrial natriuretic factor 99-126 (ANF) were examined in hypervolemic sheep and the results compared to responses previously observed in normal isovolemic sheep. Infusion of 500ml dextran over 60 min increased blood pressure by 6 ± 2 mmHg, associated with increases in cardiac output and stroke volume. No change was seen in heart rate nor total peripheral resistance. Subsequent infusion of ANF at 100 μg/h for 60 min reduced blood pressure by 6 ± 1 mmHg and decreased stroke volume and cardiac output. There was no change in heart rate. Total peripheral resistance decreased slightly, to a similar degree to that seen after control infusion of 500 ml dextran. Moderate increases in urine volume, sodium and chloride excretion were seen after infusion of dextran and subsequent infusion of ANF markedly enhanced these renal effects. The renal changes produced by ANF in volume expanded sheep were significantly greater than those observed in normal sheep. Although normal sheep are more sensitive to the hemodynamic than to the renal effects of ANF, after dextran pretreatment there was enhancement of the renal responses with little change in the effects on blood pressure.     

Effects of atrial natriuretic factor on natriuresis and cGMP in patients with essential hypertension

Human atrial natriuretic factor (h-ANF) or its vehicle only, were infused at rates of 0.8, 1.6 and 3.2 micrograms/min over three successive 30-min periods, into five patients with mild essential hypertension and seven normotensive controls. Baseline (mean +/- s.e.m.) plasma ANF levels were 13 +/- 2 in patients and 8 +/- 1 pg/ml in controls. During the first period, plasma ANF and cyclic guanosine monophosphate (cGMP) levels increased in both groups without significant alteration of blood pressure, heart rate, diuresis, natriuresis or cGMP excretion rate. During the second period of infusion, plasma ANF levels increased up to 179 +/- 39 and 177 +/- 30 pg/ml in patients and controls and plasma cGMP concentrations increased X 5.0 and X 4.9, respectively; natriuresis increased X 2.4 in patients and X 3.1 in controls while urinary cGMP increased X 10.9 in patients and X 10.5 in controls. During the last period, three controls became hypotensive while blood pressure remained stable in the other controls and in the patients with essential hypertension. During this period, the increases in plasma ANF concentration, diuresis, natriuresis and urinary cGMP excretion were similar in both groups. However, the mean plasma cGMP concentration after 90 min infusion was significantly higher in hypertensive patients than in control subjects (30.7 +/- 3.3 versus 15.6 +/- 3.4 pmol/ml, P less than 0.05). The half-life and clearance of plasma ANF, upon discontinuation of the infusion, were similar in both groups. Our data suggest that patients with mild essential hypertension have enhanced increases in plasma cGMP but normal increases in diuresis, natriuresis and cGMP excretion following infusion of h-ANF at pharmacological rates.     

Effects of low-dose epinephrine infusion on cardiovascular and renal responses to water immersion in humans

Elevated plasma epinephrine concentrations may impair blood pressure homeostasis and renal sodium and volume excretion in response to central hypervolemia. We studied the effects of a low-dose epinephrine infusion (12 ng/kg/min) on cardiovascular and renal responses to a thermoneutral head-out water immersion in eleven healthy men.Responses to water immersion without epinephrine were characterized by significant suppression of plasma renin activity (PRA), plasma aldosterone concentration, and renal norepinephrine excretion, and an augmentation of natriuresis and diuresis. Epinephrine infusion, which raised mean plasma epinephrine concentration 4.3-fold, slightly increased plasma norepinephrine and renal norepinephrine excretion, markedly stimulated PRA (+66.7%), but decreased plasma aldosterone (−11.7%), and augmented renal sodium and volume excretion. Despite the presence of the epinephrine infusion, water immersion continued both to suppress PRA and aldosterone, and to increase natriuresis and diuresis in a qualitatively similar pattern. During all conditions blood pressure and heart rate remained unchanged.It is concluded that physiologic responses to central hypervolemia are not impaired at stress levels of circulating epinephrine. During epinephrine infusion, despite a concomitant increase in plasma norepinephrine and a stimulation of PRA, blood pressure remained constant in response to water immersion due to an augmentation of natriuresis and diuresis.     

Shower versus sink bath: evaluation of heart rate, blood pressure, and subjective response of the patient with myocardial infarction

The purpose of this study was to compare the effects of a sitting shower versus a sitting sink bath in low-risk patients with myocardial infarction (MI). Heart rate, blood pressure (mean blood pressure and rate-pressure-product), ratings of perceived exertion, and occurrence of symptoms during the baths and between resting, bathing, and recovery periods were evaluated. Thirty patients with MI were tested during their first and second self-bath on 2 consecutive days between 2 and 9 days after MI. The bathing methods produced significant increases from the resting values in all the variables (p less than or equal to 0.05). No significant differences between the resting and recovery values existed (p greater than 0.05). Ten subjects experienced atypical responses to bathing as indicated by heart rate and blood pressures. Fatigue was the most frequently encountered symptom at rest and during the bathing activities. The findings suggest that low-risk patients with MI can choose between a sitting sink bath or a sitting shower as their first self-bath after MI, based on preferences. However, because the bathing activity (and not the bathing method) did produce some atypical responses in one third of the subjects, readiness to engage in bathing activities should be individually assessed by objective and subjective criteria.