Tumour biomarkers: association with heart failure outcomes.

BACKGROUND: There is increasing recognition that heart failure (HF) and cancer are conditions with a number of shared characteristics. OBJECTIVES: To explore the association between tumour biomarkers and HF outcomes. METHODS: In 2,079 patients of BIOSTAT-CHF cohort, we measured six established tumour biomarkers: CA125, CA15-3, CA19-9, CEA, CYFRA 21-1 and AFP. RESULTS: During a median follow-up of 21 months, 555 (27%) patients reached the primary end-point of all-cause mortality. CA125, CYFRA 21-1, CEA and CA19-9 levels were positively correlated with NT-proBNP quartiles (all P < 0.001, P for trend < 0.001) and were, respectively, associated with a hazard ratio of 1.17 (95% CI 1.12-1.23; P < 0.0001), 1.45 (95% CI 1.30-1.61; P < 0.0001), 1.19 (95% CI 1.09-1.30; P = 0.006) and 1.10 (95% CI 1.05-1.16; P < 0.001) for all-cause mortality after correction for BIOSTAT risk model (age, BUN, NT-proBNP, haemoglobin and beta blocker). All tumour biomarkers (except AFP) had significant associations with secondary end-points (composite of all-cause mortality and HF hospitalization, HF hospitalization, cardiovascular (CV) mortality and non-CV mortality). ROC curves showed the AUC of CYFRA 21-1 (0.64) had a noninferior AUC compared with NT-proBNP (0.68) for all-cause mortality (P = 0.08). A combination of CYFRA 21-1 and NT-proBNP (AUC = 0.71) improved the predictive value of the model for all-cause mortality (P = 0.0002 compared with NT-proBNP). CONCLUSIONS: Several established tumour biomarkers showed independent associations with indices of severity of HF and independent prognostic value for HF outcomes. This demonstrates that pathophysiological pathways sensed by these tumour biomarkers are also dysregulated in HF.

Novel endotypes in heart failure: effects on guideline-directed medical therapy.

Aims: We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains. Methods and results: We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1-1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10-1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort. Conclusion: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.

Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study.

INTRODUCTION: Despite clear guidelines recommendations, most patients with heart failure and reduced ejection-fraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers. METHODS AND RESULTS: BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centres in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n = 151) and patients with a LVEF > 40% (n = 242) were excluded. Median follow up was 21 months. We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50-99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43-2.01; for beta-blocker: HR 1.70; 95% CI 1.36-2.05). CONCLUSION: Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%.

Modulation of the renin-angiotensin-aldosterone system in heart failure.

The renin-angiotensin-aldosterone system (RAAS) is well-established and continues to be pursued as a therapeutic target in the treatment of heart failure, predominantly due to the success of agents that block RAAS in clinical trials of systolic heart failure. The optimal treatment of heart failure patients with preserved ejection fraction (HFpEF), however, remains unclear. Early trials of direct renin inhibitors have suggested that these agents may play a role in HFpEF, but recent clinical trial results have not been encouraging. Preliminary trials of angiotensin-receptor/neprilysin inhibitors look promising. Whether results with these or other drugs will alter current recommendations remains to be seen. In this review, we assess the current understanding of the role of RAAS modulation in heart failure.

Effectiveness of out-patient based acute heart failure care: a pilot randomised controlled trial.

OBJECTIVES: Acute heart failure (AHF) hospitalisation is associated with 10% mortality. Outpatient based management (OPM) of AHF appeared effective in observational studies. We conducted a pilot randomised controlled trial (RCT) comparing OPM with standard inpatient care (IPM). METHODS: We randomised patients with AHF, considered to need IV diuretic treatment for ≥2 days, to IPM or OPM. We recorded all-cause mortality, and the number of days alive and out-of-hospital (DAOH). Quality of life, mental well-being and Hope scores were assessed. Mean NHS cost savings and 95% central range (CR) were calculated from bootstrap analysis. Follow-up: 60 days. RESULTS: Eleven patients were randomised to IPM and 13 to OPM. There was no statistically significant difference in all-cause mortality during the index episode (1/11 vs 0/13) and up to 60 days follow-up (2/11 vs 2/13) [p = .86]. The OPM group accrued more DAOH {47 [36,51] vs 59 [41,60], p = .13}. Two patients randomised to IPM (vs 6 OPM) were readmitted [p = .31]. Hope scores increased more with OPM within 30 days but dropped to lower levels than IPM by 60 days. More out-patients had increased total well-being scores by 60 days (p = .04). OPM was associated with mean cost savings of £2658 (95% CR 460-4857) per patient. CONCLUSIONS: Patients with acute HF randomised to OPM accrued more days alive out of hospital (albeit not statistically significantly in this small pilot study). OPM is favoured by patients and carers and is associated with improved mental well-being and cost savings.

Prevention and early treatment of the long-term physical effects of COVID-19 in adults: design of a randomised controlled trial of resistance exercise-CISCO-21.

BACKGROUND: Coronavirus disease-19 (COVID-19) infection causes persistent health problems such as breathlessness, chest pain and fatigue, and therapies for the prevention and early treatment of post-COVID-19 syndromes are needed. Accordingly, we are investigating the effect of a resistance exercise intervention on exercise capacity and health status following COVID-19 infection. METHODS: A two-arm randomised, controlled clinical trial including 220 adults with a diagnosis of COVID-19 in the preceding 6 months. Participants will be classified according to clinical presentation: Group A, not hospitalised due to COVID but persisting symptoms for at least 4 weeks leading to medical review; Group B, discharged after an admission for COVID and with persistent symptoms for at least 4 weeks; or Group C, convalescing in hospital after an admission for COVID. Participants will be randomised to usual care or usual care plus a personalised and pragmatic resistance exercise intervention for 12 weeks. The primary outcome is the incremental shuttle walks test (ISWT) 3 months after randomisation with secondary outcomes including spirometry, grip strength, short performance physical battery (SPPB), frailty status, contacts with healthcare professionals, hospitalisation and questionnaires assessing health-related quality of life, physical activity, fatigue and dyspnoea. DISCUSSION: Ethical approval has been granted by the National Health Service (NHS) West of Scotland Research Ethics Committee (REC) (reference: GN20CA537) and recruitment is ongoing. Trial findings will be disseminated through patient and public forums, scientific conferences and journals. TRIAL REGISTRATION: ClinicialTrials.gov NCT04900961 . Prospectively registered on 25 May 2021.

Dysglycaemia and the risk of acute myocardial infarction in multiple ethnic groups: an analysis of 15,780 patients from the INTERHEART study.

AIMS/HYPOTHESIS: Although diabetes is an established risk factor for myocardial infarction (MI), disease control may vary. HbA(1c) is a reliable index of ambient glucose levels and may provide more information on MI risk than diabetes status. METHODS: The relationship between HbA(1c) levels in MI patients and controls who participated in the 52 country INTERHEART study was analysed. RESULTS: In 15,780 participants with a HbA(1c) value (1,993 of whom had diabetes), the mean (SD) levels for HbA(1c) were 6.15% (1.10) in the 6,761 MI patients and 5.85% (0.80) in the control participants. After adjustment for age, sex and nine major MI risk factors (including diabetes), higher HbA(1c) fifths above the lowest fifth (HbA(1c) <5.4%) were associated with progressively higher OR of MI, with OR for the highest HbA(1c) fifth (≥ 6.12%) being 1.55 (95% CI 1.37-1.75). When analysed as a continuous variable after adjustment for the same factors, every 1% higher HbA(1c) value was associated with 19% (95% CI 14-23) higher odds of MI, while every 0.5% higher HbA(1c) was associated with 9% higher odds of MI (95% CI 7-11). Concordant relationships were noted across subgroups, with a higher OR noted in younger people, patients without diabetes or hypertension, and those from some regions and ethnicities. CONCLUSIONS/INTERPRETATION: The HbA(1c) value provides more information on MI odds than self-reported diabetes status or many other established risk factors. Every 1% increment independently predicts a 19% higher odds of MI after accounting for other MI risk factors including diabetes.

More than skin deep: atherosclerosis as a systemic manifestation of psoriasis.

There is now growing evidence that psoriasis, like other inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus, is a systemic disorder that is associated with enhanced atherosclerosis and risk of coronary artery disease. Here we summarize the available epidemiological evidence for this association and analyse pathogenic features that are common to psoriasis and atherosclerosis. Further prospective studies are urgently needed to extend knowledge of the risk of cardiovascular morbidity and mortality in patients with psoriasis and to confirm the degree to which treatment of psoriasis reduces this risk. Nevertheless, existing data are sufficient to indicate that severe psoriasis should be more widely recognized as a potential risk factor for cardiovascular disease and should be considered with the established factors when formulating strategies for the management of cardiovascular risk.

Sacubitril and valsartan fixed combination to reduce heart failure events in post-acute myocardial infarction patients.

Heart failure is a term used to define a constellation of symptoms and signs that are commonly attributed to the inability of the heart to produce a cardiac output that meets the demands of the body. It remains a deadly disease, affecting between 1-2% of the population, and is more common in the elderly, with around 6-10% of patients over 65 suffering from the condition. Sacubitril/valsartan (LCZ-696) is a combined neprilysin inhibitor and angiotensin AT1 receptor blocker approved in recent years for the treatment of chronic heart failure with reduced ejection fraction. In an area where there have been limited pharmacological advances in the last 10 years, this drug was a game changer and a much welcomed addition to contemporary heart failure therapy. It is currently being studied in patients with heart failure with preserved ejection fraction and for the reduction of heart failure events post-acute myocardial infarction. Results from the ongoing PARADISE-MI study are awaited by the global cardiology community with great interest.

Rehabilitation Enablement in Chronic Heart Failure-a facilitated self-care rehabilitation intervention in patients with heart failure with preserved ejection fraction (REACH-HFpEF) and their caregivers: rationale and protocol for a single-centre pilot randomised controlled trial.

INTRODUCTION: The Rehabilitation EnAblement in CHronic Heart Failure in patients with Heart Failure (HF) with preserved ejection fraction (REACH-HFpEF) pilot trial is part of a research programme designed to develop and evaluate a facilitated, home-based, self-help rehabilitation intervention to improve self-care and quality of life (QoL) in heart failure patients and their caregivers. We will assess the feasibility of a definitive trial of the REACH-HF intervention in patients with HFpEF and their caregivers. The impact of the REACH-HF intervention on echocardiographic outcomes and bloodborne biomarkers will also be assessed. METHODS AND ANALYSIS: A single-centre parallel two-group randomised controlled trial (RCT) with 1:1 individual allocation to the REACH-HF intervention plus usual care (intervention) or usual care alone (control) in 50 HFpEF patients and their caregivers. The REACH-HF intervention comprises a REACH-HF manual with supplementary tools, delivered by trained facilitators over 12 weeks. A mixed methods approach will be used to assess estimation of recruitment and retention rates; fidelity of REACH-HF manual delivery; identification of barriers to participation and adherence to the intervention and study protocol; feasibility of data collection and outcome burden. We will assess the variance in study outcomes to inform a definitive study sample size and assess methods for the collection of resource use and intervention delivery cost data to develop the cost-effectiveness analyses framework for any future trial. Patient outcomes collected at baseline, 4 and 6 months include QoL, psychological well-being, exercise capacity, physical activity and HF-related hospitalisation. Caregiver outcomes will also be assessed, and a substudy will evaluate impact of the REACH-HF manual on resting global cardiovascular function and bloodborne biomarkers in HFpEF patients. ETHICS AND DISSEMINATION: The study is approved by the East of Scotland Research Ethics Service (Ref: 15/ES/0036). Findings will be disseminated via journals and presentations to clinicians, commissioners and service users. TRIAL REGISTRATION NUMBER: ISRCTN78539530; Pre-results .

Regulation of local tissue-type plasminogen activator release by endothelium-dependent and endothelium-independent agonists in human vasculature.

OBJECTIVES: This study sought to define the local regulation of vascular tissue-type plasminogen activator (t-PA) release. BACKGROUND: The vascular endothelium, through the production of t-PA and plasminogen activator inhibitor (PAI-1), is an important regulator of fibrinolysis. Plasma t-PA levels increase in response to adrenergic stimulation; however, it is unclear whether this increase is the result of systemic reflex responses or direct effects on the vascular endothelium. METHODS: Forearm blood flow dose responses were generated to low doses of agonist infused directly into the brachial artery in 15 normotensive men (mean [+/-SE] age 28.9 +/- 2.2 years). Simultaneous arterial and venous blood samples were drawn at baseline and in response to the intraarterial administration of isoproterenol (400 ng/min), methacholine (8 microg/min) and sodium nitroprusside (SNP) (8 microg/min). PAI-1 and t-PA antigen levels were measured by enzyme-linked immunosorbent assay, and the net release across the forearm was calculated. RESULTS: Forearm plasma flow increased significantly from baseline (1.4 +/- 0.2 ml/100 ml per min) after administration of isoproterenol, methacholine and SNP (9.7 +/- 1.9, 8.7 +/- 1.9 and 6.7 +/- 1.1 ml/100 ml per min, respectively) (p < 0.001 by analysis of variance). Baseline net t-PA release (0.7 +/- 0.3 ng/100 ml per min) increased significantly after administration of isoproterenol (26.2 +/- 11.6 ng/100 ml per min, p = 0.005) and methacholine (15.3 +/- 5.5 ng/100 ml per min, p = 0.001) but not after administration of SNP (1.8 +/- 2.2 ng/100 ml per min, p = 0.84). There was no net release of PAI-1 across the vascular bed. CONCLUSIONS: Marked, rapid local t-PA release occurred in response to isoproterenol, a beta-adrenoceptor agonist, and methacholine, an endothelium-dependent nitric oxide agonist, in the human forearm. This effect was selective and independent of the effects of shear stress due to increased flow because SNP induced similar increases in forearm blood flow without affecting t-PA release. Vascular t-PA release may be a potentially valuable tool for evaluating endothelial function in diseases associated with increased risk of thrombosis.

Attitudes of medical students towards euthanasia in a multicultural setting.

A cross-sectional survey of 400 medical students of multicultural backgrounds at the University of Malaya was conducted to understand their attitudes towards euthanasia and factors related to medical decisions and ethical reasoning concerning the prolongation of life, the right to die and euthanasia. The student respondents completed self-administered questionnaires that comprised of twelve questions with multiple stems addressing personal perceptions, knowledge, attitudes, and decisions about euthanasia and the relief of suffering. The majority of respondents (52%) were for the withdrawal of active therapy in a patient suffering from a terminal painful disease while 48% of them were against it. Seventy-one percent of the students involved in the study were against the idea of active euthanasia i.e. the administration of a lethal injection. However, 27% of the respondents felt that there was a moral justification to assist patients to die. Thirty-two percent of the respondents favoured the legalization of euthanasia in Malaysia while 67% of them were strongly against it. The majority (61%) of respondents would not practice euthanasia as a doctor nor would they have performed on themselves if or when it became legal. The main issue surrounding euthanasia that concerned the respondents was the misuse of it by unethical practitioners and they felt that further debate on the matter was essential, both within the local and international communities.

Natriuretic response to neutral endopeptidase inhibition is blunted by enalapril in healthy men.

We studied six healthy male subjects in a randomized, placebo-controlled, single-blind fashion to determine the comparative effects on renal hemodynamics and natriuresis of the angiotensin-converting enzyme inhibitor enalapril (5 mg on each of 5 days preceding the study), the neutral endopeptidase inhibitor candoxatrilat (200 mg IV), and the combination of enalapril and candoxatrilat. Enalapril pretreatment alone, compared with placebo, produced slight nonsignificant increments in absolute and fractional sodium excretions and a marked increase in effective renal plasma flow but no change in glomerular filtration rate. Candoxatrilat alone produced marked augmentation of both absolute and fractional sodium excretions. The candoxatrilat-mediated increment in absolute sodium excretion was significantly correlated with increases in urinary cGMP and plasma atrial natriuretic peptide in response to this drug, but neither effective renal plasma flow nor glomerular filtration rate was altered compared with placebo. Combining enalapril pretreatment with candoxatrilat significantly attenuated the increments in absolute and fractional sodium excretions in response to the neutral endopeptidase inhibitor. Blood pressure was reduced by enalapril alone compared with placebo, whereas candoxatrilat treatment alone led to a marginal but significant enhancement of blood pressure. The combination of enalapril and candoxatrilat abolished any significant blood pressure change compared with placebo. Thus, candoxatrilat-mediated natriuresis occurs via a renal tubular rather than glomerular mechanism and is blunted by enalapril. This attenuation by enalapril may occur by interference with angiotensin II-dependent effects on the renal tubule or on systemic blood pressure.

Sympathoinhibitory response to clonidine is blunted in patients with heart failure.

To determine whether alpha2-adrenergic-mediated sympathoinhibition was altered in chronic heart failure, sympathoinhibitory sensitivity was assessed using the alpha2-adrenergic agonist clonidine in 7 patients with heart failure and in 10 healthy control subjects. Basal norepinephrine spillover was significantly higher in patients with heart failure (1.3+/-0.3 microg/min) than in control subjects (0.7+/-0.1 microg/min, P=.05). Compared with control subjects, the decrement in norepinephrine spillover to cumulative doses of clonidine (1, 2, and 3 microg/kg administered intravenously) was significantly less in patients with heart failure (P<.05). Blood pressure also tended to decrease less in patients with heart failure (P=.06). The doses of clonidine required to produce a 10% decrease in blood pressure and a 25% decrease in norepinephrine spillover were significantly higher in heart failure (P<.01 and P=.05, respectively). Thus, although clonidine lowers norepinephrine spillover significantly in patients with heart failure, such patients are less sensitive to clonidine than healthy control subjects. This difference in sensitivity suggests that doses of clonidine provide effective sympathoinhibition will need to be selected for studies that will evaluate the potential therapeutic effect of clonidine in heart failure.

Blunted blood pressure response to central sympathoinhibition in normotensive blacks: increased importance of nonsympathetic factors in blood pressure maintenance in blacks.

Enhanced sympathetic reactivity may predispose blacks to the development of hypertension and may occur because of increased sympathetic stimulation and/or attenuated sympathoinhibition. A potential site for such attenuated sympathetic inhibition may be at the level of central alpha2-adrenergic receptors, which play an important role in the feedback inhibition of norepinephrine release. We used cumulative doses (1, 2, and 3 microg/kg I.V.) of the centrally acting alpha2-adrenergic agonist clonidine to measure the sensitivity of alpha2-adrenoceptor-mediated sympathoinhibition and the resultant hypotensive response in 8 normotensive blacks and 10 normotensive whites. Sympathetic activity was determined by radioisotope dilution methodology. Basal norepinephrine spillover was similar in blacks (0.80+/-0.14 microg/min) and whites (0.73+/-0.19 microg/min, P=NS) and after clonidine decreased significantly in both blacks (0.21+/-0.07 microg/min, P<.0001) and whites (0.24+/-0.06 microg/min, P<.0001), with no difference between the groups (P=NS). Despite this similar degree of sympathoinhibition, the hypotensive response to clonidine was markedly blunted in blacks, such that mean arterial pressure decreased by only 10% in blacks but by 21% in whites (P<.0001). The smaller blood pressure decrement after clonidine in normotensive blacks, in the face of an equal degree of sympathoinhibition, suggests that even when sympathetic tone is decreased to the same level in blacks and whites, normotensive blacks have less reduction in blood pressure than whites, implying that nonadrenergic mechanisms contribute more to blood pressure maintenance in blacks than whites. Whether a similar interethnic difference in response to sympathoinhibition occurs in hypertensive patients is as yet unknown.

Hypertension in black people: study of specific genotypes and phenotypes will provide a greater understanding of interindividual and interethnic variability in blood pressure regulation than studies based on race.

Hypertension is more frequent and more severe in some Black populations. Although many studies have focused on hypertension in black people in an attempt to understand the genetic and environmental factors that regulate blood pressure, this approach has not been productive. Study of the relationship between specific phenotypes and genotypes, both within and across ethnic groups, is more likely to advance our understanding of the regulation of blood pressure than studies focused on race and blood pressure.

Dose-ranging effects of candoxatril on elimination of exogenous atrial natriuretic peptide in chronic heart failure.

Seven patients with chronic heart failure were treated in single-blind crossover fashion with placebo and 10 mg, 50 mg, and 200 mg doses of the neutral endopeptidase inhibitor candoxatril to determine the effects of candoxatril on the elimination kinetics of exogenously infused atrial natriuretic peptide (ANP). An incremental dose-response effect was observed on the mean maximum observed plasma concentration (Cmax) of the active metabolite candoxatrilat (107.4, 453.5, and 1584 ng/ml in response to 10, 50, and 200 mg candoxatril, respectively). Pooled active versus placebo comparisons showed that candoxatril reduced the clearance (p = 0.021) and elimination rate constant (p = 0.006) and increased Cmax (p = 0.002) and time to reach Cmax (p = 0.01) of exogenous ANP. Individually, both 50 mg and 200 mg but not 10 mg candoxatril significantly altered the elimination kinetics of ANP. The most favorable effects were observed in response to 200 mg candoxatril, although even this dose may not have achieved the maximal modulating effect on elimination of circulating ANP.

The differential effects of circulating norepinephrine and neuronally released norepinephrine on sodium excretion in humans.

The renal effects of incremental infusions of norepinephrine (placebo, 0.025 mu/kg/min), 0.075 micrograms/kg/min, phenylephrine (placebo, 0.5 micrograms/kg/min, 2.5 micrograms/kg/min), and tyramine (placebo, 2 micrograms/kg/min, 15 micrograms/kg/min) were examined in three respective groups (n = 9, 8, and 8) of normotensive male subjects undergoing water diuresis. Tyramine is an indirect sympathetic agent that causes neuronal release of endogenous norepinephrine. Increases in mean arterial pressure during each high-dose infusion were comparable in all three groups. Both norepinephrine and phenylephrine caused a decrease in urinary sodium excretion and effective renal plasma flow, with no changes in glomerular filtration rate. Proximal tubular sodium reabsorption, as assessed by both lithium clearance and solute-free water clearance methods, was increased by pressor doses of norepinephrine and phenylephrine. In contrast, a similar pressor dose of tyramine was associated with a pressure natriuresis, an increase in effective renal plasma flow, and a decrease in proximal tubular sodium reabsorption. Our data indicate that, in normotensive humans, circulating catecholamines (norepinephrine and phenylephrine) have opposite effects on renal sodium handling from neuronally released norepinephrine (tyramine).