N-terminal proBNP and mortality in hospitalised patients with heart failure and preserved vs. reduced systolic function: data from the prospective Copenhagen Hospital Heart Failure Study (CHHF).

UNLABELLED: Preserved systolic function among heart failure patients is a common finding, a fact that has only recently been fully appreciated. The aim of the present study was to examine the value of NT-proBNP to predict mortality in relation to established risk factors among consecutively hospitalised heart failure patients and secondly to characterise patients in relation to preserved and reduced systolic function. MATERIAL: At the time of admission 2230 consecutively hospitalised patients had their cardiac status evaluated through determinations of NT-proBNP, echocardiography, clinical examination and medical history. Follow-up was performed 1 year later in all patients. RESULTS: 161 patients fulfilled strict diagnostic criteria for heart failure (HF). In this subgroup of patients 1-year mortality was approximately 30% and significantly higher as compared to the remaining non-heart failure population (approx. 16%). Using univariate analysis left ventricular ejection fraction (LVEF), New York Heart Association classification (NYHA) and plasma levels of NT-proBNP all predicted mortality independently. However, regardless of systolic function, age and NYHA class, risk-stratification was provided by measurements of NT-proBNP. Having measured plasma levels of NT-proBNP, LVEF did not provide any additional prognostic information on mortality among heart failure patients (multivariate analysis). CONCLUSION: The results show that independent of LVEF, measurements of NT-proBNP add additional prognostic information. It is concluded that NT-proBNP is a strong predictor of 1-year mortality in consecutively hospitalised patients with heart failure with preserved as well as reduced systolic function.

Cardiogenic shock complicating acute myocardial infarction; prognostic impact of early and late shock development.

AIMS: Cardiogenic shock accounts for the majority of deaths following acute myocardial infarction. The majority of outcome data on this issue are, however, derived from single hospitals, referral centers or selected patients in randomized studies. The purpose of this study was to investigate incidence, outcome and prognostic significance of cardiogenic shock in 6676 consecutive patients with acute myocardial infarction. METHODS AND RESULTS: Demographic and clinical data including the presence of cardiogenic shock were prospectively collected in 6676 non-invasively managed patients with myocardial infarction consecutively admitted to 27 different hospitals during a 2-year period. Six-year mortality data were collected in 99.9% of the population. Cardiogenic shock developed in 444 patients (6.7%). In 59% of these patients cardiogenic shock developed within 48 h, 11% developed shock during days 3 and 4 and 30% later than 4 days after the infarction. Thirty-day and 6-year mortality was 62 and 88% among shock patients compared to 9 and 45% in non-shock patients. Patients with early shock development (days 1-2) had a significantly lower 30-day mortality (45%) than those with intermediate or late shock development (>80%) (P<0.05). In 30-day survivors, survival the following years was lower than in patients without cardiogenic shock but with post-infarction heart failure. CONCLUSIONS: In this nationwide prospectively collected registry, non-invasively managed consecutive myocardial infarct patients with cardiogenic shock had an extremely reduced life expectancy. Every attempt to improve treatment, prevention and identification of patients at risk of shock development should be strongly encouraged.

Effect of early revascularisation in cardiogenic shock complicating acute myocardial infarction. A single center experience.

BACKGROUND: Five to 10% of patients with acute myocardial infarction develop cardiogenic shock and the majority of these patients are expected to die within the first few weeks. In this study, we review our recent experience in the management of patients with cardiogenic shock complicating MI and examine the effect of early invasive revascularisation on mortality. METHODS: Thirty-six consecutive patients who developed cardiogenic shock less than 48 h after MI were retrospectively evaluated and divided into two treatment groups. One group received early invasive revascularisation (n=24) and the other group had no early invasive revascularisation, but received similar conventional intensive care medical treatment (n=12). RESULTS: Baseline characteristics and hemodynamic variables were similar in both groups. Apart from invasive revascularisation and the use of intra aortic balloon counterpulsation (IABP), treatment strategies did not differ between the two groups. Thirty-day mortality was 21% in the revascularised group of patients and 58% in the non-revascularised group (P<0.05). CONCLUSIONS: Our data support previous observations suggesting that an aggressive treatment strategy including early invasive revascularisation and IABP is associated with improved short and long-term survival in patients with cardiogenic shock. Since early revascularisation appears safe with a considerable treatment benefit, this approach must be considered in patients with short shock duration early after MI.

NT-proBNP: a new diagnostic screening tool to differentiate between patients with normal and reduced left ventricular systolic function.

OBJECTIVE: To evaluate whether measurements of N-terminal pro-brain natriuretic peptide (NT-proBNP) can be used to differentiate patients with normal and reduced left ventricular ejection fraction (LVEF) in an unselected consecutive group of hospital inpatients. SETTING: City general hospital, Copenhagen, Denmark. PATIENTS AND DESIGN: During a 10 month period 2230 admissions to a city general hospital (80% of targeted patients) had an echocardiographic evaluation of left ventricular function, a comprehensive clinical evaluation, and blood analysis of N-terminal-pro-brain natriuretic peptide (NT-proBNP) within 24 hours of admission. Exclusions resulted from lack of informed consent or failure to obtain the required evaluations before death or discharge from hospital. Echocardiography was unsatisfactory in 37 patients, so the final number studied was 2193. RESULTS: A raised NT-proBNP (>or= 357 pmol/l) identified patients with an LVEF of 40% was more than 97%. This probability rapidly decreased to 70% as the measured NT-proBNP increased to 150% of the predicted value. CONCLUSIONS: A single measurement of NT-proBNP at the time of hospital admission provides important information about LVEF in unselected patients.

Cerebral blood flow in patients with chronic heart failure before and after heart transplantation.

BACKGROUND AND PURPOSE: Arterial blood pressure and cardiac output are often reduced in patients with chronic heart failure (CHF). Counterregulatory mechanisms with increased neurohormonal activation and changes in the distribution of cardiac output are assumed to secure vital organ perfusion. However, clinical examination of patients with CHF frequently reveals neurological symptoms with dizziness and memory problems, suggesting altered brain perfusion. In this study we determined whether cerebral blood flow (CBF) is reduced in patients with New York Heart Association (NYHA) functional class III and IV (n=12) compared with healthy control subjects (n=12). Furthermore, we examined whether heart transplantation (n=5) could restore CBF. METHODS: CBF was estimated by single-photon emission computed tomography and (133)Xe as tracer, and middle cerebral artery velocity was measured by transcranial Doppler ultrasound. RESULTS: In the CHF patients, CBF was 36+/-1 mL/min per 100 g, corresponding to a 31% reduction compared with the control group (52+/-5 mL/min per 100 g) (P<0.05). After heart transplantation, CBF increased from 35+/-3 mL/min per 100 g before transplantation to 50+/-3 mL/min per 100 g within the first postoperative month (P<0.05). CONCLUSIONS: We conclude that CBF is substantially, but reversibly, reduced in patients with NYHA class III/IV heart failure. This phenomenon suggests that redistribution of cardiac output inadequately secures brain perfusion in patients with severe CHF.

Endothelium-dependent vasorelaxation in inhibited by in vivo depletion of vascular thiol levels: role of endothelial nitric oxide synthase.

Thiols like glutathione may serve as reducing cofactors in the production of nitric oxide (NO) and protect NO from inactivation by radical oxygen species. Depletion of thiol compounds reduces NO-mediated vascular effects in vitro and in vivo. The mechanisms underlying these actions are not clear, but may involve decreased synthesis of NO and/or increased degradation of NO. This study investigates the effect of glutathione depletion on the response to NO-mediated vasodilation induced by acetylcholine (Ach, 10 micrograms/kg), endothelial NO synthase (eNOS) activity and potential markers of vascular superoxide anion (O2.-) production in conscious chronically catheterized rats. Thiol depletion induced by buthionine sulfoximine (BSO, 1 g i.p. within 24 h) decreased the hypotensive effect of Ach by 30% (MAP reduction before BSO 27 +/- 3 mmHg, 19 +/- 3 mmHg after BSO, (mean +/- SEM), p < .05, n = 8). The impaired effect of Ach was associated with a significant reduction in eNOS activity (control: 7.7 +/- 0.8, BSO: 3.9 +/- 0.4 pmol/min/mg protein (p < .05), n = 6). In contrast, neither NADH/NADPH driven membrane-associated oxidases nor lucigenin reductase activity were significantly (p < .05) affected by BSO (BSO: 4415 +/- 123, control: 4105 +/- 455 counts/mg; n = 6) in rat aorta. It is concluded that in vivo thiol depletion results in endothelial dysfunction and a reduced receptor-mediated vascular relaxation. This effect is caused by reduced endothelial NO formation.

Tetrahydrobiopterin improves endothelium-dependent vasodilation in nitroglycerin-tolerant rats.

Tolerance to nitroglycerin is caused by a nitroglycerin-mediated increase in vascular superoxide anion production. Administration of tetrahydrobiopterin (co-factor for endogenous nitric oxide (NO) formation) may potentially influence nitroglycerin tolerance in at least two different ways. Firstly, tetrahydrobiopterin may act as a scavenger of the nitroglycerin-mediated production of superoxide anions. Secondly, tetrahydrobiopterin may protect endothelial NO synthesis from the deleterious effects of increased oxidative stress. This study investigates whether in vivo nitroglycerin tolerance is affected by tetrahydrobiopterin supplementation and assesses the in vivo role of tetrahydrobiopterin in endogenous NO-mediated vasodilation in normal and nitroglycerin-tolerant rats. The results show that tetrahydrobiopterin does not affect nitroglycerin-derived, NO-mediated vasodilation, but reduces baseline mean arterial blood pressure (by 8 mm Hg, P<0.05) and normalizes endothelium-dependent responses to N(G)-monomethyl-L-arginine (L-NMMA) (from 7+/-1 to 22+/-4 mm Hg, P<0.05) in nitroglycerin-tolerant rats. It is concluded that altered bioavailability of tetrahydrobiopterin is involved in the pathophysiology of endothelial dysfunction seen in nitroglycerin tolerance.

Autoregulation of cerebral blood flow in patients resuscitated from cardiac arrest.

BACKGROUND AND PURPOSE: Under normal circumstances, autoregulation maintains cerebral blood flow (CBF) constant within a wide range of mean arterial pressure (MAP). It remains unknown whether patients resuscitated from cardiac arrest have preserved CBF autoregulation. In this study, CBF autoregulation was investigated within the first 24 hours after resuscitation from cardiac arrest. METHODS: Eighteen patients and 6 healthy volunteers had relative changes in CBF determined by transcranial Doppler mean flow velocity (V(mean)) in the middle cerebral artery during a stepwise rise in MAP by use of norepinephrine infusion. V(mean) was plotted against MAP, and a lower limit of autoregulation was identified by double regression analysis based on the least-squares method. RESULTS: In patients, V(mean) increased from a median of 33 (range 19 to 73) to 37 (22 to 100) cm/s (P:<0.001) during a norepinephrine-induced rise in MAP from 78 (46 to 118) to 106 (60 to 149) mm Hg. Eight of 18 patients had impaired CBF autoregulation, and in 5 of the 10 patients with preserved CBF autoregulation, the lower limit of autoregulation could be identified. The lower limit of CBF autoregulation was 76 mm Hg (41 to 105 mm Hg) in the volunteers and 114 mm Hg (80 to 120 mm Hg) in the 5 patients with preserved autoregulation (P:<0.01). CONCLUSIONS: We conclude that in a majority of patients in the acute phase after cardiac arrest, cerebral autoregulation is either absent or right-shifted. These results indicate that MAP should be kept at a higher level than commonly accepted to secure cerebral perfusion. We recommend, however, that further randomized clinical trials are performed to determine whether sympathomimetic drugs improve neurological outcome.

[Heart transplantation]. / Hjertetransplantation.

In carefully selected patients with end-stage heart failure heart transplantation has developed from an experimental procedure to standard therapy during the last 30 years. It is currently accepted as a procedure for prolonging life and also for improving quality of life. According to the Registry of the International Society for Heart and Lung Transplantation the overall one-year actuarial survival is 79% and 10-year survival barely 50%. Nine years after the start of the Heart Transplant Program at Rigshospitalet the overall actuarial survival of 157 consecutive patients is 66%. Due to the limited donor access a decline of heart transplant recipients has been recorded during the late nineties. Mechanical replacement of the heart may develop from technological advances and possibly this therapy may gain a complementary status in heart failure, however the human biological replacement is currently the standard.

[Cardiogenic shock in acute myocardial infarction. Time for a more aggressive therapeutic strategy?]. / Kardiogent shock ved akut myokardieinfarkt. Tid til en mere aggressiv behandlingsindstilling?

Cardiogenic shock following acute myocardial infarction results in the death of most affected individuals. Longitudinal data suggest that in spite of modern pharmacological inotropic support and thrombolytic regimes, survival from cardiogenic shock has not improved during the last several decades. However, recent observational and limited randomized trial data indicate that some of these high risk patients may derive particular benefit from aggressive percutaneous or surgical revascularisation procedures. This review analyses currently available treatment strategies which appear to hold promise for the future.

Myocardial perfusion scintigraphy as a screening method for significant coronary artery stenosis in cardiac transplant recipients.

BACKGROUND: Several studies have explored the feasibility of using myocardial perfusion imaging to detect allograft vasculopathy after heart transplantation. We undertook the present prospective consecutive study to comparatively evaluate the role of serial myocardial perfusion single-photon emission computed tomography (SPECT) scanning and coronary arteriography (CAG) in detecting coronary artery stenosis suitable for coronary angioplasty in heart transplant recipients. METHODS: Within a 2-week interval during a follow-up period of 5.6 (95% confidence limits 2.1 to 12) years, 255 serial CAGs and myocardial perfusion scintigraphies were performed in 67 patients. Arteriography and scintigraphy were performed once yearly after heart transplantation. We retrospectively analyzed the data. RESULTS: Myocardial scintigraphy showed pathologic reversible defects in 9 out of 67 patients. Four of these patients had significant (>50% and also >70%) focal segmental stenosis in the middle and proximal parts of the coronary arteries (Type A lesions), 1 had diffuse and circumferential narrowing in the distal parts (Type B lesions), whereas CAG showed no lesions in the remaining 4 patients. The patients with significant Type A lesions were revascularized with percutaneous coronary angioplasty. Coronary arteriography showed that 1 patient had extensive Type A and Type B lesions, whereas myocardial perfusion scans detected no. The predictive value of a negative (normal) SPECT was 98% (95% confidence limits 94% to 100%) for the detection of lesions suited for revascularization. CONCLUSIONS: Annual myocardial SPECT seems well suited to screen for significant coronary artery stenosis. A SPECT study without reversible defects virtually excludes lesions suitable for coronary artery revascularization.

[Circulatory support with the mechanical heart, "HeartMate"]. / Cirkulationsstøtte med Det mekaniske hjerte, "HeartMate".

Treatment with the mechanical heart, HeartMate, has been introduced in Denmark. Short-term circulatory support can be obtained by intraaortic balloon counterpulsation, an external centrifugal pump and the total artificial heart. Long-term circulatory support can be established by treatment with the HeartMate. The principle of the mechanical heart is simple--a pump is implanted in parallel to the existing heart and connected to external, portable batteries. The patient quickly improves and is brought in an optimal state for transplantation. A few patients have been able to omit the subsequent heart transplantation. The patient's own heart improved during the treatment and the native heart functioned again after the system was explanted. The main complications during treatment are bleeding, infection, thromboembolic events and systemic failure. Permanent, fully implantable mechanical circulatory pumps are under development--which may herald the beginning of a whole new era for treatment of cardiac failure.

[Economic aspects of implementation of the mechanical heart, "HeartMate"]. / Okonomiske betragtninger ved implementering af det mekaniske hjerte, "HeartMate".

This economic evaluation was performed to assess the economic consequences for society and for the Danish health care sector of replacing the traditional treatment with Biomedicus assist device with The Mechanical Heart, HeartMate, as a bridge to transplantation for patients with severe cardiac failure. A cost-effectiveness analysis showed that the use of HeartMate is more cost-effective than the use of Biomedicus assist device. Using HeartMate one life-year gained costs DKK 225,000. Using Biomedicus one life-year gained costs DKK 270,000. The use of HeartMate results in an additional expenditure of DKK 615,000 per patient. By this additional expenditure the patients gain 3.6 extra life-years on average. The marginal expenditure by replacing the Biomedicus treatment with HeartMate is DKK 170,000 per extra life-year gained.

Vasodilatation with felodipine in chronic asymptomatic aortic regurgitation.

BACKGROUND: Afterload reduction decreases volume overload on the left ventricle and may thereby delay the need for valve replacement in chronic asymptomatic aortic regurgitation. The aims of this randomized double-blind, placebo-controlled trial were to examine short- and long-term hemodynamic effects of felodipine in chronic asymptomatic aortic regurgitation. METHODS: Sixteen patients were randomly assigned to an intravenous infusion of either felodipine 0. 3 mg or placebo followed by 3 months' treatment with felodipine 10 mg or placebo orally once daily. Magnetic resonance imaging was performed at baseline, immediately after intravenous treatment, and after 3 months of oral treatment. RESULTS: Intravenous felodipine caused a statistically significant reduction in the systemic vascular resistance from (mean +/- SD) 1160 +/- 400 to 970 +/- 320 dynes. s. cm(-5) (P <.05), in the regurgitant volume index from 1.5 +/- 0.8 to 1.3 +/- 0.8 L. min(-1). m(-2) (P <.05), and in the regurgitant fraction from 0.31 +/- 0.15 to 0.26 +/- 0.14 (P <.05). The forward cardiac output index increased significantly from 3.2 +/- 0.9 to 3.5 +/- 0.7 L. min(-1). m(-2) (P <.05). Three months of oral treatment with felodipine caused a corresponding but more pronounced decrease in systemic vascular resistance of 880 +/- 330 dynes. s. cm(-5) (P <.05), regurgitant volume index of 1.2 +/- 0.7 L. min(-1). m(-2) (P <.05), and regurgitant fraction 0.25 +/- 0.11 (P <.05), whereas the forward cardiac output index increased to 3.6 +/- 0.7 L. min(-1). m(-2) (P <.05). No significant changes were found in the placebo group. Left ventricular volumes and ejection fraction remained unaffected by treatment, but compared with the placebo group left ventricular myocardial mass decreased significantly from 137 +/- 24 to 132 +/- 21 g. m(-2) (P <.01). CONCLUSION: In chronic asymptomatic aortic regurgitation, felodipine causes beneficial hemodynamic effects that may postpone the need for valve replacement.

Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group.

CONTEXT: Results from recent studies on the effects of beta1-blockade in patients with heart failure demonstrated a 34% reduction in total mortality. However, the effect of beta1-blockade on the frequency of hospitalizations, symptoms, and quality of life in patients with heart failure has not been fully explored. OBJECTIVE: To examine the effects of the beta1-blocker controlled-release/extended-release metoprolol succinate (metoprolol CR/XL) on mortality, hospitalization, symptoms, and quality of life in patients with heart failure. DESIGN: Randomized, double-blind controlled trial, preceded by a 2-week single-blind placebo run-in period, conducted from February 14, 1997, to October 31, 1998, with a mean follow-up of 1 year. SETTING: Three hundred thirteen sites in 14 countries. PARTICIPANTS: Patients (n = 3991) with chronic heart failure, New York Heart Association (NYHA) functional class II to IV, and ejection fraction of 0.40 or less who were stabilized with optimum standard therapy. INTERVENTIONS: Patients were randomized to metoprolol CR/XL, 25 mg once per day (NYHA class II), or 12.5 mg once per day (NYHA class III or IV), titrated for 6 to 8 weeks up to a target dosage of 200 mg once per day (n = 1990); or matching placebo (n = 2001). MAIN OUTCOME MEASURES: Total mortality or any hospitalization (time to first event), number of hospitalizations for worsening heart failure, and change in NYHA class, by intervention group; quality of life was assessed in a substudy of 741 patients. RESULTS: The incidence of all predefined end points was lower in the metoprolol CR/XL group than in the placebo group, including total mortality or all-cause hospitalizations (the prespecified second primary end point; 641 vs 767 events; risk reduction, 19%; 95% confidence interval [CI], 10%-27%; P<.001); total mortality or hospitalizations due to worsening heart failure (311 vs 439 events; risk reduction, 31%; 95% CI, 20%-40%; P<.001), number of hospitalizations due to worsening heart failure (317 vs 451; P<.001); and number of days in hospital due to worsening heart failure (3401 vs 5303 days; P<.001). NYHA functional class, assessed by physicians, and McMaster Overall Treatment Evaluation score, assessed by patients, both improved in the metoprolol CR/XL group compared with the placebo group (P = .003 and P = .009, respectively). CONCLUSIONS: In this study of patients with symptomatic heartfailure, metoprolol CR/XL improved survival, reduced the need for hospitalizations due to worsening heart failure, improved NYHA functional class, and had beneficial effects on patient well-being.

[Beta-blockade--a new therapeutic modality in chronic heart insufficiency]. / Betablokade--en ny behandlingsmodalitet ved kronisk hjerteinsufficiens.

Heart failure due to decreased left ventricular function is a condition with a considerable morbidity and mortality. Until recently beta-blocker treatment has been considered contraindicated in this condition. During the last 20 years a number of investigations have pointed to a possible positive effect of beta-blocker treatment in chronic heart failure and recently several major randomized trials have shown a significantly increased survival during beta-blocker treatment. This review summarizes the background for the use of beta-blocker treatment in chronic heart failure patients.

Pulmonary function in chronic heart failure. Changes after heart transplantation.

To investigate the impact of chronic heart failure on pulmonary function in heart transplant recipients, pulmonary function was evaluated in 41 consecutive patients (mean age 43 years, range 15-57 years) before and 6 months after successful heart transplantation. The pulmonary function tests included measurements of forced vital capacity [FVC], forced expiratory volume in 1.s [FEV1], FEV1/FVC ratio, total lung capacity [TLC], and diffusion capacity for carbon monoxide [TLCO] and KCO [TLCO per l alveolar volume]. Compared to pretransplant values, spirometry after transplantation revealed modest improvements in FVC (from 77 +/- 16 to 88 +/- 21% of predicted [%pred]; p < 0.001) and FEV1 (from 75 +/- 16 to 85 +/- 22%pred; p < 0.001), whereas the FEV1/FVC ratio was unchanged (81% +/- 11 and 80% +/- 10; p = NS). A slight but statistically significant increase in TLC (from 78 +/- 15 to 86 +/- 18%pred, p < 0.001) was also observed. Prior to transplantation the mean TLCO was 76 +/- 17%pred; 7 of the patients had a TLCO below 60%pred (mean 51% pred). In 33 of the 41 patients a reduction in TLCO was observed after transplantation; for all 41 patients the mean fall in TLCO was 14% of the predicted value (SD 12%pred) (p < 0.0001). Likewise, a significant reduction in KCO was noted (p < 0.0001). Multiple regression analysis revealed that high pretransplant TLCO %pred (p = 0.02) and FVC %pred (p = 0.04) were associated with a less favorable outcome concerning posttransplant TLCO %pred. Although normalization of FEV1, FVC and TLC can be anticipated after correction of severe chronic left ventricular failure by heart transplantation, the pronounced concomitant decline in diffusion capacity observed in this study may be explained by underlying pulmonary disease caused by factors other than long-standing heart failure. Our findings support the notion that pulmonary function abnormalities attributable to chronic heart failure should not preclude consideration for heart transplantation.

Vascular smooth muscle contraction is an independent regulator of endothelial nitric oxide production.

This investigation was conducted to determine whether endothelial nitric oxide (NO) production is regulated by vascular smooth muscle contraction. Unperfused ring segments of rat aorta and mesenteric artery were studied using isometric tension recording (n = 6-8 in all experiments). Following a reference contraction to K+ 80 mM (100%), arteries were left either unstimulated or stimulated by different concentrations of K+ or prostaglandin F2alpha (PGF2alpha) to induce different levels of vascular precontraction. N(G)-nitro-L-arginine methyl ester (L-NAME 0.1-300 microM) or NS 2028 (0.03-3 microM), which is a new specific inhibitor of the NO-sensitive guanylate cyclase, was then added at increasing concentrations to evaluate endothelial NO production. L-NAME and NS 2028 produced a concentration-dependent vasoconstrictor response which was progressively enhanced with increasing levels of precontraction. For L-NAME, this amounted in aorta to (% of reference contraction): 35+/-1% and 105 +/- 4% (precontraction by K(+) 20 and 30 mM) and 22+/-1%, 89+/-1%, 138+/-1% and 146+/-2% (precontraction by PGF2alpha 0.5, 1, 2 and 3 microM). A similar coupling was found in the mesenteric artery. A precontraction as little as 2% was enough to trigger a vasoconstrictor response to L-NAME. In contrast, L-NAME and NS 2028 had no effect in non-contracted arteries, not even when passive mechanical stretch was increased by 100%. The results suggest (i) that endothelial NO formation is progressively increased with increasing vascular tone, and (ii) that vascular isometric contraction per se stimulates endothelial NO formation. It is concluded, that active vascular smooth muscle contraction is an independent regulator of endothelial NO production.