Biomarkers of cardiovascular risk across phenotypes of osteoarthritis.

BACKGROUND: The objective of this study was to explore the associations between ultrasonographic and radiographic joint scores and levels of arterial CVD risk markers in patients with osteoarthritis (OA). Secondly, to compare the levels of arterial CVD risk markers between OA phenotypes and controls. METHOD: The "Musculoskeletal pain in Ullensaker" Study (MUST) invited residents of Ullensaker municipality with self-reported OA to a medical examination. OA was defined according to the American College of Rheumatology (ACR) criteria and phenotyped based on joint distribution. Joints of the hands, hips and knees were examined by ultrasonography and conventional radiography, and scored for osteosteophytes. Hands were also scored for inflammation by grey scale (GS) synovitis and power Doppler (PD) signal. Control populations were a cohort of inhabitants of Oslo (OCP), and for external validation, a UK community-based register (UKPC).Pulse pressure augmentation index (AIx) and pulse wave velocity (PWV) were measured using the Sphygmocor apparatus (Atcor®). Ankel-brachial index (ABI) was estimated in a subset of patients. In separate adjusted regression models we explored the associations between ultrasonography and radiograph joint scores and AIx, PWV and ABI. CVD risk markers were also compared between phenotypes of OA and controls in adjusted analyses. RESULTS: Three hundred and sixty six persons with OA were included (mean age (range); 63.0 (42.0-75.0)), (females (%); 264 (72)). Of these, 155 (42.3%) had isolated hand OA, 111 (30.3%) had isolated lower limb OA and 100 (27.3%) had generalized OA. 108 persons were included in the OCP and 963 persons in the UKPC; (mean age (range); OCP: 57.2 (40.4-70.4), UKPC: 63.9 (40.0-75.0), females (%); OCP: 47 (43.5), UKPC: 543 (56.4%). Hand osteophytes were associated with AIx while GS and PD scores were not related to CVD risk markers. All OA phenotypes had higher levels of AIx compared to OCP in adjusted analyses. External validation against UKPC confirmed these findings. CONCLUSIONS: Hand osteophytes might be related to higher risk of CVD. People with OA had higher augmented central pressure compared to controls.Words 330.

Assessment of arterial function in pregnancy: recommendations of the International Working Group on Maternal Hemodynamics.

There is strong evidence supporting the role of maternal arterial dysfunction in pregnancy-specific disorders such as pre-eclampsia and intrauterine growth restriction. As more work is focused towards this field, it is important that methods and interpretation of arterial function assessment are applied appropriately. Here, we summarize techniques and devices commonly used in maternal health studies, with consideration of their technical application in pregnant cohorts. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Preconception and early pregnancy maternal haemodynamic changes in healthy women in relation to pregnancy viability.

STUDY QUESTION: Are there differences in preconception cardiovascular function between women who have a viable pregnancy and those who have a first trimester miscarriage? SUMMARY ANSWER: Preconception cardiovascular function of central haemodynamics and arterial function are similar between women who have a viable pregnancy and those who have a first trimester miscarriage. WHAT IS KNOWN ALREADY: Miscarriages have been associated with increased long-term cardiovascular disease risk, and arterial and cardiovascular dysfunction has been hypothesised as the common link. It is not known if these risks are present prior to pregnancy or are a reflection of poor arterial and haemodynamic adaptation to pregnancy. STUDY DESIGN, SIZE, DURATION: This prospective longitudinal preconception cohort study was conducted over 18 months. In total, 367 participants were recruited pre-pregnancy, from which 197 pregnancies were recorded; 39 of these pregnancies ended in first trimester miscarriage. Complete longitudinal data were available for 172 pregnancies (140 viable pregnancies, 32 first trimester miscarriages) from pre-pregnancy to 6 weeks gestation. PARTICIPANTS/MATERIALS, SETTING, METHODS: This was a single site study based at a maternity hospital in London. Healthy women were recruited prior to natural conception and followed up once they became pregnant. All underwent haemodynamic [cardiac output (CO), peripheral vascular resistance (PVR)] and arterial function [aortic augmentation index (AIx) and pulse wave velocity (PWV)] testing prior to pregnancy and at 6 weeks gestation, using non-invasive devices (gas re-breathing method, Innocor® and an occilometric device, Vicorder®). Cross-sectional measurements at pre-pregnancy and 6 weeks gestation and a longitudinal analysis of changes were compared between women who had a subsequent viable pregnancy, and those who had a subsequent first trimester miscarriage. MAIN RESULTS AND THE ROLE OF CHANCE: There were no differences between women destined to have a healthy ongoing pregnancy compared to those who miscarried, in terms of baseline cardiovascular function, assessed by CO, PVR, PWV or AIx. Similarly, between the groups, there were no differences in pregnancy adaptation with similar trends in cardiovascular function changes from pre-pregnancy to 6 weeks gestation. LIMITATIONS, REASONS FOR CAUTION: Whilst this is the first study to investigate preconception and early pregnancy haemodynamic and arterial function in relation to viability, the relatively modest number of miscarriages may not be sufficient to show subtle differences in haemodynamic changes if these were present. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that pre-pregnancy haemodynamic and arterial function is unlikely to be the causal link between miscarriages and future cardiovascular disease. Our findings suggests that factors other than the presence of a viable embryo drive cardiovascular changes in early pregnancy. This study raises new questions about miscarriages as an independent risk event which predisposes women to increased cardiovascular risk later in life. STUDY FUNDING/COMPETING INTEREST(S): The investigators are funded by NIHR Imperial BRC, NIHR Cambridge BRC, Action Medical Research, Imperial College Healthcare Charity and Tommy's Charity. We acknowledge the loan of ultrasound equipment from Samsung Medison (South Korea)/MIS Ltd and provision of fertility monitors from SPD Development Company Ltd (Bedford, UK). There are no competing interests. C.C.L. is supported by the UK National Institute for Health Research Biomedical Research Centre based at Imperial College Healthcare National Health Service Trust and Imperial College London. TRIAL REGISTRATION NUMBER: N/A.

Change in maternal cardiac output from preconception to mid-pregnancy is associated with birth weight in healthy pregnancies.

OBJECTIVE: Birth weight (BW) is thought to be determined by maternal health and genetic, nutritional and placental factors, the latter being influenced by anatomical development and perfusion. Maternal cardiovascular changes contribute to uteroplacental perfusion; however, they have not yet been investigated in relation to fetal growth or BW. Our aim was to explore the relationship between maternal cardiovascular adaptation, fetal growth and BW in healthy pregnancies. METHODS: This was a longitudinal prospective study of women planning to conceive a pregnancy. Maternal cardiac output (CO), cardiac index (CI), pulse-wave velocity, aortic augmentation index, central blood pressure and peripheral vascular resistance were assessed prior to pregnancy and at 6, 23 and 33 weeks' gestation. Fetal growth was assessed using serial ultrasound measurements of biometry. RESULTS: In total, 143 women volunteered to participate and were eligible for study inclusion. A total of 101 women conceived within 18 months and there were 64 live births with normal pregnancy outcome. There were positive correlations between BW and the pregnancy-induced changes in CO (ρ = 0.4, P = 0.004), CI (ρ = 0.3, P = 0.02) and peripheral vascular resistance (ρ = 0.3, P = 0.02). There were significant associations between second-to-third-trimester fetal weight gain and the prepregnancy-to-second-trimester increase in CO (Δ, 0.8 ± 1.2 L/min; ρ = 0.3, P = 0.02) and CI (Δ, 0.4 ± 0.6 L/min/m2 ; ρ = 0.3, P = 0.04) and reduction in aortic augmentation index (Δ, -10 ± 9%; ρ = -0.3, P = 0.04). CONCLUSIONS: In healthy pregnancy, incremental changes in maternal CO in early pregnancy are associated with third-trimester fetal growth and BW. It is plausible that this association is causative as the changes predate third-trimester fetal growth and eventual BW. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Hypertension in pregnancy: natural history and treatment options.

Hypertensive disorders of pregnancy affect approximately 5-10% of all maternities and are major contributors of maternal and neonatal morbidity and mortality worldwide. This group of disorders encompasses chronic hypertension, as well as conditions that arise de novo in pregnancy: gestational hypertension and pre-eclampsia. The latter group is thought to be part of the same continuum but with arbitrary division. Research into the aetiology of hypertension in pregnancy have largely been focused on pre-eclampsia, with a majority of studies exploring either pregnancy-associated factors such as placental-derived or immunologic responses to pregnancy tissue, or maternal constitutional factors such as cardiovascular health and endothelial dysfunction. The evidence base for the pathophysiology and progression of hypertensive disorders in pregnancy, particularly pre-eclampsia, is reviewed. Clinical algorithms and pharmacological agents for the management of hypertension in pregnancy are summarised, with a brief focus on post-partum considerations and long-term health implications. Novel therapeutic options for the management of pre-eclampsia are also explored.

The role of epoxyeicosatrienoic acids in the cardiovascular system.

There is increasing evidence suggesting that epoxyeicosatrienoic acids (EETs) play an important role in cardioprotective mechanisms. These include regulating vascular tone, modulating inflammatory responses, improving cardiomyocyte function and reducing ischaemic damage, resulting in attenuation of animal models of cardiovascular risk factors. This review discusses the current knowledge on the role of EETs in endothelium-dependent control of vascular tone in the healthy and in subjects with cardiovascular risk factors, and considers the pharmacological potential of targeting this pathway.

Unsafe health and safety: sphygmomanometer cuffs are not interchangeable.

Unknown to its hypertension specialists, a major teaching hospital changed the cuffs on its sphygmomanometers from manufacturer-validated to a uniform washable alternative, in line with 'Health and Safety' concerns surrounding potential cross-contamination between patients. When clinic doctors suspected serious under-reading with the new cuffs, a systematic comparison was undertaken in 54 patients (mean±s.d. age, 61±17 years), using two UM-101 sphygmomanometers, one using the original, manufacturer-supplied cuff and the other with the washable replacement. The study confirmed an average under-reading of 8±10/5±5 mm Hg using the washable cuff, and a third of patients with poorly controlled hypertension were considered normotensive, after using this cuff. The UM-101 sphygmomanometers have now been re-fitted with the original cuffs. Sphygmomanometer cuffs are not interchangeable between devices and a modicum of common sense should be shown to prevent changes made in the name of Health and Safety from having the opposite effect to that intended.

Impact of ovulation and implantation timing on first-trimester crown-rump length and gestational age.

OBJECTIVE: To determine the impact of ovulation and implantation timing on first-trimester crown-rump length (CRL) and the derived gestational age (GA). METHOD: One hundred and forty-three women who were trying to conceive were recruited prospectively. The timing of ovulation and implantation and the ovulation to implantation (O-I) interval were established in 101 pregnancies using home urinary tests for luteinizing hormone and human chorionic gonadotropin. In 71 ongoing pregnancies, GA determined by measurement of fetal CRL at 10-14 weeks' gestation was compared with GA based on ovulation and implantation day. First-trimester growth was determined by serial ultrasound scans at 6-7, 8-9 and 10-14 weeks. RESULTS: The median ovulation and implantation days were 16 and 27, respectively, with an O-I interval of 11 days. GA estimated from CRL at 10-14 weeks was on average 1.3 days greater than that derived from ovulation timing. CRL Z-score was inversely related to O-I interval (ρ= -0.431, P=0.0009). There was no significant relationship between CRL growth rate and the difference between observed CRL and expected CRL based on GA from last menstrual period (ρ=0.224, P=0.08). CONCLUSIONS: Early implantation leads to a larger CRL and late implantation to a smaller CRL at 10-14 weeks, independent of CRL growth rate. Implantation timing is a major determinant of fetal size at 10-14 weeks and largely explains the variation in estimates of GA in the first trimester derived from embryonic or fetal CRL.

Raised uterine artery impedance is associated with increased maternal arterial stiffness in the late second trimester.

OBJECTIVE: To assess the relationship between uterine artery Doppler pulsatility index (PI) and maternal global arterial stiffness and aortic stiffness in women at high a priori risk of preeclampsia in the late second trimester of pregnancy. METHODS: A prospective cohort study was performed. 99 women were recruited from the high-risk obstetric ultrasound clinic in the second trimester; median (±IQR) age and gestation were 33 (29-37) years and 23(+6) (23(+3)-24(+4)) weeks respectively. Transabdominal uterine artery Doppler was performed and mean values recorded. Women returned at a later date, median gestation (±IQR) 26(+5) (25(+6)-28(+0)) weeks, for measurement of blood pressure, augmentation index (AIx) and aortic pulse wave velocity (aPWV). RESULTS: Uterine artery PI is positively associated with both AIx (r = 0.4, P <0.0001, 95% CI: 0.22-0.55) and aPWV (r = 0.22, P = 0.03, 95% CI: 0.02-0.40). No relationship was found between uterine artery PI and mean arterial pressure or pulse pressure. AIx was significantly higher in women with uterine artery PI > 1.45 (P = 0.003, 95% CI: 3.1-14.9) but not aPWV (P = 0.45). AIx, but not aPWV, was significantly higher in women who developed preeclampsia (14% vs 9%, 95% CI: 2.0-8.6, P = 0.0018) or IUGR (11% vs 9%, 95% CI: 0.3-4.2, P = 0.027). AIx showed a negative correlation with birth weight z-score (r = -0.25, 95% CI: -0.43 to -0.06, P = 0.013). CONCLUSION: Increasing uterine artery Doppler PI reflects impaired placentation and increasing risk of preeclampsia. We show a positive association between uterine artery Doppler PI and both global arterial and aortic stiffness. We also show that increased maternal arterial stiffness is associated with a lower birth weight. These findings may represent evidence of an early effect of impaired placentation on the maternal vasculature. Alternatively, given the association between preeclampsia and later cardiovascular disease, ineffective placentation may result from impaired arterial function.

Maternal arterial stiffness in pregnancies affected by Type 1 diabetes mellitus.

AIM: There is little information about maternal central haemodynamics and arterial stiffness in pregnancies affected by Type 1 diabetes mellitus. The aim of the current study was to investigate whether maternal arterial stiffness is altered in pregnant women with Type 1 diabetes mellitus compared with women with uncomplicated pregnancies. METHODS: This was a cross-sectional study involving 37 pregnant women without diabetes and 37 pregnant women with Type 1 diabetes mellitus during the second trimester of pregnancy. Maternal wave reflection (augmentation index) and pulse wave velocity of the carotid-femoral and carotid-radial part of the arterial tree were assessed non-invasively using applanation tonometry. RESULTS: Pregnant women with normal pregnancies and Type 1 diabetes mellitus had similar augmentation index (3.7 +/- 12.8 vs. 5.1 +/- 12.6%, P = 0.6), even after adjusting for possible confounders. Within the group of diabetic women, augmentation index was associated with duration of diabetes (P = 0.003, r(2) = 0.22) but not with glycated haemoglobin. Pulse wave velocities were similar between the two groups of women (carotid-femoral: 5.6 +/- 0.9 vs. 5.7 +/- 1.1 m/s, P = 0.4; carotid-radial: 7.4 +/- 1.2 vs. 7.8 +/- 1 m/s, P = 0.1). In the diabetic women there was no significant association between the pulse wave velocities and either duration of diabetes or glycated haemoglobin. CONCLUSIONS: Pregnancy in women with Type 1 diabetes mellitus is not associated with altered maternal systemic arterial stiffness. However, maternal wave reflections increase with the duration of diabetes.

Increased arterial stiffness in patients with chronic obstructive pulmonary disease: a mechanism for increased cardiovascular risk.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with a 2-3-fold increase in the risk of ischaemic heart disease, stroke and sudden death. The mechanisms responsible for this association are not clear and appear to be independent of smoking history. OBJECTIVE: We test the hypothesis that patients with COPD have increased arterial stiffness and blood pressure in comparison with age and smoking matched controls. METHODS: In a prospective case control study, we recruited 102 patients with COPD and 103 healthy controls matched for age and smoking status. Patients were assessed by clinical history and spirometry, with arterial stiffness and blood pressure determined using radial artery applanation tonometry and sphygmomanometry. RESULTS: Patients with COPD had increased arterial stiffness compared with matched controls, with elevated augmentation pressure (17 (1) vs 14 (1) mm Hg; p = 0.005) and a reduced time to wave reflection (131 (1) vs 137 (2) ms; p = 0.004). These differences were associated with increases in both diastolic (82 (1) vs 78 (1) mm Hg; p = 0.005) and systolic blood pressure (147 (2) vs 132 (2) mm Hg; p<0.001). Serum C reactive protein concentrations were threefold higher in patients (6.1 (0.9) vs 2.3 (0.4) mg/l; p = 0.001). Data are presented as mean (SEM). CONCLUSIONS: Patients with COPD have increased arterial stiffness and blood pressure in comparison with controls matched for age and smoking status. We speculate that increased systemic inflammation and vascular dysfunction could potentially explain the excess cardiovascular morbidity and mortality associated with COPD.

Is arterial stiffening in Alström syndrome linked to the development of cardiomyopathy?

BACKGROUND: Alström syndrome (AS) is a rare autosomal recessive condition characterized by retinal degeneration, childhood obesity, and severe insulin resistance. Dilated cardiomyopathy of unknown aetiology is a well-recognized and potentially lethal complication. The aim of this study was to investigate the relationship between vascular function, hyperinsulinaemia and cardiac performance in AS. MATERIALS AND METHODS: Fifteen subjects with AS (mean age 21 years, range 10-35) were studied and compared with age-, sex-, and blood pressure-matched healthy controls. Large artery stiffness and wave reflections were assessed in both groups by measuring aortic and brachial pulse wave velocity (PWV) (carotid-femoral and carotid-radial) and augmentation index (AIX) (Sphygmocor). In AS subjects, left ventricular function was assessed by echocardiography and metabolic parameters including fasting insulin, glucose, lipids and brain natriuretic peptide were also measured. RESULTS: Comparing AS subjects vs. controls (mean +/- SD), AIX was elevated in AS subjects (18 +/- 9% vs. 3 +/- 11%, P < 0.0001). No significant changes in brachial PWV (8.1 +/- 1.3 m s(-1) vs. 7.3 +/- 1.1 m s(-1), P = 0.14) or aortic PWV (6.5 +/- 1.1 m s(-1) vs. 6.0 +/- 1.0 m s(-1), P = 0.26) were observed. AS subjects were hyperinsulinaemic and had disturbances in lipid profiles relative to controls. No correlations were observed between vascular, metabolic and echocardiographic parameters. CONCLUSIONS: In AS there are alterations in the shape of the central arterial pressure waveform associated with augmented aortic systolic pressure and indicative of increased wave reflection. Unfavourable central arterial haemodynamics in AS may contribute to the development of cardiomyopathy but other aetiological factors are probably involved.

The effect of exercise on large artery haemodynamics in healthy young men.

BACKGROUND: Brachial blood pressure predicts cardiovascular outcome at rest and during exercise. However, because of pulse pressure amplification, there is a marked difference between brachial pressure and central (aortic) pressure. Although central pressure is likely to have greater clinical importance, very little data exist regarding the central haemodynamic response to exercise. The aim of the present study was to determine the central and peripheral haemodynamic response to incremental aerobic exercise. MATERIALS AND METHODS: Twelve healthy men aged 31 +/- 1 years (mean +/- SEM) exercised at 50%, 60%, 70% and 80% of their maximal heart rate (HRmax) on a bicycle ergometer. Central blood pressure and estimated aortic pulse wave velocity, assessed by timing of the reflected wave (T(R)), were obtained noninvasively using pulse wave analysis. Pulse pressure amplification was defined as the ratio of peripheral to central pulse pressure and, to assess the influence of wave reflection on amplification, the ratio of peripheral pulse pressure to nonaugmented central pulse pressure (PPP : CDBP-P1) was also calculated. RESULTS: During exercise, there was a significant, intensity-related, increase in mean arterial pressure and heart rate (P < 0.001). There was also a significant increase in pulse pressure amplification and in PPP : CDBP-P(1) (P < 0.001), but both were independent of exercise intensity. Estimated aortic pulse wave velocity increased during exercise (P < 0.001), indicating increased aortic stiffness. There was also a positive association between aortic pulse wave velocity and mean arterial pressure (r = 0.54; P < 0.001). CONCLUSIONS: Exercise significantly increases pulse pressure amplification and estimated aortic stiffness.

Infliximab improves endothelial dysfunction in systemic vasculitis: a model of vascular inflammation.

BACKGROUND: Endothelial vasomotor dysfunction and markers of systemic inflammation are independent determinants of cardiovascular risk. However, the link between clinical inflammation and endothelial dysfunction is unclear. The aim of this study was to use anti-neutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) as a model of systemic inflammation in which to test the hypothesis that inflammation is associated with endothelial dysfunction and can be reversed with anti-tumor necrosis factor-alpha (TNF-alpha) therapy. METHODS AND RESULTS: Fourteen patients with active AASV and 21 age-matched control subjects were studied. Endothelial function was assessed through the use of forearm plethysmography and related to clinical disease activity: Birmingham Vasculitis Activity Score (BVAS) and serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), and TNF-alpha. The effects of anti-TNF-alpha therapy (infliximab), either alone (n=6) or in combination with standard treatment (n=4), on endothelial function were subsequently determined. Patients had a mean BVAS of 11+/-1, and CRP and IL-6 were higher in the AASV group than in control subjects (34.8+/-10.5 versus 1.6+/-0.2 pg/mL, P<0.001; 9.0+/-0.7 versus 6.7+/-0.6 pg/mL, P=0.02). Forearm blood flow response to acetylcholine (ACh) was reduced in the patients compared with control subjects (P=0.002), but sodium nitroprusside (SNP) responses were not (P=0.3). The response to ACh improved with infliximab treatment (P=0.004) in particular, with infliximab alone (P=0.03). CONCLUSIONS: AASV is associated with endothelial dysfunction. Anti-TNF-alpha therapy, alone or in combination with standard treatment, results in clinical remission, reduced inflammation, and improved endothelium-dependent vasomotor responses.

Inflammation and arterial stiffness in systemic vasculitis: a model of vascular inflammation.

OBJECTIVE: Arterial stiffness, an independent determinant of cardiovascular risk, is regulated by both structural and functional factors, including endothelium-derived nitric oxide. Endothelial dysfunction is associated with acute and chronic systemic inflammation. However, the role of systemic inflammation in arterial stiffening has not been determined. The aim of this study was to investigate the relationship between inflammation and arterial stiffness in patients with antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) as a model of systemic inflammation. METHODS: Thirty-one patients with AASV (15 with active disease) and 32 age-matched controls were studied. Pulse wave velocity (PWV) and the augmentation index (AIx) were assessed noninvasively and related to serum levels of C-reactive protein (CRP), interleukin-6, and tumor necrosis factor alpha. RESULTS: In subjects with active disease, the AIx, PWV, and level of CRP were elevated compared with that in controls (mean +/- SEM 31 +/- 3% versus 22 +/- 2% [P = 0.003], 9.2 +/- 0.7 versus 7.5 +/- 0.3 meters/second [P = 0.03], and 16.0 +/- 4.0 versus 1.1 +/- 0.1 mg/liter [P < 0.001], respectively). However, PWV and the AIx were not significantly different between patients with disease in remission and controls (8.0 +/- 0.5 versus 7.5 +/- 0.3 meters/second and 19 +/- 3% versus 22 +/- 2%, respectively). The CRP level was positively correlated with both PWV and the AIx. Multiple regression analysis indicated that age, mean arterial pressure (MAP), and CRP were independently related to PWV, and that age, MAP, CRP, sex, and heart rate were associated with the AIx. CONCLUSION: These data indicate that AASV is associated with increased arterial stiffness, and that stiffness correlates with the degree of active inflammation.

Adrenomedullin (ADM) in the human forearm vascular bed: effect of neutral endopeptidase inhibition and comparison with proadrenomedullin NH2-terminal 20 peptide (PAMP).

AIMS: To compare the haemodynamic responses of proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (ADM) in the forearm vascular bed of healthy male volunteers, and to investigate the role of neutral endopeptidase (NEP) in the metabolism of ADM. METHODS: On two separate occasions, ADM (1-30 pmol x min(-1)) and PAMP (100-3000 pmol x min(-1)) were infused into the brachial artery of eight male subjects, and forearm blood flow (FBF) assessed using venous occlusion plethysmography. In a second study, eight male subjects received the same doses of ADM, co-infused with either the NEP inhibitor thiorphan (30 nmol x min(-1)) or the control vasoconstrictor noradrenaline (120 pmol x min(-1)), on separate occasions. Both studies were conducted in a double-blind, randomized manner. RESULTS: ADM and PAMP produced a dose-dependent increase in FBF (P < or = 0.002). Based on the dose producing a 50% increase in FBF, ADM was approximately 60 times more potent than PAMP. Thiorphan and noradrenaline produced similar reductions in FBF of 14 +/- 4% (mean +/- s.e. mean) and 22 +/- 6%, respectively (P = 0.4). However, the area under the dose-response curve was significantly greater during co-infusion of ADM with thiorphan than with noradrenaline (P = 0.028), as was the maximum increase in FBF ratio (2.1 +/- 1.0 vs 1.2 +/- 0.2; P = 0.030). CONCLUSIONS: ADM and PAMP both produce a local dose-related vasodilatation in the human forearm, but PAMP is approximately 60 times less potent than ADM. In addition, NEP inhibition potentiates the haemodynamic effects of ADM. These findings suggest that PAMP may not play a role in the physiological regulation of blood flow. However, in pathophysiological conditions such as hypertension and heart failure, NEP inhibition may exert a beneficial effect by increasing the biological activity of ADM.

The relationship between plasma potassium concentration and muscle torque during recovery following intense exercise.

The present study investigated the relationship between plasma potassium ion concentration ([K+]) and skeletal muscle torque during three different 15-min recovery periods after fatigue induced by four 30-s sprints. Four males and one female completed the multiple sprint exercise on three separate days; recovery was passive, i.e. no cycling exercise (PRec), active cycling at 30% peak oxygen consumption. VO2peak (30% Rec) and active cycling at 60% VO2peak (60% Rec). Plasma [K+] was measured from blood sampled from an antecubital vein of subjects at rest and at 0, 3, 5, 10 and 15 min into each recovery. Isokinetic leg strength was measured at rest and at 1, 6, 11 and 16 min during each recovery. Following the exhaustive sprints, [K+] increased significantly from an average mean (SEM) resting value of 3.81 (0.07) mmol.l-1 to 4.48 (0.19) mmol.l-1 (P < 0.01). In all recovery conditions, plasma [K+] returned to resting levels within 3 min following the fourth sprint. However, in the two active recovery conditions plasma [K+] increased over the remainder of the recovery periods to 4.36 (0.12) mmol.l-1 in the 30% Rec condition and 4.62 (0.12) mmol.l-1 in the 60% Rec condition, the latter being significantly higher than the former (P < 0.01). The maximum torque measured following the sprints decreased significantly, on average, to 61.1 (8.36)% of peak levels (P < 0.01). After 15 min of recovery, maximum torque was highest in the 30% Rec condition at 92.13 (3.06)% of peak levels (P < 0.01), compared to 85.23 (3.64)% and 85.71 (0.82)% for the PRec and 60% Rec conditions, respectively. In contrast to the significant differences in plasma [K+] across all three recovery conditions, muscle torque recovery was significantly different in only the 30% Rec condition. In summary, recovery of peak levels of muscle torque following fatiguing exercise does not appear to follow changes in plasma [K+].