Left ventricular mechanics in late second trimester of healthy pregnancy.

OBJECTIVE: To evaluate left ventricular (LV) mechanics in the second trimester of healthy pregnancy and to determine the influence of underpinning hemodynamics (heart rate (HR), preload and afterload) on LV mechanics during gestation. METHODS: This was a cross-sectional study of 18 non-pregnant, 14 nulliparous pregnant (22-26 weeks' gestation) and 13 primiparous postpartum (12-16 weeks after delivery) women. All pregnant and postpartum women had uncomplicated, singleton gestations. Cardiac structure and function were assessed using echocardiography. LV mechanics, specifically longitudinal strain, circumferential strain and twist/untwist, were measured using speckle-tracking echocardiography. Differences between groups were identified using ANCOVA, with age, HR, end-diastolic volume (EDV) and systolic blood pressure (SBP) as covariates. Relationships between LV mechanics and hemodynamics were examined using Pearson's correlation. RESULTS: There were no significant differences in LV structure and traditional measurements of systolic and diastolic function between the three groups. Pregnant women, compared with non-pregnant ones, had significantly higher resting longitudinal strain (-22 ± 2% vs -17 ± 3%; P = 0.002) and basal circumferential strain (-23 ± 4% vs -16 ± 2%; P = 0.001). Apical circumferential strain and LV twist and untwist mechanics were similar between the three groups. No statistically significant relationships were observed between LV mechanics and HR, EDV or SBP within the groups. CONCLUSIONS: Compared to the non-pregnant state, pregnant women in the second trimester of a healthy pregnancy have significantly greater resting systolic function, as assessed by LV longitudinal and circumferential strain. Contrary to previous work, these data show that healthy pregnant women should not exhibit reductions in resting systolic function between 22 and 26 weeks' gestation. The enhanced myocardial contractile function during gestation does not appear to be related to hemodynamic load and could be the result of other physiological adaptations to pregnancy. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Randomized clinical trial of angiotensin-converting enzyme inhibitor, ramipril, in patients with intermittent claudication.

BACKGROUND: The aim was to investigate the effect of ramipril on clinical parameters in patients with peripheral arterial disease. METHODS: Patients with intermittent claudication were randomized to receive ramipril or placebo for 24 weeks in a double-blind study. Outcome measures were walking distance, arterial stiffness measurement and quality of life (QoL). RESULTS: A total of 33 patients were included (25 men; mean(s.d.) age 64.6(7.8) years); 14 received ramipril and 19 placebo. After 24 weeks, ramipril improved maximum treadmill walking distance by an adjusted mean (95 per cent confidence interval, c.i.) of 131 (62 to 199) m (P = 0·001), improved treadmill intermittent claudication distance by 122 (56 to 188) m (P = 0.001) and improved patient-reported walking distance by 159 (66 to 313) m (P = 0.043) compared with placebo. Ramipril reduced carotid femoral pulse wave velocity by -1.47 (95 per cent c.i. -2.40 to -0.57) m/s compared with placebo (P = 0.002). Resting ankle : brachial pressure index (ABPI) improved slightly in both ramipril and placebo groups (0.02 (95 per cent c.i. -0.08 to 0.11) versus 0.03 (-0.05 to 0.10); P = 0.830). Ramipril had a slight, non-significant effect on QoL physical domains compared with placebo. CONCLUSION: Ramipril improved walking distance in patients with claudication; however, this improvement was not related to improved ABPI but might have been due to ramipril reducing arterial stiffness. REGISTRATION NUMBER: NCT01037530 (http://www.clinicaltrials.gov).

Is fatty acid intake a predictor of arterial stiffness and blood pressure in men? Evidence from the Caerphilly Prospective Study.

BACKGROUND AND AIMS: Arterial stiffness is an independent predictor of cardiovascular disease (CVD) events and all-cause mortality and may be differentially affected by dietary fatty acid (FA) intake. The aim of this study was to investigate the relationship between FA consumption and arterial stiffness and blood pressure in a community-based population. METHODS AND RESULTS: The Caerphilly Prospective Study recruited 2398 men, aged 45-59 years, who were followed up at 5-year intervals for a mean of 17.8-years (n 787). A semi-quantitative food frequency questionnaire estimated intakes of total, saturated, mono- and poly-unsaturated fatty acids (SFA, MUFA, PUFA). Multiple regression models investigated associations between intakes of FA at baseline with aortic pulse wave velocity (aPWV), augmentation index (AIx), systolic and diastolic blood pressure (SBP, DBP) and pulse pressure after a 17.8-year follow-up--as well as cross-sectional relationships with metabolic markers. After adjustment, higher SFA consumption at baseline was associated with higher SBP (P = 0.043) and DBP (P = 0.002) and after a 17.8-year follow-up was associated with a 0.51 m/s higher aPWV (P = 0.006). After adjustment, higher PUFA consumption at baseline was associated with lower SBP (P = 0.022) and DBP (P = 0.036) and after a 17.8-year follow-up was associated with a 0.63 m/s lower aPWV (P = 0.007). CONCLUSION: This study suggests that consumption of SFA and PUFA have opposing effects on arterial stiffness and blood pressure. Importantly, this study suggests that consumption of FA is an important risk factor for arterial stiffness and CVD.

Aortic stiffness and vitamin D are independent markers of aortic calcification in patients with peripheral arterial disease and in healthy subjects.

OBJECTIVE: Arterial stiffness is a significant determinant of cardiovascular risk and is related to vascular calcification. Vitamin D may regulate arterial calcification and has been associated with cardiovascular survival benefits. However, data about the relationship between arterial stiffness, aortic calcification and vitamin D levels in patients with peripheral arterial disease (PAD) and in healthy subjects are limited. We examined the potential association between aortic calcification, arterial stiffness and vitamin D levels in patients with symptomatic PAD and in healthy individuals. METHODS: We studied 78 men with PAD (aged 63 ± 7 years) and 74 healthy men (aged 61 ± 10 years). Aortic pulse wave velocity (aPWV) was determined by applanation tonometry using the Sphygmocor device. Aortic calcification score (ACS) was quantified by computed tomography. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured using a radioimmune assay. RESULTS: ACS (4.9(2.3-8.9) vs. 0.2(0.03-1.6) (cm³); p < 0.01), aPWV (9.8 ± 2.4 vs. 8.2 ± 1.6 (m s⁻¹; p < 0.01) and 25(OH)D (15.1 ± 5.4 vs. 19.0 ± 5.9 (ng ml⁻¹); p < 0.01) were different in the patients compared with the controls. In multivariate analysis, ACS was independently determined by 25(OH)D, aPWV, calcium and age in patients with PAD (R² = 0.49; p < 0.001) and by 25(OH)D, aPWV, cholesterol/high-density lipoprotein (HDL) and age in the control group (R² = 0.55; p < 0.001). Increased aPWV and lower levels of 25(OH)D were associated with decreased ankle-brachial pressure index (p = 0.03). CONCLUSION: These results indicate that calcification of the aorta is independently associated with aortic stiffness and serum 25(OH)D level in patients with PAD and in healthy subjects. Aortic stiffness and abnormal vitamin D level may contribute to vascular calcification and are related to higher severity grade of atherosclerotic disease.

Increased augmentation index in patients with cystic fibrosis.

Increased large artery stiffness occurs in a range of inflammatory conditions indicating an ageing of the vasculature and additionally being an independent risk factor for cardiovascular events. We determined large artery parameters in adults with cystic fibrosis (CF). 50 clinically stable adult patients with CF (mean+/-sd age 28.0+/-8.2 yrs) and 26 controls matched for age, sex and body mass index were studied. Central aortic blood pressure, augmentation index (AIx) and aortic pulse wave velocity (PWV) were determined using applanation tonometry. Lung function, diabetic status and C-reactive protein (CRP) were also determined. Mean+/-sd AIx was greater in patients than controls, 8.5+/-11.1% and -1.8+/-13.1%, respectively (p<0.001), while PWV was similar. Although AIx was greatest in the sub-group with CF-related diabetes (CFRD), it was also increased in the non-CFRD sub-group when compared with controls. In patients, AIx was related to log(10) CRP (r = 0.33) and forced vital capacity (r = -0.34; both p<0.05), and CRP remained predictive in multiple regression. AIx is increased in adults with CF, in the presence of a normal blood pressure and independent of diabetic status. AIx was related to the systemic inflammatory status. These findings have implications for management and require further exploration so that cardiovascular health can be maintained.

Endothelium-derived nitric oxide contributes to the regulation of venous tone in humans.

BACKGROUND: Although nitric oxide (NO) is known to play an important part in the regulation of arterial tone, little is known about its role in veins. The aim of this study was to investigate the role of basal and stimulated NO activity in the regulation of tone of the human venous capacitance bed. METHODS AND RESULTS: We measured venous tone using radionuclide forearm venous plethysmography in 24 healthy subjects with no cardiovascular risk factors. In 13 subjects, basal NO activity was assessed by measuring the effects on venous tone of an intra-arterial infusion of the NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA). In the remaining 11 subjects, stimulated NO activity was evaluated by measuring the effects of an intra-arterial infusion of incremental doses of carbachol, followed in a subgroup by coinfusion with L-NMMA. Infusion of carbachol caused dose-dependent venodilation, with a maximal reduction in forearm venous tone of 40.1+/-12.5% (P<0.0001). Carbachol-induced venodilation was inhibited by L-NMMA (48.9+/-6.2% reversal of maximal venodilation, P<0.01). Infusion of L-NMMA alone caused venoconstriction (9.1+/-6.4% increase in venous tone, P=0.002). CONCLUSIONS: Human forearm capacitance veins exhibit both stimulated and basal NO activity, which indicates that NO contributes not only to the regulation of venous tone but also to resting venous tone in healthy human subjects.

Preserved endothelial function in patients with severe hypertriglyceridemia and low functional lipoprotein lipase activity.

OBJECTIVES: We sought to determine whether hypertriglyceridemia in patients with lipoprotein lipase (LPL) dysfunction is associated with endothelial dysfunction in resistance vessels of the forearm vasculature. BACKGROUND: Vasodilator responses to acetylcholine, acting through stimulation of nitric oxide (NO) release from the endothelium, are impaired in hypercholesterolemia and normalized by L-arginine, suggesting dysfunction of the L-arginine/NO pathway. Similar abnormalities have been reported in conditions associated with hypertriglyceridemia, such as non-insulin-dependent diabetes. The relation between endothelial function and plasma triglyceride concentrations has, however, not previously been studied in vivo. METHODS: We examined forearm blood flow responses to brachial artery infusions of acetylcholine (alone and with L-arginine) and nitroprusside (an NO donor) in 17 patients with severe hypertriglyceridemia (mean [+/- SD] plasma triglyceride concentration 1,914 +/- 1,288 mg/dl) but normal low density lipoprotein cholesterol (89 +/- 31 mg/dl) and in 34 normolipidemic control subjects. Severe LPL dysfunction was demonstrated in 10 of 17 patients. RESULTS: Acetylcholine (7.5 and 15 microg/min) produced similar forearm blood flow responses in hypertriglyceridemic patients (mean [+/- SEM] 7.7 +/- 0.9 and 10.5 +/- 1.2 ml/min per 100 ml) and in control subjects (7.5 +/- 0.6 and 11.0 +/- 0.8 ml/min per 100 ml, p = 0.78 by analysis of variance). Responses to acetylcholine co-infused with L-arginine (10 mg/min) and nitroprusside (3 and 10 microg/min) were also similar in hypertriglyceridemic patients and control subjects (p = 0.93 and p = 0.27 for acetylcholine with L-arginine and nitroprusside, respectively). The ratio response to acetylcholine/response to nitroprusside differed between hypertriglyceridemic patients and control subjects by only 1%. The study had >90% power (alpha = 0.05) to detect a difference >30% in this ratio. CONCLUSIONS: Severe hypertriglyceridemia associated with LPL dysfunction is not associated with the degree of endothelial dysfunction seen in moderate hypercholesterolemia when responses to acetylcholine are impaired by >40%.

Tissue angiotensin generation and regulation of vascular tone.

The renin-angiotensin system is intimately involved in the control of sodium and water balance, the activity of the sympathetic nervous system, mitogenesis and the regulation of vascular tone. There is evidence that many of these effects may be controlled at a local level by independent tissue renin-angiotensin systems. Drugs that are specific inhibitors of the cascade have proved powerful tools for dissecting the physiology of the renin-angiotensin system, and are of major benefit in the treatment of hypertension and chronic heart failure. Recent evidence suggests that variations in the genes coding for components of the system may affect the risk of developing hypertension and ischaemic heart disease.

Correlation between baseline blood pressure and the brainstem FMRI response to isometric forearm contraction in human volunteers: a pilot study.

It has been shown previously that changes in brainstem neural activity correlate with changes in both mean arterial pressure (MAP) and muscle sympathetic nerve activity (MSNA) during static handgrip (SHG). However, the relationship between baseline MAP and brainstem neural activity is unclear. We investigated changes in blood oxygen level-dependent (BOLD) signal induced by SHG in 12 young adults using BOLD functional magnetic resonance imaging (FMRI). An estimation of the blood pressure response to SHG was obtained in seven subjects during a session outside the MRI scanner and was used to model the blood pressure response to SHG inside the scanner. SHG at 40% of maximum grip increased MAP (mean ± s.d.) at the end of the 180-s squeeze from 85 ± 6 mm Hg to 108 ± 15 mm Hg, P = 0.0001. The brainstem BOLD signal change associated with SHG was localised to the ventrolateral medulla. This regional BOLD signal change negatively correlated with baseline MAP, r = -0.61, P = 0.01. This relationship between baseline MAP and brainstem FMRI responses to forearm contraction is suggestive of a possible role for brainstem activity in the control of MAP and may provide mechanistic insights into neurogenic hypertension.

Prostacyclin and thromboxane biosynthesis in mild essential hypertension.

The possibility that prostacyclin or thromboxane biosynthesis is abnormal in patients with established mild essential hypertension was investigated in 46 patients. These eicosanoids have opposing effects both on vascular smooth muscle and on platelets. An imbalance in their biosynthesis could therefore influence both vascular tone and predisposition to thrombosis. We studied the relation between blood pressure and the biosynthesis of prostacyclin and thromboxane A2 by measuring urinary excretion rates of stable breakdown products of prostacyclin (6-oxo-prostaglandin F1 alpha and 2,3-dinor-6-oxo-prostaglandin F1 alpha) and of thromboxane A2 (thromboxane B2 and 2,3-dinor-thromboxane B2) using immunoaffinity chromatography and gas chromatography/electron capture mass spectrometry. Excretion rates of both of the prostacyclin-derived products ranged from less than 5 to more than 100 ng/g creatinine; each was significantly negatively correlated with blood pressure (r = 0.36-0.45). A reduction of 2,3-dinor-6-oxo-prostaglandin F1 alpha excretion of 100 ng/g creatinine was associated with an increase in arterial pressure of 14 mm Hg (systolic) and 8 mm Hg (diastolic) in patients who had been without antihypertensive medication for 2 weeks. The same reduction in 6-oxo-prostaglandin F1 alpha excretion was associated with an increased pressure of 19 mm Hg (systolic) and 12 mm Hg (diastolic) (2p less than 0.05 for diastolic pressure and 2p less than 0.01 for systolic pressure in each case). There were similar correlations between the excretion rates of these products and blood pressure in the same patients while they were receiving antihypertensive therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer.

Sex hormones appear to play a pivotal role in determining cardiovascular risk. Androgen deprivation therapy for males with prostate cancer results in a hypogonadal state that may have important, but as yet undetermined, effects on the vasculature. We studied the effects of androgen deprivation therapy on large artery stiffness in 22 prostate cancer patients (mean age, 67 +/- 8 yr) over a 6-month period. Arterial stiffness was assessed using pulse-wave analysis, a technique that measures peripheral arterial pressure waveforms and generates corresponding central aortic waveforms. This allows determination of the augmentation of central pressure resulting from wave reflection and the augmentation index, a measure of large artery stiffness. Body compositional changes were assessed using bioelectrical impedance analysis. Fasting lipids, glucose, insulin, testosterone, and estradiol were measured. After a 3-month treatment period, the augmentation index increased from 24 +/- 6% (mean +/- SD) at baseline to 29 +/- 9% (P = 0.003) despite no change in peripheral blood pressure. Timing of wave reflection was reduced from 137 +/- 7 to 129 +/- 10 msec (P = 0.003). Fat mass increased from 20.2 +/- 9.4 to 21.9 +/- 9.6 kg (P = 0.008), whereas lean body mass decreased from 63.2 +/- 6.8 to 61.5 +/- 6.0 kg (P = 0.016). There were no changes in lipids or glucose during treatment. Median serum insulin rose from 11.8 (range, 5.6-49.1) to 15.1 (range, 7.3-83.2) mU/liter at 1 month (P = 0.021) and to 19.3 (range, 0-85.0 mU/liter by 3 months (P = 0.020). There was a correlation between the changes in fat mass and insulin concentration over the 3-month period (r = 0.56; P = 0.013). In a subgroup of patients whose treatment was discontinued after 3 months, the augmentation index decreased from 31 +/- 7% at 3 months to 29 +/- 5% by 6 months, in contrast to patients receiving continuing treatment in whom the augmentation index remained elevated at 6 months compared with baseline (P = 0.043). These data indicate that induced hypogonadism in males with prostate cancer results in a rise in the augmentation of central arterial pressure, suggesting large artery stiffening. Adverse body compositional changes associated with rising insulin concentrations suggest reduced insulin sensitivity. These adverse hemodynamic and metabolic effects may increase cardiovascular risk in this patient group.

Augmentation of central arterial pressure in mild primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is associated with increased cardiovascular risk, although the mechanisms involved remain unclear. Recent evidence has shown increased pulse pressure to be a powerful predictor of cardiovascular events. As increases in pulse pressure are due largely to arterial stiffening, we measured arterial stiffness in 21 subjects with PHPT (18 women and 3 men; 46-71 yr old) and 21 age- and sex-matched healthy controls using pulse wave analysis, a technique that measures peripheral arterial pressure waveforms and generates corresponding central aortic waveforms. This allows determination of the augmentation of central pressure resulting from wave reflection and augmentation index, a measure of vessel stiffness. Metabolic parameters were also measured. The serum calcium level among PHPT subjects was (mean +/- SD) 2.74+/-0.14 mmol/L. pulse wave analysis showed that both augmentation and the augmentation index were significantly higher in the PHPT group vs. controls [16+/-5 vs. 10+/-4 mm Hg (P < 0.001) and 36+/-9% vs. 25+/-6% (P < 0.001)] despite comparable brachial systolic pressures between groups (136+/-13 vs. 134+/-18 mm Hg). Patients with PHPT had higher fasting serum insulin levels [median (range), 15.8 (7.4-39.4) vs. 11.6 (5.1-23) mU/L; P < 0.05] and triglyceride (1.6+/-0.6 vs. 1.2+/-0.4 mmol/L; P < 0.05), but lower high density lipoprotein cholesterol (1.4+/-0.4 vs. 1.6+/-0.3 mmol/L; P < 0.05). These data indicate that subjects with mild PHPT (calcium, <3.0 mmol/L) have increased arterial stiffness, as evidenced by higher augmentation of central aortic pressures. Enhanced vessel stiffness may arise from a combination of structural and functional vascular changes due to hypercalcemia and/or metabolic abnormalities. Increased vascular stiffness in subjects with PHPT may account in part for the increased cardiovascular risk in this group.

Haemodynamic effects of inhibition of nitric oxide synthase and of L-arginine at rest and during exercise.

OBJECTIVE: To compare effects of N(G)-monomethyl-L-arginine (L-NMMA; a NO synthase inhibitor) and L-arginine (a NO synthase substrate) on haemodynamics in healthy men at rest and during exercise. METHODS: We infused L-NMMA and saline placebo intravenously in two groups of eight healthy men. Each group underwent a two-phase, randomized, single-blind crossover study. Men in one group received 3 mg/kg L-NMMA and men in the other group received 6 mg/kg L-NMMA. Haemodynamic measurements were performed before, during and after a 12 min stepped exercise protocol starting 6 min after the intravenous infusion. A further six men received, according to the same study design, 30 g L-arginine over 30 min and saline placebo before exercise. Blood pressure was measured by sphygmomanometry and cardiac output by bioimpedance, allowing computation of total systemic vascular resistance index (SVRI). RESULTS: Infusion of 6 mg/kg L-NMMA into men at rest produced modest increases (compared with effect of saline placebo) in systolic and diastolic blood pressures of 4.1 +/- 1.1 and 12.6 +/- 3.5%, respectively (means +/- SEM, P < 0.01 for both comparisons) and a marked increase in SVRI of 39.2 +/- 5.2% (P < 0.01). Cardiac index and heart rate were 22.0 +/- 3.3 and 17.0 +/- 4.4% lower after administration of L-NMMA (P < 0.01 for each comparison) than after infusion of saline placebo. During exercise there was no significant difference between total SVRI after infusions of L-NMMA and saline (difference not significant, diminished with increasing exercise). Six minutes into recovery the difference between total SVRI after infusions of L-NMMA and saline reappeared with SVRI 25 +/- 6.9% higher after infusion of L-NMMA than after infusion of saline (P < 0.01). Administration of L-arginine had no significant effect on haemodynamics in men at rest, during exercise and during recovery. CONCLUSIONS: Effects of L-NMMA on total systemic vascular resistance during exercise are less marked than are those on subjects at rest, probably because vasodilatation of resistance vessels of skeletal muscle during exercise is mediated mainly by factors other than NO. Our results also suggest that NO synthesis in healthy men is not substrate limited either at rest or during exercise.

Reproducibility of pulse wave velocity and augmentation index measured by pulse wave analysis.

OBJECTIVE: The aim of this study was to determine the reproducibility of pulse wave velocity (PWV) and augmentation index (AIx) measured using pulse wave analysis (PWA), prior to its use in large-scale clinical trials. METHODS: Arterial pressure waveforms were recorded and analysed using an established technique (Sphygmocor). Subjects with and without a range of recognized cardiovascular risk factors were studied to provide a wide range of values. Measurements were made after a brief introduction to the technique in a clinical setting. Two observers recorded aortic and brachial PWV in 24 subjects, each on two occasions, in a random order. In a separate study, two different observers used PWA to determine AIx in 33 subjects, each on two occasions, in a random order. Data were analysed using Bland-Altman plots and presented as mean +/- SD. RESULTS: Brachial PWV was 8.65+/-1.58 m/s (range 6.16-10.95 m/s) and aortic PWV was 8.15+/-3.01 m/s (5.01-17.97 m/s). Within-observer variability was 0.14+/-0.82 m/s for brachial PWV and 0.07+/-1.17 m/s for aortic PWV. Corresponding between-observer values were -0.44+/-1.09 m/s and -0.30+/-1.25 m/s. AIx ranged from -15.0 to +45.0%, with a group mean of +19.6+/-12.0%. The within-observer difference was 0.49+/-5.37% and between-observer difference 0.23+/-3.80%. CONCLUSION: PWA is a simple and reproducible technique with which to measure PWV and AIx. Reproducibility accords with that reported by other workers using different methodologies. PWA may, therefore, be suitable for large-scale population and intervention studies investigating the clinical relevance of vascular stiffness.

Differential inhibition by NG-monomethyl-L-arginine of vasodilator effects of acetylcholine and methacholine in human forearm vasculature.

1. We compared the effects of NG-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor, on vasodilatation produced by acetylcholine and methacholine in human forearm vasculature. 2. Acetylcholine (83 nmol min-1) infused into the brachial artery of 8 healthy volunteers caused a submaximal increase in forearm blood flow, measured by venous occlusion plethysmography, from 3.3 +/- 0.5 (mean +/- s.e. mean) to 13.3 +/- 1.7 ml min-1 100 ml-1. 3. Co-infusion of L-NMMA (4 mumol min-1) with acetylcholine (83 nmol min-1) over 6 min resulted in a 58% +/- 12% fall in the response to acetylcholine whereas during co-infusion of saline over the same time period in the same subjects (n = 8) on a different day the response to acetylcholine fell by only 9% +/- 17% (P < 0.01). 4. Methacholine (1.5 and 15 nmol min-1) increased forearm blood flow from 2.5 +/- 0.4 to 5.9 +/- 0.9 and from 3.2 +/- 0.4 to 17.0 +/- 1.9 ml min-1 100 ml-1 respectively. 5. Co-infusion of L-NMMA (4 mumol min-1) had no significant effect on the response to methacholine (1.5 or 15 nmol min-1) when compared with saline control (n = 8). Co-infusion of a higher dose of L-NMMA (8 mumol min-1) with methacholine (1.5 nmol min-1) did not significantly inhibit the vasodilator response (n = 7). 6. These results suggest that, in human forearm vasculature, methacholine acts predominantly through mechanisms other than the L-arginine/nitric oxide pathway.

Augmentation of sympathetic venoconstriction by angiotensin II in human dorsal hand veins.

The constriction produced by a single deep breath was measured simultaneously in two adjacent hand veins in normal subjects. One vein was infused with saline or angiotensin II; the other acted as a control. A dose of angiotensin II (1 pmol/min) that did produce venous constriction directly significantly augmented the constriction caused by deep breath in eight subjects (P less than .01). In a further six subjects the same dose had no effect on venoconstriction caused by infused noradrenaline. We conclude that angiotensin II causes venoconstriction indirectly by augmenting sympathetically mediated responses, possibly by a presynaptic mechanism.

Cardiovascular implications of exposure to traffic air pollution during exercise.

Regular aerobic exercise is recommended by physicians to improve health and longevity. However, individuals exercising in urban regions are often in contact with air pollution, which includes particles and gases associated with respiratory disease and cancer. We describe the recent evidence on the cardiovascular effects of air pollution, and the implications of exercising in polluted environments, with a view to informing clinicians and other health professionals. There is now strong evidence that fine and ultra fine particulate matter present in air pollution increases cardiovascular morbidity and mortality. The main mechanisms of disease appear to be related to an increase in the pathogenic processes associated with atherosclerosis. People exercising in environments pervaded by air contaminants are probably at increased risk, due to an exercise-induced amplification in respiratory uptake, lung deposition and toxicity of inhaled pollutants. We make evidence-based recommendations for minimizing exposure to air-borne toxins while exercising, and suggest that this advice be passed on to patients where appropriate.

Increased augmentation index and systolic stress in type 1 diabetes mellitus.

Type 1 diabetes mellitus is associated with endothelial dysfunction and increased arterial stiffness, both of which may contribute to the excess cardiovascular mortality in such patients. Arterial stiffening increases pulse wave velocity and wave reflection, which augments central systolic pressure and stress. Using the non-invasive technique of pulse wave analysis, we investigated aortic augmentation and central pressure in 35 patients with type 1 diabetes and 35 matched controls. Peripheral pulse waveforms were recorded from the radial artery. Central aortic waveforms were then generated, and augmentation index (AIx), ascending aortic pressure and tension time index (TTI), a measure of systolic load, were calculated. Peripheral and central blood pressure did not differ between the two groups. AIx was significantly elevated in the diabetic patients compared with controls (7.1+/-1.6% vs. 0.4+/-2.0%; p=0.01), as was the TTI (2307+/-51 mmHg x s x min(-1) vs. 2010+/-61 mmHg. s x min(-1); p<0.001). Estimated pulse wave velocity was also higher in the diabetic group. Type 1 diabetes is associated with an increased AIx and rate of wave travel, indicating enhanced wave reflection and increased systemic arterial stiffness, and elevation of the TTI. Such haemodynamic effects may contribute to the increased left ventricular mass and risk of cardiovascular disease associated with type 1 diabetes mellitus.

The effect of local angiotensin converting enzyme inhibition on the action of atrial natriuretic peptide in the human forearm.

It has been suggested that angiotensin converting enzyme (ACE) may play a role in the metabolism of atrial natriuretic peptide (ANP), and that ANP may interfere with angiotensin-induced vasoconstriction. This has been investigated within the forearm vascular bed during local ANP infusion and ACE inhibition. Six normotensive volunteers were studied, each on two occasions. On both occasions, after saline infusion, volunteers were given initially a 20 min infusion of ANP at 0.1 microgram/min via the brachial artery. This was followed, after 20 min, by a second infusion of ANP at the same dose, co-infused with enalaprilat (5 micrograms/min) on one occasion, and placebo (saline) on the other (in random order). Forearm blood flow was measured using venous occlusion plethysmography with mercury-in-silastic strain gauges. Blood flow in the cannulated arm increased significantly during the first ANP infusion; by 52 +/- 15% before placebo (P less than 0.05), and by 41 +/- 8% before enalaprilat (P less than 0.005). This increase was similar with the second ANP infusion during co-infusion of either placebo (40 +/- 10%) or enalaprilat (45 +/- 11%). Enalaprilat did not affect the half-life of vasodilatation produced by ANP (t1/2 = 5 min). These studies in healthy subjects demonstrate no effect of local ACE inhibition on resting blood flow, or on the vasodilatation produced by ANP in the human forearm, and provide no evidence of a role of ACE in the metabolism of ANP in this vascular bed.

Clinical pharmacology of angiotensin and bradykinin in human forearm vasculature.

HYPOTHESIS: Losartan inhibits the renin-angiotensin system by blockade of angiotensin II receptors, whereas enalapril blocks the renin-angiotensin system by inhibiting the conversion of angiotensin I to angiotensin II by the angiotensin converting enzyme (ACE). Since ACE inactivates bradykinin in addition to its action on angiotensin I we hypothesized that losartan and enalapril have different effects on the response to angiotensin and bradykinin. METHODS: We studied healthy volunteers dosed with placebo, enalapril and losartan 4-6 h before measurement of forearm blood flow by venous occlusion plethysmography. Saline, angiotensin I, angiotensin II and bradykinin were infused into the left brachial artery. RESULTS: Losartan produced a similar inhibition of the vasoconstriction induced by angiotensin I and angiotensin II without significantly influencing the bradykinin-induced vasodilation, whereas enalapril potentiated the vasodilator effect of bradykinin and selectively inhibited the vasoconstriction induced by angiotensin I without altering the response to angiotensin II. CONCLUSION: These pharmacological differences suggest that angiotensin II receptor antagonists and ACE inhibitors may not be therapeutically equivalent.