Forearm Vascular Responses Research Articles

Morphine is an arteriolar vasodilator in man

The mechanisms of action of morphine on the arterial system are not well understood. The aim was to report forearm vascular responses, and their mediation, to intra-arterial morphine in healthy subjects. Three separate protocols were performed: (i) dose ranging; (ii) acute tolerance; (iii) randomized crossover mechanistic study on forearm blood flow (FBF) responses to intrabrachial infusion of morphine using venous occlusion plethysmography. Morphine was infused either alone (study 1 and 2), or with an antagonist: naloxone, combined histamine-1 and histamine-2 receptor blockade or during a nitric oxide clamp. Morphine caused an increase in FBF at doses of 30 microg min(-1)[3.25 (0.26) ml min(-1) 100 ml(-1)][mean (SEM)] doubling at 100 microg min(-1) to 5.23 (0.53) ml min(-1) 100 ml(-1). Acute tolerance was not seen to 50 microg min(-1) morphine, with increased FBF [3.96 (0.35) ml min(-1) 100 ml(-1)] (P = 0.003), throughout the 30-min infusion period. Vasodilatation was abolished by pretreatment with antihistamines (P = 0.008) and the nitric oxide clamp (P < 0.001), but not affected by naloxone. The maximum FBF with pretreatment with combined H1/H2 blockade was 3.06 (0.48) and 2.90 (0.17) ml min(-1) 100 ml(-1) after 30 min, whereas with morphine alone it reached 4.3 (0.89) ml min(-1) 100 ml(-1). Intra-arterial infusion of morphine into the forearm circulation causes vasodilatation through local histamine-modulated nitric oxide release. Opioid receptor mechanisms need further exploration.

Effects of glucose tolerance on the changes provoked by glucose ingestion in microvascular function

Hyperglycaemia and hyperinsulinaemia have opposite effects on endothelium-dependent vasodilatation in microcirculation, but the net effect elicited by glucose ingestion and the separate influence of glucose tolerance are unknown. In participants with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or diabetic glucose tolerance, multiple plasma markers of both oxidative stress and endothelial activation, and forearm vascular responses (plethysmography) to intra-arterial acetylcholine (ACh) and sodium nitroprusside (SNP) infusions were measured before and after glucose ingestion. In another IGT group, we evaluated the time-course of the skin vascular responses (laser Doppler) to ACh and SNP (by iontophoresis) 1, 2 and 3 h into the OGTT; the plasma glucose profile was then reproduced by means of a variable intravenous glucose infusion and the vascular measurements repeated. Following oral glucose, plasma antioxidants were reduced by 5% to 10% (p < 0.01) in all patient groups. The response to acetylcholine was not affected by glucose ingestion in any group, while the response to SNP was attenuated, particularly in the IGT group. The ACh:SNP ratio was slightly improved therefore in all groups, even in diabetic participants, in whom it was impaired basally. A time-dependent improvement in ACh:SNP ratio was also observed in skin microcirculation following oral glucose; this improvement was blunted when matched hyperglycaemia was coupled with lower hyperinsulinaemia (intravenous glucose). Regardless of glucose tolerance, oral glucose does not impair endothelium-dependent vasodilatation either in resistance arteries or in the microcirculation, despite causing increased oxidative stress; the endogenous insulin response is probably responsible for countering any inhibitory effect on vascular function.

Exercise training in heart failure: reduction in angiotensin II, sympathetic nerve activity, and baroreflex control

neurohumoral excitation has been considered the hallmark of heart failure. At the humoral level, cardiac dysfunction has been shown to be associated with increased angiotensin II, aldosterone, and vasopressin levels. The clinical implication for such humoral dysregulation is the increase in salt and

Effect of graded leg cycling on postischaemic forearm blood flow in healthy subjects

This study assessed in healthy subjects, the effect of leg cycling on the forearm vascular responses to ischaemia to confirm previous results showing that exercise-induced sympathetic activation during leg cycling reduced postischaemic forearm hyperaemia. Seven young healthy subjects performed two bouts of cycling exercises at 50% and 80% of their maximal aerobic capacity (Ex(50), Ex(80) respectively) during which forearm arterial blood flow was successively occluded for 40, 90 and 180 s. Control forearm blood flow (FBF) and postischaemic forearm blood flow (pi-FBF) measured at the release of arterial occlusions were assessed using plethysmography. Digital arterial pressure was continuously monitored allowing calculation of control and postischaemic forearm conductance (FC and pi-FC respectively). At rest, pi-FBF increased with the duration of ischaemia (5 +/- 1, 19 +/- 3, 29 +/- 3, 31 +/- 4 ml min(-1) 100 ml(-1) after 0, 40, 90 and 180 s of ischaemia respectively). During Ex(50), FBF and pi-FBF did not change significantly although pi-FC was significantly reduced (Deltapi-FC = -39%, -33%, -27% for 40, 90, 180 s of ischaemia respectively). During Ex(80), there was a further dramatic decrease in pi-FC (-53%, -66%, -62% from rest) and pi-FBF were largely blunted (13 +/- 4 versus 19 +/- 3, 14 +/- 4 versus 29 +/- 3, 17 +/- 5 versus 31 +/- 4 ml min(-1) 100 ml(-1)). These results demonstrated that forearm responses to ischaemia depended on leg activities. It was suggested that exercise-induced sympathetic activation may have interfered on local vasodilatation because of ischaemia.

Forearm vascular responses to combined muscle metaboreceptor activation in the upper and lower limbs in humans

Our previous studies showed that venous occlusion or passive stretch of the lower limb, assuming a mechanical stimulus, attenuates the vasoconstriction in the non-exercised forearm during postexercise muscle ischaemia (PEMI) of the upper limb. In this study, we investigated whether a metabolic stimulus to the lower limb induces a similar response. Eight subjects performed a 2 min static handgrip exercise at 30% maximal voluntary contraction (MVC) followed by 3 min PEMI of the upper limb, concomitant with or without 2 min static ankle dorsiflexion at 30% MVC followed by 2 min PEMI of the lower limb. During PEMI of the upper limb alone, forearm blood flow (FBF) and forearm vascular conductance (FVC) in the non-exercised arm decreased significantly, whereas during combined PEMI of the upper and lower limbs, the decreases in FBF and FVC produced by PEMI of the upper limb was attenuated. Forearm blood flow and FVC were significantly greater during combined PEMI of the upper and lower limbs than during PEMI of the upper limb alone. When PEMI of the lower limb was released after combined PEMI of the upper and lower limbs (only PEMI of the upper limb was maintained continuously), the attenuated decreases in FBF and FVC observed during combined PEMI of the upper and lower limbs was not observed. Thus, forearm vascular responses differ when muscle metaboreceptors are activated in the upper limb and when there is combined activation of muscle metaboreceptors in both the upper and lower limbs.

Metformin Improves Endothelial Vascular Reactivity in First-Degree Relatives of Type 2 Diabetic Patients With Metabolic Syndrome and Normal Glucose Tolerance

Endothelial dysfunction is an early marker of atherosclerosis seen in type 2 diabetic subjects. Metformin is commonly used in the treatment of type 2 diabetes and has known vasculoprotective effects beyond its hypoglycemic ones. We aimed to investigate the vascular effects of metformin in first-degree relatives with metabolic syndrome of type 2 diabetic patients. The study included 31 subjects (age 38.3 +/- 7.6 years and BMI 36.3 +/- 5.2 kg/m2), who were first-degree relatives of type 2 diabetic patients and who had metabolic syndrome and normal glucose tolerance. The subjects were randomly assigned 1:1 in a double-blind fashion to receive placebo (n = 15) or metformin (n = 16). Endothelial function was assessed by venous occlusion plethysmography, measuring forearm blood flow (FBF) and vascular resistance responses to three intra-arterial infusions of endothelium-dependent (acetylcholine 7.5, 15, and 30 microg/min) and independent (sodium nitroprusside 2, 4, and 8 microg/min) vasodilators. Weight, BMI, systolic and diastolic blood pressure, waist, and laboratory parameters (lipid profile and fasting plasma glucose [FPG]) were assessed at baseline and after treatment. The metformin and placebo groups did not differ in anthropometric, clinical, laboratory, and vascular measurements at baseline. The metformin group had decreased weight, BMI, systolic blood pressure, and FPG and improved lipid profile. Endothelium-dependent FBF responses were also improved, without any effect on endothelium-independent responses. There was no correlation between the improvement on FBF responses and the observed changes on anthropometric, clinical, and laboratory parameters. We concluded that metformin improved vascular endothelial reactivity in first-degree relatives with metabolic syndrome of type 2 diabetic patients, independently of its known antihyperglycemic effects.

Metformin Improves Endothelial Vascular Reactivity in First-Degree Relatives of Type 2 Diabetic Patients With Metabolic Syndrome and Normal Glucose Tolerance

OBJECTIVE—Endothelial dysfunction is an early marker of atherosclerosis seen in type 2 diabetic subjects. Metformin is commonly used in the treatment of type 2 diabetes and has known vasculoprotective effects beyond its hypoglycemic ones. We aimed to investigate the vascular effects of metformin in first-degree relatives with metabolic syndrome of type 2 diabetic patients. RESEARCH DESIGN AND METHODS—The study included 31 subjects (age 38.3 ± 7.6 years and BMI 36.3 ± 5.2 kg/m2), who were first-degree relatives of type 2 diabetic patients and who had metabolic syndrome and normal glucose tolerance. The subjects were randomly assigned 1:1 in a double-blind fashion to receive placebo (n = 15) or metformin (n = 16). Endothelial function was assessed by venous occlusion plethysmography, measuring forearm blood flow (FBF) and vascular resistance responses to three intra-arterial infusions of endothelium-dependent (acetylcholine 7.5, 15, and 30 μg/min) and independent (sodium nitroprusside 2, 4, and 8 μg/min) vasodilators. Weight, BMI, systolic and diastolic blood pressure, waist, and laboratory parameters (lipid profile and fasting plasma glucose [FPG]) were assessed at baseline and after treatment. RESULTS—The metformin and placebo groups did not differ in anthropometric, clinical, laboratory, and vascular measurements at baseline. The metformin group had decreased weight, BMI, systolic blood pressure, and FPG and improved lipid profile. Endothelium-dependent FBF responses were also improved, without any effect on endothelium-independent responses. There was no correlation between the improvement on FBF responses and the observed changes on anthropometric, clinical, and laboratory parameters. CONCLUSIONS—We concluded that metformin improved vascular endothelial reactivity in first-degree relatives with metabolic syndrome of type 2 diabetic patients, independently of its known antihyperglycemic effects.

Vascular adrenergic responsiveness is inversely related to tonic activity of sympathetic vasoconstrictor nerves in humans

In humans, sympathetic nerve activity (SNA) at rest can vary several-fold among normotensive individuals with similar blood pressures. We recently showed that a balance exists between SNA and cardiac output, which may contribute to the maintenance of normal blood pressures over the range of resting SNA levels. In the present studies, we assessed whether variability in vascular adrenergic responsiveness has a role in this balance. We tested the hypothesis that forearm vascular responses to noradrenaline (NA) and tyramine (TYR) are related to SNA such that individuals with lower resting SNA have greater adrenergic responsiveness, and vice-versa. We measured multifibre muscle SNA (MSNA; microneurography), arterial pressure (brachial catheter) and forearm blood flow (plethysmography) in 19 healthy subjects at baseline and during intrabrachial infusions of NA and TYR. Resting MSNA ranged from 6 to 34 bursts min(-1), and was inversely related to vasoconstrictor responsiveness to both NA (r = 0.61, P = 0.01) and TYR (r = 0.52, P = 0.02), such that subjects with lower resting MSNA were more responsive to NA and TYR. We conclude that interindividual variability in vascular adrenergic responsiveness contributes to the balance of factors that maintain normal blood pressure in individuals with differing levels of sympathetic neural activity. Further understanding of this balance may have important implications for our understanding of the pathophysiology of hypertension.

Phase of the menstrual cycle does not affect orthostatic tolerance in healthy women

Women of child-bearing age have a lower orthostatic tolerance (OT) than older women or men, and women suffering from frequent syncopal episodes often comment that their symptoms occur at certain times of the menstrual cycle. However, it is not known whether, in asymptomatic women, OT varies at different phases of the menstrual cycle. We studied 8 healthy asymptomatic women aged 26.8 +/- 3.4 years. We determined OT using a test of combined head-up tilting and lower body suction. We continuously monitored beat-to-beat blood pressure (Finapres), heart rate (ECG), and cerebral and forearm blood flow velocities (Doppler ultrasound). On each test day we assessed carotid baroreceptor sensitivity from suction/pressure applied to a neck chamber. We also determined estradiol and progesterone levels from a venous blood sample. Tests were performed in early follicular and late luteal phases, and during ovulation. Serum concentrations of estradiol (pmol x l(-1)) and progesterone (nmol x l(-1)) were in follicular phase 464.1 +/- 63 and 6.3 +/- 2.8; ovulation 941.6 +/- 298 and 5.8 +/- 1.2; luteal phase 698 +/- 188 and 32.3 +/- 9.6. Progesterone levels were significantly higher in the luteal phase (p < 0.001). OT was not different on any test day: follicular 31.9 +/- 1.6 min, ovulation 31.3 +/- 0.7 min; luteal 31.1 +/- 2.2 min. Supine and tilted heart rates and blood pressures, the maximum heart rate, and the cerebral autoregulatory and forearm vascular resistance responses to the orthostatic stress were similar during all studies. Both cardiac and vascular resistance carotid baroreceptor sensitivities were also similar on all test days. These results suggest that there is no difference in either OT or cardiovascular control at the tested phases of the menstrual cycle in healthy women.

Elevated HDL Cholesterol is Functionally Ineffective in Cardiac Transplant Recipients: Evidence for Impaired Reverse Cholesterol Transport

Cardiac transplant recipients frequently have high plasma HDL levels but it is unclear whether these promote a cardioprotective profile. Parameters of reverse cholesterol transport and endothelial function were compared in 25 cardiac transplant recipients with low (<1.4 mmol/L; n=11) or high (>1.4 mmol/L; n=14) plasma levels of HDL and in a reference healthy group. Patients with high HDL had lower levels of triglyceride and prebeta1-HDL and a higher proportion of large HDL particles. When normalized to apoA-I content, non-ABCA1-dependent cholesterol efflux from RAW 264.7 macrophage cells to plasma from high HDL patients was 33% lower when compared to plasma from patients with low HDL, whereas ABCA1-dependent cholesterol efflux was not impaired. Forearm vascular responses to acetylcholine and sodium nitroprusside were not influenced by HDL levels in these patients. Compared to a reference healthy group (n=26), cardiac transplant recipients had higher levels of triglyceride, lower levels of prebeta1-HDL and LCAT, and lower activities of cholesteryl ester transfer protein and phospholipid transfer protein. Hyperalphalipoproteinaemia in cardiac transplant recipients is associated with the formation of partially dysfunctional HDL. We conclude that high levels of HDL may not confer cardioprotection in this group of patients.

Forearm Vascular Response to Nitric Oxide and Calcitonin Gene- Related Peptide: Comparison between Migraine Patients and Control Subjects

The forearm vascular response to nitric oxide (NO) and calcitonin gene-related peptide (CGRP) was investigated in 10 migraine patients and 10 matched control subjects. Changes in forearm blood flow (FBF) during intrabrachial infusion of: (i) serotonin (releasing endogenous NO), (ii) sodium nitroprusside (SNP, exogenous NO-donor), and (iii) CGRP were measured using venous occlusion plethysmography. Flow-mediated dilation (FMD) of the brachial artery, a measure for the endogenous release of NO reactive to occlusion, was measured using ultrasound and expressed as percentage change vs. baseline diameter. FBF ratio (i.e. FBF in the infused over the control arm) at baseline (1.1 +/- 0.1) did not differ between both populations. Serotonin, SNP and CGRP induced a dose-dependent increase (P < 0.001) in FBF ratio in controls (to 2.8 +/- 0.3, 6.7 +/- 1.4 and 6.9 +/- 1.2 at the highest dose, respectively) and migraineurs (2.5 +/- 0.4, 5.6 +/- 0.8 and 6.5 +/- 1.3, respectively); these ratios did not differ between both groups. FMD was comparable in control subjects (5.8 +/- 1%) and migraine patients (5.2 +/- 1%). Based on the forearm vascular response to NO and CGRP, migraine patients do not display generalized changes in vascular function.

Responses to neither exogenous nor endogenous endothelin-1 are altered in patients with hypercholesterolemia

There is some controversy regarding whether vascular responses to endothelin are altered in hypercholesterolemia. Studies performed to date have been compromised by the use of endothelin antagonists at inappropriate concentrations. In the current study, we examine the role of endothelin-1 in hypercholesterolemic patients using lower, more selective doses of specific endothelin antagonists. Twenty-two patients with hypercholesterolemia (total plasma cholesterol > 6.0 mmol/l) and 17 healthy controls were recruited. Forearm vascular responses to endothelin-1 (5 pmol/min), the endothelin A antagonist BQ-123 (10 nmol/min), and the endothelin B antagonist BQ-788 (1 nmol/min) were obtained. Endothelin-1 caused a significant vasoconstriction in both hypercholesterolemic and control subjects, an effect that was not significantly different between the two groups (P = 0.784). BQ-123 caused a significant vasodilatation that was not significantly different between the two groups (P = 0.899). Similarly, responses to BQ-788 (P = 0.774) and mean plasma endothelin-1 levels were not different (control vs. hypercholesterolemia, 1.16 +/- 0.18 vs. 1.06 +/- 0.15 fmol/ml; P = 0.64). Responses to neither exogenous nor endogenous endothelin are influenced by plasma cholesterol levels in humans. It is thus unlikely that the endothelin system contributes to early vascular disease pathology in patients with hypercholesterolemia.

Endothelin-1 levels predict 3-year survival in patients who have amputation for critical leg ischaemia

Most patients with critical leg ischaemia (CLI) have co-existing coronary heart disease, which is the main cause of their increased mortality rate. The aim of this study was to investigate whether any markers of endothelial function could predict death in these patients. In a cohort of 39 patients with CLI who were scheduled for lower-limb amputation, blood levels of vascular endothelial growth factor, homocysteine, endothelin (ET) 1, von Willebrand factor and vascular cell adhesion molecule 1 were measured, as well as forearm vascular responses to the endothelium-dependent vasodilator acetylcholine. Levels of ET-1 were significantly higher in patients who subsequently died within 3 years than in those who were still alive (P = 0.002) and Cox proportional hazards regression analysis demonstrated that ET-1 was an independent predictor of all-cause mortality:hazard ratio 3.53 (95 per cent confidence interval (c.i.) 1.29 to 9.70; P = 0.007) and cardiovascular mortality:hazard ratio 4.15 (95 per cent c.i. 1.30 to 13.23); P = 0.014. ET-1 was an independent predictor of death in these patients with CLI.

Reversal of Inappropriate Peripheral Vascular Responses in Hypertrophic Cardiomyopathy

We assessed the frequency of abnormal forearm vasodilator responses during lower body negative pressure (LBNP) in 21 non-obstructive hypertrophic cardiomyopathy (HCM) patients (31 +/- 8 [20 to 43] years) with abnormal blood pressure response (ABPR) to exercise and the effects of three drugs used to treat vasovagal syncope (propranolol, clonidine, and paroxetine) in a double-blind crossover study. Some HCM patients have an ABPR to exercise, which may be due to paradoxical peripheral vasodilatation. A similar proportion has paradoxical forearm vasodilatation during central volume unloading using LBNP. These abnormal reflexes may be caused by left ventricular mechanoreceptor activation. Similar mechanisms may also contribute to some cases of vasovagal syncope. Blood pressure changes were assessed during exercise, and forearm vascular responses and baroreceptor sensitivity were assessed during LBNP using plethysmography. Nine (43%) patients (group A) had paradoxical vasodilator responses (forearm vascular resistance [FVR] fell by 7.5 +/- 4.6 U), and 12 (57%) patients (group B) had normal vasoconstrictor responses during LBNP (FVR increased by 7.7 +/- 4.9 U). Paroxetine augmented systolic blood pressure (SBP) during exercise in group A (21 +/- 6 mm Hg vs. 14 +/- 11 mm Hg at baseline, p = 0.02); no effect was detected in group B. Paroxetine reversed paradoxical vascular responses during LBNP in seven (78%) patients from group A. Propranolol and clonidine had no significant effect on SBP during exercise but reversed paradoxical vascular responses in some patients from group A (n = 5 and n = 3). Paradoxical vasodilatation during LBNP occurs in 40% of patients with ABPR during exercise and is reversed by propranolol, clonidine, and paroxetine. Paroxetine also improved SBP response to exercise.

Central command and the cutaneous vascular response to isometric exercise in heated humans

Cutaneous vascular conductance (CVC) decreases during isometric handgrip exercise in heat stressed individuals, and we hypothesized that central command is involved in this response. Seven subjects performed 2 min of isometric handgrip exercise (35% of maximal voluntary contraction) followed by postexercise ischaemia in normothermia and during heat stress (increase in internal temperature approximately 1 degrees C). To augment the contribution of central command independent of force generation, on a separate day the protocol was repeated following partial neuromuscular blockade (PNB; i.v. cisatracurium). Forearm skin blood flow was measured by laser-Doppler flowmetry, and CVC was the ratio of skin blood flow to mean arterial pressure. The PNB attenuated force production despite encouragement to attain the same workload. During the heat stress trials, isometric exercise decreased CVC by approximately 12% for both conditions, but did not change CVC in either of the normothermic trials. During isometric exercise in the heat, the increase in mean arterial pressure (MAP) was greater during the control trial relative to the PNB trial (31.0+/-9.8 versus 18.6+/-6.4 mmHg, P<0.01), while the elevation of heart rate tended to be lower (19.4+/-10.4 versus 27.4+/-8.1 b.p.m., P=0.15). During postexercise ischaemia, CVC and MAP returned to pre-exercise levels in the PNB trial but remained reduced in the control trial. These findings suggest that central command, as well as muscle metabo-sensitive afferent stimulation, contributes to forearm cutaneous vascular responses in heat stressed humans.

Effects of cerivastatin on forearm vascular responses, blood pressure responsiveness and ambulatory blood pressure in type 2 diabetic men

The objective of the study was to investigate the effects of cerivastatin therapy on forearm endothelial dependent acetylcholine (ACH) and independent (nitroprusside) vasodilator responses, blood pressure (BP) responses to intravenous infusions of angiotensin II (AII) and noradrenaline (NA) and on 24-h ambulatory BP recordings in type 2 diabetic men. Eleven type 2 diabetic men aged 59 +/- 9 years with total cholesterol levels of 5.0 +/- 1.26 mmol/l, triglycerides of 2.23 mmol/l and high-density lipoprotein cholesterol levels of 1.24 mmol/l completed a double-blind, randomized, crossover trial comparing 8 weeks of cerivastatin therapy (800 microg of nocte) with placebo. Forearm vascular resistance (FVR) responses to intrabrachial-arterial infusions of ACH (3-24 microg/min), nitroprusside (2-16 microg/min), the nitric oxide(NO) synthase inhibitor l-nitro-mono-methyl arginine (l-nmma) (8 micromol/min), ACH during l-NMMA infusion and BP responses to intravenous infusions of AII (12.5-50 ng/min) and NA (20-400 ng/min) were measured at the end of each treatment period. Twenty-four-hour ambulatory BP recordings were also performed. FVR responses to ACH during l-NMMA infusion were significantly (p = 0.026) greater during cerivastatin than during placebo therapy. In contrast, FVR responses to ACH in the absence of NO synthase inhibition did not differ significantly between cerivastatin and placebo therapies (p = 0.81). FVR increased by 31.4 +/- 57.3% in response to l-NMMA infusion during cerivastatin therapy compared with 6.1 +/- 41.2% during placebo therapy (p = 0.20). FVR responses to nitroprusside did not differ between cerivastatin and placebo therapies (p = 0.28), nor did BP responses to AII (systolic BP, p = 0.99; diastolic BP, p = 0.98) or NA (systolic BP, p = 0.21; diastolic BP, p = 0.48). Mean 24-h BP was similar during cerivastatin (123 +/- 10 or 70 +/- 7 mmHg) and placebo therapies (129 +/- 11 or 74 +/- 7 mmHg) (systolic BP, p = 0.26; diastolic BP, p = 0.41). Cerivastatin increases FVR responses to ACH in type 2 diabetic men with mild dyslipidaemia but only following NO synthase inhibition. This may indicate an improvement in endothelium-derived hyperpolarizing factor-mediated responses.

Gly16 + Glu27 β2-adrenoceptor polymorphisms cause increased forearm blood flow responses to mental stress and handgrip in humans

We hypothesized that the muscle vasodilatation during mental stress and exercise would vary among humans who are polymorphic at alleles 16 and 27 of the beta(2)-adrenoceptors. From 216 preselected volunteers, we studied 64 healthy, middle-aged normotensive women selected to represent three genotypes: homozygous for the alleles Arg(16) and Gln(27) (Arg(16)/Gln(27), n = 34), Gly(16) and Gln(27) (Gly(16)/Gln(27), n = 20), and Gly(16) and Glu(27) (Gly(16)/Glu(27), n = 10). Forearm blood flow (plethysmography) and muscle sympathetic nerve activity (microneurography) were recorded during 3-min Stroop color-word test and 3-min handgrip isometric exercise (30% maximal voluntary contraction). Baseline muscle sympathetic nerve activity, forearm vascular conductance, mean blood pressure, and heart rate were not different among groups. During mental stress, the peak forearm vascular conductance responses were greater in Gly(16)/Glu(27) group than in Gly(16)/Gln(27) and Arg(16)/Gln(27) groups (1.79 +/- 0.66 vs. 0.70 +/- 0.11 and 0.58 +/- 0.12 units, P = 0.03). Similar results were found during exercise (0.80 +/- 0.25 vs. 0.28 +/- 0.08 and 0.31 +/- 0.08 units, P = 0.02). Further analysis in a subset of subjects showed that brachial intra-arterial propranolol infusion abolished the difference in vasodilatory response between Gly(16)/Glu(27) (n = 6) and Arg(16)/Gln(27) (n = 7) groups during mental stress (0.33 +/- 0.20 vs. 0.46 +/- 0.21 units, P = 0.50) and exercise (0.08 +/- 0.06 vs. 0.03 +/- 0.03 units, P = 0.21). Plasma epinephrine concentration in Arg(16)/Gln(27) and Gly(16)/Glu(27) groups was similar. In conclusion, women who are homozygous for Gly(16)/Glu(27) of the beta(2)-adrenoceptors have augmented muscle vasodilatory responsiveness to mental stress and exercise.

Acute effects of hydrocortisone on plasma nitrate/nitrite activity and forearm vasodilator responsiveness in normal human subjects

1. The aim of the present study was to examine the acute effects of cortisol infusion on plasma nitrate/nitrite (NO) activity and forearm vascular responsiveness to acetylcholine. 2. We performed two randomized, placebo-controlled, cross-over studies. Study A examined the effects of intravenous hydrocortisone (200 mg over a 3 h period) on blood pressure (BP) and plasma NO activity in six healthy male volunteers. Study B examined the effects of intra-arterial hydrocortisone on cholinergic vasodilator responsiveness in six healthy male volunteers. Vasodilator responsiveness was measured by bilateral strain gauge plethysmography. 3. In study A, there was no significant change in BP during the hydrocortisone infusion. Comparing values obtained following 180 min infusion of hydrocortisone and control, there were significant increases in plasma cortisol (3441 +/- 342 vs 209 +/- 29 nmol/L, respectively; P < 0.001) and glucose (5.7 +/- 0.2 vs 4.6 +/- 0.2 mmol/L, respectively; P < 0.05) and a reduction in plasma renin concentration (PRC) (8.1 +/- 1.2 vs 11.0 +/- 1.8 pg/mL, respectively; P < 0.05) following hydrocortisone infusion. However, there were no significant changes in either plasma NO or in the endogenous NO synthase inhibitors asymmetrical and symmetrical dimethylarginine. 4. In study B, there was no significant change in BP or in cholinergic vasodilator responsiveness during the hydrocortisone infusion. 5. Short-term cortisol infusions do not alter biochemical or physiological markers of NO activity. If cortisol-induced hypertension is mediated by suppression of NO activity in humans, it seems likely that these changes take more than 3 h to become detectable.

Increase in systemic blood pressure during intra‐arterial PD123319 Infusion: Evidence for functional expression of angiotensin type 2 receptors in normal volunteers

The functional existence of angiotensin type 2 (AT2) receptors in healthy humans is uncertain. A double‐blind, randomized, crossover study was performed comparing forearm vascular responses to intra‐brachial arterial PD123319 (a selective AT2 receptor antagonist, 10 μg/min) in healthy young, non‐smoking volunteers following 1 week of telmisartan therapy (40–80 mg once daily) and 1 week of placebo therapy. No significant difference was found in baseline mean arterial pressure between telmisartan and placebo treatment. Baseline forearm blood flow (FBF) was significantly higher during telmisartan (2.69 ± 1.28 ml/s) therapy than during placebo (1.86 ± 0.75 ml/s). PD123319 did not alter FBF on either telmisartan or placebo therapy. However, significant increases in mean arterial pressure were observed during intra‐brachial arterial infusions of PD123319 (p = 0.003) during both placebo (80 ± 9 to 92 ± 17 mmHg) and telmisartan (80 ± 11 to 90 ± 14 mmHg) therapy suggesting the presence of functional AT2 receptors, possibly in locations other than the forearm resistance vessels. Intra‐brachial arterial infusion of PD123319 (10 μg/min) has significant systemic effects, which appear more prominent than local changes in FBF and which are not influenced by angiotensin type 1 receptor blockade.

Plasma C-reactive protein, but not protein S, VCAM-1, von Willebrand factor or P-selectin, is associated with endothelium dysfunction in coronary artery disease

Abnormal endothelium-dependent vasodilatation is well documented in coronary artery disease (CAD), as are significant increases of acute phase inflammatory proteins and other soluble hepatic and endothelium derived proteins. In the current study we investigated whether there is a relationship between endothelium-dependent vasodilatation and the plasma levels of such proteins. Further we examined the association between these proteins, together with age, cholesterol and endothelium function, and participant status (i.e. healthy, smoker, coronary artery disease). Three groups of participants were recruited: healthy controls ( n=20), cigarette smokers ( n=20) and patients with coronary artery disease ( n=20). Forearm vascular dilatation responses to the endothelium-dependent agonist acetylcholine were obtained using venous occlusion plethysmography. Blood was sampled at the time of study for the measurement of the serological proteins described above. Responses to acetylcholine were significantly dampened in patients with CAD when compared with control and smoker groups (forearm blood flow at acetylcholine 37 μg/min): control, smokers, CAD, 12.14±2.14, 12.35±0.94, 5.12±0.81, ANOVA, P<0.05). Responses to acetylcholine were not different between controls and smokers. C-reactive protein (C-RP) levels (controls, smokers, CAD, 1.40±0.19, 2.27±0.71, 4.73±1.09, P<0.05) and protein S levels were significantly higher in the CAD group compared with the other two groups. There was a significant inverse correlation between forearm blood flow responses to acetylcholine and C-reactive proteins. Both responses to acetylcholine and C-RP levels demonstrated a significant association with participant status with the r value increasing from 0.405 for responses to acetylcholine to 0.491 for the combination of responses to acetylcholine and C-RP. We conclude that there is an inverse correlation between C-reactive protein, but not protein S, VCAM-1, P-selectin nor von Willebrand factor, levels and abnormal endothelium-dependent vasodilation and further that responses to acetylcholine together with C-RP protein have a strong association with cardiovascular risk and disease.