Sally Brett

Gender differences in sensitivity to adrenergic agonists of forearm resistance vasculature.

OBJECTIVES The goal of this study was to investigate the mechanism of reduced vasoconstrictor sensitivity to norepinephrine in women compared with men. BACKGROUND beta2-adrenergic agonists such as albuterol dilate forearm resistance vessels, partly by activating the L-arginine/nitric oxide pathway. Norepinephrine (which acts as beta- as well as alpha-adrenergic receptors) causes less forearm vasoconstriction in women than it does in men. This could be explained by a greater sensitivity to beta2-receptor stimulation in women than in men. METHODS Forearm blood flow was measured by venous occlusion plethysmography in healthy women (days 10 to 14 of the menstrual cycle) and in men. Drugs were administered via the brachial artery in three separate protocols: albuterol +/- NG-monomethyl-L-arginine (an inhibitor of nitric oxide synthase); substance P, nitroprusside and verapamil (control vasodilators); norepinephrine (+/- propranolol, a beta-adrenergic receptor antagonist). RESULTS Vasodilator responses to albuterol were greater in women than they were in men (p = 0.02 by analysis of variance). NG-monomethyl-L-arginine reduced these similarly in men and women. Responses to control vasodilators were less in women than they were in men (each p < 0.05). Norepinephrine caused less vasoconstriction in women than it did in men (p = 0.02). Propranolol did not influence basal flow in either gender nor responses of men to norepinephrine but increased vasoconstriction to each dose of norepinephrine in women (p < 0.0001 for interaction between gender and propranolol). Responses to norepinephrine coinfused with propranolol were similar in men and women. CONCLUSIONS Stimulation of beta2-adrenergic receptors causes greater forearm vasodilation in premenopausal women, at midmenstrual cycle, than it does in men. This is sufficient to explain why vasoconstriction to brachial artery norepinephrine is attenuated in such women.

Neuronal Nitric Oxide Synthase Regulates Basal Microvascular Tone in Humans In Vivo

Background— Nitric oxide (NO) has a pivotal role in the regulation of vascular tone and blood flow, with dysfunctional release contributing to disease pathophysiology. These effects have been attributed to NO production by the endothelial NO synthase (eNOS); however, recent evidence suggests that a neuronal NO synthase (nNOS) may also be expressed in arterial vessels. Methods and Results— We undertook a first-in-humans investigation of the role of nNOS in the local regulation of vascular blood flow in healthy subjects. Brachial artery infusion of the nNOS-specific inhibitor S-methyl-l-thiocitrulline (SMTC, 0.025 &mgr;mol/min to 0.2 &mgr;mol/min) caused a dose-dependent reduction in basal flow, with a 30.1±3.8% decrease at the highest dose (n=10; mean±SE; P<0.01). The effect of SMTC was abolished by coinfusion of the NO synthase substrate l-arginine but was unaffected by d-arginine. A similar reduction in basal flow with the nonselective NO synthase inhibitor NG-monomethyl-l-arginine (L-NMMA; 37.4±3.1%, n=10) required a 20-fold higher dose of 4 &mgr;mol/min. At doses that produced comparable reductions in basal flow, only L-NMMA (4 &mgr;mol/min) and not SMTC (0.2 &mgr;mol/min) inhibited acetylcholine-induced vasodilation; however, both SMTC and L-NMMA inhibited the forearm vasodilator response to mental stress. Conclusions— Basal forearm blood flow in humans is regulated by nNOS-derived NO, in contrast to the acetylcholine-stimulated increase in blood flow, which, as shown previously, is mediated primarily by eNOS. These data indicate that vascular nNOS has a distinct local role in the physiological regulation of human microvascular tone in vivo.

Exercise reduces arterial pressure augmentation through vasodilation of muscular arteries in humans

Exercise markedly influences pulse wave morphology, but the mechanism is unknown. We investigated whether effects of exercise on the arterial pulse result from alterations in stroke volume or pulse wave velocity (PWV)/large artery stiffness or reduction of pressure wave reflection. Healthy subjects (n = 25) performed bicycle ergometry. with workload increasing from 25 to 150 W for 12 min. Digital arterial pressure waveforms were recorded using a servo-controlled finger cuff. Radial arterial pressure waveforms and carotid-femoral PWV were determined by applanation tonometry. Stroke volume was measured by echocardiography, and brachial and femoral artery blood flows and diameters were measured by ultrasound. Digital waveforms were recorded continuously. Other measurements were made before and after exercise. Exercise markedly reduced late systolic and diastolic augmentation of the peripheral pressure pulse. At 15 min into recovery, stroke volume and PWV were similar to baseline values, but changes in pulse wave morphology persisted. Late systolic augmentation index (radial pulse) was reduced from 54 +/- 3.9% at baseline to 42 +/- 3.7% (P < 0.01), and diastolic augmentation index (radial pulse) was reduced from 37 +/- 1.8% to 25 +/- 2.9% (P < 0.001). These changes were accompanied by an increase in femoral blood flow (from 409 +/- 44 to 773 +/- 48 ml/min, P < 0.05) and an increase in femoral artery diameter (from 8.2 +/- 0.4 to 8.6 +/- 0.4 mm, P < 0.05). In conclusion, exercise dilates muscular arteries and reduces arterial pressure augmentation, an effect that will enhance ventricular-vascular coupling and reduce load on the left ventricle.

Oral treatment with an antioxidant (raxofelast) reduces oxidative stress and improves endothelial function in men with Type II diabetes

Aims/hypothesis. To determine whether raxofelast, a new water soluble antioxidant decreases oxidative stress and improves endothelial function in men with Type II (non-insulin dependent) diabetes mellitus. Methods. We treated ten normotensive, normocholesterolaemic men with Type II diabetes and as controls ten healthy men matched with them for age with raxofelast (600 mg twice daily) for 1 week. Plasma 8-epi-PGF2α, a non-enzymic oxidation product of arachidonic acid was measured by gas chromatography/mass spectrometry as an index of oxidative stress. Forearm vasodilator responses to brachial artery infusion of acetylcholine (7.5, 15 and 30 μg min–1) and of the nitric oxide donor nitroprusside (1, 3 and 10 μg min–1) were measured by strain gauge plethysmography. Results. Plasma concentrations of 8-epi-PGF2α were greater in diabetic than in control men (0.99 ± 0.20 vs 0.18 ± 0.01 nmol l–1, means ± SEM, p < 0.001) and fell after raxofelast (from 0.99 ± 0.20 to 0.47 ± 0.07 nmol l–1, p < 0.05) in diabetic men but not in control men. Blood flow responses to acetylcholine were lower (p < 0.05) in diabetic than in control men (7.4 ± 1.0 vs 12.9 ± 2.3 ml · min–1· 100 ml–1 for the highest dose). In diabetic men, but not in control men, raxofelast increased (p < 0.05) blood flow responses to acetylcholine (from 7.4 ± 1.0 ml · min–1· 100 ml–1 to 11.3 ± 2.3 ml · min–1· 100 ml–1 at highest dose). Blood flow responses to nitroprusside were similar in control and diabetic men and in both groups were similar before and after raxofelast. Conclusion/interpretation. Oral treatment with raxofelast for 1 week reduces oxidative stress and improves endothelial function in men with Type II diabetes. [Diabetologia (2000) 43: 974–977]

Augmentation pressure is influenced by ventricular contractility/relaxation dynamics: novel mechanism of reduction of pulse pressure by nitrates.

Augmentation pressure (AP), the increment in aortic pressure above its first systolic shoulder, is thought to be determined mainly by pressure wave reflection but could be influenced by ventricular ejection characteristics. We sought to determine the mechanism by which AP is selectively reduced by nitroglycerin (NTG). Simultaneous measurements of aortic pressure and flow were made at the time of cardiac catheterization in 30 subjects (11 women; age, 61±13 years [mean±SD]) to perform wave intensity analysis and calculate forward and backward components of AP generated by the ventricle and arterial tree, respectively. Measurements were made at baseline and after NTG given systemically (800 &mgr;g sublingually, n=20) and locally by intracoronary infusion (1 &mgr;g/min; n=10). Systemic NTG had no significant effect on first shoulder pressure but reduced augmentation (and central pulse pressure) by 12.8±3.1 mm Hg (P<0.0001). This resulted from a reduction in forward and backward wave components of AP by 7.0±2.4 and 5.8±1.3 mm Hg, respectively (each P<0.02). NTG had no significant effect on the ratio of amplitudes of either backward/forward waves or backward/forward compression wave energies, suggesting that effects on the backward wave were largely secondary to those on the forward wave. Time to the forward expansion wave was reduced (P<0.05). Intracoronary NTG decreased AP by 8.3±3.6 mm Hg (P<0.05) with no significant effect on the backward wave. NTG reduces AP and central pulse pressure by a mechanism that is, at least in part, independent of arterial reflections and relates to ventricular contraction/relaxation dynamics with enhanced myocardial relaxation.Augmentation pressure (AP), the increment in aortic pressure above its first systolic shoulder, is thought to be determined mainly by pressure wave reflection but could be influenced by ventricular ejection characteristics. We sought to determine the mechanism by which AP is selectively reduced by nitroglycerin (NTG). Simultaneous measurements of aortic pressure and flow were made at the time of cardiac catheterization in 30 subjects (11 women; age, 61±13 years [mean±SD]) to perform wave intensity analysis and calculate forward and backward components of AP generated by the ventricle and arterial tree, respectively. Measurements were made at baseline and after NTG given systemically (800 μg sublingually, n=20) and locally by intracoronary infusion (1 μg/min; n=10). Systemic NTG had no significant effect on first shoulder pressure but reduced augmentation (and central pulse pressure) by 12.8±3.1 mm Hg ( P <0.0001). This resulted from a reduction in forward and backward wave components of AP by 7.0±2.4 and 5.8±1.3 mm Hg, respectively (each P <0.02). NTG had no significant effect on the ratio of amplitudes of either backward/forward waves or backward/forward compression wave energies, suggesting that effects on the backward wave were largely secondary to those on the forward wave. Time to the forward expansion wave was reduced ( P <0.05). Intracoronary NTG decreased AP by 8.3±3.6 mm Hg ( P <0.05) with no significant effect on the backward wave. NTG reduces AP and central pulse pressure by a mechanism that is, at least in part, independent of arterial reflections and relates to ventricular contraction/relaxation dynamics with enhanced myocardial relaxation. # Novelty and Significance {#article-title-30}

Augmentation Pressure Is Influenced by Ventricular Contractility/Relaxation DynamicsNovelty and Significance: Novel Mechanism of Reduction of Pulse Pressure by Nitrates

Augmentation pressure (AP), the increment in aortic pressure above its first systolic shoulder, is thought to be determined mainly by pressure wave reflection but could be influenced by ventricular ejection characteristics. We sought to determine the mechanism by which AP is selectively reduced by nitroglycerin (NTG). Simultaneous measurements of aortic pressure and flow were made at the time of cardiac catheterization in 30 subjects (11 women; age, 61±13 years [mean±SD]) to perform wave intensity analysis and calculate forward and backward components of AP generated by the ventricle and arterial tree, respectively. Measurements were made at baseline and after NTG given systemically (800 &mgr;g sublingually, n=20) and locally by intracoronary infusion (1 &mgr;g/min; n=10). Systemic NTG had no significant effect on first shoulder pressure but reduced augmentation (and central pulse pressure) by 12.8±3.1 mm Hg (P<0.0001). This resulted from a reduction in forward and backward wave components of AP by 7.0±2.4 and 5.8±1.3 mm Hg, respectively (each P<0.02). NTG had no significant effect on the ratio of amplitudes of either backward/forward waves or backward/forward compression wave energies, suggesting that effects on the backward wave were largely secondary to those on the forward wave. Time to the forward expansion wave was reduced (P<0.05). Intracoronary NTG decreased AP by 8.3±3.6 mm Hg (P<0.05) with no significant effect on the backward wave. NTG reduces AP and central pulse pressure by a mechanism that is, at least in part, independent of arterial reflections and relates to ventricular contraction/relaxation dynamics with enhanced myocardial relaxation.Augmentation pressure (AP), the increment in aortic pressure above its first systolic shoulder, is thought to be determined mainly by pressure wave reflection but could be influenced by ventricular ejection characteristics. We sought to determine the mechanism by which AP is selectively reduced by nitroglycerin (NTG). Simultaneous measurements of aortic pressure and flow were made at the time of cardiac catheterization in 30 subjects (11 women; age, 61±13 years [mean±SD]) to perform wave intensity analysis and calculate forward and backward components of AP generated by the ventricle and arterial tree, respectively. Measurements were made at baseline and after NTG given systemically (800 μg sublingually, n=20) and locally by intracoronary infusion (1 μg/min; n=10). Systemic NTG had no significant effect on first shoulder pressure but reduced augmentation (and central pulse pressure) by 12.8±3.1 mm Hg ( P <0.0001). This resulted from a reduction in forward and backward wave components of AP by 7.0±2.4 and 5.8±1.3 mm Hg, respectively (each P <0.02). NTG had no significant effect on the ratio of amplitudes of either backward/forward waves or backward/forward compression wave energies, suggesting that effects on the backward wave were largely secondary to those on the forward wave. Time to the forward expansion wave was reduced ( P <0.05). Intracoronary NTG decreased AP by 8.3±3.6 mm Hg ( P <0.05) with no significant effect on the backward wave. NTG reduces AP and central pulse pressure by a mechanism that is, at least in part, independent of arterial reflections and relates to ventricular contraction/relaxation dynamics with enhanced myocardial relaxation. # Novelty and Significance {#article-title-30}

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

Objective To compare effects of NG-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.

Dominance of the Forward Compression Wave in Determining Pulsatile Components of Blood Pressure: Similarities Between Inotropic Stimulation and Essential Hypertension

Pulsatile components of blood pressure may arise from forward (ventricular generated) or backward wave travel in the arterial tree. The objective of this study was to determine the relative contributions of forward and backward waves to pulsatility. We used wave intensity and wave separation analysis to determine pulsatile components of blood pressure during inotropic and vasopressor stimulation by dobutamine and norepinephrine in normotensive subjects and compared pulse pressure components in hypertensive (mean±SD, 48.8±11.3 years; 165±26.6/99±14.2 mm Hg) and normotensive subjects (52.2±12.6 years; 120±14.2/71±8.2 mm Hg). Dobutamine (7.5 &mgr;g/kg per minute) increased the forward compression wave generated by the ventricle and increased pulse pressure from 36.8±3.7 to 59.0±3.4 mm Hg (mean±SE) but had no significant effect on mean arterial pressure or the midsystolic backward compression wave. By contrast, norepinephrine (50 ng/kg per minute) had no significant effect on the forward compression wave but increased the midsystolic backward compression wave. Despite this increase in the backward compression wave, and an increase in mean arterial pressure, norepinephrine increased central pulse pressure less than dobutamine (increases of 22.1±3.8 and 7.2±2.8 mm Hg for dobutamine and norepinephrine, respectively; P<0.02). An elevated forward wave component (mean±SE, 50.4±3.4 versus 35.2±1.8 mm Hg, in hypertensive and normotensive subjects, respectively; P<0.001) accounted for approximately two thirds of the total difference in central pulse pressures between hypertensive and normotensive subjects. Increased central pulse pressure during inotropic stimulation and in essential hypertension results primarily from the forward compression wave.Pulsatile components of blood pressure may arise from forward (ventricular generated) or backward wave travel in the arterial tree. The objective of this study was to determine the relative contributions of forward and backward waves to pulsatility. We used wave intensity and wave separation analysis to determine pulsatile components of blood pressure during inotropic and vasopressor stimulation by dobutamine and norepinephrine in normotensive subjects and compared pulse pressure components in hypertensive (mean±SD, 48.8±11.3 years; 165±26.6/99±14.2 mm Hg) and normotensive subjects (52.2±12.6 years; 120±14.2/71±8.2 mm Hg). Dobutamine (7.5 μg/kg per minute) increased the forward compression wave generated by the ventricle and increased pulse pressure from 36.8±3.7 to 59.0±3.4 mm Hg (mean±SE) but had no significant effect on mean arterial pressure or the midsystolic backward compression wave. By contrast, norepinephrine (50 ng/kg per minute) had no significant effect on the forward compression wave but increased the midsystolic backward compression wave. Despite this increase in the backward compression wave, and an increase in mean arterial pressure, norepinephrine increased central pulse pressure less than dobutamine (increases of 22.1±3.8 and 7.2±2.8 mm Hg for dobutamine and norepinephrine, respectively; P <0.02). An elevated forward wave component (mean±SE, 50.4±3.4 versus 35.2±1.8 mm Hg, in hypertensive and normotensive subjects, respectively; P <0.001) accounted for approximately two thirds of the total difference in central pulse pressures between hypertensive and normotensive subjects. Increased central pulse pressure during inotropic stimulation and in essential hypertension results primarily from the forward compression wave. # Novelty and Significance {#article-title-19}

Cardiovascular risk factors and endothelial dysfunction

Endothelial dysfunction is a feature of atherosclerosis and is associated with CHD (coronary heart disease) risk factors. This study aimed to determine the relationship between the degree of endothelial dysfunction and calculated cardiovascular risk. Endothelial function, as determined by the ACh/NP (acetycholine/sodium nitroprusside response) ratio on brachial plethysmography, was compared with cardiovascular risk as calculated from the Framingham, PROCAM (Prospective Cardiovascular Munster) and MRFIT (Multiple Risk Factor Intervention Trial) algorithms in 246 (187 male) patients, including 44 (22%) with established CHD. Endothelial dysfunction correlated with the total number of risk factors (r2=0.22; P=0.002) and was related to LDL (low-density lipoprotein)-cholesterol in men and triacylglycerols (triglycerides) in women. The ACh/NP ratio correlated with the occurrence of diabetes, CHD and the LDL-cholesterol concentration (r2=0.58; P<0.001). Endothelial dysfunction was associated with presence of CHD on receiver-operating characteristic plot analysis (area=0.706+/-0.04; P=0.001). There was no correlation between ACh/NP ratio and CHD risk calculated with the Framingham algorithm in men, although both ACh and NP response correlated separately with risk in women. The endothelial ACh/NP ratio correlated with absolute risk in the PROCAM algorithm (r2=0.41; P<0.005). Intermediate results were obtained with MRFIT. Individual risk factors make different contributions to endothelial dysfunction compared with their role in risk calculators. The stronger relationship of endothelial dysfunction with PROCAM risk reflects the contribution of male sex, LDL-cholesterol and triacylglycerols to risk calculated by this algorithm.

Estimating central Sbp from the peripheral pulse: influence of waveform analysis and calibration error

Objective To compare estimation of central cSBP by application of a generalized transfer function (GTF) to a peripheral arterial waveform and from the late systolic shoulder (SBP2) of such a waveform and assess errors introduced by noninvasive calibration of the waveform. Methods The digital arterial pulse was acquired noninvasively with a servo-controlled finger cuff. A high fidelity pressure tipped catheter was placed in the proximal aortic root. Measurements were made at baseline (n = 40), after nitrovasodilation, handgrip exercise (n = 18) and during pacing (n = 10). Estimates of cSBP obtained using a GTF and from SBP2 (using an algorithm applied to individual cardiac cycles) of the digital arterial waveform were compared with values measured at the aortic root. Results When arterial waveforms were calibrated from aortic intra-arterial mean and DBP there was close agreement between estimated and measured cSBP: mean difference between estimated and measured cSBP (SD): 1.0 (5.7) and −0.7 (5.5) mmHg for GTF and SBP2, respectively. Noninvasive oscillometric calibration increased variability in estimation of cSBP [mean difference, 1.3 (11) mmHg for SBP2] but estimates of the cSBP to peripheral systolic pressure increment from oscillometric calibration of SBP2 agreed well with those obtained using invasive calibration [mean difference −2.4 (6.1) mmHg]. Conclusion SBP2 potentially provides a simple measure of cSBP and is of comparable accuracy to a GTF. Noninvasive calibration increases variability for both methods but has less effect on the cSBP to peripheral SBP increment.