Differential Cross Section and Photon-Beam Asymmetry for the γ[over →]p → π

Differential cross sections and photon-beam asymmetries for the γ[over →]p→π^{-}Δ^{++}(1232) reaction have been measured for 0.7

Interference Effect between ϕ and Λ(1520) Production Channels in the γp→K

The ϕ-Λ(1520) interference effect in the γp→K^{+}K^{-}p reaction has been measured for the first time in the energy range from 1.673 to 2.173 GeV. The relative phases between ϕ and Λ(1520) production amplitudes were obtained in the kinematic region where the two resonances overlap. The measurement results support strong constructive interference when K^{+}K^{-} pairs are observed at forward angles but destructive interference for proton emission at forward angles. Furthermore, the observed interference effect does not account for the sqrt[s]=2.1 GeV bump structure in forward differential cross sections for ϕ photoproduction. This fact suggests possible exotic structures such as a hidden-strangeness pentaquark state, a new Pomeron exchange, or rescattering processes via other hyperon states.

Neutron resonance absorption imaging of simulated high-level radioactive waste in borosilicate glass.

We performed a preliminary study of neutron resonance absorption imaging to investigate the spatial distribution of constituent elements in borosilicate glasses containing simulated high-level radioactive waste, in which elemental inhomogeneities affect the physical and chemical stabilities of the glass. Dips generated by the resonance absorptions of Rh, Pd, Na, Gd, Cs, and Sm were observed in the neutron transmission spectra of the glass samples. The spatial distributions of these elements were obtained from the neutron transmission images at the resonance energies. The distributions of Rh and Pd visualized the sedimentation of these platinum group elements. In contrast, the lanthanides (Gd and Sm) and Cs were uniformly dispersed. These results show that neutron resonance absorption imaging is a promising tool for characterizing borosilicate glasses and investigating the vitrification mechanism of high-level radioactive waste.

Evolutionary potential of root chemical defense: genetic correlations with shoot chemistry and plant growth.

Root herbivores can affect plant fitness, and roots often contain the same secondary metabolites that act as defenses in shoots, but the ecology and evolution of root chemical defense have been little investigated. Here, we investigated genetic variance, heritability, and correlations among defensive phenolic compounds in shoot vs. root tissues of common evening primrose, Oenothera biennis. Across 20 genotypes, there were roughly similar concentrations of total phenolics in shoots vs. roots, but the allocation of particular phenolics to shoots vs. roots varied along a continuum of genotype growth rate. Slow-growing genotypes allocated 2-fold more of the potential pro-oxidant oenothein B to shoots than roots, whereas fast-growing genotypes had roughly equivalent above and belowground concentrations. Phenolic concentrations in both roots and shoots were strongly heritable, with mostly positive patterns of genetic covariation. Nonetheless, there was genotype-specific variation in the presence/absence of two major ellagitannins (oenothein A and its precursor oenothein B), indicating two different chemotypes based on alterations in this chemical pathway. Overall, the presence of strong genetic variation in root defenses suggests ample scope for the evolution of these compounds as defenses against root herbivores.

Is tranexamic acid toxic to articular cartilage when administered topically? What is the safe dose?

Aims: The intra-articular administration of tranexamic acid (TXA) has been shown to be effective in reducing blood loss in unicompartmental knee arthroplasty and anterior cruciate reconstruction. The effects on human articular cartilage, however, remains unknown. Our aim, in this study, was to investigate any detrimental effect of TXA on chondrocytes, and to establish if there was a safe dose for its use in clinical practice. The hypothesis was that TXA would cause a dose-dependent damage to human articular cartilage. Materials and Methods: The cellular morphology, adhesion, metabolic activity, and viability of human chondrocytes when increasing the concentration (0 mg/ml to 40 mg/ml) and length of exposure to TXA (0 to 12 hours) were analyzed in a 2D model. This was then repeated, excluding cellular adhesion, in a 3D model and confirmed in viable samples of articular cartilage. Results: Increasing concentrations above 20 mg/ml resulted in atypical morphology, reduced cellular adhesion and metabolic activity associated with increased chondrocyte death. However, the cell matrix was not affected by the concentration of TXA or the length of exposure, and offered cellular protection for concentrations below 20 mg/ml. Conclusion: These results show that when in vitro chondrocytes are exposed to higher concentrations of TXA, such as that expected following recommended intra-articular administration, cytotoxicity is observed. This effect is dose-dependent, such that a tissue concentration of 10 mg/ml to 20 mg/ml could be expected to be safe. Cite this article: Bone Joint J 2018;100-B:404-12.

Muscarinic receptor modulation of basal and beta-adrenergic stimulated function of the failing human left ventricle.

The objective of this study was to evaluate the effect of muscarinic receptor modulation on basal and beta-adrenergic stimulated left ventricular function in patients with heart failure. 21 heart failure patients and 14 subjects with normal ventricular function were studied. In Protocol 1 intracoronary acetylcholine resulted in a 60+/-8% inhibition of the left ventricular +dP/dt response to intracoronary dobutamine in the normal group, and a similar 70+/-13% inhibition in the heart failure group. Acetylcholine also attenuated the dobutamine-mediated acceleration of isovolumic relaxation (Tau) in both groups. Acetylcholine alone had no effect on Tau in the normal group, while it prolonged Tau in the heart failure group. In Protocol 2 intracoronary atropine resulted in a 35+/-10% augmentation of the inotropic response to dobutamine in the normal group, versus a non-significant 12+/-15% augmentation of the dobutamine response in the heart failure group. In Protocol 3, in 6 heart failure patients, both effects of acetylcholine, the slowing of ventricular relaxation and the inhibition of beta-adrenergic responses, were reversed by the addition of atropine. Therefore, in the failing human left ventricle muscarinic stimulation has an independent negative lusitropic effect and antagonizes the effects of beta-adrenergic stimulation.

Parasympathetic control of cardiac sympathetic activity: normal ventricular function versus congestive heart failure.

BACKGROUND: Muscarinic receptors on adrenergic nerve terminals attenuate norepinephrine release. The role of these receptors in the modulation of cardiac norepinephrine release in humans remains uncertain. METHODS AND RESULTS: Twelve patients with normal left ventricular (LV) function and 18 with congestive heart failure (CHF) were studied. A radiotracer technique was used to measure cardiac norepinephrine spillover (CANESP) in response to intracoronary acetylcholine (ACh, 5x10(-5) Mol), and in response to intracoronary atropine (12 micrograms/min). ACh did not affect CANESP in the group of subjects with normal LV function, but it caused a significant reduction in those with CHF [197 (150 to 302) versus 168 (87 to 288) pmol/min, P<0.05]. Atropine caused a significant increase in CANESP in those with normal LV function [47 (27 to 51) versus 64 (38 to 139) pmol/min, P<0.05], but no change was observed in the CHF group. CONCLUSIONS: Therefore, in the setting of heart failure and sympathetic activation, muscarinic receptor stimulation decreases CANESP, an effect not observed in patients with preserved LV function. Blockade of muscarinic receptors with atropine increased CANESP in patients with normal LV function, suggesting that cardiac parasympathetic tone has inhibitory effects on cardiac sympathetic activity. This basal inhibition was not observed in CHF patients in response to atropine. The lack of basal parasympathetic inhibition of cardiac sympathetic activity may play a role in the pathogenesis of cardiac sympathetic activation in heart failure.

Reducing cardiac filling pressure lowers norepinephrine spillover in patients with chronic heart failure.

BACKGROUND: We studied the cardiac sympathetic response to selective unloading of cardiopulmonary baroreceptors in subjects with normal left ventricular (LV) function and congestive heart failure (CHF). METHODS AND RESULTS: Eight patients with normal LV function (age 57+/-5 years, ejection fraction 58+/-2%) and 8 patients with CHF (age 60+/-2 years; ejection fraction 19+/-2%) were studied. Instrumentation consisted of an arterial line, a pulmonary artery catheter, and a coronary sinus thermodilution catheter. The radiotracer technique was used for measurement of cardiac norepinephrine spillover (CANESP) and total-body norepinephrine spillover. Lower-body negative pressure (LBNP) was applied at 2 levels: nonhypotensive and hypotensive LBNP. Nonhypotensive LBNP reduced filling pressures significantly in both groups. Arterial pressure did not change. This reduction in filling pressures caused a significant reduction in CANESP in the CHF group (from 167+/-53 to 125+/-37 pmol/min, P<0.05) but no change in the normal LV function group. Hypotensive LBNP caused a significant increase in CANESP in the normal group (73+/-13 vs 122+/-27 pmol/min, P<0.05) but no significant change in those with CHF. CONCLUSIONS: We conclude that selective reduction in filling pressures lowers cardiac norepinephrine spillover in patients with CHF. These findings suggest that a goal of CHF management should be to reduce cardiac filling pressures while avoiding systemic hypotension.

Inotropic and sympathetic responses to the intracoronary infusion of a beta2-receptor agonist: a human in vivo study.

BACKGROUND: On the basis of the presence of beta2-receptors within the sympathetic nervous system, beta2-stimulation may increase cardiac sympathetic outflow. We addressed the hypothesis that sympathoexcitatory beta2-receptors are present in the human left ventricle. METHODS AND RESULTS: The beta2-agonist salbutamol was infused into the left coronary artery in 3 groups of patients: group 1 (n=9, no beta-blocker therapy), group 2 (n=7, beta1-selective blockade with atenolol), and group 3 (n=6, nonselective beta-blockade with nadolol). Left ventricular +dP/dt in response to increasing concentrations of salbutamol was measured in all groups, and cardiac norepinephrine spillover was measured in group 1. There were no systemic hemodynamic changes in any group. Salbutamol resulted in a 44+/-6% increase in +dP/dt in group 1, a 25+/-6% increase in group 2 (P<0.05 versus group 1), and no increase in group 3. Salbutamol also resulted in a 124+/-37% increase in cardiac norepinephrine spillover in group 1 (P<0.05). CONCLUSIONS: Evidence that salbutamol increased norepinephrine release from cardiac sympathetic nerves was provided by the observations that atenolol suppressed the salbutamol inotropic response, demonstrating that this response was mediated in part by beta1-receptors and that salbutamol also resulted in an increase in cardiac norepinephrine spillover. This result provides in vivo evidence, in humans, for the role of sympathoexcitatory cardiac beta2-receptors.

Nonselective versus selective beta-adrenergic receptor blockade in congestive heart failure: differential effects on sympathetic activity.

BACKGROUND: Activation of the sympathetic nervous system has important prognostic implications in chronic heart failure. Nonselective versus selective beta-adrenergic receptor antagonists may have differential effects on norepinephrine release from nerve terminals mediated by prejunctional beta(2)-adrenergic receptors. METHODS AND RESULTS: Thirty-six patients with chronic heart failure were randomized to the nonselective beta-blocker carvedilol or the selective beta-blocker metoprolol (double-blind). Measurements of hemodynamics and cardiac and systemic norepinephrine spillover as well as microneurographic recordings of muscle sympathetic nerve traffic were made before and after 4 months of therapy. In the carvedilol group (n=17), there were significant reductions in both total body (-1.7+/-0.5 nmol/min, P<0.01) and cardiac norepinephrine spillover (-87+/-29 pmol/min, P<0.01). By contrast, in the metoprolol group (n=14), there were no significant changes in total body or cardiac norepinephrine spillover. Responses in the carvedilol group were significantly different from those observed in the metoprolol group (P<0.05). Both agents caused a reduction in heart rate and increases in pulse pressure, although mean arterial pressure did not change. Importantly, microneurographic measures of sympathetic nerve traffic to skeletal muscle did not change in either group. CONCLUSIONS: Therapy with carvedilol caused significant decreases in systemic and cardiac norepinephrine spillover, an indirect measure of norepinephrine release. Such changes were not observed in patients treated with metoprolol. There was no effect of either agent on sympathetic efferent neuronal discharge to skeletal muscle. These findings suggest that carvedilol, a nonselective beta-blocker, caused its sympathoinhibitory effect by blocking peripheral, prejunctional beta-adrenergic receptors.

Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study.

BACKGROUND: In healthy humans, continuous treatment with nitroglycerin (GTN) causes nitric oxide synthase dysfunction, probably through the reduced bioavailability of tetrahydrobiopterin. Recent studies proposed that folic acid is involved in the regeneration of tetrahydrobiopterin in different disease states. Therefore, we investigated whether folic acid administration would prevent this phenomenon. We also sought to determine if folic acid supplementation could prevent the development of tolerance to GTN. METHODS AND RESULTS: On the first visit, 18 healthy male volunteers (aged 19 to 32 years) were randomized to receive either oral folic acid (10 mg once a day) or placebo for 1 week in a double-blind designed study. All subjects also received continuous transdermal GTN (0.6 mg/h). On the second visit, forearm blood flow was measured with venous occlusion strain gauge plethysmography in response to incremental infusions of acetylcholine (7.5, 15, and 30 microgram/min), N-monomethyl-L-arginine (1, 2, and 4 micromol/min), and GTN (11 and 22 nmol/min). Folic acid prevented GTN-induced endothelial dysfunction, as assessed by responses to intraarterial acetylcholine and N-monomethyl-L-arginine (P<0.01). Moreover, in the subjects treated with folic acid plus transdermal GTN, responses to intraarterial GTN were significantly greater than those observed after transdermal GTN plus placebo (P<0.05). CONCLUSION: Our data demonstrate that supplemental folic acid prevents both nitric oxide synthase dysfunction induced by continuous GTN and nitrate tolerance in the arterial circulation of healthy volunteers. We hypothesize that the reduced bioavailability of tetrahydrobiopterin is involved in the pathogenesis of both phenomena. Our results confirm the view that oxidative stress contributes to nitrate tolerance.

L-arginine transport in the human coronary and peripheral circulation.

BACKGROUND: Nitric oxide synthase (NOS) uses arginine for the production of nitric oxide (NO). High intracellular concentrations of arginine suggest that NOS activity should be independent of plasma arginine supply. However, under certain conditions, increased plasma arginine concentrations appear to be associated with increased NOS activity. The purpose of this study was to explore arginine transport within the human coronary and peripheral circulation METHODS AND RESULTS: Mass-labeled 15N2-arginine was infused to steady state before cardiac catheterization in 31 patients. After diagnostic angiography, a catheter was placed in the coronary sinus. The transcardiac concentration gradient (aorta-coronary sinus) of 15N2-arginine was used as a measure of arginine transport at baseline and during infusions of acetylcholine and N(G)-monomethyl-L-arginine (L-NMMA). No gradient was detected at rest. During the infusion of acetylcholine, a significant gradient was detected (2.5+/-1.2 micromol/L, P=0.01) corresponding to a fractional extraction of 11.7+/-7.5%. This is consistent with in vitro studies that suggest that stimulation of NOS induces arginine transport. During the infusion of L-NMMA, the concentration of 15N2-arginine increased in the coronary sinus, producing a gradient of -3.9+/-1.3 micromol/L (P=0.0002), corresponding to a fractional production of 20.5+/-5.0%. This is consistent with in vitro studies that suggest that L-NMMA induces the efflux of arginine from the cell to the extracellular space via transporter-mediated transstimulation. CONCLUSIONS: The use of steady-state 15N2-arginine to examine transorgan L-arginine gradients represents a novel tool for the study of L-arginine transport and the mechanisms of endothelial and NOS dysfunction.

Effect of therapy with an angiotensin-converting enzyme inhibitor on hemodynamic and counterregulatory responses during continuous therapy with nitroglycerin.

OBJECTIVES: We sought to characterize the reflex counterregulatory responses throughout a 6-day period of continuous nitroglycerin therapy and to examine the effect of concurrent administration of a non-thiol angiotensin-converting enzyme inhibitor (benazepril) on the nature of those responses. BACKGROUND: Therapy with nitroglycerin has been shown to be associated with reflex counterregulatory responses. METHODS: Standing systolic blood pressure, hormonal responses, urinary sodium and hematocrit levels were monitored during 6 days of continuous transdermal nitroglycerin therapy in normal volunteers. Using a double-blind randomized parallel design, 11 subjects received placebo and 9 received benazepril. Hemodynamic responses to sublingual nitroglycerin administration were evaluated before and after sustained therapy with transdermal nitroglycerin. RESULTS: Attenuation of the hypotensive response to transdermal nitroglycerin was rapid in the group receiving placebo and the group receiving benazepril. There were no significant hormonal responses to transdermal nitroglycerin in either group, and sodium retention was modest and transient. Hematocrit levels decreased after transdermal nitroglycerin therapy and remained depressed for the duration of nitroglycerin therapy, a finding that suggests plasma volume expansion. Blood pressure responses to sublingual nitroglycerin in both groups were similar before and after continuous transdermal nitroglycerin therapy. CONCLUSIONS: These data suggest that plasma volume expansion plays a more important role than neurohormonal responses in the loss of nitrate effects during sustained therapy. That therapy with an angiotensin-converting enzyme inhibitor did not modify the hemodynamic responses to continuous nitroglycerin therapy supports this conclusion. Further investigation will be necessary to confirm whether therapy with an angiotensin-converting enzyme inhibitor has any role in the prevention of nitrate tolerance.

Effects of diuretic therapy on the development of tolerance during continuous therapy with nitroglycerin.

OBJECTIVES: This study examined the effects of concurrent diuretic therapy on the hemodynamic responses to short-term and sustained therapy with transdermal nitroglycerin. BACKGROUND: Sodium retention and plasma volume expansion occur during therapy with nitroglycerin and may play a role in the loss of nitroglycerin effects during sustained therapy. METHODS: Twenty-two normal male volunteers were treated for 1 week with either hydrochlorothiazide and amiloride (50 + 5 mg) (n = 11) or placebo (n = 11) in a randomized, double-blind fashion. All 22 subjects then received continuous transdermal nitroglycerin (19 +/- 1 mg/24 h) for 5 to 7 days. RESULTS: On the first and last day of transdermal nitroglycerin therapy, standing heart rate, systolic blood pressure and hematocrit values were assessed at 8, 9 and 10 AM and 12 noon. Heart rate and blood pressure responses to sublingual nitroglycerin (0.6 mg) were also evaluated before and after sustained transdermal nitroglycerin therapy. A significant loss of the hemodynamic effects of transdermal and sublingual nitroglycerin occurred during sustained therapy in both the diuretic and placebo therapy groups. In both groups, transdermal nitroglycerin therapy was associated with a significant decrease in hematocrit that persisted for the entire treatment period. CONCLUSIONS: These results suggest that diuretic therapy does not prevent plasma volume expansion or the loss of hemodynamic effects during sustained transdermal nitroglycerin therapy. The persistent decrease in hematocrit suggests that plasma volume expansion plays a role in the attenuation of nitrate effects. It also provides evidence of continued vascular activity of nitroglycerin despite loss of systemic hemodynamic effects.

Nitroglycerin withdrawal increases endothelium-dependent vasomotor response to acetylcholine.

OBJECTIVES: We sought to determine whether nitroglycerin (NTG) withdrawal contributes to worsening of endothelial dysfunction and development of the rebound phenomenon during intermittent transdermal NTG therapy. BACKGROUND: Intermittent transdermal NTG therapy is recommended to avoid the development of tolerance. However, this regimen may precipitate worsening angina in the NTG-free interval. METHODS: Twenty patients were randomized to intermittent transdermal NTG (0.6 mg/h; NTG group) or no treatment (control group) five days before angiography. The risk factors for endothelial dysfunction were similar in both groups. After diagnostic angiography, the patients underwent quantitative angiography before and after intracoronary acetylcholine (ACh), 10(-4) mol/liter. Immediately after the morning study, the patch was removed from the NTG group, and 3 h later, the ACh infusion was repeated in both groups. All patients had mild to moderate coronary artery disease (CAD). RESULTS: The diameter of the left anterior descending coronary artery at baseline was 2.0 +/- 0.1 mm in the control group and 2.6 +/- 0.1 mm in the NTG group (p < 0.05). Acetylcholine caused mild vasoconstriction in the control group in the morning and afternoon (2.7 +/- 5.3% and 2.4 +/- 3.9%, respectively; p = NS). The NTG group demonstrated mild vasoconstriction to ACh in the morning (3.2 +/- 2.8%; p = NS vs. control group). After patch removal, there was a significant increase in the magnitude ofvasoconstriction in the NTG group (11.6 +/- 3.9%, p = 0.04 vs. morning constriction). CONCLUSIONS: These results confirm that NTG withdrawal increases the coronary vasomotor response to ACh in patients with mild CAD and suggests that the rebound phenomena may be secondary to the development of endothelial dysfunction after discontinuation of NTG therapy.

Evidence supporting abnormalities in nitric oxide synthase function induced by nitroglycerin in humans.

OBJECTIVES: We studied the effects of nitroglycerin (GTN) therapy on the response to endothelium-dependent and independent vasoactive agents in the forearm circulation of healthy subjects. BACKGROUND: Recent evidence suggests that therapy with GTN may induce specific changes in endothelial cell function, including increased superoxide anion production and sensitivity to vasoconstrictors. Additionally, continuous GTN therapy worsens endothelial function in the coronary circulation of patients with ischemic heart disease. METHODS: Forearm blood flow was measured with venous occlusion, mercury-in-silastic strain gauge plethysmography. RESULTS: Sixteen male volunteers (26 +/- 6 years) were randomized to no therapy (control) or GTN, 0.6 mg/h/24 h, for six days in an investigator-blind, parallel-design study. The flow responses to brachial artery infusions of acetylcholine ([Ach] 7.5, 15.0, 30.0 microg/min), N-monomethyl-L-arginine (L-NMMA) (1, 2, 4 micromol/min) and sodium nitroprusside (SNP) (0.8, 1.6, 3.2 microg/min) were recorded. The vasodilator responses to Ach were blunted in the GTN group as compared with the control group (p < 0.05). The vasoconstrictor responses to L-NMMA were also blunted in the GTN group (p < 0.001). In the GTN group, paradoxical vasodilation was observed in response to the lowest infused concentration of L-NMMA. The vasodilator responses to SNP did not differ between groups. CONCLUSIONS: The response to Ach confirms the hypothesis that continuous GTN causes endothelial dysfunction. The responses to L-NMMA suggest that GTN therapy causes abnormalities in nitric oxide synthase (NOS) function; the vasodilation observed at the lowest infused concentration of L-NMMA in the GTN group also suggests that continuous GTN therapy is associated with a NOS-mediated production of a vasoconstrictor.

Cardiac and systemic sympathetic activity in response to clonidine in human heart failure.

OBJECTIVES: We studied the effects of clonidine on cardiac sympathetic activity and left ventricular function in patients with congestive heart failure (CHF). BACKGROUND: Sympathetic activation has major prognostic implications in patients with heart failure. Clonidine, an imidazoline and alpha2-receptor agonist, has been shown to cause a reduction in generalized sympathetic activity. METHODS: Nine patients with CHF (left ventricular ejection fraction 22+/-4% [mean+/-SEM]) received a 50 microg and 100 microg bolus of clonidine intravenously. Study measurements included right and left heart hemodynamics, cardiac output, rate of rise in left ventricular peak positive pressure (LV + dP/dt) and tau, along with cardiac and total body norepinephrine spillover. The radiotracer method was used for calculation of norepinephrine spillover. RESULTS: Right and left heart filling pressures did not change in response to either dose of clonidine. Mean arterial pressure fell after the second dose of clonidine, from 94+/-8 to 82+/-6 mm Hg (p < 0.05). The LV + dP/dt was reduced from 737+/-53 to 629+/-43 mm Hg/s (p < 0.05). Clonidine also caused a significant increase in tau, as measured by the method of Weiss (65+/-3 vs. 74+/-4 ms, p < 0.01) and the direct pressure half-time technique (48+/-2 vs. 54+/-3 ms, p < 0.01). Cardiac norepinephrine spillover fell from 121+/-29 to 52+/-20 pmol/min in response to 100 microg of clonidine (p < 0.01 vs. control). CONCLUSIONS: Despite a significant fall in arterial pressure, clonidine caused a marked reduction in sympathetic activity directed at the heart. The negative inotropic and lusitropic effects appear to be secondary to this reduction in sympathetic drive. Because increased cardiac and generalized sympathetic activity are strong predictors of an adverse outcome in patients with CHF, the role of centrally active sympathoinhibitory agents in the therapy of CHF deserves further exploration.

Lack of evidence for peripheral alpha(1)- adrenoceptor blockade during long-term treatment of heart failure with carvedilol.

OBJECTIVES: The purpose of this study was to determine whether carvedilol's alpha(1)-adrenoceptor antagonism persists during long-term therapy of patients with congestive heart failure (CHF). BACKGROUND: Carvedilol and metoprolol differ in that carvedilol also antagonizes beta(2)- and alpha(1)-adrenoceptors. We hypothesized that in contrast to metoprolol, carvedilol would increase calf vascular conductance (CVC), blunt neurally mediated vasoconstriction and attenuate neuroeffector transfer function gain. METHODS: We randomized 36 patients with CHF (age 55 +/- 1 years, ejection fraction 19 +/- 1%, means +/- SE) to either drug. Blood pressure (BP), heart rate, muscle sympathetic nerve activity (MSNA) and CVC were assessed before and after four months of treatment. The variability of BP and MSNA was determined using fast Fourier transformation. RESULTS: Paired data were obtained in 23 (carvedilol, 13; metoprolol, 10) subjects. Both beta-blockers decreased heart rate, but neither affected mean BP or CVC (carvedilol: 0.016 +/- 0.002 to 0.018 +/- 0.003 U; metoprolol: 0.020 +/- 0.002 to 0.020 +/- 0.004 U). Isometric handgrip exercise (30% of maximum) increased heart rate, mean BP and MSNA. The calf vasoconstrictor response to handgrip exercise was not affected by carvedilol (from 16 +/- 6 resistance U to 25 +/- 10 resistance U, NS). The gain of the transfer of oscillations in MSNA into BP under resting conditions was not attenuated by carvedilol. CONCLUSIONS: Carvedilol did not increase CVC, blunt the calf vasoconstrictor response to handgrip or attenuate the gain of the neuroeffector transfer function, indicating the absence of functionally important peripheral alpha(1)-adrenoceptor antagonism during long-term treatment of CHF.