Biomedical subjects

J A Panza

Publications and source records attributed to J A Panza.

At least 37 records · Page 2Linked to original sources

PubMed2000

Interactions between nitric oxide and endothelin in the regulation of vascular tone of human resistance vessels in vivo.

Endothelial release of nitric oxide (NO) contributes to the regulation of vascular tone by inducing vascular relaxation. In addition, NO may inhibit the synthesis and hemodynamic effects of endothelin-1 (ET-1), a powerful endothelium-derived vasoconstrictor peptide that may stimulate NO production. However, whether NO and ET-1 physiologically interact to regulate vascular tone in humans has not been defined. In this study, the interactions between the L-arginine NO pathway and the ET-1 system in the regulation of vascular tone in human forearm resistance vessels were examined in vivo. Vasomotor response to the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 4 micromol/min for 30 minutes) was measured during either saline infusion or blockade of ET-1 receptors. Endothelin-A (ET(A)) and endothelin-B (ET(B)) receptor blockade was achieved by infusion of BQ-123 (100 nmol/min) and BQ-788 (50 nmol/min), respectively, separately and in combination. Drugs were infused into the brachial artery, and the forearm blood flow (FBF) response was measured by strain-gauge plethysmography. During saline infusion, L-NMMA administration significantly decreased FBF (25%, P<0.01 versus baseline). This effect was significantly blunted during nonselective blockade of ET-1 receptors (7% decrease in FBF, P=0.02 versus the effect of L-NMMA during saline infusion). Selective ET(A) blockade did not modify the vasoconstrictor response to L-NMMA (26% decrease in FBF, P=0.66 versus the effect of L-NMMA during saline infusion), but selective ET(B) receptor antagonism caused significant diminution of the hemodynamic response to NO inhibition (8% decrease in FBF, P=0.04 versus the effect of L-NMMA during saline infusion). Thus ET-1 contributes to the regulation of vascular tone by stimulating NO activity. This effect is mediated through endothelial ET(B) receptors and may be relevant in conditions associated with endothelial dysfunction.

Endothelin Receptor Antagonists↗

PubMed2000

Transient hypertension directly impairs endothelium-dependent vasodilation of the human microvasculature.

Hypertension is associated with decreased endothelium-dependent vasodilation. However, whether endothelial dysfunction is a cause or a consequence of elevated blood pressure is unknown. Therefore, to determine whether hypertension can directly induce endothelial dysfunction, we investigated the effect of increases in intra-arterial pressure on endothelium-dependent vasodilation of the human microvasculature. Small arteries (internal diameter 202+/-75 micrometer) were isolated from gluteal fat biopsies in 12 healthy normotensive subjects (8 men and 4 women; age, 46+/-10 years). Arteries were cannulated and perfused in chambers oxygenated at 37 degrees C. Endothelium-dependent and -independent responses to acetylcholine (Ach; 10(-9) to 10(-4) mol/L) and sodium nitroprusside (SNP; 10(-9) to 10(-4) mol/L), respectively, were obtained after incubating the vessel with incremental intravascular pressures of 50, 80, and 120 mm Hg for 60 minutes each. The response to Ach was also obtained in different arteries after 3 consecutive incubation periods at 50 mm Hg. Arterial internal diameter was measured directly from amplified digital images. A significant reduction in the vasodilator response to Ach was observed with increases in intravascular pressure (mean vasodilation, 62%, 49%, and 26% at 50, 80, and 120 mm Hg, respectively; P<0.001). In contrast, the response to SNP showed a nonsignificant trend toward greater vasodilation with increases in pressure (mean vasodilation, 40%, 52%, and 57% at 50, 80, and 120 mm Hg, respectively; P=0.10). There was no difference in the consecutive dose-response curves to Ach obtained at the same intravascular pressure (mean vasodilation: 48%, 46%, and 49%; P=0.61). Transient increases in intravascular pressure significantly depress endothelium-dependent vasodilation in human resistance arteries. These findings suggest that elevated blood pressure per se may cause endothelial dysfunction in humans and have implications for the pathophysiology of endothelial dysfunction in hypertension.

Blood Pressure↗

PubMed2000

Impact of temporal resolution on flow quantification by real-time 3D color Doppler echocardiography: numerical modeling and animal validation study.

Real-time, 3D color Doppler echocardiography (RT3D) is capable of quantifying flow at the LV outflow tract (LVOT). However, previous works have found significant underestimation for flow rate estimation due to finite scanning time (ST) of the color Doppler. The authors have, therefore, developed a mathematical model to correct the impact of ST on flow quantification and validated it by an animal study. Scanning time to cover the entire cross-sectional image of the LVOT was calculated as 60 ms, and the underestimation due to temporal averaging effect was predicted as 18 +/- 7%. In the animal experiment, peak flow rates were obtained by spatially integrating the velocity data front the cross-sectional color images of the LVOT. By applying a correction factor, there was an excellent agreement between reference flow rate by an electromagnetic flow meter and RT3D (angstroms=-5.6 ml/s, r=0.93), which was significantly better than without correction (p<0.001). Real-time, color 3D echocardiography was capable of quantifying flow accurately by applying the mathematical correction.

Animals↗

PubMed1999

Real-time three-dimensional echocardiography for measurement of left ventricular volumes.

Left ventricular (LV) volumes are important prognostic indexes in patients with heart disease. Although several methods can evaluate LV volumes, most have important intrinsic limitations. Real-time 3-dimensional echocardiography (RT3D echo) is a novel technique capable of instantaneous acquisition of volumetric images. The purpose of this study was to validate LV volume calculations with RT3D echo and to determine their usefulness in cardiac patients. To this end, 4 normal subjects and 21 cardiac patients underwent magnetic resonance imaging (MRI) and RT3D echo on the same day. A strong correlation was found between LV volumes calculated with MRI and with RT3D echo (r = 0.91; y = 20.1 + 0.71x; SEE 28 ml). LV volumes obtained with MRI were greater than those obtained with RT3D echo (126 +/- 83 vs 110 +/- 65 ml; p = 0.002), probably due to the fact that heart rate during MRI acquisition was lower than that during RT3D echo examination (62 +/- 11 vs 79 +/- 16 beats/min; p = 0.0001). Analysis of intra- and interobserver variability showed strong indexes of agreement in the measurement of LV volumes with RT3D echo. Thus, LV volume measurements with RT3D echo are accurate and reproducible. This technique expands the use of ultrasound for the noninvasive evaluation of cardiac patients and provides a new tool for the investigational study of cardiovascular disease.

Adult↗

PubMed1999

Vascular effects of estrogen and vitamin E therapies in postmenopausal women.

BACKGROUND: Estrogen and vitamin E therapies have been suggested to reduce cardiovascular risk, but comparison of the vascular effects of these therapies to determine mechanisms of potential benefit has not been performed in postmenopausal women. METHODS AND RESULTS: In a double-blind, 3-period crossover study, we randomly assigned 28 healthy postmenopausal women to conjugated equine estrogens (CE) 0. 625 mg/d, vitamin E 800 IU/d, and their combination, with measurements made before and after each 6-week treatment period. The ratio of LDL to HDL cholesterol and lipoprotein(a) decreased on therapies including CE but increased on vitamin E alone (P<0.001 and P=0.002, respectively, by ANOVA). Brachial artery flow-mediated dilation improved on all therapies (all P<0.001 versus pretreatment values) and to a similar degree (P=0.267 by ANOVA). No therapy improved the dilator response to nitroglycerin. CE lowered serum levels of cell adhesion molecules E-selectin, ICAM-1, and VCAM-1 (all P<0.05 versus pretreatment values). Vitamin E had no significant effect on levels of these markers of inflammation (P<0. 001 by ANOVA for E-selectin). CE alone or combined with vitamin E but not vitamin E alone lowered or showed a trend for lowering plasma levels of plasminogen activator inhibitor type-1 (P=0.069 by ANOVA). CONCLUSIONS: Estrogen and vitamin E therapies similarly improved arterial endothelium-dependent vasodilator responsiveness consistent with increased nitric oxide in healthy postmenopausal women, despite divergent effects on atherogenic lipoproteins. However, only estrogen reduced markers of vascular disease.

Analysis of Variance↗

PubMed1999

Insulin stimulates both endothelin and nitric oxide activity in the human forearm.

BACKGROUND: The mechanism of the hemodynamic effect of insulin in the skeletal muscle circulation has not been fully elucidated. The purpose of this study was to assess whether the hemodynamic response to insulin involves the concurrent release of endothelin (ET-1) and nitric oxide (NO), 2 substances with opposing vasoactive properties. METHODS AND RESULTS: Bioactivity of ET-1 and NO was assessed without insulin and during insulin infusion in the forearm circulation of healthy subjects by use of blockers of ET-1 receptors and by NO synthesis inhibition. In the absence of hyperinsulinemia, ET-1 receptor blockade did not result in any significant change in forearm blood flow from baseline (P=0.29). Intra-arterial insulin administration did not significantly modify forearm blood flow (P=0. 88). However, in the presence of hyperinsulinemia, ET-1 receptor antagonism was associated with a significant vasodilator response (P<0.001). In the presence of ET-1 receptor blockade, the vasoconstrictor response to NO inhibition by N(G)-monomethyl-L-arginine was significantly higher after insulin infusion than in the absence of hyperinsulinemia (P=0.006). CONCLUSIONS: These findings suggest that in the skeletal muscle circulation, insulin stimulates both ET-1 and NO activity. An imbalance between the release of these 2 substances may be involved in the pathophysiology of hypertension and atherosclerosis in insulin-resistant states associated with endothelial dysfunction.

Endothelin-1↗

PubMed1999

Mechanism by which quinapril improves vascular function in coronary artery disease.

Angiotensin-converting enzyme (ACE) inhibition has been shown to improve endothelium-dependent vasodilator responsiveness, but the contribution and mechanism of enhanced nitric oxide (NO) bioactivity to this effect in patients with coronary artery disease are unknown. We investigated the effect of ACE inhibition on brachial artery dilator responsiveness to increased shear stress after forearm ischemia by ultrasonography as a bioassay for endothelial NO available to vascular smooth muscle in 9 men with coronary artery disease. Serum nitrogen oxides were measured after 3 days of nitrate-restricted diet as an index of endothelial NO release. Patients received quinapril 20 to 40 mg/day for 8 weeks. Relative to pretreatment measurements, quinapril increased flow-mediated dilation (from 2.4+/-0.4 to 10.8+/-2.2, p <0.001), with significant improvement persisting 1 week after discontinuation of therapy (6.7+/-2.5%, p <0.01). However, quinapril decreased serum nitrogen oxide levels by 19+/-17% compared with pretreatment values (from 58.2+/-19.0 to 46.0+/-13.3 micromol/L, p <0.01). Thus, ACE inhibitor therapy with quinapril selectively improves endothelium-dependent vasodilator responsiveness by increased NO bioactivity in relation to vascular smooth muscle in patients with coronary artery disease, an effect achieved at a lower rate of NO release from the endothelium. These findings suggest that ACE inhibitors may reduce angiotensin II-induced oxidant stress within the vessel wall and protect NO from oxidative inactivation. This effect may reduce endothelial NO synthesis required for vasomotor regulation.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1999

Vascular effects of estrogen and cholesterol-lowering therapies in hypercholesterolemic postmenopausal women.

BACKGROUND: Lipoproteins affect endothelium-dependent vasomotor responsiveness. Because lipoprotein effects of estrogen and cholesterol-lowering therapies differ, we studied the vascular responses to these therapies in hypercholesterolemic postmenopausal women. METHODS AND RESULTS: We randomly assigned 28 women to conjugated equine estrogen (CE) 0.625 mg, simvastatin 10 mg, and their combination daily for 6 weeks. Compared with respective baseline values, simvastatin alone and combined with CE reduced LDL cholesterol to a greater extent than CE alone (both P<0.05). CE alone and combined with simvastatin raised HDL cholesterol and lowered lipoprotein(a) to a greater extent than simvastatin alone (all P<0.05). Flow-mediated dilation of the brachial artery (by ultrasonography) improved (all P<0.001 versus baseline values) on CE (4.0+/-2.6% to 10.2+/-3.9%), simvastatin (4.3+/-2.4% to 10.0+/-3.9%), and CE combined with simvastatin (4.6+/-2.0% to 9.8+/-2.6%), but similarly among therapies (P=0.507 by ANOVA). None of the therapies improved the dilator response to nitroglycerin (all P>/=0.184). Only therapies including CE lowered levels of plasminogen activator inhibitor type 1 and the cell adhesion molecule E-selectin (all P<0. 05 versus simvastatin). CONCLUSIONS: Although estrogen and statin therapies have differing effects on lipoprotein levels, specific improvement in endothelium-dependent vasodilator responsiveness is similar. However, only therapies including estrogen improved markers of fibrinolysis and vascular inflammation. Thus, estrogen therapy appears to have unique properties that may benefit the vasculature of hypercholesterolemic postmenopausal women, even if they are already on cholesterol-lowering therapy.

Aged↗

PubMed1999

Transesophageal echocardiography with stress for the evaluation of patients with coronary artery disease.

Echocardiography permits a comprehensive assessment of resting regional and global left ventricular function, the presence and extent of inducible myocardial ischemia, and the identification of myocardial viability. Accordingly, stress echocardiography has become a valuable tool for the evaluation of patient with known or suspected coronary artery disease. In some patients however, a suboptimal transthoracic echocardiogram may limit the performance of interpretation of the test. Transesophageal echocardiography in combination with stress has been recently used for the evaluation of patients with coronary artery disease. This technique is semi-invasive, more time-consuming, and requires a greater degree of expertise on the part of the personnel assisting with the test. In general, complications and side-effects are self-limited and rarely affect the diagnostic accuracy of the test. Based on its ability to provide high quality images, transesophageal stress echocardiography should be considered in patients who have suboptimal transthoracic ultrasound window for the quantitative assessment of myocardial wall-thickening in clinical investigations of ischemic heart disease.

Adrenergic beta-Agonists↗

PubMed1999

Role of endothelin in the increased vascular tone of patients with essential hypertension.

We investigated the possible role of endothelin in the increased vasoconstrictor tone of hypertensive patients using antagonists of endothelin receptors. Forearm blood flow (FBF) responses (strain-gauge plethysmography) to intraarterial infusion of blockers of endothelin-A (ETA) (BQ-123) and endothelin-B (ETB) (BQ-788) receptors, separately and in combination, were measured in hypertensive patients and normotensive control subjects. In healthy subjects, BQ-123 alone or in combination with BQ-788 did not significantly modify FBF (P=0.78 and P=0.63, respectively). In hypertensive patients, in contrast, BQ-123 increased FBF by 33+/-7% (P<0.001 versus baseline), and the combination of BQ-123 and BQ-788 resulted in a greater vasodilator response (63+/-12%; P=0.006 versus BQ-123 alone in the same subjects). BQ-788 produced a divergent vasoactive effect in the two groups, with a decrease of FBF (17+/-5%; P=0.004 versus baseline) in control subjects and transient vasodilation (15+/-7% after 20 minutes) in hypertensive patients (P<0.001, hypertensives versus controls). The vasoconstrictor response to endothelin-1 was slightly higher (P=0.04) in hypertensive patients (46+/-4%) than in control subjects (32+/-4%). Our data indicate that patients with essential hypertension have increased vascular endothelin activity, which may be of pathophysiological relevance to their increased vascular tone. In these patients, nonselective ETA and ETB blockade seems to produce a greater vasodilator effect than selective ETA blockade.

Endothelin-1↗

PubMed1998

Comparison of coronary endothelial dynamics with electrocardiographic and left ventricular contractile responses to stress in the absence of coronary artery disease.

Coronary artery endothelial dysfunction has been proposed as a cause of myocardial ischemia and symptoms in patients with angina-like chest pain despite normal coronary angiograms, especially those with ischemic-appearing ST-segment depression during exercise (syndrome X). We measured coronary vasomotor responses to acetylcholine (3 to 300 microg/min) in 42 patients (27 women and 15 men) with effort chest pain and normal coronary angiograms who also had normal electrocardiograms and echocardiograms at rest. All patients underwent treadmill exercise testing and measurement of systolic wall thickening responses to dobutamine (40 microg/kg/min) during transesophageal echocardiography. There were no differences in the acetylcholine-stimulated epicardial coronary diameter (+5+/-13% vs +1+/-13%, p=0.386) and flow (+179+/-90% vs +169+/-96%, p=0.756), or in the systolic wall thickening responses (+134+/-65% vs +118+/-57%, p=0.445) from baseline values in the 12 syndrome X patients compared with the 30 patients with negative exercise test results. In patients in the lowest quartile of coronary flow responses to acetylcholine, dobutamine increased systolic wall thickening by 121+/-73%; 3 had ischemic-appearing ST-segment depression during this stress. This contractile response to dobutamine was no different than the increase in systolic wall thickening (129+/-48%, p=0.777) in patients in the highest quartile of coronary flow responses, 3 of whom also had ischemic-appearing ST-segment depression during this stress. Thus, coronary endothelial dysfunction in the absence of coronary artery disease does not account for ischemic-appearing ST-segment depression in patients with chest pain despite normal coronary angiograms. Further, coronary endothelial dysfunction is not associated with myocardial contractile responses to stress consistent with myocardial ischemia.

Acetylcholine↗

PubMed1998

Selective defect in nitric oxide synthesis may explain the impaired endothelium-dependent vasodilation in patients with essential hypertension.

BACKGROUND: Patients with essential hypertension have impaired endothelial NO activity, but the mechanism underlying this abnormality is unknown. METHODS AND RESULTS: To investigate whether the endothelial dysfunction of hypertensive patients is related to a selective defect in NO synthesis, we studied the forearm blood flow responses to intra-arterial infusion of acetylcholine (7.5 to 30 microg/min), an endothelial agonist linked to NO synthase through the Ca2+ signaling pathway, and isoproterenol (50 to 200 ng/min), a beta-adrenoceptor agonist that stimulates NO production by increasing intracellular cAMP, in 12 normotensive subjects and 12 hypertensive patients. The infusion of isoproterenol was repeated during the concurrent blockade of NO synthesis by NG-monomethyl-L-arginine (L-NMMA; 4 micromol/min). The vasodilator response to acetylcholine was significantly reduced in hypertensives compared with normotensives (maximum blood flow: 10.4+/-4.6 versus 14.4+/-3.7 mL x min[-1] x dL[-1]; P=.008). However, the vasodilator effect of isoproterenol was similar in normotensives and hypertensives (maximum blood flow: 14.4+/-5.4 versus 13.5+/-5 mL x min[-1] x dL[-1]; P=.56) and was significantly (both P<.01) and equally blunted by L-NMMA in both groups (maximum blood flow: 11+/-3 mL x min[-1] x dL[-1] in normotensives versus 10.8+/-3.9 mL x min[-1] x dL[-1] in hypertensives; P=.77). The vasodilator response to sodium nitroprusside (0.8 to 3.2 microg/min), an exogenous NO donor, was similar in both groups and was not modified by L-NMMA. CONCLUSIONS: Hypertensive patients have impaired endothelium-dependent vasodilation in response to acetylcholine but preserved NO activity in response to beta-adrenergic stimulation. These findings suggest that the endothelial dysfunction in essential hypertension is due to a selective abnormality of NO synthesis, probably related to a defect in the phosphatidylinositol/Ca2+ signaling pathway.

Acetylcholine↗

PubMed1998

Aspirin improves endothelial dysfunction in atherosclerosis.

BACKGROUND: The beneficial effects of aspirin in atherosclerosis are generally attributed to its antiplatelet activities, but its influence on endothelial function remains uncertain. We hypothesized that a cyclooxygenase-dependent constricting factor contributes to the endothelial dysfunction in atherosclerosis and that its action can be reversed by aspirin. METHODS AND RESULTS: In 14 patients with coronary atherosclerosis and 5 with risk factors, we tested femoral vascular endothelial function with acetylcholine and substance P and endothelium-independent function with sodium nitroprusside before and after intravenous aspirin. Drugs were infused into the femoral artery, and Doppler flow velocity was measured. Acetylcholine-induced but not substance P-or sodium nitroprusside-induced vasodilation was lower in patients with atherosclerosis than in those with only risk factors. Aspirin had no baseline effect but improved acetylcholine-mediated vasodilation only in patients with atherosclerosis; at the peak dose, acetylcholine-mediated femoral vascular resistance index was 19 +/- 5%, P=.002 lower. There was a correlation between the baseline response to acetylcholine and the magnitude of improvement with aspirin (r=.5, P=.05). Thus, patients with a depressed response to acetylcholine had greater improvement with aspirin, and vice versa. The presence of atherosclerosis was an independent determinant of improvement with aspirin. Aspirin had no effect on the responses to either substance P or sodium nitroprusside. CONCLUSIONS: Cyclooxygenase-dependent, endothelium-derived vasoconstrictor release modulates acetylcholine-induced peripheral vasodilation in patients with atherosclerosis. Improvement of endothelial dysfunction with aspirin may improve vasodilation, reduce thrombosis, and inhibit progression of atherosclerosis and provides a pathophysiological basis for the beneficial effects of aspirin in atherosclerosis.

Acetylcholine↗

PubMed1998

Phase III multicenter trial comparing the efficacy of 2% dodecafluoropentane emulsion (EchoGen) and sonicated 5% human albumin (Albunex) as ultrasound contrast agents in patients with suboptimal echocardiograms.

OBJECTIVES: This study was performed to compare the safety and efficacy of intravenous 2% dodecafluoropentane (DDFP) emulsion (EchoGen) with that of active control (sonicated human albumin [Albunex]) for left ventricular (LV) cavity opacification in adult patients with a suboptimal echocardiogram. BACKGROUND: The development of new fluorocarbon-based echocardiographic contrast agents such as DDFP has allowed opacification of the left ventricle after peripheral venous injection. We hypothesized that DDFP was clinically superior to the Food and Drug Administration-approved active control. METHODS: This was a Phase III, multicenter, single-blind, active controlled trial. Sequential intravenous injections of active control and DDFP were given 30 min apart to 254 patients with a suboptimal echocardiogram, defined as one in which the endocardial borders were not visible in at least two segments in either the apical two- or four-chamber views. Studies were interpreted in blinded manner by two readers and the investigators. RESULTS: Full or intermediate LV cavity opacification was more frequently observed after DDFP than after active control (78% vs. 31% for reader A; 69% vs. 34% for reader B; 83% vs. 55% for the investigators, p < 0.0001). LV cavity opacification scores were higher with DDFP (2.0 to 2.5 vs. 1.1 to 1.5, p < 0.0001). Endocardial border delineation was improved by DDFP in 88% of patients versus 45% with active control (p < 0.001). Similar improvement was seen for duration of contrast effect, salvage of suboptimal echocardiograms, diagnostic confidence and potential to affect patient management. There was no difference between agents in the number of patients with adverse events attributed to the test agent (9% for DDFP vs. 6% for active control, p = 0.92). CONCLUSIONS: This Phase III multicenter trial demonstrates that DDFP is superior to sonicated human albumin for LV cavity opacification, endocardial border definition, duration of effect, salvage of suboptimal echocardiograms, diagnostic confidence and potential to influence patient management. The two agents had similar safety profiles.

Adult↗

PubMed1998

Myocardial viability during dobutamine echocardiography predicts survival in patients with coronary artery disease and severe left ventricular systolic dysfunction.

OBJECTIVES: The purpose of this study was to assess whether the presence or absence of myocardial viability during dobutamine echocardiography (DE) predicts survival in patients with coronary artery disease (CAD) and severe left ventricular (LV) dysfunction. BACKGROUND: In patients with CAD, the presence of myocardial viability during DE identifies viable myocardium and predicts recovery of LV systolic function after revascularization. However, there is little data on the relation between myocardial viability and clinical outcome in patients with CAD and severe LV dysfunction. METHODS: We studied 318 patients with CAD and a LV ejection fraction (EF) < or =35% who underwent DE and were followed for 18+/-10 months. Patients were classified into four groups. Group I (n=85) consisted of patients who had evidence of myocardial viability and subsequently underwent revascularization. Group II (n=119) consisted of patients with myocardial viability who did not undergo revascularization. Group III (n=30) consisted of patients who did not have myocardial viability and underwent revascularization. Finally, group IV (n=84) patients lacked myocardial viability and did not undergo revascularization. RESULTS: The four groups had similar baseline characteristics and rest LVEF. During follow-up there were 51 deaths (16%). The mortality rate was 6% in group I, 20% in group II, 17% in group III and 20% in group TV (p=0.01, group I vs. other groups). CONCLUSIONS: In patients with CAD and severe LV dysfunction who demonstrated myocardial viability during DE, revascularization improved survival compared with medical therapy.

Aged↗

PubMed1998

Impairment of the nitric oxide-mediated vasodilator response to mental stress in hypertensive but not in hypercholesterolemic patients.

OBJECTIVES: This study investigated whether mental stress-induced vasodilation mediated by endothelium-derived nitric oxide (NO) is defective in conditions with endothelial dysfunction, such as hypertension and hypercholesterolemia. BACKGROUND: Vascular release of NO modulates the vasodilator response to mental stress in healthy subjects. Previous studies have shown that hypertensive and hypercholesterolemic patients have impaired endothelium-dependent vasodilation to pharmacologic agents due to decreased NO activity. However, whether this abnormality also operates in response to physiologic stimuli such as mental stress has not been defined. METHODS: Forearm blood flow responses (plethysmography) to mental stress were compared in 12 normal subjects, 12 hypertensive patients and 10 hypercholesterolemic patients before and during NO synthesis inhibition with N(G)-monomethyl-L-arginine (4 micromol/min). Vascular responses to acetylcholine (7.5, 15 and 30 microg/min), an endothelium-dependent vasodilator, and sodium nitroprusside (0.8, 1.6 and 3.2 microg/min), an exogenous NO donor, were also assessed in each group. RESULTS: During saline the vasodilator response to mental stress was significantly blunted in hypertensive (37+/-11%; p=0.01) but not in hypercholesterolemic (85+/-21%; p=0.78) patients compared with controls (93+/-15%). N(G)-Monomethyl-L-arginine administration significantly blunted mental stress-induced vasodilation in healthy subjects (p=0.004 vs. saline) and hypercholesterolemic patients (p=0.03 vs. saline), but not in hypertensive patients (p=0.69 vs. saline). The vasodilator effect of the highest dose of acetylcholine was similarly blunted in hypertensive (215+/-44%; p=0.02) and hypercholesterolemic (172+/-71%; p=0.02) patients compared with controls (364+/-34), whereas the vasorelaxing response to sodium nitroprusside was similar in the three groups. CONCLUSIONS: Hypertensive but not hypercholesterolemic patients have impaired NO-dependent vasodilation during mental stress. These findings may be accounted for by different mechanisms underlying endothelial dysfunction in these two conditions and might explain an increased susceptibility of hypertensive patients to vascular damage over repeated exposure to stressful situations.

Acetylcholine↗

PubMed1998

Racial differences in nitric oxide-mediated vasodilator response to mental stress in the forearm circulation.

An abnormal hemodynamic response to stressful stimuli has been proposed as a mechanism involved in the higher prevalence of hypertension in blacks. Given the important role of nitric oxide (NO) in the regulation of cardiovascular homeostasis, we investigated the possibility of racial differences in vascular NO activity during mental stress. To test this hypothesis, we compared the forearm blood flow (FBF) response to mental stress in 14 white and 12 black healthy subjects during intra-arterial infusion of either saline or NO synthesis inhibitor N(G)-monomethyl-L-arginine (L-NMMA; 4 micromol/min). We also examined vascular responses of the two groups to intra-arterial infusion of sodium nitroprusside (0.8 to 3.2 microg/min), an exogenous NO donor. During saline infusion, the increase in FBF from baseline induced by mental stress was significantly higher in whites than in blacks (109+/-20% versus 58+/-8%; P=0.03). L-NMMA significantly reduced stress-induced increase in FBF in whites (from 109+/-20% to 54+/-11%; P=0.004) but not in blacks (from 58+/-8% to 42+/-10%; P=0.24); thus, the vasodilator effect of stress testing during L-NMMA was similar in whites and blacks (54+/-11% versus 42+/-10%; P=0.44). The vasodilator response to sodium nitroprusside was also lower in blacks than in whites (maximum flow, 6.9+/-2 versus 11.6+/-3.5 mL x min(-1) x dL(-1); P=0.001) and was not significantly modified by L-NMMA in either group. Our findings indicate that blacks have a reduced NO-dependent vasodilator activity during mental stress. This difference seems related to reduced sensitivity of smooth muscle to the vasodilator effect of NO and may play some role in the increased prevalence of hypertension and its complications in blacks.

Adult↗

PubMed1998

Contribution of nitric oxide to reactive hyperemia: impact of endothelial dysfunction.

Our objectives were to (1) test the hypothesis that nitric oxide (NO) contributes to peak reactive hyperemia (RH) in the human peripheral vasculature, (2) examine the impact of atherosclerosis and its risk factors on RH, and (3) investigate whether L-arginine will improve RH in patients with endothelial dysfunction. The endothelium contributes to shear stress-mediated vasomotion by releasing a variety of dilating factors, including NO, but the contribution of NO to peak RH in patients with and without endothelial dysfunction is unknown. Endothelium-dependent and endothelium-independent function was assessed with intrafemoral arterial acetylcholine (ACh) and sodium nitroprusside. RH was produced by occlusion of blood flow to the leg for 3 minutes. The study was repeated after NG-monomethyl-L-arginine (L-NMMA) in 44 subjects and L-arginine in 9 patients with atherosclerosis. There were 15 normal control subjects without risk factors for atherosclerosis and 29 patients with risk factors or angiographic atherosclerosis. Microvascular vasodilation in response to ACh, but not to sodium nitroprusside, was lower in the patients with risk factors or atherosclerosis compared with normal control subjects, P=0.048, and the inhibition of ACh-induced microvascular dilation by L-NMMA was also greater in normal control subjects (P=0.045). Similarly, RH, including the peak response, was inhibited by L-NMMA in normal control subjects (P=0.0011) but not in patients with risk factors or atherosclerosis, suggesting that the contribution of NO to both ACh-induced dilation and RH was diminished in patients with risk factors or atherosclerosis. L-Arginine did not affect vasodilation in response to ACh, sodium nitroprusside, or RH. We concluded that (1) NO contributes to all phases of RH in the normal human peripheral vasculature, (2) patients with atherosclerosis or its risks have abnormal NO bioactivity in response to pharmacological and physiological stimulation, and (3) L-arginine does not improve RH in atherosclerosis. Reduced physiological vasodilation in atherosclerosis may contribute to or exacerbate hypertension and ischemia.

Acetylcholine↗