Biomedical subjects

J M Ritter

Publications and source records attributed to J M Ritter.

At least 19 recordsLinked to original sources

PubMed2004

Block of inward rectifying K+ channels (KIR) inhibits bradykinin-induced vasodilatation in human forearm resistance vasculature.

OBJECTIVE: To investigate the possible involvement of inward rectifying K(+) channels (K(IR)) in the response of human resistance vessels to bradykinin in vivo. METHODS AND RESULTS: Drugs were administered via the brachial artery in healthy male volunteers and forearm blood flow was measured by venous occlusion plethysmography. Inhibition of K(IR) by barium chloride (4 micromol min(-1)) alone or with additional inhibition of Na(+)/K(+) ATPase (ouabain 2.7 micromol min(-1)) reduced responses to bradykinin (30 pmol min(-1)), by 26+/-8.3% and 36+/-7.2%, respectively (each P<0 0.05). Barium with ouabain plus inhibitors of prostaglandin (PG) and nitric oxide synthesis inhibited but did not abolish responses to bradykinin (51+/-2.8% inhibition; P<0.01); norepinephrine (240 pmol min(-1)) caused similar reduction of baseline blood flow, as did this combination of inhibitors, but did not significantly inhibit the response to bradykinin. Barium plus ouabain did not significantly reduce responses to acetylcholine or albuterol. CONCLUSIONS: A component of the vasodilator response to bradykinin in human forearm vasculature is mediated by K(IR). The possible involvement of inward-rectifying K+ channels (KIR) in the action of bradykinin was investigated by administering drugs via the brachial artery in healthy men. Barium selectively inhibited the forearm blood flow response to bradykinin, indicating that a component of this response is mediated by KIR.

Acetylcholine↗

PubMed2003

Hypertriglyceridaemia and NK cell lymphoma.

This case report describes a patient who presented with pyrexia of unknown origin allied with hypertriglyceridaemia (16.2 mmol/l) but not hypercholesterolaemia (4.1 mmol/l). Investigations identified the cause of the pyrexia as an adult T-cell lymphoma of natural killer cell phenotype (CD3[+], CD7[+], anti-TCR alpha/beta[+], CD8[+], CD56[+]). Hypertriglyceridaemia has been reported with non-Hodgkin s lymphoma, and an animal model suggests that antilipoprotein lipase antibodies may be made as an immunological response to the tumour. Lymphomas should be considered as part of the differential diagnosis in type IV-V hyperlipidaemia.

Adult↗

PubMed2002

Divergent effects of vitamin C on relaxations of rabbit aortic rings to acetylcholine and NO-donors.

1. Vitamin C may influence NO-dependent relaxation independently of effects on oxidant stress. 2. We investigated effects of vitamin C (0.1 -- 10 mmol l(-1)) on relaxation of pre-constricted rabbit aortic rings to acetylcholine (ACh), authentic NO and the NO-donors glyceryl trinitrate (GTN), nitroprusside (NP) and S-nitroso-N-acetyl-penicillamine (SNAP). DETCA (2 -- 6 mmol l(-1)), a cell permeable inhibitor of endogenous Cu-Zn superoxide dismutase (SOD) was used to increase intracellular superoxide anion (O(2)(-)). 3. Vitamin C reduced the response to ACh (71 +/- 7% inhibition of maximum relaxation at 10 mmol l(-1)) and inhibited relaxation to authentic NO. Vitamin C inhibited relaxation to GTN but potentiated relaxations to NP and SNAP, causing a parallel shift to a lower concentration range of the log dose-response curve by approximately one log unit at the highest dose. 4. Vitamin C increased the concentration of NO in bath solution (plus EDTA, 1.0 mmol l(-1)) following the addition of SNAP from 53 +/- 14 to 771 +/- 101 nmol l(-1) over the range 0.1-3.0 mmol l(-1). 5. DETCA inhibited relaxation to ACh (71 +/- 9% inhibition of maximum relaxation). This inhibition was abolished by a cell permeable SOD mimetic, but not by vitamin C. DETCA inhibited relaxation to SNAP but not that to NP nor to GTN. 6. Vitamin C inhibits endothelium-dependent relaxations of rabbit aortic rings to ACh and authentic NO and does not reverse impaired relaxation resulting from increased intracellular oxidant stress. Vitamin C potentiates relaxation to the NO-donors NP and SNAP by a mechanism that could involve release of NO from nitrosothiols.

Acetylcholine↗

PubMed2002

Lack of effect of oral vitamin C on blood pressure, oxidative stress and endothelial function in Type II diabetes.

Type II diabetes is characterized by increased oxidative stress, endothelial dysfunction and hypertension. We investigated whether short-term treatment with oral vitamin C reduces oxidative stress and improves endothelial function and blood pressure in subjects with Type II diabetes. Subjects ( n =35) received vitamin C (1.5 g daily in three doses) or matching placebo for 3 weeks in a randomized, double-blind, parallel-group design. Plasma concentrations of 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)), a non-enzymically derived oxidation product of arachidonic acid, were used as a marker of oxidative stress. Endothelial function was assessed by measuring forearm blood flow responses to brachial artery infusion of the endothelium-dependent vasodilator acetylcholine (with nitroprusside as an endothelium-independent control) and by the pulse wave responses to systemic albuterol (endothelium-dependent vasodilator) and glyceryl trinitrate (endothelium-independent vasodilator). Plasma concentrations of vitamin C increased from 58+/-6 to 122+/-10 micromol/l after vitamin C, but 8-epi-PGF(2alpha) levels (baseline, 95+/-4 pg/l; after treatment, 99+/-5 pg/l), blood pressure (baseline, 141+/-5/80+/-2 mmHg; after treatment, 141+/-5/81+/-3 mmHg) and endothelial function, as assessed by the systemic vasodilator response to albuterol and by the forearm blood flow response to acetylcholine, were not significantly different from baseline or placebo. Thus treatment with vitamin C (1.5 g daily) for 3 weeks does not significantly improve oxidative stress, blood pressure or endothelial function in patients with Type II diabetes.

Acetylcholine↗

PubMed2002

Determination of age-related increases in large artery stiffness by digital pulse contour analysis.

The stiffness of the aorta can be determined by measuring carotid-femoral pulse wave velocity (PWV(cf)). PWV may also influence the contour of the peripheral pulse, suggesting that contour analysis might be used to assess large artery stiffness. An index of large artery stiffness (SI(DVP)) derived from the digital volume pulse (DVP) measured by transmission of IR light (photoplethysmography) was examined. SI(DVP) was obtained from subject height and from the time delay between direct and reflected waves in the DVP. The timing of these components of the DVP is determined by PWV in the aorta and large arteries. SI(DVP) was, therefore, expected to provide a measure of stiffness similar to PWV. SI(DVP) was compared with PWV(cf) obtained by applanation tonometry in 87 asymptomatic subjects (21-68 years; 29 women). The reproducibility of SI(DVP) and PWV(cf) and the response of SI(DVP) to glyceryl trinitrate were assessed in subsets of subjects. The mean within-subject coefficient of variation of SI(DVP), for measurements at weekly intervals, was 9.6%. SI(DVP) was correlated with PWV(cf) ( r =0.65, P <0.0001). SI(DVP) and PWV(cf) were each independently correlated with age and mean arterial blood pressure (MAP) with similar regression coefficients: SI(DVP)=0.63+0.086 x age+0.042 x MAP ( r =0.69, P <0.0001); PWV(cf)=0.76+0.080 x age+0.053 x MAP ( r =0.71, P <0.0001). Administration of glyceryl trinitrate (3, 30 and 300 microg/min intravenous; each dose for 15 min) in nine healthy men produced similar changes in SI(DVP) and PWV(cf). Thus contour analysis of the DVP provides a simple, reproducible, non-invasive measure of large artery stiffness.

Adult↗

PubMed2001

The phytoestrogen genistein produces acute nitric oxide-dependent dilation of human forearm vasculature with similar potency to 17beta-estradiol.

BACKGROUND: Genistein, a phytoestrogen, may have estrogenic cardioprotective actions. We investigated whether genistein influences endothelium-dependent vasodilation in forearm vasculature of healthy human subjects and compared the effects of genistein with those of 17beta-estradiol. METHODS AND RESULTS: The brachial arterial was cannulated with a 27-gauge needle for drug infusion. Forearm blood flow responses were measured with strain-gauge plethysmography. Genistein (10 to 300 nmol/min, each dose for 6 minutes) produced a dose-dependent increase in forearm blood flow from 3.4+/-0.3 to 9.6+/-1.3 mL x min(-1) x 100 mL forearm(-1) (mean+/-SEM) in men (n=9, P:<0.0001 by ANOVA). The mean forearm venous concentration of genistein during infusion of the highest dose was 1.8+/-0.3 micromol/L in 6 additional men. Genistein produced a similar increase in blood flow in premenopausal women. Daidzein, another phytoestrogen, was ineffective, but equimolar concentrations of 17beta-estradiol caused similar vasodilation to genistein. Responses to genistein and 17beta-estradiol were inhibited to the same degree by the NO synthase inhibitor N:(G)-monomethyl-L-arginine. A threshold dose of genistein potentiated the endothelium-dependent vasodilator acetylcholine but not the endothelium-independent vasodilator nitroprusside. CONCLUSIONS: Genistein causes L-arginine/NO-dependent vasodilation in forearm vasculature of human subjects with similar potency to 17beta-estradiol and potentiates endothelium-dependent vasodilation to acetylcholine.

Acetylcholine↗

PubMed2001

Endothelium-dependent vasodilation is independent of the plasma L-arginine/ADMA ratio in men with stable angina: lack of effect of oral L-arginine on endothelial function, oxidative stress and exercise performance.

OBJECTIVES: This study was designed to determine the effect of two weeks' treatment with L-arginine on the ratio of plasma L-arginine to asymmetric dimethylarginine (ADMA), oxidative stress, endothelium-dependent vasodilatation to acetylcholine, exercise performance and heart rate variability in men with stable angina. BACKGROUND: The ratio of plasma L-arginine:ADMA has been proposed as a determinant of endothelium-dependent dilation; dietary supplementation with L-arginine has been shown to improve endothelium-dependent vasodilation and symptoms in some conditions. METHODS: Men (n = 40) with stable angina, at least one epicardial coronary artery with a stenosis >50% and a positive exercise test were randomized to receive L-arginine (15 g daily) or placebo for two weeks according to a double-blind parallel-group design. Plasma L-arginine, ADMA, 8-epi-prostaglandin F2alpha (a marker of oxidative stress) and forearm vasodilator responses to brachial artery infusion of nitroprusside and acetylcholine (+/-L-arginine) were measured. A standard Bruce protocol exercise test was performed before and at the end of the treatment period. RESULTS: Plasma L-arginine increased after oral L-arginine, whereas ADMA remained unchanged, leading to an increase in the L-arginine/ADMA ratio of 62 +/- 11% (mean +/- SE, p < 0.01). Despite a significant enhancement in acetylcholine response by intra-arterial L-arginine at baseline, this response remained unchanged after oral L-arginine. Measures of oxidative stress and exercise performance after L-arginine/placebo were similar in placebo and active groups. CONCLUSIONS: In men with stable angina, an increase in plasma L-arginine/ADMA ratio after two weeks' oral supplementation with L-arginine is not associated with an improvement in endothelium-dependent vasodilatation, oxidative stress or exercise performance.

Administration, Oral↗

PubMed2001

Quantitative aspects of the inhibition by N(G)-monomethyl-L-arginine of responses to endothelium-dependent vasodilators in human forearm vasculature.

1. N(G)-monomethyl-L-arginine (L-NMMA) constricts human forearm resistance vasculature and selectively attenuates vasodilator responses to endothelium-dependent vasodilators. Incomplete inhibition of such responses could be due to an inadequate dose of L-NMMA or to NO-independent vasodilator mechanisms. 2. This study sought to determine doses of L-NMMA that are maximally effective in reducing basal and stimulated forearm blood flow. Drugs were infused via the brachial artery in 32 healthy men. Acetylcholine (11 - 330 nmol min(-1)) was compared with albuterol (0.33 - 10 nmol min(-1)), and nitroprusside (1.7 - 20 nmol min(-1)). 3. The effect of L-NMMA on basal flow approached maximum (53+/-2% reduction) at a dose of 16 micromol min(-1). L-NMMA (16 micromol min(-1)) did not significantly influence responses to nitroprusside, but antagonized acetylcholine and albuterol (each P<0.001, by repeated measures analysis of variance). 4. Inhibition of acetylcholine by L-NMMA (16 micromol min(-1)) was strongly influenced by acetylcholine dose (73+/-7% inhibition at 11 nmol min(-1), P<0.01; 4+/-11% inhibition at 330 nmol min(-1), P=NS, Student's paired t-test). Significant inhibition of albuterol was observed at all doses. 5. A higher dose of L-NMMA (64 micromol min(-1)) did not significantly inhibit the response to acetylcholine (330 nmol min(-1)). Responses to this dose of acetylcholine were unaffected by a cyclo-oxygenase (COX) inhibitor (indometacin) alone but combined COX and NO inhibition attenuated acetylcholine responses by 42+/-19%, implying that there is a compensatory increase in the contribution of prostaglandins or NO to acetylcholine-induced dilatation when one or other pathway is inhibited.

Acetylcholine↗

PubMed2001

Assessment of forearm vasodilator responses to acetylcholine and albuterol by strain gauge plethysmography: reproducibility and influence of strain gauge placement.

AIMS: To determine the within-subject reproducibility of the forearm blood flow response to acetylcholine and the beta2-adrenoceptor agonist albuterol as measured by strain gauge plethysmography. To examine the influence of strain gauge placement on these responses. METHODS: Vasodilator response to brachial artery infusion of drugs was assessed by strain gauge plethysmography in six healthy men on each of three occasions separated by 1 week. Strain gauges were placed on both arms at the point of maximum diameter. On the infused arm two further gauges were positioned approximately 4 cm proximal and distal to the middle gauge. RESULTS: Within-subject coefficients of variation (WCV) of absolute blood flow responses for each dose of acetylcholine (7.5, 15, 30 micrograms min(-1)) ranged from 24% to 27%, as compared with WCV values of 41% to 62% for the percentage changes in blood flow ratio (infused : noninfused arm). For albuterol (0.3, 1, 3 micrograms min(-1)) the corresponding WCV values were 16% to 19% and 30% to 55% for absolute blood flow and percentage change in blood flow ratio, respectively. WCV for the area under dose-response curve (AUC) for absolute blood flow was 18% and 13% for acetylcholine and albuterol, respectively. Vasodilator responses were similar whether recorded proximal to or at the point of maximal forearm circumference. Distal strain gauge misplacement underestimated responses and the difference was greater for acetylcholine than for albuterol. CONCLUSIONS: In healthy men, the WCV for responses expressed as absolute blood flow, to acetylcholine and albuterol ranges from 16% to 27%.

Acetylcholine↗

PubMed2001

Nebivolol: endothelium-mediated vasodilating effect.

Nebivolol, a racemic mixture of (S,R,R,R) and (R,S,S,S) enantiomers, is the most beta1-selective adrenoceptor antagonist currently available for clinical use. However, its haemodynamic effects differ from those of classical beta-adrenoceptor antagonists as a result of a vasodilating action. Nebivolol is devoid of alpha-adrenergic antagonist actions, and the detailed mechanism of its vasodilator action is unknown. Nebivolol relaxes precontracted strips of canine coronary and carotid artery only if the endothelium is intact, and such relaxation is antagonized by inhibition of nitric oxide (NO) synthase, implicating the endothelial L-arginine/NO mechanism. Nebivolol and atenolol have been compared in phenylephrine preconstricted dorsal hand veins of 11 healthy men. Nebivolol caused venodilation, which was antagonized by N(G)-monomethyl-L-arginine (LNMMA), whereas atenolol did not, suggesting that such a mechanism could also operate in human veins. Venodilation could be functionally important in reducing cardiac pre-load. Beta2-adrenoceptor stimulation increases forearm blood flow (FBF) by activating the L-arginine/NO pathway but nebivolol lacks direct beta2-adrenoceptor agonist activity. Resistance vessel function has been studied by measuring FBF by venous occlusion plethysmography in healthy men during brachial artery infusions of racemic nebivolol and its enantiomers, atenolol, carbachol (a stable analogue of acetylcholine that vasodilates this vascular bed, in part by activating the L-arginine/NO pathway), nitroprusside (a NO donor that causes non-endothelium-dependent vasodilation through the same effector mechanism as endothelium-dependent agonists) and LNMMA. Nebivolol (354 microg/min) increased FBF by 91 +/- 18% (mean +/- SE, n = 8; p < 0.01), whereas an equimolar dose of atenolol had no significant effect. LNMMA inhibited responses to nebivolol and carbachol to a significantly greater extent than it reduced responses to nitroprusside. Antagonism of nebivolol by LNMMA was abolished by L-arginine. The (S,R,R,R) and (R,S,S,S) enantiomers caused similar increases of FBF. To determine whether brachial artery infusion of nebivolol causes vasodilation in the forearm resistance vasculature of patients with essential hypertension and to investigate the possible involvement of the L-arginine/NO pathway, we studied otherwise healthy volunteers with uncomplicated essential hypertension. Nebivolol (88.5, 177 and 354 microg/min, each dose for 6 min) caused similar vasodilatation as in normotensive subjects, and these responses were sensitive to inhibition by LNMMA. If acute effects of nebivolol on the L-arginine/NO pathway persist during chronic treatment of patients with hypertension or heart failure, this could reduce cardiac after-load as well as pre-load, improve organ perfusion and reduce atherogenesis and thrombosis.

Adrenergic beta-1 Receptor Antagonists↗

PubMed2001

Vasoactive drugs influence aortic augmentation index independently of pulse-wave velocity in healthy men.

Aortic augmentation index, a measure of central systolic blood pressure augmentation arising mainly from pressure-wave reflection, increases with vascular aging. The augmentation index is influenced by aortic pulse-wave velocity (related to aortic stiffness) and by the site and extent of wave reflection. To clarify the relative influence of pulse-wave velocity and wave reflection on the augmentation index, we studied the association between augmentation index, pulse-wave velocity, and age and examined the effects of vasoactive drugs to determine whether altering vascular tone has differential effects on pulse-wave velocity and the augmentation index. We made simultaneous measurements of the augmentation index and carotid-to-femoral pulse-wave velocity in 50 asymptomatic men aged 19 to 74 years at baseline and, in a subset, during the administration of nitroglycerin, angiotensin II, and saline vehicle. The aortic augmentation index was obtained by radial tonometry (Sphygmocor device, PWV Medical) with the use of an inbuilt radial to aortic transfer function. In multiple regression analysis, the aortic augmentation index was independently correlated only with age (R=0.58, P<0.0001). Nitroglycerin (3 to 300 microg/min IV) reduced the aortic augmentation index from 4.8+/-2.3% to -11.9+/-5.3% (n=10, P<0.002). Angiotensin II (75 to 300 ng/min IV) increased the aortic augmentation index from 9.3+/-2.4% to 18.3+/-2.9% (n=12, P<0.001). These drugs had small effects on aortic pulse-wave velocity, producing mean changes from baseline of <1 m/s (each P<0.05). In healthy men, vasoactive drugs may change aortic augmentation index independently from aortic pulse-wave velocity.

Adult↗

PubMed2000

Diastolic blood pressure changes during exercise positively correlate with serum cholesterol and insulin resistance.

BACKGROUND: Metabolic factors, including plasma concentrations of cholesterol and insulin resistance, may influence blood pressure through effects on vascular reactivity. Such effects might influence blood pressure during exercise more strongly than at rest. METHODS AND RESULTS: We examined whether there is an association between serum cholesterol or insulin resistance and change in blood pressure during mild exercise. Blood pressure was measured at rest and during fixed low-workload bicycle ergometry (50, 75, and 100 W, each for 3 minutes) in 75 healthy active men (age, 18 to 66 years). Blood pressure at rest was not significantly correlated with serum cholesterol or insulin resistance (estimated from the fasting glucose-insulin product). The change from resting values in diastolic but not systolic blood pressure during exercise was correlated with serum cholesterol (R>0.47, P<0.0001 for each workload) and insulin resistance (R>0.38, P<0.01 for each workload). Serum cholesterol and insulin resistance were the only independent predictors of the change in diastolic blood pressure during exercise in a stepwise regression model incorporating age, body mass index, serum cholesterol, triglycerides, HDL cholesterol, insulin resistance, and heart rate during exercise. In a further study, the change in diastolic blood pressure during exercise was greater in men with uncomplicated type 2 diabetes (13.6 mm Hg [95% CI, 8.5 to 18.8]; n=10) than in nondiabetic control men (2.7 mm Hg [95% CI, -2. 0 to 7.3]; n=10; P=0.002). CONCLUSIONS: Changes in diastolic blood pressure during gentle exercise are strongly associated with serum concentrations of total cholesterol and insulin resistance. This may contribute to development of hypertensive complications in dyslipidemic and/or insulin-resistant patients.

Adolescent↗

PubMed2000

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-PGF(2a), 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 microg min(-1)) and of the nitric oxide donor nitroprusside (1, 3 and 10 microg min(-1)) were measured by strain gauge plethysmography. RESULTS: Plasma concentrations of 8-epi-PGF(2a), were greater in diabetic than in control men (0.99 +/- 0.20 vs 0.18 +/- 0.01 nmol 1(-1), means +/- SEM, p < 0.001) and fell after raxofelast (from 0.99 +/- 0.20 to 0.47 +/- 0.07 nmol 1(-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) x 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 m x min(-1) x 100 ml(-1) to 11.3 +/- 2.3 ml x min(-1) x 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.

Acetylcholine↗

PubMed2000

Transforming growth factor-beta1 gene transfer ameliorates acute lung allograft rejection.

BACKGROUND: The aim of the current work was to study the feasibility of functional gene transfer using the gene encoding for transforming growth factor-beta1, a known immunosuppressive cytokine, on rat lung allograft function in the setting of acute rejection. METHODS: The rat left lung transplant technique was used in all experiments, with Brown Norway donor rats and Fischer recipient rats. After harvest, left lungs were transfected ex vivo with either sense or antisense transforming growth factor-beta1 constructs complexed to cationic lipids, then implanted into recipients. On postoperative days 2, 5, and 7, animals were put to death, arterial oxygenation measured, and acute rejection graded histologically. RESULTS: On postoperative day 2, there were no differences in acute rejection or lung function between animals treated with transforming growth factor-beta1 and control animals. On postoperative day 5, oxygenation was significantly improved in grafts transfected with the transforming growth factor-beta1 sense construct compared with antisense controls (arterial oxygen tension = 411 +/- 198 vs 103 +/- 85 mm Hg, respectively; P =.002). Acute rejection scores from lung allografts were also significantly improved, corresponding to decreases in both vascular and airway rejection (vascular rejection scores: 2.0 +/- 0. 5 vs 2.8 +/- 0.6; P =.04; airway rejection scores: 1.3 +/- 0.7 vs 2. 3 +/- 0.8, respectively; P =.02). The amelioration of acute rejection was temporary and decreased by postoperative day 7. CONCLUSIONS: The feasibility of using gene transfer techniques to introduce novel functional genes in the setting of lung transplantation is demonstrated. In this model of rat lung allograft rejection, gene transfer of transforming growth factor-beta1 resulted in temporary but significant improvements in lung allograft function and acute rejection pathology.

Acute Disease↗

PubMed2000

Inhibitory effects of low-density lipoproteins from men with type II diabetes on endothelium-dependent relaxation.

OBJECTIVES: The object of the present study is to determine whether native (n) low-density lipoprotein (LDL) isolated from men with type II diabetes and abnormal endothelial function inhibits endothelium-dependent relaxation more than n-LDL isolated from nondiabetic control subjects. BACKGROUND: Endothelium-dependent vasodilation is impaired in men with type II diabetes and this may result from qualitative rather than quantitative abnormalities of LDL. METHODS: Forearm blood flow responses to brachial artery infusions of acetylcholine (endothelium-dependent vasodilator) and nitroprusside (endothelium-independent vasodilator) were measured in 10 men with uncomplicated type II diabetes and 10 nondiabetic men of similar age and with similar plasma concentrations of LDL cholesterol. Native LDL was isolated by discontinuous density gradient ultracentrifugation using EDTA to prevent oxidation. Preconstricted rabbit aortic ring bioassay was used to determine inhibitory properties of n-LDL on endothelium-dependent relaxation by measuring relaxation to acetylcholine (and nitroprusside) in the presence and absence of n-LDL. RESULTS: Forearm blood flow responses to acetylcholine but not nitroprusside were significantly impaired (p < 0.01) in diabetic men compared with control subjects. Native LDL (10 and 100 microg protein/ml) from diabetic men inhibited relaxation to acetylcholine by 13.9 +/- 4.8% and 61.9 +/- 7.8% (mean inhibition for all doses +/- SE), respectively, whereas n-LDL from control subjects inhibited relaxation by 7.3 +/- 3.0% and 23.9 +/- 5.7% (p < 0.01 for a difference between diabetic and control n-LDL). Relaxation to nitroprusside was not significantly inhibited by n-LDL. CONCLUSIONS: A qualitative abnormality of LDL may account for endothelial dysfunction in men with type II diabetes.

Acetylcholine↗

PubMed2000

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.

Adrenergic alpha-Agonists↗

PubMed2000

Evidence for cytotoxic T lymphocyte response against human lung cancer: reconstitution of antigenic epitope with peptide eluted from lung adenocarcinoma MHC class I.

BACKGROUND: Cancer-associated, major histocompatibility complex (MHC)-restricted peptide antigens have been elucidated in human melanomas and ovarian, breast, and renal carcinomas; but relatively little is known about lung cancer antigens. METHODS: To work toward delineation of lung cancer-associated antigens, we developed tumor infiltrating lymphocytes (TILs), peripheral blood mononuclear cell-derived cytolytic T cell lines (CTL), autologous lung cancer cell lines, and normal lung cell lines from 17 patients undergoing lung cancer resections. The TILs and CTL lines were subsequently evaluated for markers of activation and specific lysis of autologous or allogeneic lung cancer cell lines or both. RESULTS: Freshly isolated TILs contained a more activated T cell population compared with the patients' peripheral blood T cells as evidenced by an increased expression of HLA-DR, CD25, and CD45RO. TILs isolated from 15 patients lysed allogeneic lung cancer lines. TILs lysed autologous lung cancer but not autologous normal lung or Epstein-Barr virus transformed B cell lines (B-LCL) in 4 of 8 cases tested, suggesting tumor specificity. A CTL line (RHPBL57.1) was generated from peripheral blood mononuclear cells of an HLA-A24(+) patient by stimulation against an established HLA-A24(+) allogeneic lung cancer cell line. RHPBL57.1 lysed the lung cancer cell line in an HLA-A24-restricted manner. Moreover, RHPBL57.1 specifically lysed autologous B-LCL pulsed with peptides, eluted from MHC class I and isolated from the HLA-A24(+) lung cancer cell line. CONCLUSIONS: TILs isolated from patients with lung cancer are predominantly an activated population of T cells with evidence of tumor and MHC class I-restricted lysis. Furthermore, we provide evidence for a lung cancer-associated, MHC class I-bound peptide antigen(s) that reconstitutes the epitope recognized by a lung cancer specific CD8(+) T cell line derived from a patient with lung cancer.

Adenocarcinoma↗

PubMed2000

Sodium-hydrogen exchange in human platelets exposed to weak acid: comparison between measurements of platelet swelling and cytoplasmic sodium ion concentration.

Increased Na+-H+ exchange activity has been demonstrated in various pathological states using the rate constant of platelet swelling (ks). This indirect measure of exchange activity could, however, be influenced by conditions that alter platelet distensibility independent of Na+-H+ exchange activity. To determine the validity of ks, the change in light transmission and hence ks, was measured at 24 degrees and 37 degrees C (temperatures associated with alterations in membrane fluidity), and compared with the rate constant (kNa) for the increase in cytoplasmic sodium ion concentration ([Na+]i) and the rate constant of Na+-influx (kphiNa) under the same conditions. Both ks and kNa were dependent on Na+-H+ exchange; the rate constants differed in the order ks< kphiNa < kNa (P<0.01). Neither kNa or kphiNa changed with temperature, whereas ks was significantly lower at 24 degrees than at 37 degrees C (7.49 +/- 0.31 x 10(-3) s(-1) versus 9.96 +/- 0.42 x 10(-3) s(-1), P<0.0001). While both ks and kNa are dependent on Na+-H+ exchange, ks may underestimate the activity of the exchanger and may in part, be influenced by membrane fluidity. This could be important in interpreting data where ks has been measured in different groups of subjects.

Blood Platelets↗