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Biomedical subjects

J R Cockcroft

Publications and source records attributed to J R Cockcroft.

At least 37 records · Page 2Linked to original sources
PubMed2000

Endothelium-derived nitric oxide contributes to the regulation of venous tone in humans.

BACKGROUND: Although nitric oxide (NO) is known to play an important part in the regulation of arterial tone, little is known about its role in veins. The aim of this study was to investigate the role of basal and stimulated NO activity in the regulation of tone of the human venous capacitance bed. METHODS AND RESULTS: We measured venous tone using radionuclide forearm venous plethysmography in 24 healthy subjects with no cardiovascular risk factors. In 13 subjects, basal NO activity was assessed by measuring the effects on venous tone of an intra-arterial infusion of the NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA). In the remaining 11 subjects, stimulated NO activity was evaluated by measuring the effects of an intra-arterial infusion of incremental doses of carbachol, followed in a subgroup by coinfusion with L-NMMA. Infusion of carbachol caused dose-dependent venodilation, with a maximal reduction in forearm venous tone of 40.1+/-12.5% (P<0.0001). Carbachol-induced venodilation was inhibited by L-NMMA (48.9+/-6.2% reversal of maximal venodilation, P<0.01). Infusion of L-NMMA alone caused venoconstriction (9.1+/-6.4% increase in venous tone, P=0.002). CONCLUSIONS: Human forearm capacitance veins exhibit both stimulated and basal NO activity, which indicates that NO contributes not only to the regulation of venous tone but also to resting venous tone in healthy human subjects.

Adult↗
PubMed2000

Increased augmentation index and systolic stress in type 1 diabetes mellitus.

Type 1 diabetes mellitus is associated with endothelial dysfunction and increased arterial stiffness, both of which may contribute to the excess cardiovascular mortality in such patients. Arterial stiffening increases pulse wave velocity and wave reflection, which augments central systolic pressure and stress. Using the non-invasive technique of pulse wave analysis, we investigated aortic augmentation and central pressure in 35 patients with type 1 diabetes and 35 matched controls. Peripheral pulse waveforms were recorded from the radial artery. Central aortic waveforms were then generated, and augmentation index (AIx), ascending aortic pressure and tension time index (TTI), a measure of systolic load, were calculated. Peripheral and central blood pressure did not differ between the two groups. AIx was significantly elevated in the diabetic patients compared with controls (7.1+/-1.6% vs. 0.4+/-2.0%; p=0.01), as was the TTI (2307+/-51 mmHg x s x min(-1) vs. 2010+/-61 mmHg. s x min(-1); p<0.001). Estimated pulse wave velocity was also higher in the diabetic group. Type 1 diabetes is associated with an increased AIx and rate of wave travel, indicating enhanced wave reflection and increased systemic arterial stiffness, and elevation of the TTI. Such haemodynamic effects may contribute to the increased left ventricular mass and risk of cardiovascular disease associated with type 1 diabetes mellitus.

Adolescent↗
PubMed2000

Beta(2)-adrenoceptor polymorphism determines vascular reactivity in humans.

Altered beta-adrenergic regulation has been reported in individuals with hypertension. The variability in vascular responsiveness to beta-agonists, such as isoproterenol, observed in humans may be explained partially by beta(2)-adrenoceptor polymorphism. Individuals with the Gln27 form of the receptor may show reduced vascular reactivity because of downregulation expression of the receptor in the vasculature. We screened 127 normotensive white subjects, 37 of whom were homozygous for these alleles. Thirty-two subjects (17 Gln27 and 15 Glu27) agreed to receive brachial artery infusions of isoproterenol at doses of 1 to 300 ng. min(-1); forearm blood flow was measured by using venous occlusion plethysmography. Of these subjects, 25 (12 Glu27 and 13 Gln27) received local doses of isoproterenol (0.3 to 30.0 ng. min(-1)) via a dorsal hand vein preconstricted with norepinephrine. Compared with subjects homozygous for the Glu27 allele, subjects with the Gln27 substitution had lower baseline blood flow and, in response to isoproterenol, had a significantly attenuated increase in forearm blood flow. This pattern was more marked in veins. We also studied the relationship between the position 16 polymorphism and vascular reactivity. Homozygotes for Arg16 had significantly lower basal blood flow and attenuated increases in forearm blood flow compared with the Gly16 homozygotes. This was significant in veins but not in arteries. Thus, beta(2)-adrenoceptor genotype determines vascular responses to isoproterenol in forearm resistance vessels and in capacitance vessels. Further studies are necessary to establish whether beta(2)-adrenoceptor polymorphisms are important in the genesis of hypertension.

Adrenergic beta-Agonists↗
PubMed2000

Noninvasive assessment of the digital volume pulse. Comparison with the peripheral pressure pulse.

The digital volume pulse can be recorded simply and noninvasively by photoplethysmography. The objective of the present study was to determine whether a generalized transfer function can be used to relate the digital volume pulse to the peripheral pressure pulse and, hence, to determine whether both volume and pressure pulse waveforms are influenced by the same mechanism. The digital volume pulse was recorded by photoplethysmography in 60 subjects (10 women, aged 24 to 80 years), including 20 subjects with previously diagnosed hypertension. Simultaneous recordings of the peripheral radial pulse and digital artery pulse were obtained by applanation tonometry and a servocontrolled pressure cuff (Finapres), respectively. In 20 normotensive subjects, measurements were obtained after the administration of nitroglycerin (NTG, 500 microgram sublingually). Transfer functions obtained by Fourier analysis of the waveforms were similar in normotensive and hypertensive subjects. In normotensive subjects, transfer functions were similar before and after NTG. By use of a single generalized transfer function for all subjects, the radial and digital artery pressure waveforms could be predicted from the volume pulse with an average root mean square error of 4.4+/-2.0 and 4.3+/-1.9 mm Hg (mean+/-SD) for radial and digital artery waveforms, respectively, similar to the error between the 2 pressure waveforms (4.4+/-1.4 mm Hg). The peripheral pressure pulse is related to the digital volume pulse by a transfer function, which is not influenced by effects of hypertension or NTG. Effects of NTG on the volume pulse and pressure pulse are likely to be determined by a similar mechanism.

Adult↗
PubMed2000

Augmentation of central arterial pressure in mild primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is associated with increased cardiovascular risk, although the mechanisms involved remain unclear. Recent evidence has shown increased pulse pressure to be a powerful predictor of cardiovascular events. As increases in pulse pressure are due largely to arterial stiffening, we measured arterial stiffness in 21 subjects with PHPT (18 women and 3 men; 46-71 yr old) and 21 age- and sex-matched healthy controls using pulse wave analysis, a technique that measures peripheral arterial pressure waveforms and generates corresponding central aortic waveforms. This allows determination of the augmentation of central pressure resulting from wave reflection and augmentation index, a measure of vessel stiffness. Metabolic parameters were also measured. The serum calcium level among PHPT subjects was (mean +/- SD) 2.74+/-0.14 mmol/L. pulse wave analysis showed that both augmentation and the augmentation index were significantly higher in the PHPT group vs. controls [16+/-5 vs. 10+/-4 mm Hg (P < 0.001) and 36+/-9% vs. 25+/-6% (P < 0.001)] despite comparable brachial systolic pressures between groups (136+/-13 vs. 134+/-18 mm Hg). Patients with PHPT had higher fasting serum insulin levels [median (range), 15.8 (7.4-39.4) vs. 11.6 (5.1-23) mU/L; P < 0.05] and triglyceride (1.6+/-0.6 vs. 1.2+/-0.4 mmol/L; P < 0.05), but lower high density lipoprotein cholesterol (1.4+/-0.4 vs. 1.6+/-0.3 mmol/L; P < 0.05). These data indicate that subjects with mild PHPT (calcium, <3.0 mmol/L) have increased arterial stiffness, as evidenced by higher augmentation of central aortic pressures. Enhanced vessel stiffness may arise from a combination of structural and functional vascular changes due to hypercalcemia and/or metabolic abnormalities. Increased vascular stiffness in subjects with PHPT may account in part for the increased cardiovascular risk in this group.

Aged↗
PubMed1999

Effect of oral vitamin E (alpha-tocopherol) supplementation on vascular endothelial function in Type 2 diabetes mellitus.

AIMS: Vascular endothelial dysfunction, an early marker of atherosclerosis, has been demonstrated in Type 2 diabetes mellitus (DM). Vitamin E preserves endothelial function in animal models of diabetes and reduces cardiovascular risk. We examined endothelial function and the effect of vitamin E supplements in uncomplicated Type 2 DM. METHODS: Forty-eight subjects with Type 2 DM and 21 controls had endothelial function assessed using forearm venous occlusion plethysmography with endothelium-independent (sodium nitroprusside) and dependent (acetylcholine, bradykinin) vasodilators. Those with diabetes received 1600 i.u. daily oral alpha-tocopherol or placebo, double-blind for 8 weeks, and had endothelial function reassessed. RESULTS: The diabetic group had higher HbA1c (6.9+/-1.4 vs 4.8+/-0.6%; P<0.01) and systolic (145+/-15 vs. 130+/-16 mm Hg; P<0.01) but not diastolic blood pressure (79+/-8 vs. 76+/-9 mm Hg; P = 0.15). There was blunted vasodilation to acetylcholine (15 microg/min; P<0.01) in subjects with diabetes. Vasodilation to sodium nitroprusside and bradykinin was similar (all P>0.1). Alpha-tocopherol did not affect vasodilation to nitroprusside (P>0.1), acetylcholine (P>0.1) or bradykinin (P>0.1). CONCLUSIONS: There may be receptor-specific endothelial dysfunction in subjects with uncomplicated Type 2 DM. This is not improved by treatment with alpha-tocopherol.

Administration, Oral↗
PubMed1999

Oral vitamin C reduces arterial stiffness and platelet aggregation in humans.

Atherosclerosis is associated with stiffening of conduit arteries and increased platelet activation, partly as a result of reduced bioavailability of nitric oxide (NO), a mediator that normally has a variety of protective effects on blood vessels and platelets. Increased levels of oxygen free radicals are a feature of atherosclerosis that contributes to reduced NO bioavailability and might lead to increased arterial stiffness and platelet activation. Vitamin C is a dietary antioxidant that inactivates oxygen free radicals. This placebo-controlled, double-blind, randomized study was designed to establish whether acute oral administration of vitamin C (2 g), would reduce arterial stiffness and in vitro platelet aggregation in healthy male volunteers. Plasma vitamin C concentrations increased from 42+/-8 to 104+/-8 microM at 6 h after oral administration, and were associated with a significant reduction in augmentation index, a measure of arterial stiffness (by 9.6+/-3.0%; p = 0.016), and ADP-induced platelet aggregation (by 35+/-13%; p = 0.046). There was no change in these parameters after placebo. Vitamin C, therefore, appears to have beneficial effects, even in healthy subjects. The mechanism responsible is likely to involve protection of NO from inactivation by oxygen free radicals, but this requires confirmation. If similar effects are observed in patients with atherosclerosis or risk factors, vitamin C supplementation might prove an effective therapy in cardiovascular disease.

Administration, Oral↗
PubMed1999

Forearm vasoconstriction in response to noradrenaline and NG-monomethyl-L-arginine in essential hypertension.

A role for abnormal NO production in essential hypertension remains controversial. Blunted vasoconstriction of forearm resistance vasculature in response to N(G)-monomethyl-L-arginine (L-NMMA; an inhibitor of NO biosynthesis), relative to the response to noradrenaline, has been reported in hypertensive patients and interpreted as evidence of reduced basal NO biosynthesis. We sought to determine whether reduced sensitivity of forearm vasculature to the vasoconstrictor action of L-NMMA relative to that of noradrenaline is a consistent finding in essential hypertension. We studied a group of patients (n=32; blood pressure 176+/-4/102+/-2 mmHg; means+/-S.E.M.) and a group of healthy normotensive controls (n=32; blood pressure 130+/-2/75+/-1 mmHg). Noradrenaline (60-240 pmol.min(-1)) and L-NMMA (1-4 micromol.min(-1)) were infused into the brachial artery, and forearm blood flow was measured by venous occlusion plethysmography. The effects of each vasoconstrictor were similar in hypertensive and control subjects. The highest dose of L-NMMA reduced forearm blood flow by 0.75+/-0.12 ml.min(-1).dl(-1) in the control group and by 0.89+/-0.10 ml.min(-1).dl(-1) in the hypertensive group. The study had 90% power (with P=0.05) to detect a 10% difference in forearm blood flow response between the hypertensive and control groups. We conclude that reduced sensitivity of forearm resistance vasculature to the vasoconstrictor action of L-NMMA is not a universal feature of essential hypertension. This argues against a primary role for reduced basal NO biosynthesis in skeletal muscle resistance vessels in the pathogenesis of essential hypertension.

Adult↗
PubMed1998

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

OBJECTIVE: To compare effects of N(G)-monomethyl-L-arginine (L-NMMA; a NO synthase inhibitor) and L-arginine (a NO synthase substrate) on haemodynamics in healthy men at rest and during exercise. METHODS: We infused L-NMMA and saline placebo intravenously in two groups of eight healthy men. Each group underwent a two-phase, randomized, single-blind crossover study. Men in one group received 3 mg/kg L-NMMA and men in the other group received 6 mg/kg L-NMMA. Haemodynamic measurements were performed before, during and after a 12 min stepped exercise protocol starting 6 min after the intravenous infusion. A further six men received, according to the same study design, 30 g L-arginine over 30 min and saline placebo before exercise. Blood pressure was measured by sphygmomanometry and cardiac output by bioimpedance, allowing computation of total systemic vascular resistance index (SVRI). RESULTS: Infusion of 6 mg/kg L-NMMA into men at rest produced modest increases (compared with effect of saline placebo) in systolic and diastolic blood pressures of 4.1 +/- 1.1 and 12.6 +/- 3.5%, respectively (means +/- SEM, P < 0.01 for both comparisons) and a marked increase in SVRI of 39.2 +/- 5.2% (P < 0.01). Cardiac index and heart rate were 22.0 +/- 3.3 and 17.0 +/- 4.4% lower after administration of L-NMMA (P < 0.01 for each comparison) than after infusion of saline placebo. During exercise there was no significant difference between total SVRI after infusions of L-NMMA and saline (difference not significant, diminished with increasing exercise). Six minutes into recovery the difference between total SVRI after infusions of L-NMMA and saline reappeared with SVRI 25 +/- 6.9% higher after infusion of L-NMMA than after infusion of saline (P < 0.01). Administration of L-arginine had no significant effect on haemodynamics in men at rest, during exercise and during recovery. CONCLUSIONS: Effects of L-NMMA on total systemic vascular resistance during exercise are less marked than are those on subjects at rest, probably because vasodilatation of resistance vessels of skeletal muscle during exercise is mediated mainly by factors other than NO. Our results also suggest that NO synthesis in healthy men is not substrate limited either at rest or during exercise.

Adult↗