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Biomedical subjects

J Cockcroft

Publications and source records attributed to J Cockcroft.

9 recordsLinked to original sources
PubMed2003

The effects of depot long-acting somatostatin analog on central aortic pressure and arterial stiffness in acromegaly.

Acromegaly is associated with increased cardiovascular risk. Although conventional risk factors such as glucose intolerance, hypertension, and dyslipidemia probably contribute, there may also be direct effects of GH/IGF-I excess on the vasculature. To study the effects of GH excess on the vasculature, we have assessed arterial stiffness in acromegalic subjects with and without active disease and have investigated the effects of Sandostatin LAR (OCT-LAR) on vascular function. Sixteen normotensive subjects with acromegaly (10 males and 6 females) and 8 healthy controls were studied. Of the acromegalic subjects, eight had active disease (group A), and eight were cured (GH < 2.5 mU/liter; group B). The three groups were age, sex, and blood pressure matched. Group A subjects were restudied after 3 and 6 months of OCT-LAR therapy. Arterial stiffness was assessed by analyzing central arterial pressure waveforms derived from measured radial artery waveforms. This allowed determination of the augmentation of central pressure and the augmentation index. Lipids, glucose, and IGF-I were also measured. Comparing the three groups (ANOVA; mean +/- SD), the augmentation index was higher in group A (28 +/- 12 vs. 12 +/- 13%; P < 0.01) but not in group B (22 +/- 7 vs. 12 +/- 13%; P = 0.60), compared with controls. IGF-I was higher in group A (50.3 +/- 21.2 nmol/liter; P < 0.01), compared with group B (22.5 +/- 8.9 nmol/liter) and controls (19.5 +/- 5.3 nmol/liter). On regression analysis, IGF-I concentration was identified as a strong independent predictor of the augmentation index (beta = 0.50; P = 0.007). There were no significant differences in aortic systolic pressure, aortic diastolic pressure, lipids, or glucose. Compared with baseline, OCT-LAR treatment resulted in a lowering of augmentation index at 3 months (20 +/- 15 vs. 28 +/- 12%; P < 0.05), but at 6 months (24 +/- 16%; P = 0.21) there was no significant change. IGF-I was reduced from 50.3 +/- 21.2 nmol/liter at baseline to 31.4 +/- 13.2 nmol/liter at 3 months (P < 0.05) and 26.6 +/- 15.8 nmol/liter at 6 months (P < 0.05). In conclusion, acromegaly is associated with changes in the central arterial pressure waveform, suggesting large artery stiffening. This may have important implications for cardiac morphology and performance in acromegaly as well as increasing the susceptibility to atheromatous disease. Large artery stiffness is reduced in cured acromegaly and partially reversed after pharmacological treatment of active disease.

Acromegaly↗
PubMed2000

Association analysis of beta2 adrenoceptor polymorphisms with hypertension in a Black African population.

OBJECTIVE: To determine whether or not beta2 adrenoceptor polymorphism is a risk factor for the development of hypertension in a Black South African population. BACKGROUND: Attenuated vasodilator responses to endogenous catecholamines may contribute to the aetiology of hypertension. Downregulation of beta2 adrenoreceptors (beta2AR) following stimulation with agonists is determined in part by variation at the beta2AR gene locus. The Glu27 beta2AR genotype results in attenuated downregulation compared with the wild-type Gln27 receptor, whereas Gly16 exhibits enhanced down-regulation compared to Arg16. Possible racial differences in the prevalence of the beta2AR polymorphisms may be an explanation for the blunted responses to isoprenaline and the increased prevalence of hypertension in Black African populations. METHODS: One hundred and ninety-two unrelated hypertensives and 123 normotensives of Black South African origin were studied. Hypertensives were recruited from hospital hypertension clinics in the province of Gauteng and if on treatment, had a 2-4 week washout period before 24-h ambulatory blood pressure assessment Normotensive controls were recruited from the same community. RESULTS: There was no significant association between either the Arg-Gly16 polymorphism or the Gln-Glu27 polymorphism and hypertension status. Furthermore, in the hypertensives, no significant association was seen between beta2AR genotype at either site and clinical blood pressure, 24-h blood pressure or left ventricular mass. A significant association was seen between Arg16 homozygotes and lower body mass index in hypertensives (P = 0.007) although this was not a primary end point. Interestingly, the Glu27 polymorphism was much rarer in this population (allelic frequency 17%) compared to a Caucasian population. CONCLUSION: These data suggest that beta2AR polymorphism is not a risk factor for hypertension per se in this defined population. The possibility that the decreased prevalence of Glu27 in black South African populations explains blunted vasodilator responses to isoprenaline requires further study.

Adrenergic beta-Agonists↗
PubMed1999

Diminished wave reflection in the aorta. A novel physiological action of insulin on large blood vessels.

Epidemiological data suggest that insulin may have direct effects on large-vessel function, but thus far insulin has only been shown, after prolonged infusions, to slowly decrease peripheral vascular resistance by increasing muscle blood flow. We determined whether physiological doses of insulin affect function of large arteries, before any changes in peripheral blood flow, in vivo using pulse wave analysis. Nine normal men were studied on 2 occasions: once during a 6-hour infusion of saline and once under normoglycemic hyperinsulinemic conditions (sequential 2-hour insulin infusions of 1, 2, and 5 mU/kg. min). Central aortic pressure waves were synthesized from those recorded in the periphery with the use of applanation tonometry and a validated reverse transfer function every 30 minutes. This allowed determination of central aortic augmentation (the pressure difference between early and late systolic pressure peaks) and augmentation index (augmentation expressed as a percentage of pulse pressure). Both augmentation and augmentation index decreased significantly within 1 hour after administration of insulin (P<0.001) but not saline. Systolic and diastolic blood pressure and heart rate remained unchanged for the first 2 hours. A significant increase in peripheral (forearm) blood flow was not observed until 2.5 hours after start of the insulin infusion. These data demonstrate that insulin, in normal subjects, rapidly decreases wave reflection in the aorta. This beneficial effect is consistent with increased distensibility or vasodilatation of large arteries. In contrast to the effect of insulin on peripheral blood flow, this action of insulin is observed under conditions in which both the insulin dose and duration of insulin exposure are physiological. Resistance to this action of insulin could provide a mechanism linking insulin resistance and conditions such as hypertension at the level of large arteries.

Adult↗
PubMed1999

Marked resistance of the ability of insulin to decrease arterial stiffness characterizes human obesity.

We tested the hypothesis that insulin has effects on large artery stiffness in addition to its slow vasodilatory effect on resistance vessels in skeletal muscle, and whether such an effect might be altered in obesity. Eight nonobese (aged 25 +/- 1 years, BMI 22.7 +/- 0.4 kg/m2) and eight obese (aged 27 +/- 2 years, BMI 30.6 +/- 0.9 kg/m2) men were studied under normoglycemic-hyperinsulinemic (sequential 2-h insulin infusions of 1 [step 1] and 2 [step 2] mU x kg(-1) x min(-1)) conditions, and another seven men participated in a saline control study. Central aortic pressure waves were synthesized from those recorded in the periphery using applanation tonometry and a validated reverse transfer function every 30 min. This allowed determination of augmentation (the pressure difference between early and late systolic pressure peaks) and the augmentation index (augmentation divided by pulse pressure), a measure of arterial stiffness. Whole-body glucose uptake was reduced by 48 (step 1) and 41% (step 2) (P < 0.01) in the obese subjects versus the nonobese subjects. Basal forearm blood flow averaged 2.5 +/- 0.2 and 2.6 +/- 0.2 ml x dl(-1) x min(-1) in the obese and nonobese subjects, respectively (NS). Insulin induced a significant increase in forearm blood flow after 2.5 h (3.6 +/- 0.4 ml x dl(-1) x min(-1), P < 0.05 vs. basal) in the nonobese subjects and after 4 h in the obese subjects (3.2 +/- 0.2, P < 0.05). In contrast to these slow changes in peripheral blood flow, augmentation and the augmentation index decreased significantly in the nonobese subjects after 1 h (-3.0 +/- 1.6 mmHg and -10.0 +/- 5.4%, respectively, P < 0.001 vs. basal), but remained unchanged until 3 h in the obese subjects. Percent fat (r = 0.86, P < 0.0001) and whole-body glucose uptake (r = -0.72, P < 0.01) correlated with the change in the augmentation index by insulin. These data demonstrate temporal dissociation in insulin's vascular actions. Insulin's effect to decrease arterial stiffness in nonobese subjects (a decrease in wave reflection) is observed under physiological conditions and precedes a slow vasodilatory effect in the periphery. In the obese subjects, insulin's normal effect to decrease central wave reflection is severely blunted. The degree of impairment in this novel vascular action of insulin is closely correlated with the degree of obesity and insulin action on glucose uptake.

Adult↗
PubMed1996

Chronic hyperglycemia impairs endothelial function and insulin sensitivity via different mechanisms in insulin-dependent diabetes mellitus.

BACKGROUND: We explored whether chronic hyperglycemia is associated with defects in endothelium-dependent vasodilatation in vivo and whether defects in the hemodynamic effects of insulin explain insulin resistance. METHODS AND RESULTS: Vasodilator responses to brachial artery infusions of acetylcholine, sodium nitroprusside, and NG-monomethyl-L-arginine and, on another occasion, in vivo insulin sensitivity (euglycemic insulin clamp combined with the forearm catheterization technique) were determined in 18 patients with insulin-dependent diabetes mellitus (IDDM) and 9 normal subjects. At identical glucose and insulin levels, insulin stimulation of whole-body and forearm glucose uptake was 57% reduced in the IDDM patients compared with normal subjects (P < .001). The defect in forearm glucose uptake was attributable to a defect in glucose extraction (glucose AV difference, 1.1 +/- 0.2 versus 1.9 +/- 0.2 mmol/L, P < .001, IDDM versus normal subjects), not blood flow. Within the group of IDDM patients, hemoglobin A1c was inversely correlated with forearm blood flow during administration of acetylcholine (r = -.50, P < .02) but not sodium nitroprusside (r = .07). The ratio of endothelium-dependent to endothelium-independent blood flow was approximately 40% lower in patients with poor glycemic control than in normal subjects or patients with good or moderate glycemic control. CONCLUSIONS: We conclude that chronic hyperglycemia is associated with impaired endothelium-dependent vasodilatation in vivo and with a glucose extraction defect during insulin stimulation. These data imply that chronic hyperglycemia impairs vascular function and insulin action via distinct mechanisms. The defect in endothelium-dependent vasodilatation could contribute to the increased cardiovascular risk in diabetes.

Acetylcholine↗
PubMed1992

Effects of peptide YY on the human cardiovascular system: reversal of responses to vasoactive intestinal peptide.

Peptide YY (PYY) reverses the increased intestinal secretion stimulated by vasoactive intestinal peptide (VIP) in humans. VIP also dilates blood vessels, so we investigated the effect of PYY on the cardiovascular system. Six volunteers received PYY, 0.4 and 1.2 pmol.kg-1 x min-1 i.v. for 2 h, reproducing plasma levels seen postprandially and during a diarrheal illness, respectively. Cardiac function was assessed by echocardiography. PYY infused at 0.4 pmol.kg-1 x min-1 had no effect on cardiovascular parameters. PYY infused at 1.2 pmol.kg-1 x min-1 caused a fall in both stroke volume from 128 +/- 8 to 110 +/- 8 ml/beat (mean +/- 95 confidence interval, P < 0.01) and cardiac output from 7.2 +/- 0.4 to 6.1 +/- 0.4 l/min (P < 0.01). Effects of infusion of PYY into the brachial artery at doses of 0-16 pmol/min were assessed using venous occlusion plethysmography in six subjects. PYY infusion caused a dose-dependent fall in forearm blood flow. Six subjects received VIP, 5 pmol.kg-1 x min-1 i.v., causing a rise in heart rate from 55 +/- 3 to 70 +/- 3 beats/min and increased cardiac output from 7.3 +/- 1.1 to 13.1 +/- 1.1 l/min. The addition of PYY, 0.4 pmol.kg-1 x min-1 i.v., did not affect the heart rate significantly but decreased the cardiac output to 10.4 +/- 1.1 l/min (P < 0.01). Infusions of PYY into the brachial artery at 5 pmol/min decreased local vasodilation induced by VIP infused at 2 pmol/min at the same site by 40% (P < 0.01), even though this dose of PYY had no significant effect on local blood flow when given alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Identification of 13,14-dihydro-15-oxo-prostaglandin F2 alpha in the circulation during infusions of bradykinin and prostaglandin E2 in man.

Bradykinin, prostaglandin E2 (PGE2), PGD2 and vehicle (saline) were each administered intravenously on separate occasions to 6 healthy men for a period of 60 min. 13,14-Dihydro-15-oxo-PGF2 alpha was identified in plasma samples obtained during intravenous infusions of bradykinin and PGE2 but not during infusions of PGD2 or saline. The structure of this metabolite was verified by comparison of three different derivatives with authentic standards, using gas chromatography/electron capture mass spectrometry. Bradykinin increased plasma concentrations of 13,14-dihydro-15-oxo-PGF2 alpha from baseline values in the range less than 5-10 pg ml-1 to 28-403 pg ml-1. PGE2 increased plasma concentrations of 13,14-dihydro-15-oxo-PGF2 alpha from baseline values in the range less than 5-17 pg ml-1 to 160-603 pg ml-1. Neither PGD2 nor the vehicle affected 13,14-dihydro-15-oxo-PGF2 alpha concentrations. We conclude that bradykinin-stimulated 13,14-dihydro-15-oxo-PGF2 alpha may be derived from PGE2 or PGF2 alpha. The possibility that these prostaglandins are synthesized by stimulation of microvascular endothelium during bradykinin infusion is discussed.

Adult↗