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Biomedical subjects

S Shaw

Publications and source records attributed to S Shaw.

At least 145 records · Page 8Linked to original sources
PubMed1998

Endothelin-1 infusion inhibits plasma insulin responsiveness in normal men.

OBJECTIVES: Elevated plasma endothelin (ET)-1 levels have been described in insulin-resistant states such as syndrome X, obesity, non-insulin-dependent diabetes mellitus, and in some studies in essential hypertension. To investigate whether increases in circulating ET-1 to levels observed in insulin-resistant states can modulate insulin levels and/or insulin sensitivity in humans, we assessed these variables during low, non-pressor-dose ET-1 compared with placebo infusion. DESIGN: In a randomized, single blind, crossover design, 10 lean normotensive male subjects received either an intravenous infusion of subpressor doses of ET-1 dissolved in polygeline or a control infusion of polygeline only (placebo). Using dynamic assessment by the minimal model approach with the modified frequent sampling intravenous glucose tolerance test (FSIGT) the following and other parameters were measured: insulin sensitivity; acute insulin response to glucose (AIR(G)) calculated as the average of the three peak values between 2 and 5 min after injection of glucose from which the basal insulin levels were subtracted; the initial area under the curve (AUC(1-19)) from insulin values between time 0 and 19 min and the first-phase insulin secretion (phi1) from insulin kinetics parameters. RESULTS: ET-1 infusion reduced AIR(G) (to 34.85 +/- 4.27 compared with 49.3 +/- 6.9 microU/ml during placebo, P=0.017) and the acute C-peptide response to glucose (to 2.33 +/- 0.41 compared with 3.1 +/- 0.44 ng/ml, P=0.018), decreased plasma insulin levels during the FSIGT compared with placebo (analysis of variance P<0.0001) and decreased the AUC(1-19) (to 2.1 +/- 0.2 compared with 2.9 +/- 0.3 U/l per 20 min, P<0.01) while phi1 tended to be lower. S1 measured during ET-1 infusion was unaltered (11.11 +/- 1.91 x 10(-4) versus 10.88 +/- 2.11 10(-4)/min per mU per l, NS). CONCLUSIONS: These findings demonstrate that an increase in circulating ET-1 to levels observed in insulin-resistant states acutely diminishes the insulin secretory response but does not significantly modify insulin sensitivity.

Adult↗
PubMed1998

Differential modulation of the renal and myocardial endothelin system by angiotensin II in Vivo. Effects of chronic selective ETA receptor blockade.

Angiotensin II (Ang II) stimulates endothelin-1 (ET-1) production in glomerular endothelial and mesangial cells and in cardiac fibroblasts in vitro. We investigated the effects of Ang II in vivo (200 ng/kg/min for 2 weeks) with or without the ETA receptor antagonist LU135252 (50 mg/kg/day) on blood pressure, renal and myocardial ET-1 protein expression, and [125I]ET-1 uptake in male Wistar-Kyoto (WKY) rats. ET-1 was extracted from whole kidneys and ventricular myocardium and was measured by radioimmunoassay (pg ET-1/g tissue). Organ tissue uptake was calculated as percentage of total DPM recovered after i.v. administration of radiolabeled [125I]ET-1. Ang II treatment increased blood pressure by 35 +/- 3 mm Hg, which was partly reduced by LU135252 (15 +/- 2 mm Hg, p < 0.05). LU135252 in part prevented the impaired weight gain induced by Ang II (p < 0.05). Ang II induced a threefold increase in expression of ET-1 (pg/g tissue) in kidneys (from 19 +/- 2 to 58 +/- 10, p < 0.05), which was normalized by LU135252 (20 +/- 9, p < 0.05). In myocardial tissue, Ang II had only minor effects (5 +/- 1 vs. 3.6 +/- 1, n.s.). However, concomitant LU135252 treatment reduced myocardial ET-1 levels (1.4 +/- 0.4, p < 0.05 vs. Ang II and control). Ang II increased uptake of [125I]ET-1 in kidneys (from 6.9 +/- 0.1% to 10.9 +/- 0.9% of total DPM, p < 0.05) but not in myocardium (1.45 +/- 0.26% vs. 1.59 +/- 0.18% of total DPM), which was unaffected by LU135252 treatment. These data suggest that the kidney, but not the ventricular myocardium, is a target for Ang II-mediated activation of the ET system in vivo, leading to expression and uptake of ET-1. ETA antagonists may provide a new approach to inhibit production and effects of ET-1 in diseases associated with increased activity of the renin-angiotensin system.

Angiotensin II↗
PubMed1998

Developing "out of hours" primary health care. Some key qualitative factors in service selection and evaluation by patients in the UK.

The issue of "out of hours" provision of primary care services by family doctors has excited particularly marked debate in the UK. This article considers the implications for this debate of results from a project designed to elicit the views of users of out of hours primary care provision. Focus groups were used to gauge definitions of "out of hours" services, factors governing the use of some services rather than others and influences on the evaluation of different options. The centrality accorded by patients to the social dimensions of a more "traditional" relationship with family doctors was central to the selection and evaluation of alternative provision. Any significant initiative in the reconfiguration of local health care services might thus be regarded as much a social enterprise as a technical challenge based on the most equitable and efficient application of resources.

England↗
PubMed1998

Clinical morphology of sodium lauryl sulfate (SLS) and nonanoic acid (NAA) irritant patch test reactions at 48 h and 96 h in 152 subjects.

In this study of 152 women, comparison of patch test responses between 2 irritants over 96 h at 2 symmetrical anatomical sites is studied. 2 irritants, each at 4 different concentrations (nonanoic acid (NAA) 80%, 40%, 20%, 10%; sodium lauryl sulfate (SLS) 3%, 2%, 1% and 0.5%) and using propan-1ol and 'water for injection' as the respective controls, were placed as 15 microl aliquots, soaked onto filter paper discs in Finn Chambers, on the volunteer's left and right lower back. The patches were removed at 47, and read at 48 and 96 h. Irritant reactions were evaluated for erythema and surface changes by degree and area affected. Statistical analysis of the results showed that erythema decreased with time for all concentrations of NAA, and at higher concentrations for SLS. Surface changes increased with time for SLS and at higher concentrations of NAA. There was no statistically significant difference comparing left and right sides. Traditionally in patch testing, reactions which fade after 48 h have been regarded as irritant rather than allergic. This study refutes that assumption. Data from our left to right comparisons, made in the same individuals at the same time, show that irritant reactions may be more reproducible than previously appreciated.

Adolescent↗
PubMed1998

ET(A) receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in salt-sensitive hypertension.

Sodium plays an important role in the pathogenesis and therapy of hypertension, a major risk factor for cardiovascular disease. This study investigated the involvement of endothelin in vascular alterations in salt-induced Dahl hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated with a high-sodium diet (NaCl 4%) with or without ET(A) receptor antagonist LU135252 for two months, and effects of treatments on systolic blood pressure, vascular endothelin-1 (ET-1) protein content, aortic hypertrophy, and vascular reactivity of isolated aortic rings were studied. In DS rats, a high-sodium diet increased systolic pressure (190+/-4 versus 152+/-2 mm Hg, P<.05) and aortic ET-1 protein content (4.2-fold, P<.0001) and induced aortic hypertrophy as assessed by tissue weight (P<.0001). Sodium diet markedly reduced NO-mediated endothelium-dependent relaxations to acetylcholine (49+/-4% versus 81+/-4%, P<.0001) and contractions to ET-1 (92+/-7 versus 136+/-8% of KCl, P=.0011). ET-1 tissue levels were highly and inversely correlated with endothelium-dependent relaxations (r=0.931, P<.0001) and contractions to ET (r=0.77, P=.0007). LU135252 treatment reduced systolic blood pressure only in part (168+/-3 versus 190+/-4 mm Hg, P<.05) but normalized sodium-induced changes of vascular reactivity, tissue ET-1 protein content, and vascular structure (P<.001 versus sodium). None of these effects were observed in DR rats. These results suggest that ET-1 acts as a local mediator of vascular dysfunction and aortic hypertrophy in Dahl salt-induced hypertension. ET(A) receptor antagonism may have therapeutic potential for lowering vascular ET-1 content, improving endothelial function, and preventing structural changes in salt-sensitive hypertension.

Acetylcholine↗
PubMed1998

Losartan but not verapamil inhibits angiotensin II-induced tissue endothelin-1 increase: role of blood pressure and endothelial function.

Endothelin partially mediates angiotensin (Ang) II-induced vascular changes in vivo. This study investigated the effects of the angiotensin type 1 receptor antagonist losartan and the calcium channel blocker verapamil on vascular reactivity and tissue endothelin-1 levels in aortas of Wistar-Kyoto rats treated for 2 weeks with Ang II (200 ng x kg(-1) x min(-1)). Ang II increased systolic blood pressure (39+/-4 mm Hg, P<0.05). Concomitant treatment with losartan abolished the Ang II-induced pressure increase (P<0.05), whereas verapamil reduced it only partially (P<0.05). In the aortas of rats with Ang II-induced hypertension, tissue endothelin-1 content was increased threefold and contractions to endothelin-1 were impaired (P<0.05). Interestingly, these alterations were normalized by losartan (P<0.05) but not by verapamil. Hence, there was a strong, negative correlation between contractions to endothelin-1 and tissue endothelin-1 content (r=-0.733, P<0.0001). In contrast, both antihypertensive drugs normalized impaired endothelium-dependent relaxations to acetylcholine and reduced the sensitivity of vascular smooth muscle to sodium nitroprusside compared with Ang II-treated rats (P<0.05). Ang II-induced hypertension enhanced endothelium-dependent contractions to acetylcholine, and these were normalized by either drug. In conclusion, these findings suggest that long-term treatment with Ang II modulates endothelin-1 protein expression in the rat aorta. Although both antihypertensive agents lowered blood pressure and normalized endothelial function, only losartan prevented the increase in tissue endothelin-1 content, suggesting that angiotensin type 1 receptor antagonists but not calcium antagonists modulate tissue endothelin-1 in vivo.

Angiotensin II↗
PubMed1998

I1-imidazoline agonist moxonidine decreases sympathetic nerve activity and blood pressure in hypertensives.

Moxonidine is an I1-imidazoline receptor agonist that reduces blood pressure in hypertensives. Experimental data suggest that moxonidine inhibits central sympathetic activity. However, whether such a mechanism is involved in vivo in humans is still unclear. We investigated the effects of 0.4 mg moxonidine orally on muscle sympathetic nerve activity and heart rate in an open study in 8 healthy volunteers. Furthermore, we studied the effects of 0.4 mg moxonidine on muscle sympathetic nerve activity, heart rate, blood pressure, 24-hour blood pressure profile, and hormone plasma levels in 25 untreated hypertensives in a double-blind, placebo-controlled study. Moxonidine decreased muscle sympathetic nerve activity in both healthy volunteers (P<0.05 versus baseline) and hypertensives (P<0.02 versus placebo). Plasma norepinephrine also decreased (P<0. 01), whereas plasma epinephrine and renin levels did not change (P=NS). Furthermore, moxonidine decreased systolic (P<0.0001) and diastolic (P<0.001) blood pressure. Heart rate decreased after moxonidine in healthy subjects (P<0.05); in hypertensives, heart rate decreased during the night hours (P<0.05) but not during daytime (P=NS). Plasma levels of LDL, HDL, and total cholesterol were not influenced by the drug (P=NS). Moxonidine decreases systolic and diastolic blood pressure by inhibiting central nervous sympathetic activity. This makes this new drug suitable for the treatment of human hypertension and possibly for other cardiovascular diseases with increased sympathetic nerve activity, ie, ischemic heart disease and heart failure.

Adult↗
PubMed1998

Calcium antagonists and sympathetic nerve activation: are there differences between classes?

ACTIONS OF THE SYMPATHETIC NERVOUS SYSTEM: The sympathetic nervous system is an important cardiovascular regulator, particularly during stress and exercise; its sympathetic nervous activity is regulated in centers in the brain stem and transmitted to organs and blood vessels that are innervated by sympathetic nerve endings. In the heart, the sympathetic nervous system increases heart rate and contractility. The effect of the sympathetic nervous system in different vascular beds depends on the degree of innervation, the distribution of postjunctional receptors and the effect of local mediators. Overactivation of the sympathetic nervous system may lead to hypertension and is involved in heart failure. The degree of sympathetic activation determines prognosis in heart failure. Hence, vasodilators ideally should also blunt sympathetic activity, or at least avoid activating it. DIFFERENCES AMONG CALCIUM ANTAGONISTS: Calcium antagonists are widely used for the treatment of hypertension and coronary artery disease. Their main mechanism of action is inhibition of L-type Ca2+ channels. Short-acting nifedipine leads to a marked increase in heart rate, sympathetic nerve activity and plasma catecholamines, similar to those induced by a cold pressor test. With long-acting nifedipine heart rate does not increase, but sympathetic nerve activity does increase. Other calcium antagonists have been less thoroughly investigated, but indirect evidence suggests differences between the different classes. Verapamil and diltiazem lower heart rate. Plasma noradrenalin measurements suggest that verapamil does not stimulate the sympathetic nervous system, but tends to suppress it. Second-generation dihydropyridines with longer duration of action do not increase heart rate; their effects on peripheral sympathetic nerve activity are not clear. Thus, in summary, the different classes of calcium antagonists differ with regard to their effects on sympathetic nerve activation. A decrease in heart rate and nerve activity might be beneficial for long-term prognosis, particularly in hypertension and heart failure.

Blood Circulation↗
PubMed1998

A study of new fragrance mixtures.

OBJECTIVE: To determine the frequency of responses to four mixtures of fragrance materials in routine clinic patients undergoing patch testing for suspect allergic contact dermatitis. The validity of using fragrance mixtures alone, or in combination, was evaluated in terms of predicting allergy to fragrance judged on the basis of finding a response to at least one of the fragrance mixtures. METHODS: A total of 752 subjects were patch tested in five centers worldwide with (1) fragrance mix 8% (FM), (2) balsam of Peru 25%, (3) a mixture of seven of the eight FM 8% ingredients and other fragrance ingredients including jasmine absolute (jasmine/FM mix), and (4) a mixture of five selected natural fragrance ingredients (NM). RESULTS: Of 752 subjects, 100 (13%) had positive patch tests to at least one of the four fragrance mixtures. The age of the patients was 45.2 +/- 18.3 years (mean +/- SD). Ninety-six percent were Caucasian. Facial eruptions and hand involvement were the most common topographic sites. Of subjects exhibiting a positive response, 67% reacted to FM, 63% to the jasmine/FM mix, 47% to the NM, and 38% to balsam of Peru. Testing with FM and NM identified 84% of the perfume-allergic patients. FM 8% tested simultaneously with the jasmine/FM mix identified 86% of the perfume-allergic patients. Testing simultaneously with three test materials combining either the NM or the jasmine/FM mix with balsam of Peru and FM identified 95% of the perfume-sensitive patients. CONCLUSIONS: The simultaneous testing of NM or jasmine/FM mix, in addition to the conventional use of FM 8% and balsam of Peru, increases the sensitivity of testing for fragrance allergy from 81% to 95%.

Balsams↗
PubMed1998

Bulimic adolescents benefit from massage therapy.

Twenty-four female adolescent bulimic inpatients were randomly assigned to a massage therapy or a standard treatment (control) group. Results indicated that the massaged patients showed immediate reductions (both self-report and behavior observation) in anxiety and depression. In addition, by the last day of the therapy, they had lower depression scores, lower cortisol (stress) levels, higher dopamine levels, and showed improvement on several other psychological and behavioral measures. These findings suggest that massage therapy is effective as an adjunct treatment for bulimia.

Adolescent↗
PubMed1998

Effects of continuous ambulatory peritoneal dialysis and kidney transplantation on advanced glycation endproducts in the skin and peritoneum.

Advanced glycation endproducts (AGE) form as a result of non-enzymatic reaction of reducing sugars with proteins. Patients with chronic renal failure (CRF) have elevated AGE in plasma, skin and peritoneum. We measured AGE in the skin and peritoneum of individuals with CRF, patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and in renal transplant recipients (TR). Pentosidine concentration and collagen-linked fluorescence (CLF) were measured. Pentosidine and CLF correlated in all patient groups (CRF r=0.688, p<0.01; CAPD r=0.674, p<0.05; TR r=0.811, p<0.01). Successful kidney transplant reduced AGE levels in the skin (CRF 11.7 +/- 4.51 U/mg; TR 5.02 +/- 3.13 U/mg, p<0.00001) and peritoneum (CRF 17.5 +/- 6.16 U/mg, TR 9.4 +/- 4.97 U/mg, p<0.0001). However in contrast to the TR group, CLF in peritoneum increased following CAPD (CRF 17.5 +/- 6.16 U/mg; CAPD 24.2 +/- 10.4 U/mg; p=0.06). Our results suggest that AGE might be formed in the peritoneum during CAPD treatment.

Adolescent↗
PubMed1997

Angiotensin II increases vascular and renal endothelin-1 and functional endothelin converting enzyme activity in vivo: role of ETA receptors for endothelin regulation.

Angiotensin II (Ang II)-stimulated expression of endothelin-1 (ET-1) mRNA is blocked by ETA antagonists in vitro. We studied effects of Ang II (200 ng/kg/min) and ETA antagonist LU135252 (50 mg/kg/d) in WKY rats in vivo investigating vascular and renal ET-1 protein expression, functional endothelin converting enzyme (ECE) activity, and clearance of (125I)ET-1. Infusion of Ang II for two weeks increased ET-1 protein content in aorta (4.7-fold) and femoral artery (1.6-fold) with and without endothelium and in kidneys (3-fold, p<0.05) and enhanced functional ECE activity (p<0.05). The Ang II-induced increase in tissue ET-1 content and functional ECE activity was completely prevented by LU135252 (p<0.05). Chronic treatment of control animals with LU135252 lowered basal vascular but not renal ET-1 content (p<0.05 vs. control). Clearance of 125IET-1 was unaffected by the treatments. It is concluded that Ang II increases ET-1 protein and functional ECE activity in vascular smooth muscle and kidney through ETA-receptors in vivo.

Angiotensin II↗
PubMed1997

Angiotensin II increases tissue endothelin and induces vascular hypertrophy: reversal by ET(A)-receptor antagonist.

BACKGROUND: In vitro studies on vascular smooth muscle cells suggest that endothelin has a stimulating effect on cellular proliferation. This study was designed to determine the endogenous effect of endothelin on angiotensin II-induced hypertrophy of small arteries in vivo. METHODS AND RESULTS: Two weeks of angiotensin II administration (200 ng x kg[-1] x min[-1]) increased media thickness, media/lumen ratio, and cross-sectional area of basilar and small mesenteric arteries, confirming the proliferative properties of angiotensin II. The tissue levels of endothelin-1 were elevated in mesenteric arteries after angiotensin II administration. The administration of the selective and specific ET(A)-receptor antagonist LU135252 (50 mg x kg[-1] x d[-1]) in combination with angiotensin II prevented the changes of vascular geometry and partially reduced the increase in blood pressure induced by angiotensin II. Indeed, part of the effect on the vascular structure of the endothelin-receptor antagonist seemed pressure-independent. CONCLUSIONS: Our results therefore demonstrate that angiotensin II increases the production of endothelin in the blood vessel wall that, via ET(A) receptors, mediates changes in vascular structure of the cerebral and mesenteric circulation. Endothelin antagonists may therefore be of value to reduce blood pressure and to prevent vascular structural changes in conditions of increased activity of the renin-angiotensin system.

Angiotensin II↗
PubMed1997

Differential effects of captopril and nitrates on muscle sympathetic nerve activity in volunteers.

BACKGROUND: The sympathetic nervous system (SNS) is an important regulator of cardiovascular function. Activation of SNS plays an important role in the pathophysiology and the prognosis of cardiovascular diseases such as heart failure, acute coronary syndromes, arrhythmia, and possibly hypertension. Vasodilators such as adenosine and sodium nitroprusside are known to activate SNS via baroreflex mechanisms. Because vasodilators are widely used in the treatment of patients with cardiovascular diseases, the aim of the present study was to assess the influence of clinically used dosages of isosorbide dinitrate and captopril on sympathetic nerve activity at rest and during stimulatory maneuvers. METHODS AND RESULTS: Twenty-eight healthy volunteers were included in this double-blind placebo-controlled study, and muscle sympathetic nerve activity (MSA; with microelectrodes in the peroneal nerve), blood pressure, heart rate, and neurohumoral parameters were measured before and 90 minutes after the oral administration of 40 mg isosorbide dinitrate or 6.25 mg captopril. Furthermore, a 3-minute mental stress test and a cold pressor test were performed before and 90 minutes after drug administration. Resting MSA did not change after captopril and decreased compared with placebo (P < .05 versus placebo), whereas isosorbide dinitrate led to a marked increase in MSA (P < .05). Systolic blood pressure was reduced by isosorbide dinitrate (P < .05), whereas captopril decreased diastolic blood pressure (P < .05). The increases in MSA, blood pressure, and heart rate during mental stress were comparable before and after drug administration regardless of the medication. During cold pressor test, MSA and systolic and diastolic blood pressures increased to the same degree independent of treatment, but after isosorbide dinitrate, the increase in MSA seemed to be less pronounced. Heart rate did not change during cold stimulation. Plasma renin activity increased after captopril and isosorbide dinitrate (P < .05), whereas placebo had no effect. Endothelin-1 increased after placebo and isosorbide dinitrate (P < .05) but not after captopril. CONCLUSIONS: Thus, captopril suppressed MSA despite lowering of diastolic blood pressure but allowed normal adaptation of the SNS during mental or physical stress. In contrast, the nitrate strongly activated the SNS under baseline conditions. These findings demonstrate that vasodilators differentially interact with the SNS, which could be of importance in therapeutic strategies for the treatment of patients with cardiovascular diseases.

Adult↗