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Biomedical subjects

D J Webb

Publications and source records attributed to D J Webb.

At least 127 records · Page 7Linked to original sources
PubMed1998

Peripheral vascular tone in patients with cirrhosis: role of the renin-angiotensin and sympathetic nervous systems.

OBJECTIVE: The aims of the study were to establish the roles of angiotensin II and of the cardiopulmonary baroreceptor reflex in the regulation of peripheral vascular tone in patients with cirrhosis. METHODS: Forearm blood flow responses to subsystemic, locally active intrabrachial infusions were measured in patients with Child's Grade C cirrhosis and matched controls using bilateral venous occlusion plethysmography. Responses were determined to the angiotensin II type I receptor antagonist, losartan, noradrenaline, angiotensin II and the nitric oxide synthase inhibitor, L-NG-monomethyl arginine. RESULTS: Losartan at 30 and 90 micrograms/min caused no significant change in blood flow in controls, but caused 23 +/- 6% and 27 +/- 5% increases in patients respectively (p < 0.001). Lower body negative pressure caused a mean bilateral reduction in forearm blood flow of 20 +/- 4% in controls (p < 0.001) but only tended to reduce flow (9 +/- 5%; p = 0.06) in patients (p < 0.001; controls vs. patients). Noradrenaline, angiotensin II and L-NG-monomethyl arginine caused significant vasoconstriction (p < 0.001) in both patients and controls although angiotensin II caused significantly less vasoconstriction in patients (p = 0.01). CONCLUSIONS: We conclude that angiotensin II makes an important contribution to basal peripheral vascular tone in patients with cirrhosis in the face of reduced vascular responses to its local administration. In addition, the vasoconstrictor response to cardiopulmonary baroreceptor unloading is attenuated despite normal vascular responses to noradrenaline. These responses are consistent with chronic activation of the renin-angiotensin and sympathetic nervous systems in patients with advanced cirrhosis.

Analysis of Variance↗
PubMed1998

Impairment of forearm vasodilatation to acetylcholine in hypercholesterolemia is reversed by aspirin.

OBJECTIVE: Impaired cholinergic vasodilatation in the forearm in hypertension and hypercholesterolemia has been attributed to impaired nitric oxide bioavailability. However, inhibition of cyclooxygenase reverses the impaired cholinergic dilatation in hypertensive animals and patients. The aim of this study was to examine the effect of aspirin on cholinergic vasodilatation in hypercholesterolemic patients. METHODS: We examined responses to brachial artery infusion of acetylcholine and the endothelium-independent vasodilator sodium nitroprusside in the presence or absence of aspirin in 10 hypercholesterolemic patients (7 men/3 women; aged 38-63 yr; systolic blood pressure 133 +/- 5 mmHg; diastolic blood pressure 80 +/- 3) compared with 10 matched controls (7 men/3 women; aged 38-63 yr; systolic blood pressure 126 +/- 2; diastolic blood pressure 77 +/- 2). RESULTS: In hypercholesterolemic patients, forearm vasodilatation was impaired in response to acetylcholine (112 +/- 20 vs. 346 +/- 30% increase in blood flow in controls, at the highest dose [15 micrograms min-1]; P < 0.0001) but not in response to sodium nitroprusside. With the addition of aspirin, baseline forearm blood flow was unaltered. However, forearm vasodilatation to acetylcholine was partially restored in hypercholesterolemics (from 112 +/- 20 to 193 +/- 30%; P < 0.001) though not affected in controls. Vasodilator responses to sodium nitroprusside were unaffected by aspirin in either group. CONCLUSIONS: In hypercholesterolemia, an altered balance between vasoconstrictor and dilator prostanoids, favouring constrictors, may contribute to endothelial dysfunction either directly or through an effect on nitric oxide synthesis. Restoration of this imbalance may be a component of the therapeutic benefit of aspirin in cardiovascular disease.

Acetylcholine↗
PubMed1998

The L-arginine/nitric oxide pathway contributes to the acute release of tissue plasminogen activator in vivo in man.

OBJECTIVE: Effective endogenous fibrinolysis requires rapid release of endothelial tissue plasminogen activator (t-PA). Using the nitric oxide synthase inhibitor, L-NG-monomethylarginine (L-NMMA), we examined the contribution of endogenous nitric oxide to substance P-induced t-PA release in vivo in man. METHODS: Blood flow and plasma fibrinolytic and haemostatic factors were measured in both forearms of 8 healthy male volunteers who received unilateral brachial artery infusions of substance P (2-8 pmol/min) and L-NMMA (1-4 micrograms/min). RESULTS: Substance P caused dose-dependent increases in blood flow (P < 0.001) and plasma t-PA antigen (P = 0.04) and activity (P < 0.001) concentrations confined to the infused forearm, but had no effect on plasminogen activator inhibitor type I (PAI-I) or von Willebrand factor concentrations. In the presence of L-NMMA, substance P again caused significant increases in blood flow (P < 0.001) and t-PA antigen (P = 0.003) and activity (P < 0.001) concentrations but these increases were significantly less than with substance P alone (P < 0.001, P = 0.05 and P < 0.01, respectively). L-NMMA alone significantly reduced blood flow in the infused arm, but had no measurable effect on t-PA or PAI-1 concentrations. CONCLUSIONS: The L-arginine/nitric oxide pathway contributes to substance P-induced t-PA release in vivo in man. This provides an important potential mechanism whereby endothelial dysfunction increases the risk of atherothrombosis through a reduction in the acute fibrinolytic capacity.

Adult↗
PubMed1998

Endothelin: new discoveries and rapid progress in the clinic.

This fifth international conference on ET serves to underline the rapid pace of development of our understanding of the very versatile ET system. On the one hand, the body uses ETs at several stages in embryonic development, in normal postnatal growth, and in cardiovascular homeostasis under healthy conditions. On the other hand, overwhelming evidence now exists that ET-1 plays important pathophysiological roles in conditions of decompensated vascular homeostasis. Indeed, in CHF this evidence is sufficient to justify the large-scale studies of morbidity and mortality needed to market ET antagonists as medicines. Other potentially important cardiovascular indications for ET antagonists are still emerging--including hypertension, stroke, subarachnoid haemorrhage and renal failure--and all are likely to be the subject of clinical trials over the next few years. As yet, there has been little work outside the cardiovascular and renal fields, but other areas, such as cancer treatment, may also prove promising. New molecules with increasing selectivity (ETA and ETB) continue to emerge and may be valuable. Inhibition of ECE-1 remains as an alternative approach and nonpeptide ECE inhibitors now exist. There appears to be a consensus that ETA blockade is beneficial in cardiovascular and renal disease. However, several strands of work presented at the meeting--the hypertensive salt-sensitive phenotype of rescued ETB knockout mice, the sustained and progressive hypertensive effects of ETB-selective antagonism in rats, ETB-mediated vasodilatation and natriuresis in dogs, and nitric oxide-dependent ETB-mediated vasodilatation in humans--all suggest that ETB-mediated vascular and renal responses may be protective. The development of selective ETA antagonists, therefore, now seems fully justified. In the future, direct comparisons in animal models, and patients, of ETA and ETA/B antagonists will be important in determining the value of additional ETB receptor blockade in individual diseases.

Animals↗
PubMed1998

Reduced responsiveness to endothelin-1 in peripheral resistance vessels of patients with syndrome X.

OBJECTIVES: This study sought to assess the contribution and action of nitric oxide and endothelin-1 in peripheral resistance vessels of patients with syndrome X. BACKGROUND: Patients with syndrome X may have a generalized disorder of vascular and endothelial function, promoting vasospasm. METHODS: Changes in blood flow responses to intrabrachial infusion of the endothelium-dependent vasodilators substance P and acetylcholine, the endothelium-independent nitric oxide donor sodium nitroprusside and the endothelin type A (ET(A)) receptor antagonist BQ-123 were assessed using venous occlusion plethysmography in 10 patients with syndrome X and 10 matched control subjects. Vasoconstrictor responses to the nitric oxide synthase inhibitor L-N(G)-monomethyl arginine (L-NMMA) and endothelin-1 were also determined. RESULTS: There were no significant differences in the responses to acetylcholine, substance P, sodium nitroprusside or BQ-123 between patients and control subjects. However, despite similar degrees of vasoconstriction in response to L-NMMA in both groups, endothelin-1 caused a reduction in forearm blood flow of only 20 +/- 2% in patients with syndrome X compared with 35 +/- 3% in matched control subjects at 90 min (p < 0.001). Although plasma endothelin-1 concentrations were not significantly higher in patients with syndrome X (4.8 vs. 4.0 pg/ml, p = 0.17), the vasoconstriction caused by endothelin-1 infusion correlated inversely with plasma endothelin-1 concentrations (r = -0.51, p = 0.04). CONCLUSIONS: Patients with syndrome X had normal basal and stimulated nitric oxide activity and basal endogenous ET(A) receptor-mediated vascular tone. However, despite otherwise normal vascular function, there was reduced responsiveness to exogenous endothelin-1, possibly reflecting overactivity of this system and ET(A) receptor downregulation.

Analysis of Variance↗
PubMed1998

Clinical experience with endothelin antagonists.

Endothelin-1, discovered in 1988, is a 21-amino-acid peptide and currently the most potent vasoconstrictor and pressor substance known. Generated by vascular endothelial cells in response to a variety of chemical and mechanical signals, endothelin-1 is known to potentiate the actions of other vasoconstrictor substances and act as a comitogen in addition to directly causing vasoconstriction. There is evidence that endothelin-1 may contribute to the pathophysiology of conditions associated with sustained vasoconstriction, such as hypertension and heart failure, vasospastic conditions, such as subarachnoid hemorrhage, and atherogenesis. Studies using endothelin receptor antagonists show that endothelin-1 plays an important role in the maintenance of vascular tone and blood pressure in healthy humans, predominantly via an effect on the vascular smooth muscle ETA receptors. The endothelin receptor antagonist bosentan also effectively lowers blood pressure in hypertensive subjects and produces sustained and favorable effects on systemic and pulmonary hemodynamics in patients with chronic heart failure. A good side-effect profile, together with a potential for inhibition of atherogenesis, makes the endothelin receptor antagonists a potentially interesting class of novel agents for the treatment of cardiovascular disease.

Amino Acid Sequence↗
PubMed1998

Characterization of the binding sites for plasminogen and tissue-type plasminogen activator in cytokeratin 8 and cytokeratin 18.

Cytokeratin 8 (CK8) is an intermediate filament protein that penetrates to the external surfaces of breast cancer cells and is released from cells in the form of soluble heteropolymers. CK8 binds plasminogen and tissue-type plasminogen activator (t-PA) and accelerates plasminogen activation on cancer cell surfaces. The plasminogen-binding site is located at the C-terminus of CK8. In this study, we prepared GST-fusion proteins which contained either 174 amino acids from the C-terminus of CK8 (CK8f) or 134 amino acids from the C-terminus of CK18 (CK18f). A third GST-CK fusion protein was identical to CK8fexcept that the C-terminal lysine was mutated to glutamine (CK8fK483Q). CK8f bound plasminogen; the K(D) was 0.5 microM. Binding was completely inhibited by epsilonACA. CK8fK483Q also bound plasminogen, albeit with decreased affinity (K(D) approximately 1.5 microM). CK18f did not bind plasminogen at all. All three fusion proteins bound t-PA equivalently, providing the first evidence that CK18 may function as a t-PA receptor, t-PA and plasminogen cross-competed for binding to CK8f. Thus, t-PA and plasminogen cannot bind to the same CK8f monomer simultaneously. Nevertheless, CK8f still promoted plasminogen activation, probably reflecting the fact that CK8f was purified in dimeric or tetrameric form. These studies demonstrate that CK8 may promote plasminogen activation by t-PA only when present in an oligomerized state. CK18 may participate in the oligomer, together with CK8, based on its ability to bind t-PA.

Aminocaproic Acid↗
PubMed1998

Nitric oxide and gall-bladder motor function.

BACKGROUND: The L-arginine: nitric oxide (NO) pathway has been shown to be important in the regulation of intestinal motility and NO may be the mediator for nonadrenergic noncholinergic (NANC) neurotransmission. AIM: To determine the role of the L-arginine: NO pathway in gall-bladder motor function. METHODS: Strips of fresh bovine and human gall-bladders were stimulated with cholecystokinin (CCK). The effects of glyceryl trinitrate (GTN), sodium nitroprusside and Kreb's solution upon CCK-stimulated muscle contraction were examined. The effect of the NO synthase inhibitor, L-NG-monomethyl-arginine (L-NMMA) upon basal muscle tone was also examined. Ten human gall-bladders were immunohistochemically stained for nitric oxide synthase (NOS) and product 9.5 to identify neurones. Postprandial gall-bladder emptying was measured on separate occasions in six healthy volunteers during systemic intravenous infusion of normal saline; glyceryl trinitrate; sodium nitroprusside (SNP), hydralazine and L-NMMA. RESULTS: In the in vitro study, GTN and SNP significantly reduced the tension of CCK-stimulated muscle contraction whilst Kreb's solution had no effect. L-NMMA increased tonic and phasic muscle contractions. Immunohistochemical staining for NOS was consistently absent in human gall-bladders. In the in vivo study, both GTN and SNP caused significant impairment of gall-bladder emptying; the ejection fraction was only 50% at the end of the study period involving these infusates, this contrasted with ejection fractions in excess of 80% during infusions with hydralazine, saline and L-NMMA. CONCLUSION: Pharmacological doses of NO donors impair postprandial gall-bladder emptying in vivo and relax gall-bladder smooth muscle in vitro. However, negative immunohistochemical staining suggest NOS is unlikely to be the neurotransmitter for NANC innervation regulating gall-bladder motility.

Adult↗
PubMed1998

Studies with iontophoretic administration of drugs to human dermal vessels in vivo: cholinergic vasodilatation is mediated by dilator prostanoids rather than nitric oxide.

AIMS: Impaired function of the vascular endothelium has been well documented in hypertension and hypercholesterolaemia. However, the 'gold standard' method for assessing endothelial function, using intra-arterial drug infusion, is invasive and has only been applied in the forearm and coronary circulations in vivo. The aim of the present study was to establish the non-invasive technique of transdermal drug iontophoresis to assess endothelial function in human dermal vessels in vivo. METHODS: In healthy male volunteers, we delivered acetylcholine (ACh) and sodium nitroprusside (SNP) to dermal vessels of the forearm using iontophoresis, and measured vasodilatation using laser Doppler fluximetry. Drugs were diluted in a methylcellulose gel vehicle which did not induce vasodilatation. To assess the contribution of nitric oxide and vasoactive prostanoids to cholinergic dilatation, the procedure was repeated during brachial artery infusion of the nitric oxide synthase inhibitor, L-N(G)-monomethyl-arginine (L-NMMA) and after intravenous administration of the cyclooxygenase inhibitor, aspirin. As a control for the vasoconstrictor effect of L-NMMA, which was measured by venous occlusion plethysmography, iontophoresis was repeated during brachial artery infusion of noradrenaline. RESULTS: Flux increased in response to iontophoresis of ACh (from 45 +/- 9 to 499 +/- 80 units; P < 0.0001) and SNP (from 32 +/- 11 to 607 +/- 82 units; P < 0.0001). Brachial artery infusions of L-NMMA or noradrenaline caused reductions in forearm blood flow (by 43 +/- 2% and 44 +/- 2%, respectively) but did not inhibit vasodilatation in response to iontophoresis of ACh or SNP. In contrast, aspirin inhibited the response to iontophoresis of ACh (from 473 +/- 81 to 222 +/- 43 units; P < 0.0001) but did not affect the response to SNP (from 348 +/- 59 to 355 +/- 58). CONCLUSIONS: We conclude that in healthy subjects, in contrast to the forearm circulation, dermal vasodilatation in response to iontophoresis of ACh is mediated predominately by a dilator prostanoid rather than by nitric oxide generation. Furthermore, the non-invasive technique of iontophoresis could complement existing invasive tests of endothelial function in future clinical studies.

Acetylcholine↗
PubMed1998

Endothelin as a regulator of cardiovascular function in health and disease.

The endothelins are a family of endothelium-derived peptides that possess characteristically sustained vasoconstrictor properties. Endothelin-1 appears to be the predominant member of the family generated by vascular endothelial cells. In addition to its direct vascular effects, endothelin-1 has inotropic and mitogenic properties, influences homeostasis of salt and water, alters central and peripheral sympathetic activity and stimulates the renin-angiotensin-aldosterone system. Studies with endothelin receptor antagonists have indicated that endothelin-1 probably has complex opposing vascular effects mediated through vascular smooth muscle and endothelial ET(A) and ET(B)receptors. Endogenous generation of endothelin-1 appears to contribute to maintenance of basal vascular tone and blood pressure through activation of vascular smooth muscle ET(A)receptors. At the same time, endogenous endothelin-1 acts through endothelial ET(B) receptors to stimulate formation of nitric oxide tonically and to oppose vasoconstriction. In view of the multiple cardiovascular actions of endothelin-1, there has been much interest in its contribution to the pathophysiology of hypertension. Results of most studies suggest that generation of, or sensitivity to, endothelin-1 is no greater in hypertensive than it is in normotensive subjects. Nonetheless, the deleterious vascular effects of endogenous endothelin-1 may be accentuated by reduced generation of nitric oxide caused by hypertensive endothelial dysfunction. It also appears likely that endothelin participates in the adverse cardiac and vascular remodelling of hypertension, as well as in hypertensive renal damage. Irrespective of whether vascular endothelin activity is increased in hypertension, anti-endothelin agents do produce vasodilatation and lower blood pressure in hypertensive humans. There is more persuasive evidence for increased endothelin-1 activity in secondary forms of hypertension, including pre-eclampsia and renal hypertension. Endothelin-1 also appears to play an important role in pulmonary hypertension, both primary and secondary to diseases such as chronic heart failure. The hypotensive effects of endothelin converting enzyme inhibitors and endothelin receptor antagonists should be useful in the treatment of hypertension and related diseases. Development of such agents will increase knowledge of the physiological and pathological roles of the endothelins, and should generate drugs with novel benefits.

Amino Acid Sequence↗
PubMed1998

Reproducibility of pulse wave velocity and augmentation index measured by pulse wave analysis.

OBJECTIVE: The aim of this study was to determine the reproducibility of pulse wave velocity (PWV) and augmentation index (AIx) measured using pulse wave analysis (PWA), prior to its use in large-scale clinical trials. METHODS: Arterial pressure waveforms were recorded and analysed using an established technique (Sphygmocor). Subjects with and without a range of recognized cardiovascular risk factors were studied to provide a wide range of values. Measurements were made after a brief introduction to the technique in a clinical setting. Two observers recorded aortic and brachial PWV in 24 subjects, each on two occasions, in a random order. In a separate study, two different observers used PWA to determine AIx in 33 subjects, each on two occasions, in a random order. Data were analysed using Bland-Altman plots and presented as mean +/- SD. RESULTS: Brachial PWV was 8.65+/-1.58 m/s (range 6.16-10.95 m/s) and aortic PWV was 8.15+/-3.01 m/s (5.01-17.97 m/s). Within-observer variability was 0.14+/-0.82 m/s for brachial PWV and 0.07+/-1.17 m/s for aortic PWV. Corresponding between-observer values were -0.44+/-1.09 m/s and -0.30+/-1.25 m/s. AIx ranged from -15.0 to +45.0%, with a group mean of +19.6+/-12.0%. The within-observer difference was 0.49+/-5.37% and between-observer difference 0.23+/-3.80%. CONCLUSION: PWA is a simple and reproducible technique with which to measure PWV and AIx. Reproducibility accords with that reported by other workers using different methodologies. PWA may, therefore, be suitable for large-scale population and intervention studies investigating the clinical relevance of vascular stiffness.

Adult↗
PubMed1998

A nonradioactive method for localization of endothelin receptor mRNA in situ.

To investigate relationships between the distribution of endothelin (ET) receptor expression and histopathology of heart and blood vessels, we developed a method of nonradioactive in situ hybridization in paraffin sections. Rat mesenteric bed, rat heart, and human uterine artery were fixed in formalin and embedded in paraffin ETA and ETB receptor cDNAs were subcloned into plasmid vectors for synthesis of sense and anti-sense probes. Digoxigenin (DIG)-UTP was incorporated into every twentieth to twenty-fifth nucleotide of the newly transcribed cRNA. mRNA was detected in situ using an anti-DIG alkaline phosphatase antibody and an alkaline phosphatase substrate. In blood vessels, ETA receptor mRNA was localized to the medial smooth muscle layer and ETB receptor mRNA to the endothelial and adventitial layers. Hearts from rats that had undergone coronary artery ligation for induction of CHF showed intense staining for ETB receptor mRNA in the scarred and infarcted zone of the left ventricle. This method provides a suitable alternative to radioisotope-labeled probes for detection of ET receptor mRNA. It allows better preservation of tissues, shorter detection time, and improved morphology for microscopic analysis.

Animals↗
PubMed1998

Functional studies in small arteries do not support a primary role for endothelin in the pathogenesis of Raynaud's disease.

Endothelin-1 (ET-1) has been implicated in the pathogenesis of Raynaud's disease (RD). This study examined the effect of cooling on the response to ET-1 in human microvessels. Subcutaneous small arteries were dissected from gluteal fat biopsies taken from patients with RD (n = 20) and from age- and sex-matched control subjects (n = 17) and were cannulated in a small vessel arteriograph. Cumulative concentration-response curves to ET-1 (10(-12) to 3 x 10(-7) M) were obtained in vessels at 37 degrees C and 24 degrees C, with the endothelium either intact or removed (n = 6 per group). There were no significant differences in responses to ET-1 between RD patients and controls in either intact or denuded vessels, at either 37 degrees C or at 24 degrees C. There was, however, a significant endothelium-dependent interaction between the groups when the effect of temperature on the response to ET-1 was examined (p = 0.01; two-way ANOVA). Whereas cooling tended to reduce the sensitivity in RD, the opposite effect was observed in controls. Measurements of plasma ET-1 did not reveal any significant difference between patients with RD and healthy controls. These results suggest that ET-1 does not play a primary pathophysiologic role in RD. ET-1 might be responsible for mediating the prolonged vasospasm in RD, but secondary to another factor(s), such as impaired endothelium-dependent vasodilation.

Adult↗
PubMed1998

Hemodialysis and L-arginine, but not D-arginine, correct renal failure-associated endothelial dysfunction.

In end-stage renal failure (ESRF) symptomatic hemodialysis-related hypotension may prevent effective provision of renal replacement therapy. Endogenous inhibitors of nitric oxide synthase accumulate in ESRF and are cleared by dialysis. We, therefore, hypothesised that removal of these inhibitors by hemodialysis would increase endothelial nitric oxide generation and promote venodilation. In vivo responses of norepinephrine preconstricted dorsal hand veins to locally active doses of acetylcholine (an activator of nitric oxide synthase) and glyceryl trinitrate (GTN; a nitric oxide donor) were examined in patients undergoing maintenance hemodialysis for ESRF and in healthy age- and sex-matched controls. Patient studies were undertaken before and after dialysis. Studies before dialysis were repeated with co-infusion of either L-arginine or its inactive enantiomer D-arginine. Venodilation in response to acetylcholine was impaired before, and corrected by, dialysis whereas venodilation to GTN was similar before and after dialysis. Venodilation in response to acetylcholine before dialysis was restored by co-infusion of L- but not D-arginine. Therefore, patients with ESRF undergoing hemodialysis have impaired acetylcholine-mediated venodilation consistent with the accumulation in ESRF of functionally important inhibitors of nitric oxide synthase that are cleared by dialysis.

Adult↗
PubMed1998

Regulation of peripheral vascular tone in patients with heart failure: contribution of angiotensin II.

OBJECTIVE: To determine directly the contribution of angiotensin II to basal and sympathetically stimulated peripheral arteriolar tone in patients with heart failure. DESIGN: Parallel group comparison. SUBJECTS: Nine patients with New York Heart Association grade II-IV chronic heart failure, and age and sex matched controls. INTERVENTIONS: Forearm plethysmography, lower body negative pressure, local intra-arterial administration of losartan, angiotensin II, and noradrenaline, and estimation of plasma hormone concentrations. MAIN OUTCOME MEASURES: Forearm blood flow responses, plasma hormone concentrations. RESULTS: Baseline blood pressure, heart rate, and forearm blood flow did not differ between patients and controls. In comparison with the non-infused forearm, losartan did not affect basal forearm blood flow (95% confidence interval -5.5% to +7.3%) or sympathetically stimulated vasoconstriction in controls. However, the mean (SEM) blood flow in patients increased by 13(5)% and 26(7)% in response to 30 and 90 micrograms/min of losartan respectively (p < 0.001). Lower body negative pressure caused a reduction in forearm blood flow of 20(5)% in controls (p = 0.008) and 13(5)% (p = 0.08) in patients (p = 0.007, controls v patients). Blood flow at 90 micrograms/min of losartan correlated with plasma angiotensin II concentration (r = 0.77; p = 0.03). Responses to angiotensin II and noradrenaline did not differ between patients and controls. CONCLUSIONS: Losartan causes acute local peripheral arteriolar vasodilation in patients with heart failure but not in healthy control subjects. Endogenous angiotensin II directly contributes to basal peripheral arteriolar tone in patients with heart failure but does not augment sympathetically stimulated peripheral vascular tone.

Analysis of Variance↗
PubMed1998

Increased glucocorticoid activity in men with cardiovascular risk factors.

The association between hypertension and insulin resistance might be explained by increased activity of the principal glucocorticoid, cortisol. Recent data show that the intensity of dermal vasoconstriction after topical application of glucocorticoids is increased in patients with essential hypertension. In this report, we examine whether increased glucocorticoid sensitivity or secretion is associated with insulin resistance and is a cause or consequence of hypertension. We studied 32 men (aged 47 to 56 years) from a cross-sectional study and 105 men (aged 23 to 33 years) in whom predisposition to high blood pressure has been defined by their own blood pressure and the blood pressures of their parents. In both populations, increased dermal glucocorticoid sensitivity was associated with relative hypertension, insulin resistance, and hyperglycemia. In young men with higher blood pressure whose parents also had high blood pressure, enhanced glucocorticoid sensitivity was accompanied by enhanced secretion of cortisol, enhanced ligand-binding affinities for dexamethasone in leukocytes, and impaired conversion of cortisol to inactive metabolites (cortisone and 5beta-dihydrocortisol). Increased tissue sensitivity to cortisol, amplified by enhanced secretion of cortisol, is a feature of the familial predisposition to high blood pressure rather than a secondary effect of high blood pressure. It may be mediated by an abnormal glucocorticoid receptor, and it may contribute to the association between hypertension and insulin resistance.

Administration, Topical↗
PubMed1998

A modified human alpha 2-macroglobulin derivative that binds tumor necrosis factor-alpha and interleukin-1 beta with high affinity in vitro and reverses lipopolysaccharide toxicity in vivo in mice.

The plasma protein alpha 2-macroglobulin (alpha 2M) has been reported to bind the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta), which play a central role in the pathogenesis of chronic inflammatory disorders, including Crohn's disease and rheumatoid arthritis. In this study, we chemically modified alpha 2M to stabilize a conformation of the protein (termed MAC, Macroglobulin Activated for Cytokine binding) with greatly increased TNF-alpha- and IL-1 beta-binding activity. The equilibrium dissociation constant (KD) for the binding of TNF-alpha to MAC was 80 +/- 20 nM, reflecting a 100-fold increase in affinity compared with native alpha 2M. To test the ability of MAC to neutralize proinflammatory cytokines in vivo, we treated mice with lipopolysaccharide (LPS) by intravenous injection. When MAC (2.5 mg) was administered by intraperitoneal injection 1 hour before the LPS, 12 of 12 mice survived and were without signs of toxicity at 5 days. None of the mice survived in the untreated control group (0/26) or in the group treated with 2.5 mg of unmodified alpha 2M (0/4). MAC also prevented the large increase in expression of inducible nitric oxide synthase in the liver, kidneys, and heart of LPS-treated mice. A novel property of MAC, compared with previously studied anticytokine agents, was its ability to reverse LPS toxicity in 12 of 24 mice when administered after the plasma level of TNF-alpha was elevated. These studies demonstrate that a naturally occurring protein, alpha 2M, can be modified so that it acquires the properties of clinically active monoclonal antibodies. Thus, MAC may have therapeutic potential in the control of chronic inflammatory disorders.

Animals↗