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Biomedical subjects

D J Webb

Publications and source records attributed to D J Webb.

At least 91 records · Page 5Linked to original sources
PubMed2000

Big endothelin-3 constricts forearm resistance vessels but not hand veins in humans.

BACKGROUND: Endothelin-3 (ET-3) and its inactive precursor, big endothelin-3 (big ET-3), are both found in human plasma. We investigated whether big ET-3 is converted to ET-3 in the human forearm resistance vessels and dorsal hand veins in vivo. METHODS: In a 4-phase study, 6 subjects received 90 minute intrabrachial artery infusions of big ET-3 (50 and 100 pmol x min(-1)) and ET-3 (5 and 10 pmol x min(-1)) in random order. Forearm blood flow was measured by venous occlusion plethysmography. In a second 3-phase study, 6 subjects received 90-minute dorsal hand vein infusions of saline solution, big ET-3 (50 pmol x min(-1)) and ET-3 (5 pmol x min(-1)) in random order. In a third 2-phase study, 6 subjects received 90-minute dorsal hand vein infusions of big ET-3 (100 pmol x min(-1)) and ET-3 (10 pmol x min(-1)). In the dorsal hand vein studies, vessel diameter was measured by the Aellig technique. RESULTS: Intra-arterial ET-3 caused local forearm vasoconstriction of 20%+/-9% (P = .009) at 5 pmol x min(-1) and 20%+/-10% (P = .001) at 10 pmol x min(-1) after 90 minutes, with no difference between doses (P = .69). Intra-arterial big ET-3 also caused local forearm vasoconstriction of 22%+/-6% at 50 pmol x min(-1) (P = .004) and 18%+/-3% at 100 pmol x min(-1) (P<.0001) after 90 minutes, with no difference between doses (P = .44). There were no significant differences between the responses to intra-arterial big ET-3 and ET-3 at these doses. Local intravenous ET-3 caused a constriction of 9%+/-2% at 5 pmol x min(-1) (P = .04) and 22%+/-8% at 10 pmol x min(-1) (P = .002) after 90 minutes. Big ET-3 at 50 pmol x min(-1) and 100 pmol x min(-1) did not affect hand vein tone. All responses were slowly progressive. CONCLUSIONS: Based on vasoconstriction, measurable conversion of big ET-3 to ET-3 occurs in forearm resistance vessels but not in dorsal hand veins in vivo. An endothelin-converting enzyme, capable of converting exogenously administered big ET-3 to ET-3, appears to be present in upper limb resistance arteries but not in capacitance vessels in humans.

Adult↗
PubMed2000

Interleukin-4 and IL-10 bind covalently to activated human alpha2-macroglobulin by a mechanism that requires Cys949.

Alpha2-macroglobulin (alpha2M) functions as an extracellular carrier of diverse cytokines, including transforming growth factor-beta1 (TGF-beta1), that expresses anti-inflammatory activities. The results presented here demonstrate that interleukin-10 (IL-10) and IL-4, which also regulate the inflammatory response, bind to alpha2M. Unlike TGF-beta, IL-4 and IL-10 bind almost exclusively to the receptor-recognized, or activated, form of alpha2M. Purified IL-4-alpha2M complexes were predominantly covalent due to thiol disulfide exchange involving Cys949 in the alpha2M subunit. Blocking Cys949 with iodoacetamide significantly inhibited IL-4- and IL-10 binding. Bovine serum albumin (BSA), which possesses a free Cys residue and undergoes thiol disulfide exchange reactions, did not compete with alpha2M for the binding of IL-4 or IL-10. These results suggest a model in which IL-4 and IL-10 associate with activated alpha2M to form complexes that are initially noncovalent but unstable. In these complexes, Cys949 is properly aligned to undergo thiol disulfide exchange and generate stable, covalent IL-4-alpha2M and IL-10-alpha2M complexes.

Animals↗
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

Plasma endothelin concentrations in hypertension.

The endothelins comprise a family of potent vasoconstricting peptides. Endothelin-1 appears to be the predominant isoform produced by the vascular endothelium, acting mainly in a paracrine fashion on vascular smooth muscle cells to cause vasoconstriction. It also has a range of other local actions--in the kidney, in the nervous system and on other hormone systems--that could, potentially, play a part in the genesis of hypertension. The association of raised plasma endothelin concentrations in human hypertension has caused much interest, but the literature is not consistent. Given the generally low plasma concentration of the endothelins, and their mainly paracrine actions, it remains unclear whether plasma endothelin has a functional role in hypertension. Additionally, problems remain with the measurement of plasma endothelin that raise doubts about the validity of conclusions drawn from these measurements.

Endothelin-1↗
PubMed2000

Regulation of the myocardial endothelin system by angiotensin-II and losartan.

Evidence for interactions between the endothelin (ET) and renin-angiotensin systems is plentiful in vitro, but few studies have investigated these interactions in vivo. In the study reported here, we have investigated the influence of chronic angiotensin-II (A-II) infusion in vivo on expression of preproendothelin-1 (PPET-1) and endothelin-A- (ET(A)) and endothelin-B- (ET(B)) receptor mRNA in the heart. The role of the angiotensin type 1 (AT1)-receptor in mediating the actions of A-II was studied using losartan, the selective AT1-receptor antagonist. Male rats received an infusion of A-II (200 ng/kg/min) or vehicle for 14 days via mini-osmotic pumps; losartan (10 mg/kg/day) was administered in the drinking water. PPET-1 and ET(A)- and ET(B)-receptor mRNA were detected in heart sections using nonradioactive antisense in situ hybridization. Independent treatments with either A-II or losartan had no significant effect on PPET-1, ET(A)- or ET(B)-receptor expression. Combined treatment resulted in an increase in PPET-1 mRNA (p < 0.001) and ET(B)-receptor mRNA expression (p < 0.01), while ET(A)-receptor mRNA expression was decreased (p < 0.001). These results suggest that selective AT1-receptor blockade, in the presence of an elevated plasma A-II concentration, causes upregulation of ET-1 synthesis in the myocardium as well as modification of ET receptor expression. These effects may be mediated via angiotensin type 2 (AT2)-receptors.

Aldosterone↗
PubMed2000

A 16-amino acid peptide from human alpha2-macroglobulin binds transforming growth factor-beta and platelet-derived growth factor-BB.

Alpha2-macroglobulin (alpha2M) is a major carrier of transforming growth factor-beta (TGF-beta) in vitro and in vivo. By screening glutathione S-transferase (GST) fusion proteins with overlapping sequences, we localized the TGFbeta-binding site to aa 700-738 of the mature human alpha2M subunit. In separate experiments, we screened overlapping synthetic peptides corresponding to aa 696-777 of alpha2M and identified a single 16-mer (718-733) that binds TGF-beta1. Platelet-derived growth factor-BB (PDGF-BB) bound to the same peptide, even though TGF-beta and PDGF-BB share almost no sequence identity. The sequence of the growth factor-binding peptide, WDLVVVNSAGVAEVGV, included a high proportion of hydrophobic amino acids. The analogous peptide from murinoglobulin, a human alpha2M homologue that does not bind growth factors, contained only three nonconservative amino acid substitutions; however, the MUG peptide failed to bind TGF-beta1 and PDGF-BB. These results demonstrate that a distinct and highly-restricted site in alpha2M, positioned near the C-terminal flank of the bait region, mediates growth factor binding. At least part of the growth factor-binding site is encoded by exon 18 of the alpha2M gene, which is notable for a 5' splice site polymorphism that has been implicated in Alzheimer's Disease.

Amino Acid Sequence↗
PubMed2000

First in-vivo trials of a fiber Bragg grating based temperature profiling system.

We describe the results of in-vivo trials of a portable fiber Bragg grating based temperature profile monitoring system. The probe incorporates five Bragg gratings along a single fiber and prevents the gratings from being strained. Illumination is provided by a superluminescent diode, and a miniature CCD based spectrometer is used for demultiplexing. The CCD signal is read into a portable computer through a small A/D interface; the computer then calculates the positions of the center wavelengths of the Bragg gratings, providing a resolution of 0.2 degree C. Tests were carried out on rabbits undergoing hyperthermia treatment of the kidney and liver via inductive heating of metallic implants and comparison was made with a commercial Fluoroptic thermometry system.

Animals↗
PubMed2000

Endogenous endothelin maintains coronary artery tone by endothelin type A receptor stimulation in patients undergoing coronary arteriography.

OBJECTIVE: To examine the contribution of endothelin type A (ET(A)) receptor stimulation by endogenously generated endothelin-1 (ET-1) to the maintenance of coronary vascular tone in humans. DESIGN: Controlled clinical study. SETTING: Tertiary cardiovascular referral centre. PATIENTS: 14 subjects were studied, seven with normal coronary arteries and seven with coronary artery disease, mean (SEM) age, 53 (2) years. INTERVENTIONS: After diagnostic coronary arteriography, BQ-123 (a selective ET(A) receptor antagonist; 100 nmol/min) in 0.9% saline, was infused into the left coronary artery at a rate of 1 ml/min for 60 minutes. Eight control subjects received saline alone. MAIN OUTCOME MEASURES: Blood flow velocity in the left anterior descending coronary artery, measured using a Doppler flow guidewire; coronary arteriography performed at baseline and immediately at the end of the BQ-123 or saline infusion to measure the diameter of proximal and distal left anterior descending coronary artery segments. RESULTS: The diameter of the proximal segment increased by 6 (2)%, while that of the distal segment increased by 12 (3)% after BQ-123 (both p < 0.05 v baseline). Coronary blood flow increased from 75 (10) to 92 (10) ml/min and coronary vascular resistance decreased from 1.99 (0.36) to 1.44 (0. 22) mm Hg/ml/min after BQ-123 (both p < 0.05 v baseline). The response to BQ-123 of patients with and without coronary artery disease was similar. There was no effect of saline in the controls. CONCLUSIONS: Endogenously produced ET-1 contributes to the maintenance of basal coronary artery tone in humans by ET(A) receptor stimulation. The role of ET(B) receptors remains to be defined.

Blood Flow Velocity↗
PubMed2000

Extracellular signal-regulated kinase functions in the urokinase receptor-dependent pathway by which neutralization of low density lipoprotein receptor-related protein promotes fibrosarcoma cell migration and matrigel invasion.

The low density lipoprotein receptor-related protein (LRP) has been reported to regulate cellular migration. In this study, an antisense RNA expression strategy was used to reduce LRP to undetectable levels in HT 1080 fibrosarcoma cells. The LRP-deficient cells demonstrated increased levels of cell-surface uPAR, higher levels of uPA in conditioned medium, increased migration on vitronectin-coated surfaces, and increased invasion of Matrigel. LRP-deficient cells also demonstrated increased levels of phosphorylated extracellular signal-regulated kinase (ERK) in the absence of exogenous stimulants. Antibodies which block binding of endogenously produced uPA to uPAR reduced ERK phosphorylation and migration of LRP-deficient cells to the levels observed with control cells. Inhibitors of ERK activation, including PD098059 and dominant-negative MEK1, also decreased the migration of LRP-deficient but not control cells. By contrast, constitutively active MEK1 stimulated the migration of control but not LRP-deficient cells. Although Matrigel invasion by LRP-deficient cells was inhibited by the proteinase inhibitor, aprotinin, PD098059 in combination with aprotinin was necessary for an optimal effect. Expression of the VLDL receptor in LRP-deficient cells reversed the changes in cellular migration and invasion. These studies demonstrate that binding of endogenously produced uPA to uPAR may serve as a major determinant of basal levels of activated ERK and, by this mechanism, regulate cellular migration and invasion. By regulating the uPA/uPAR system, LRP may also regulate ERK activation, cellular migration, and invasion.

Aprotinin↗
PubMed2000

Venous endothelin receptor function in patients with chronic heart failure.

Cardiac preload reduction through venodilatation is beneficial in chronic heart failure. The recent development of endothelin receptor antagonists for possible therapeutic use in heart failure has hastened the need for a clearer understanding of the venoconstrictor actions of endothelin-1 in this disease. Two main subtypes of endothelin receptor, ET(A) and ET(B), exist in human blood vessels. We studied the venoconstrictor effects of endothelin-1 (a non-selective ET(A) and ET(B) agonist) and sarafotoxin S6c (a selective ET(B) agonist) in vivo in patients with chronic heart failure and in age-matched healthy controls. On separate days at least 1 week apart, locally active doses of endothelin-1 or sarafotoxin S6c were infused into a suitable dorsal hand vein for 1 h, and the venous internal diameter was measured using a displacement technique. Venoconstriction in response to endothelin-1 was significantly blunted in heart failure patients compared with controls (26+/-7% and 51+/-6% peak reduction in vein calibre respectively; P=0.013). Venoconstriction to sarafotoxin S6c was similar in heart failure patients and controls (17+/-5% and 17+/-4% peak reduction in vein calibre respectively). Both ET(A) and ET(B) receptors mediate venoconstriction in healthy subjects and in patients with chronic heart failure. Optimal inhibition of the venoconstrictor effects of endothelin-1 in chronic heart failure may therefore require administration of an antagonist with ET(A)- and ET(B)-receptor-blocking properties. Chronic heart failure may be associated with a selective decrease in venous ET(A) receptor sensitivity, but further studies are required to clarify the functional significance of this observation.

Aged↗
PubMed2000

Local and systemic effects of intra-arterial desmopressin in healthy volunteers and patients with type 3 von Willebrand disease. Role of interleukin-6.

Intra-arterial desmopressin caused dose and time dependent increases (p <0.001 for all) in forearm blood flow (all doses) and plasma tissue plasminogen activator (t-PA) concentrations (desmopressin > or = 70 ng/min). Although plasma t-PA concentrations rose in both forearms, there was a modest local release of t-PA in the infused forearm (14 ng/100 mL of tissue/min, p <0.05). At desmopressin doses > or = 300 ng/min, plasma von Willebrand factor (vWf) and Factor VIII:C concentrations rose in both forearms (p <0.001) and correlated with the rise in interleukin-6 concentrations (r = 0.92, p <0.001: r = 0.85, p = 0.002 respectively). Neither desmopressin nor substance P caused t-PA, vWf or Factor VIII:C release in the patients, although desmopressin increased plasma interleukin-6 concentrations as in healthy volunteers. We conclude that desmopressin releases t-PA, vWf and Factor VIII:C predominantly via systemic mechanisms, possibly mediated by cytokine release. Patients with type 3 vWD appear to have a generalised failure to release t-PA acutely despite a normal interleukin-6 response to desmopressin infusion.

Adult↗
PubMed1999

Myosin light chain kinase functions downstream of Ras/ERK to promote migration of urokinase-type plasminogen activator-stimulated cells in an integrin-selective manner.

Urokinase-type plasminogen activator (uPA) activates the mitogen activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK) 1 and 2, in diverse cell types. In this study, we demonstrate that uPA stimulates migration of MCF-7 breast cancer cells, HT 1080 fibrosarcoma cells, and uPAR-overexpressing MCF-7 cells by a mechanism that depends on uPA receptor (uPAR)-ligation and ERK activation. Ras and MAP kinase kinase (MEK) were necessary and sufficient for uPA-induced ERK activation and stimulation of cellular migration, as demonstrated in experiments with dominant-negative and constitutively active mutants of these signaling proteins. Myosin light chain kinase (MLCK) was also required for uPA-stimulated cellular migration, as determined in experiments with three separate MLCK inhibitors. When MCF-7 cells were treated with uPA, MLCK was phosphorylated by a MEK-dependent pathway and apparently activated, since serine-phosphorylation of myosin II regulatory light chain (RLC) was also increased. Despite the transient nature of ERK phosphorylation, MLCK remained phosphorylated for at least 6 h. The uPA-induced increase in MCF-7 cell migration was observed selectively on vitronectin-coated surfaces and was mediated by a beta1-integrin (probably alphaVbeta1) and alphaVbeta5. When MCF-7 cells were transfected to express alphaVbeta3 and treated with uPA, ERK was still phosphorylated; however, the cells did not demonstrate increased migration. Neutralizing the function of alphaVbeta3, with blocking antibody, restored the ability of uPA to promote cellular migration. Thus, we have demonstrated that uPA promotes cellular migration, in an integrin-selective manner, by initiating a uPAR-dependent signaling cascade in which Ras, MEK, ERK, and MLCK serve as essential downstream effectors.

Antibodies↗
PubMed1999

Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction.

BACKGROUND: Effective endogenous fibrinolysis requires rapid release of tissue plasminogen activator (tPA) from the vascular endothelium. Smoking is a known risk factor for arterial thrombosis and myocardial infarction, and it causes endothelial dysfunction. We therefore examined the effects of cigarette smoking on substance P-induced tPA release in vivo in humans. METHODS AND RESULTS: Blood flow and plasma fibrinolytic factors were measured in both forearms of 12 smokers and 12 age- and sex-matched nonsmokers who received unilateral brachial artery infusions of substance P (2 to 8 pmol/min). In both smokers and nonsmokers, substance P caused dose-dependent increases in blood flow and local release of plasma tPA antigen and activity (P<0.001 for all) but had no effect on the local release of plasminogen activator inhibitor type 1. Compared with nonsmokers, increases in forearm blood flow (P=0.03) and release of tPA antigen (P=0.04) and activity (P<0.001) caused by substance P were reduced in smokers. The area under the curve for release of tPA antigen and activity decreased by 51% and 53%, respectively. CONCLUSIONS: Cigarette smoking causes marked inhibition of substance P-induced tPA release in vivo in humans. This provides an important mechanism whereby endothelial dysfunction may increase the risk of atherothrombosis through a reduction in the acute fibrinolytic capacity.

Adult↗
PubMed1999

The very low density lipoprotein receptor regulates urokinase receptor catabolism and breast cancer cell motility in vitro.

The very low density lipoprotein receptor (VLDLr) binds diverse ligands, including urokinase-type plasminogen activator (uPA) and uPA-plasminogen activator inhibitor-1 (PAI-1) complex. In this study, we characterized the effects of the VLDLr on the internalization, catabolism, and function of the uPA receptor (uPAR) in MCF-7 and MDA-MB-435 breast cancer cells. When challenged with uPA.PAI-1 complex, MDA-MB-435 cells internalized uPAR; this process was inhibited by 80% when the activity of the VLDLr was neutralized with receptor-associated protein (RAP). To determine whether internalized uPAR is degraded, we studied the catabolism of [35S]methionine-labeled uPAR. In the absence of exogenous agents, the uPAR catabolism t(1)/(2) was 8.2 h. uPA.PAI-1 complex accelerated uPAR catabolism (t(1)/(2) to 1.8 h), while RAP inhibited uPAR catabolism in the presence (t(1)/(2) of 7.8 h) and absence (t(1)/(2) of 16.9 h) of uPA.PAI-1 complex, demonstrating a critical role for the VLDLr. When MCF-7 cells were cultured in RAP, cell surface uPAR levels increased gradually, reaching a new steady-state in 3 days. The amount of uPA which accumulated in the medium also increased. Culturing in RAP for 3 days increased MCF-7 cell motility by 2.2 +/- 0.1-fold and by 4.4 +/- 0.3-fold when 1.0 nM uPA was added. The effects of RAP on MCF-7 cell motility were entirely abrogated by an antibody which binds uPA and prevents uPA binding to uPAR. MCF-7 cells that were cultured in RAP demonstrated increased levels of activated mitogen-activated protein kinases. Furthermore, the MEK inhibitor, PD098059, decreased the motility of RAP-treated cells without affecting control cultures. These studies suggest a model in which the VLDLr regulates autocrine uPAR-initiated signaling and thereby regulates cellular motility.

Breast Neoplasms↗
PubMed1999

Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist.

Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), is a well-tolerated and highly effective treatment for erectile dysfunction. The mechanism of action of sildenafil depends on activation of the nitric oxide (NO)-cGMP pathway during sexual stimulation, which results in corpus cavernosal smooth muscle relaxation and penile erection. Endogenously derived NO is also involved in blood pressure regulation through its effect on basal vascular tone, which is mediated by cGMP levels. Organic nitrates and NO donors exert their therapeutic effects on blood pressure and vascular smooth muscle by the same mechanism as endogenous NO. Since both sildenafil and organic nitrates exert their pharmacologic effects via increases in cGMP concentrations, a double-blind, placebo-controlled, crossover study was undertaken to investigate the effects of sildenafil coadministered with glyceryl trinitrate on blood pressure and heart rate in healthy male subjects. The hemodynamic effects of sildenafil were also evaluated in a second placebo-controlled crossover study in men with hypertension who were taking the calcium antagonist amlodipine, which has a mechanism of action that does not involve the cGMP pathway. In the first crossover study, subjects were treated with oral sildenafil (25 mg, 3 times a day for 4 days) or placebo and then challenged on day 4 with a 40-minute, stepwise, intravenous infusion of glyceryl trinitrate (0.5 mg/mL in 5% dextrose at an initial infusion rate of 2.5 microg/min and doubling every 5 minutes to a maximum rate of 40 microg/min) 1 hour after taking sildenafil or placebo. On day 5, subjects received a sublingual glyceryl trinitrate tablet (500 microg) 1 hour after taking 25 mg of sildenafil or placebo. During sildenafil treatment, the subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo treatment, based on the occurrence of a >25 mm Hg decrease in blood pressure or the incidence of symptomatic hypotension (p <0.01). When a sublingual glyceryl trinitrate tablet was administered on day 5, a 4-fold greater decrease in systolic blood pressure was observed for the subjects during the sildenafil treatment period than during the placebo treatment period. The changes in heart rate were negligible during both glyceryl trinitrate challenges. In conclusion, sildenafil potentiated the hypotensive effects of glyceryl trinitrate, an organic nitrate. Thus, sildenafil administration to patients who are using organic nitrates, either regularly and/or intermittently, in any form is contraindicated. In the second crossover study, men with hypertension, who were taking 5 or 10 mg/day of amlodipine, received a single oral dose of 100 mg sildenafil or placebo. Coadministration of sildenafil did not significantly affect the pharmacokinetics of amlodipine. In the 4 hours after dosing, differences in the mean maximum change from baseline in supine systolic and diastolic blood pressures between the sildenafil plus amlodipine and the placebo plus amlodipine treatment periods were -8 mm Hg and -7 mm Hg, respectively (p < or =0.002). The mean maximum supine heart rate increased 2.1 beats/min during sildenafil plus amlodipine treatment and decreased 1.5 beats/min during placebo plus amlodipine treatment (p <0.02). The adverse events in this study were predominantly mild or moderate and did not cause discontinuation of treatment. Adverse events considered to be related to sildenafil treatment included headache, nausea, and dyspepsia. In patients with hypertension who were taking amlodipine therapy, sildenafil produced additive, but not synergistic, reductions in blood pressure. The difference in the mean maximum change from baseline in blood pressure between sildenafil plus amlodipine and placebo plus amlodipine was comparable to the decrease in blood pressure reported for healthy men taking sildenafil alone. (ABSTRACT TRUNCATED)

Adult↗
PubMed1999

The role of endothelin-1 in pressure autoregulation of cerebral blood flow in rats.

OBJECTIVE: To investigate the role of the endothelin system in pressure autoregulation of cerebral blood flow (CBF) in rats. DESIGN: We tested pressure autoregulation by increasing cerebral perfusion pressure (CPP; mean arterial pressure-intracranial pressure) with norepinephrine (0.08 microgram.kg-1.min-1 for 30 min) twice in ten anesthetized normocapnic rats. The first test was performed without (control test) and the second test after administration of the combined endothelin ETA/B receptor antagonist, bosentan, i.v. (30 mg/kg; drug test). CBF was measured by the hydrogen clearance technique. RESULTS: During the control test, norepinephrine infusion increased CPP by 21 +/- 2 (23 +/- 2%) mmHg (mean +/- SEM; p < 0.001) and CBF by 3.6 +/- 3.1 (6 +/- 8%) ml/100 g/min (p = 0.5, Fig. 1); during the drug test, norepinephrine infusion increased CPP by 18 +/- 1 (20 +/- 2%) mmHg (p < 0.001) and CBF by 15.8 +/- 4.1 (46 +/- 13%) ml/100 g/min (p = 0.004). Mean arterial pressure was not affected by bosentan infusion (p = 0.2). PaCO2 levels were stable during the tests (40.2 +/- 1.4 mmHg). CONCLUSIONS: The endothelin system is involved in cerebral pressure autoregulation in a rodent model in vivo. The role of this system under pathophysiologic conditions such as subarachnoid hemorrhage, where basal vascular tone and its regulation may be altered, remains to be defined.

Analysis of Variance↗