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Biomedical subjects

B Battistini

Publications and source records attributed to B Battistini.

At least 19 recordsLinked to original sources
PubMed2001

Prostaglandin E(2) increases cyclic AMP and inhibits endothelin-1 production/secretion by guinea-pig tracheal epithelial cells through EP(4) receptors.

Prostaglandin E(2) (PGE(2)) increased adenosine 3' : 5'-cyclic monophosphate (cyclic AMP) formation in tracheal epithelial cells and concomitantly decreased the production/secretion of immunoreactive endothelin (irET). Naturally occurring prostanoids and selective and non-selective EP receptor agonists showed the following rank order of potency in stimulating cyclic AMP generation by epithelial cells: PGE(2) (EP-selective)>16,16-dimethyl PGE(2) (EP-selective)>11-deoxy PGE(2) (EP-selective)>>>iloprost (IP/EP(1)/EP(3)-selective), butaprost (EP(2)-selective), PGD(2) (DP-selective), PGF(2alpha) (FP-selective). The lack of responsiveness of the latter prostanoids indicated that the prostanoid receptor present in these cells is not of the DP, FP, IP, EP(1), EP(2) or EP(3) subtype. Pre-incubating the cells with the selective TP/EP(4)-receptor antagonists AH23848B and AH22921X antagonized the PGE(2)-evoked cyclic AMP generation. This suggested that EP(4) receptors mediate PGE(2) effects. However, in addition to any antagonistic effects at EP(4)-receptors, both compounds, to a different extent, modified cyclic AMP metabolism. The selective EP(1), DP and EP(2) receptor antagonist (AH6809) failed to inhibit PGE(2)-evoked cyclic AMP generation which confirmed that the EP(2) receptor subtype did not contribute to the change in cyclic AMP formation in these cells. The PGE(2)-induced inhibition of irET production by guinea-pig tracheal epithelial cells was due to cyclic AMP generation and activation of the cyclic AMP-dependent protein kinase since this effect was reverted by the cyclic AMP antagonist Rp-cAMPS. These results provide the first evidence supporting the existence of a functional prostaglandin E(2) receptor that shares the pharmacological features of the EP(4)-receptor subtype in guinea-pig tracheal epithelial cells. These receptors modulate cyclic AMP formation as well as ET-1 production/secretion in these cells.

Adenosine↗
PubMed2001

N(G)-monomethyl-L-arginine alters insulin-mediated calf blood flow but not glucose disposal in the elderly.

It has been proposed that an important component of glucose disposal is insulin-mediated vasodilation via a nitric oxide (NO)-dependent mechanism. Normal aging is characterized by a resistance to insulin-mediated glucose disposal and deficient endothelial NO production. Impairment of insulin-mediated vasodilation could contribute to this insulin resistance. We tested the hypothesis that the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) would decrease insulin-mediated calf vasodilation and whole-body glucose disposal in young subjects but would have little or no effect in the elderly. Experiments were performed on healthy young (n = 10) and old (n = 10) subjects on 2 study days. Insulin was infused for 4 hours at 40 mU/m(2)/min (young) and 34 mU/m(2)/min (old) during both studies, and L-NMMA (0.1 mg/kg/min) was coinfused during the last 2 hours of insulin on one of these sessions. Calf blood flow was measured by venous occlusion plethysmography, and calf vascular conductance was derived from calf blood flow and mean arterial blood pressure (MABP). L-NMMA increased whole-body insulin-mediated glucose uptake (IMGU) in young subjects (from 11.22 +/- 0.08 to 12.22 +/- 0.87 mg/kg/min, P <.05) but decreased calf blood flow (from 6.53 +/- 0.62 to 5.49 +/- 0.43 mL/100 mL/min, P <.05). In contrast, L-NMMA had no effect on IMGU in elderly subjects (control v L-NMMA, 7.58 +/- 0.46 v 7.86 +/- 0.37 mg/kg/min, P = nonsignificant) but increased calf blood flow (from 3.65 +/- 0.36 to 4.50 +/- 0.32 mL/100 mL/min, P <.01). L-NMMA decreased calf vascular conductance in young subjects (from 0.083 +/- 0.008 to 0.064 +/- 0.005 mL/100 mL/min/mm Hg, P <.05) but not in the elderly (control v L-NMMA, 0.038 +/- 0.004 v 0.040 +/- 0.002 mL/100 mL/min/mm Hg), consistent with the concept that skeletal muscle endothelial NO production is reduced with age. We therefore conclude that (1) L-NMMA has different or opposite actions on calf blood flow and IMGU in both age groups, indicating that the effect of insulin on skeletal muscle blood flow is independent of its influence on glucose disposal in young and old, and (2) skeletal muscle NO production decreases with age.

Adult↗
PubMed2001

Contrasting effects of L-arginine on insulin-mediated blood flow and glucose disposal in the elderly.

Insulin increases skeletal muscle blood flow in healthy young subjects by a nitric oxide (NO)-dependent mechanism. Impairment of this mechanism may contribute to the insulin resistance of normal aging. We tested the hypothesis that L-arginine, the endogenous precursor for NO synthesis, would augment insulin-mediated vasodilation and in so doing increase insulin-mediated glucose uptake (IMGU) in healthy elderly subjects. Experiments were conducted on healthy young (n = 9; age, 24 +/- 1 years; body mass index, 24 +/- 1 kg/m2) and old (n = 9; age, 77 +/- 2 years; BMI, 25 +/- 1 kg/m2) subjects. Each underwent two euglycemic clamp studies. On both occasions, insulin was infused from 0 to 120 minutes (young, 40 mU/m2/min; old, 34 mU/m2/min). On 1 day, insulin was continued and L-arginine (7.5 mg/kg/min) was coinfused from 120 to 240 minutes. On the second study day, the insulin infusion from 120 minutes onward was adjusted in each subject to match corresponding plasma concentrations during the L-arginine infusion. Calf blood flow was measured bilaterally using venous occlusion plethysmography. Mean arterial blood pressure decreased in response to L-arginine in both young (77 +/- 1 v 73 +/- 1 mm Hg; P < .05) and old (103 +/- 2 v 94 +/- 2 mm Hg; P < .01). Calf vascular conductance increased in young (from 0.094 +/- 0.009 to 0.113 +/- 0.012 mL/100 mL/min/mm Hg; P < .01) and old (from 0.035 +/- 0.003 to 0.050 +/- 0.003 mL/100 mL/min/mm Hg; P < .01), consistent with the concept that the addition of substrate can augment skeletal muscle endothelial NO production in both age groups. Calf blood flow increased in both young (control, 7.04 +/- 0.73; L-arginine, 8.02 +/- 0.78 mL/100 mL/min; P < .05) and old (control, 3.60 +/- 0.27: L-arginine, 4.65 +/- 0.23 mL/100 mL/min; P < .0001) subjects, yet L-arginine had no impact on glucose disposal in either age group. In conclusion, L-arginine caused skeletal muscle vasodilation in the elderly, indicating that this endothelially mediated response is not attenuated with age. However, this increase in blood flow had no impact on insulin-mediated glucose uptake.

Adult↗
PubMed2001

Effect of ECE and NEP inhibition on cigarette smoke-induced cell proliferation in the rat lung.

To investigate the role of endothelins in cigarette smoke-induced cell proliferation, we assessed the effect of two dual nonselective neutral endopeptidase (NEP)/endothelin-converting enzyme (ECE) inhibitors, phosphoramidon and CGS 26303, and of a specific NEP inhibitor, CGS 24592, on cell proliferation in the airways and arterial vasculature of the rat lung. Eight groups of rats were exposed to either room air (group 1, control), the smoke of 10 cigarettes (group 2, smoke only) or groups 1 and 2 in addition to a continuous iv infusion of CGS 24592, CGS 26303, or phosphoramidon (10 mg/kg/24 h). Cigarette smoke produced significant cell proliferation in the airways (epithelium and wall) and in the perialveolar ductular vessels (endothelium and wall). CGS 26303 reduced the smoke-induced proliferation in the endothelium and walls of the vessels adjacent to the alveolar ducts, and in the airway walls, but did not affect proliferation in the airway epithelium. CGS 24592 reduced cell proliferation in the airway wall. Phosphoramidon had no effect. These findings indicate that acute cigarette smoke-induced cell proliferation of the rat airways and pulmonary arterial vessels is mediated, at least in part, through release and actions of endothelins. The effectiveness of the more potent inhibitor, CGS 26303, appears to conform to its site of predominant expression.

Administration, Inhalation↗
PubMed2000

Lack of effect of sodium nitroprusside on insulin-mediated blood flow and glucose disposal in the elderly.

Insulin increases skeletal muscle blood flow in healthy young subjects by a nitric oxide (NO)-dependent mechanism. Impairment of this mechanism may contribute to the insulin resistance of normal aging, a state characterized by reduced endothelial production of NO, an attenuated effect of insulin on skeletal muscle blood flow, and resistance to insulin-mediated glucose uptake (IMGU). We tested the hypothesis that the NO donor sodium nitroprusside (SNP) would augment insulin-mediated vasodilation and thus increase IMGU in healthy elderly subjects. Experiments were performed with young (n = 9; age, 25 +/- 1 years; body mass index [BMI], 24 +/- 1 kg/m2) and old (n = 10; age, 78 +/- 2 years; BMI, 25 +/- 1 kg/m2) healthy subjects. Each group underwent two studies in random order. In one study (control), insulin was infused using the euglycemic clamp protocol for 240 minutes at a rate of 40 mU/m2/min (young) and 34 mU/m2/min (old). In the other study (SNP), SNP was coinfused with insulin from 120 to 240 minutes. At regular intervals in each study, blood samples were obtained and calf blood flow was measured using venous occlusion plethysmography. Glucose and insulin values were similar in control and SNP studies in both age groups. In the young, SNP had no effect on blood flow to the calf, but its action in calf resistance vessels augmented insulin-mediated vasodilation, since incremental calf vascular conductance was greater during SNP infusion (control v SNP, 0.027 +/- 0.002 v 0.040 +/- 0.008 mL/100 mL/min/mm Hg, P< .0001). However, SNP had no effect on insulin-mediated glucose disposal. In the elderly, SNP reduced the blood flow to the calf, but this was countered by its effect on calf resistance vessels such that vascular conductance was unaffected (control v SNP, 0.012 +/- 0.003 v 0.011 +/- 0.003 mL/100 mL/min/mm Hg, P = nonsignificant [NS]). Steady-state (180 to 240 minutes) glucose disposal (control v SNP, 7.47 +/- 0.47 v 6.54 +/- 0.56 mg/kg/min, P < .01) rates were significantly lower during SNP infusion. In summary, systemic infusion of SNP did not increase insulin-mediated glucose disposal in either young or old subjects. Thus, the present findings do not support the concept that increasing NO availability will enhance glucose disposal in either age group. However, because the incremental increases in IMGU during SNP infusion paralleled the changes in blood supply to the calf rather than calf vascular conductance, any potential benefits on NO delivery in elderly subjects may have been offset by the direct or reflex effects of systemic hypotension. Other stimuli to NO production that do not cause hypotension must be tested before this therapeutic strategy can be considered as a potential means for enhancing the metabolic actions of insulin in the elderly.

Adult↗
PubMed2000

Effects of tranexamic acid and aprotinin, two antifibrinolytic drugs, on PAF-induced plasma extravasation in unanesthetized rats.

Two antifibrinolytic drugs, tranexamic acid (TXA), and aprotinin (APR), are currently used to improve the recovery of patients following major surgery while reducing blood loss. Their mechanisms of action have yet to be fully understood. Here, we examined (1) the effects of TXA or APR on basal vascular permeability (VP) and (2) the effects of TXA or APR on platelet-activating factor (PAF)-induced increase of VP in normal unanesthetized rats. Evans blue dye (EB) bound to albumin was used as the marker of extravasation in selected tissues. In normal rats, PAF (1 microg/kg i.v.) increased VP in most selected tissues including bronchi, aorta, duodenum and pancreas without affecting blood pressure. TXA (up to 300 mg/kg i.v.) had no significant effect on basal VP in any tissues, while APR (30000 KIU/kg i.v.) decreased basal VP in 5 out of 8 tissues. Pre-treatment with TXA decreased PAF-induced increases of VP in the microcirculation of the thoracic and abdominal aorta, the duodenum and the pancreas, from 35% to 41%. TXA was mostly effective at an i.v. dose of 100 mg/kg with a 2 h of pre-treatment period. Pre-treatment with APR also reduced PAF-induced increases of VP in selected tissues by 35 to 61%. The i.v. dose of 30000 KIU/mg was optimal when injected at least 30 min before the administration of PAF + Evans blue. These results suggest that the beneficial effect of APR and TXA, following cardiopulmonary bypass (CPB) and other type of surgeries, may be attributed to the inhibition of plasma exudation mediated, at least in part, by PAF. Thus, TXA and APR may improve patients recovery by reducing the capillary leakage of albumin, associated with interstitial edema formation, and maintaining intravascular fluid volume.

Animals↗
PubMed2000

Adenosine induces cyclic-AMP formation and inhibits endothelin-1 production/secretion in guinea-pig tracheal epithelial cells through A(2B) adenosine receptors.

1. The adenosine receptor subtype mediating adenosine 3' : 5'-cyclic monophosphate (cyclic AMP) formation and the effect of its activation on endothelin-1 (ET-1) secretion were studied in primary cultures of tracheal epithelial cells. 2. Adenosine analogues showed the following rank order of potency (pD(2) value) and intrinsic activity on the generation of cyclic AMP by tracheal epithelial cells: 5'-N-ethylcarboxyamidoadenosine (NECA, A(1)/A(2A)/A(2B), pD(2): 5.44+/-0.16)>adenosine (ADO, non selective, pD(2): 4.99+/-0. 09; 71+/-9% of NECA response) >/=2-Cl-adenosine (2CADO, non selective, pD(2): 4.72+/-0.14; 65+/-9% of NECA response)>>>CGS21680 (A(2A); inactive at up to 100 microM). 3. Cyclic AMP formation stimulated by NECA in guinea-pig tracheal epithelial cells was inhibited by adenosine receptor antagonist with the following order of apparent affinity (pA(2) value): Xanthine amine congeners (XAC, A(2A)/A(2B), 7.89+/-0.22)>CGS15943 (A(2A)/A(2B), 7.24+/-0. 26)>ZM241385 (A(2A), 6.69+/-0.14)>DPCPX (A(1), 6.51+/-0. 14)>3n-propylxanthine (weak A(2B), 4.30+/-0.10). This rank order of potency is typical for A(2B)-adenosine receptor. 4. Adenosine decreased basal and LPS-stimulated irET production in a concentration-dependent manner. Moreover, NECA but not CGS21680 inhibited LPS-induced irET production. 5. The inhibitory effect of NECA on LPS-induced irET production was reversed by XAC (pA(2)=8.84+/-0. 12) and DPCPX (pA(2)=8.10+/-0.22). 6. These results suggested that adenosine increased cyclic AMP formation and inhibited irET production/secretion by guinea-pig tracheal epithelial cells through the activation of a functional adenosine receptor that is most likely the A(2B) subtype. This adenosine receptor may be involved in the regulation of the level of ET-1 production/secretion by guinea-pig tracheal epithelial cells in physiological as well as in pathophysiological conditions.

Adenosine↗
PubMed2000

Contraction to big endothelin-1, big endothelin-2 and big endothelin-3, and endothelin-converting enzyme inhibition in human isolated bronchi.

All three endothelin precursor peptides, i.e. big endothelin-1 (big ET-1), big endothelin-2 (big ET-2) and big endothelin-3 (big ET-3), produced contractile responses in human isolated bronchi, demonstrating the presence of functional endothelin-converting enzyme (ECE) in this tissue. The maximal contractile responses were equal to 108.4+/-8.0% (0.1 microM big ET-1; n=4), 85.2+/-11.8% (0.1 microM big ET-2; n=7) and 43.0+/-7.2% (0.1 microM big ET-3; n=5) of the reference response to acetylcholine (1 mM). The response to big ET-1 (0.1 microM), but not endothelin-1 (ET-1, 0.1 microM), was diminished after overnight storage of the tissue at 4 degrees C, demonstrating instability of the enzyme. The responses to all three big-endothelins were significantly inhibited, by the ECE inhibitors CGS 26393 and CGS 26303, in a concentration-related manner. The responses to the mature peptides ET-1, endothelin-2 (ET-2), and endothelin-3 (ET-3) were unaffected by CGS 26393 and CGS 26303. Phosphoramidon (10 microM) also produced an inhibition of the response to big ET-1 that was equivalent to that produced by CGS 26393 (10 microM). Combination of CGS 26393 (10 microM) and phosphoramidon (10 microM) did not produce an additive inhibition. These results demonstrate the presence of functional ECE for all three big endothelins in human bronchus and inhibition of the enzyme by newly developed orally active ECE inhibitors, as well as phosphoramidon. British Journal of Pharmacology (2000) 129, 170 - 176

Aspartic Acid Endopeptidases↗
PubMed2000

Effect of CGS 26303, an endothelin-converting enzyme-neutral endopeptidase inhibitor, on nitrofen-induced congenital diaphragmatic hernia in the rat.

BACKGROUND/PURPOSE: The pathophysiology of congenital diaphragmatic hernia (CDH) associated with lung hypoplasia and pulmonary hypertension is not understood fully. Endothelins (ETs) are the most potent vasoconstrictors that also act as promitogenic agents. They may play a role during pregnancy in leading to the condition found at birth and ongoing mortality in CDH. Therefore, the authors studied the effect of CGS 26303, a nonselective endothelin-converting enzyme and neutral endopeptidase inhibitor, in the rat model of CDH. METHODS: Pregnant Sprague-Dawley rats were divided into 3 groups: group 1 (n = 4) received CGS 26303 (50 mg/kg, subcutaneously, twice a day), from gestational day 12 until term (21 to 23 days); group 2 (n = 8) received nitrofen (100 mg/kg, orally) at gestational day 11.5; group 3 (n = 8) received both nitrofen and CGS 26303. The survival of the newborn rats was monitored up to 240 minutes. After natural death or euthanasia, they were weighed and microdissected. The degree of hernia was quantified as small, moderate, or severe, and lungs and liver were harvested and weighed. RESULTS: Newborn rats from mothers of group 3 (n = 81) survived 196 +/- 8 minutes compared with 173 +/- 9 minutes of those of group 2 (n = 97). Severe CDH from group 3 (n = 20) had a mean survival time of 66 +/- 13 minutes compared with 26 +/- 4 minutes for those of group 2 (n = 27). Lung index in severe CDH pups of group 3 was increased by 13% compared with those from group 2 (P < .0001), whereas their liver index went down by 8% (P < .05). CONCLUSIONS: These results suggest that CGS 26303 might have a beneficial effect when given during pregnancy in increasing survival at birth and reducing the severity of the pulmonary hypoplasia in newborn rats with nitrofen-induced CDH.

Animals↗
PubMed2000

Biphasic release of immunoreactive endothelins following acute pulmonary thromboembolism in pigs.

The purpose of this investigation was to study the role of endothelins (ETs) in the pathogenesis of acute pulmonary thromboembolism (PTE). Eighteen piglets (20 +/- 3 kg) were anesthetized and ventilated with 100% oxygen, five of them then served as controls. Acute thromboembolic injury in the lung was induced by injecting 15-25 ml of preformed clots into the left lower lobar pulmonary artery during thoracotomy. Pulmonary arterial pressure (Ppa) increased by at least 2.5-fold from baseline. During the subsequent 8 h, seven blood samples were collected from the left atrium and assayed for immunoreactive ETs. The results showed that following PTE: (1) Ppa remained elevated but cardiac output remained constant throughout the experiments; (2) plasma level of immunoreactive ETs increased in the embolized group compared to controls and the profile of immunoreactive ET release suggested a biphasic response. We conclude that the release of these vasocontractile and bronchoconstrictive mediators after PTE may contribute to ventilation perfusion mismatching and account for the pulmonary hypertension and deterioration of gas exchange that are often seen clinically.

Acute Disease↗
PubMed2000

Effects of a selective neutral endopeptidase and a nonselective neutral endopeptidase/endothelin-converting enzyme inhibitor on lipopolysaccharide-induced endotoxaemia in anaesthetized Sprague-Dawley rats.

The gene expression and levels of endothelins (ETs) are increased in various animal models of lipopolysaccharide-(LPS) induced septic shock as well as in patients with endotoxaemia (ENDO). A positive correlation was reported between the expression and production of ETs, and the severity of haemodynamic and haematological disturbances, organ injury and circulatory failure in ENDO. Previous studies using ET(A)- and/or ET(B)-receptor antagonists exacerbated the effects of LPS in anaesthetized and conscious rats. We investigated the effect of a selective neutral endopeptidase (NEP) (CGS 24592) or a mixed NEP/endothelin-converting enzyme (ECE) (CGS 26303) inhibitor in LPS-induced ENDO in anaesthetized Sprague-Dawley rats. Four hours post-LPS injection, blood pressure was 39% lower in the presence of CGS 26303, compared to control-saline or LPS-injected rats. In rats treated with CGS 26303, white blood cells and platelet counts decreased, whereas lymphocytes increased. In addition, progressive liver dysfunction, characterized by increases in plasma bilirubin and alanine transferase, became even more apparent (higher than in those injected with LPS). Plasma creatinine and blood urea were similar to those of the LPS-injected group. Similar results were observed with CGS 24592. Thus, these inhibitors enhanced some, but not all, of the LPS-induced deleterious effects.

Acid-Base Equilibrium↗
PubMed2000

The differential effect of VIP and PACAP on guinea pig gallbladder in vitro.

OBJECTIVES: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a recently identified member of the secretin/glucagon/vasoactive intestinal peptide (VIP) family. Like VIP, PACAP is largely inhibitory in the gastrointestinal tract. The aim of our work was to characterize the effects of PACAP on both contraction and relaxation of guinea pig gallbladder (GPGB) muscle. METHODS: Gallbladder muscle strips were obtained from male Dunkin-Hartley guinea pigs (250-350 g). Isometric tension was measured in strips suspended in gassed (95% O2, 5% CO2) Krebs' solution at 37 degrees C and equilibrated for 60 min. Cumulative additions of VIP or PACAP (10(-9)-10(-6) mol/l) were performed with strips at basal tone or with strips pre-contracted with cholecystokinin-octapeptide (CCK-8). RESULTS: VIP had no effect on basal tone, in contrast with PACAP which produced concentration-dependent contraction to a maximum of 57.9 +/- 24.3% of control (CCK 3 x 10(-7) mol/l). The highest concentration (10(-6) mol/l) of VIP produced a 32 +/- 6% relaxation of 3 x 10(-9) mol/l CCK-8-contracted GPGB. With 3 x 10(-8) mol/l CCK-contracted GPGB strips, VIP produced a 26.7 +/- 6.6% relaxation. PACAP produced a further concentration-dependent contraction of 3 x 10(-9) mol/l CCK-contracted strips which reached 17.5 +/- 9.9% at the maximal concentration used (10(-6) mol/l). PACAP produced a concentration-dependent relaxation of 3 x 10(-8) mol/l CCK-contracted strips which reached a maximum relaxation of 19 +/- 5% of the control. CONCLUSIONS: PACAP has a dual effect on guinea pig gallbladder motility in vitro, producing contraction in the basal state, and both contraction and relaxation in the CCK-contracted state. This is in contrast to the effects of VIP, a closely related peptide.

Animals↗
PubMed2000

Changes in plasma levels of ET-1 and its precursor, big ET-1, in the arterial and venous circulation following double myocardial ischemia-reperfusion injury in dogs.

Upregulation of the endothelin (ET) system, following coronary ischemia-reperfusion injury, may contribute to coronary vasospasm and congestive heart failure. Because endothelin-1 (ET-1) is rapidly cleared from the circulation, the levels of its inactive precursor big ET-1 and the ET-1/big ET-1 ratio may constitute better ways to assess the activation of the ET system in both venous and arterial beds. Anesthetized dogs (n = 6-12) were subjected to two successive coronary artery occlusions (with intervening 60 min reperfusion) over 6 h. Cardiac hemodynamics and electrocardiogram (ECG) were recorded and blood samples were drawn simultaneously from the internal thoracic artery and coronary sinus (venous blood). Under basal conditions at t = -20 min, arterial plasma levels of ET-1 and big ET-1 were 2.05 +/- 0.21 and 2.00 +/- 0.51 pg/ml (ratio: 1.00; n = 12); venous values were 2.29 +/- 0.25 and 3.14 +/- 0.77, respectively (ratio: 0.73, n = 12). Both arterial and venous plasma levels of ET-1 increased (by 46 and 56%) after 5 and 15 min of reperfusion, respectively, following the initial 120 min ischemic period compared to baseline values, and returned to near baseline values after 60 min reperfusion. Both arterial and venous values for big ET-1 increased steadily by 2.2 and 2.3 times maximum, respectively, during the initial 60 min reperfusion period; these values increased by 3.4 and 3.2 times, respectively by the end of the second 120 min reperfusion period. ET-1/big ET-1 ratios dropped to 0.39, in arterial, and 0.21, in venous plasma, at the end of the second reperfusion period. In conclusion, plasma ET-1 levels increase significantly but transiently after the first ischemic injury; the increased plasma big ET-1 levels were more pronounced in both the arterial and venous circulation along with ischemia-reperfusion injuries. These results suggest an upregulation of the ET system that was easily monitored by increased production of big ET-1. During ischemia-reperfusion injuries, the conversion to the active mature peptide ET-1 is either impaired, or ET-1 is more rapidly degraded.

Animals↗
PubMed1998

Preface

Explore the source record for details and available documents.

Journal Article↗
PubMed1998

Effects of dual endothelin-converting enzyme/neutral endopeptidase inhibitors, CGS 26303 and CGS 26393, on lipopolysaccharide or interleukin-1 beta-stimulated release of endothelin from guinea pig tracheal epithelial cells.

A number of studies using endothelin (ET) receptor antagonists support the participation of ETs in a variety of cardiovascular, renal, and other disorders. It has also been established that a number of cytokines, which are released in such diseases, modulate the expression and production of ETs and thus activate the ET system. This effect may represent one pathway by which these inflammatory mediators operate. By regulating endothelin-converting enzyme (ECE) activities, and thus ET synthesis, one can potentiate or attenuate the production of ETs and the receptor affinity/density in such pathologic conditions. Here, the stimulated (lipopolysaccharide or interleukin-1 beta) production of ET-1 from guinea pig tracheal epithelial cells was abolished by CGS 26303 or CGS 26393, two ECE/neutral endopeptidase (NEP) inhibitors, but was unaffected by CGS 24592, a specific NEP inhibitor. Therefore, such dual, and eventually selective ECE inhibitors are effective agents to prevent the stimulated production of ETs.

Animals↗
PubMed1998

Contractile activity of endothelins and their precursors in human umbilical artery and vein: identification of distinct endothelin-converting enzyme activities.

A number of studies using endothelin (ET) precursors, commonly termed big ETs, have revealed the presence of endothelin-converting enzyme (ECE) activity in various vascular and nonvascular preparations. Since then, more than one ECE has been cloned. It has also been observed that big ET-1 and big ET-3 are not converted by the same enzyme. The ECE responsible for big ET-3 conversion is rarely present because big ET-3 does not induce a contractile response in most isolated preparations tested. In this study we characterized ECE activities present in two human preparations, the umbilical artery and vein, testing the contractile activities of the three human Big ETs in the presence or absence of phosphoramidon, a dual ECE/neutral endopeptidase inhibitor. The results show that human big ET-1(1-38) is 6.3-fold more potent than big ET-2(1-38) in the human umbilical artery (an ETA preparation), whereas big ET-1 is equipotent to big ET-2 in the vein (which contains ETA and ETB receptors). Human big ET-3(1-41) is inactive on both vessels. Furthermore, phosphoramidon attenuated human big ET-1-induced contractions only in the umbilical artery and not in the vein. Such observations, in terms of substrate selectivity and phosphoramidon sensitivity, suggest the presence of distinct ECE activities in human vein and arteries.

Aspartic Acid Endopeptidases↗