bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nitric oxide mediated modulation of norepinephrine transport: identification of a potential target for S‐nitrosylation
Authors: Kaye David M , Gruskin Sara , Smith A Ian , Esler Murray D 
Published: January 2005

Carrier mediated uptake (uptake‐1) transport of norepinephrine (NE) plays a key role in the regulation of sympathetic neurotransmission. Recent investigations indicate that nitric oxide (NO) may modulate uptake‐1 activity, possibly in a cyclic GMP independent manner.
Carrier mediated transport of [3H‐NE] and [3H‐dopamine, DA] was examined in CHO cells transfected with cDNA for the NE and DA transporters (NET, DAT) respectively.
While exposure to the NO donor S‐nitroso‐N‐acetylpenicillamine (100 μM, SNAP) significantly reduced [3H‐NE] uptake (P<0.001), no effect on [3H‐DA] transport was apparent.
Comparison of the amino acid sequences for NET and DAT identified cysteine residue 351 in NET, which was not present in DAT. Site‐directed mutagenesis of Cys 351 to Ser produced a functional NET that was resistant to the inhibitory effects of SNAP.
The presence of SNAP mediated nitrosylation of the cysteine residue in an 8‐mer model peptide based around Cys 351 in NET was confirmed by both biochemical and mass spectroscopic means.
These data indicate the potential regulatory role for NO in modulating sympathetic neurotransmission, and further confirm the importance of non‐cyclic GMP dependent mechanisms in mediating the actions of NO.

British Journal of Pharmacology (2000) 130, 1060–1064; doi:10.1038/sj.bjp.0703416
Effect of cytochrome P‐450 inhibitors econazole, bifonazole and clotrimazole on prostanoid formation
Authors: Köfeler Harald C , Fauler Günter , Windischhofer Werner , Leis Hans J 
Published: January 2005

The present study was carried out to clarify the effect of the imidazole antimycotics econazole, bifonazole and clotrimazole on prostanoid biosynthesis. Osteoblast‐like MC3T3‐E1 cells stimulated by endothelin‐1, melittin, ionomycin or arachidonic acid showed diminished prostaglandin E2 (PGE2) production upon pretreatment with econazole. Following pretreatment with bifonazole, stimulation with ionomycin or arachidonic acid also resulted in decreased PGE2 formation. Clotrimazole inhibited ionomycin but not arachidonic acid stimulated PGE2 synthesis in MC3T3‐E1 cells.
The results observed in osteoblast‐like UMR‐106 cells pretreated with econazole, bifonazole or clotrimazole and stimulated by arachidonic acid were similar with the exception of clotrimazole which was a more effective inhibitor of PGE2 biosynthesis than in MC3T3‐E1 cells.
Upon treatment with arachidonic acid thromboxane B2 (TXB2) production in human platelets was abolished completely at concentrations of the three imidazole antimycotics higher than 5 μM (IC50<1 μM).
These data were confirmed by a direct assay using purified ram seminal vesicle prostaglandin H2 synthase‐1 (PGHS‐1), which clearly showed inhibitory properties of econazole (IC50 4.7±2.3 μM), bifonazole (IC50 9.4±0.8 μM) and clotrimazole (IC50 4.4±0.6 μM).
Summarizing, these results indicate an inhibitory effect of econazole, bifonazole and clotrimazole on PGHS‐1, varying in its potency dependent on the cell system used. In addition TXB2 formation is affected at doses even lower than those needed to suppress PGE2 biosynthesis.

British Journal of Pharmacology (2000) 130, 1241–1246; doi:10.1038/sj.bjp.0703427
Sodium reabsorption in thick ascending limb of Henle's loop: effect of potassium channel blockade in vivo
Authors: Huang Dan Y , Osswald Hartmut , Vallon Volker 
Published: January 2005

Based on previous in vitro studies, inhibition of K+ recycling in thick ascending limb (TAL) is expected to lower Na+ reabsorption through (i) reducing the luminal availability of K+ to reload the Na+‐2Cl−‐K+ cotransporter and (ii) diminishing the lumen positive transepithelial potential difference which drives paracellular cation transport.
This issue was investigated in anaesthetized rats employing microperfusion of Henle's loop downstream from late proximal tubular site with K+‐free artificial tubular fluid in nephrons with superficial glomeruli.
The unselective K+ channel blocker Cs+ (5–40 mM) dose‐dependently increased early distal tubular delivery of fluid and Na+ with a maximum increase of ∼20 and 185%, respectively, indicating predominant effects on water‐impermeable TAL.
The modest inhibition of Na+ reabsorption in response to the 15 mM of Cs+ but not the enhanced inhibition by 20 mM Cs+ was prevented by luminal K+ supplementation. Furthermore, pretreatment with 20 mM Cs+ did not attenuate the inhibitory effect of furosemide (100 μM) on Na+‐2Cl−‐K+ cotransport.
Neither inhibitors of large (charybdotoxin 1 μM) nor low (glibenclamide 250 μM; U37883A 100 μM) conductance K+ channels altered loop of Henle fluid or Na+ reabsorption.
The intermediate conductance K+ channel blockers verapamil and quinine (100 μM) modestly increased early distal tubular Na+ but not fluid delivery, indicating a role for this K+ channel in Na+ reabsorption in TAL. As observed for equieffective concentrations of Cs+ (15 mM), Na+ reabsorption was preserved by K+ supplementation.
The results indicate that modest inhibition of K+ channels lowers the luminal availability of K+ and thus transcellular Na+ reabsorption in TAL. More complete inhibition lowers paracellular Na+ transport probably by reducing or even abolishing the lumen positive transepithelial potential difference. Under the latter conditions, transcellular Na+ transport may be restored by paracellular K+ backleak.

British Journal of Pharmacology (2000) 130, 1255–1262; doi:10.1038/sj.bjp.0703429
Mutational analysis of the interaction of the N‐ and C‐terminal ends of angiotensin II with the rat AT1A receptor
Authors: Costa‐Neto Claudio M , Miyakawa Ayumi A , Oliveira Laerte , Hjorth Siv A , Schwartz Thue W , Paiva Antonio C M 
Published: January 2005

The role of different residues of the rat AT1A receptor in the interaction with the N‐ and C‐terminal ends of angiotensin II (AngII) was studied by determining ligand binding and production of inositol phosphates (IP) in COS‐7 cells transiently expressing the following AT1A mutants: T88H, Y92H, G196I, G196W and D278E.
G196W and G196I retained significant binding and IP‐production properties, indicating that bulky substituents in position 196 did not affect the interaction of AngII's C‐terminal carboxyl with Lys199 located three residues below.
Although the T88A mutation did not affect binding, the T88H mutant had greatly decreased affinity for AngII, suggesting that substitution of Thr88 by His might hinder binding through an indirect effect.
The Y92H mutation caused loss of affinity for AngII that was much less pronounced than that reported for Y92A, indicating that His in that position can fulfil part of the requirements for binding.
Replacing Asp278 by Glu caused a much smaller reduction in affinity than replacing it by Ala, indicating the importance of Asp's β‐carboxyl group for AngII binding.
Mutations in residues Thr88, Tyr92 and Asp278 greatly reduced affinity for AngII but not for Sar1 Leu8‐AngII, suggesting unfavourable interactions between these residues and AngII's aspartic acid side‐chain or N‐terminal amino group, which might account for the proposed role of the N‐terminal amino group of AngII in the agonist‐induced desensitization (tachyphylaxis) of smooth muscles.

British Journal of Pharmacology (2000) 130, 1263–1268; doi:10.1038/sj.bjp.0703430
The MAP kinase inhibitors, PD098059, UO126 and SB203580, inhibit IL‐1β‐dependent PGE2 release via mechanistically distinct processes
Authors: Newton Robert , Cambridge Lisa , Hart Lorraine A , Stevens David A , Lindsay Mark A , Barnes Peter J 
Published: January 2005

In common with human bronchial epithelial cells, pulmonary A549 cells release prostaglandin (PG) E2 in response to pro‐inflammatory cytokines. We have therefore used these cells to examine the effect of the selective mitogen activated protein (MAP) kinase inhibitors; PD098059, a mitogen activated and extracellular regulated kinase kinase (MEK) 1 inhibitor, UO126, a dual MEK1 & MEK2 inhibitor, and SB203580, a p38 MAP kinase inhibitor in the IL‐1β‐dependent release of PGE2.
Following IL‐1β treatment the extracellular regulated kinases (ERKs) and the p38 MAP kinases were rapidly phosphorylated.
PD09059, UO126 and SB203580 prevented IL‐1β‐induced PGE2 release at doses that correlated closely with published IC50 values. Small or partial effects at the relevant doses were observed on induction of cyclo‐oxygenase (COX) activity or COX‐2 protein suggesting that the primary effects were at the level of arachidonate availability.
Neither PD098059 nor SB203580 showed any effect on IL‐1β‐induced arachidonate release. We therefore speculate that the MEK1/ERK and p38 kinase cascades play a role in the functional coupling of arachidonate release to COX‐2.
In contrast, UO126 was highly effective at inhibiting IL‐1β‐dependent arachidonate release, implicating MEK2 in the activation of the PLA2 that is involved in IL‐1β‐dependent PGE2 release.
We conclude that the MEK1, MEK2 and p38 MAP kinase inhibitors, PD098059, UO126 and SB203580, are highly potent in respect of inflammatory PG release. Finally, we conclude that these inhibitors act via mechanistically distinct processes, which may have anti‐inflammatory benefits.

British Journal of Pharmacology (2000) 130, 1353–1361; doi:10.1038/sj.bjp.0703431
Involvement of central opioid systems in human interferon‐α induced immobility in the mouse forced swimming test
Authors: Makino Mitsuhiro , Kitano Yutaka , Komiyama Chika , Hirohashi Masaaki , Takasuna Kiyoshi 
Published: January 2005

We investigated the mechanism by which human interferon‐α (IFN‐α) increases the immobility time in a forced swimming test, an animal model of depression.
Central administration of IFN‐α (0.05–50 IU per mouse, i.cist.) increased the immobility time in the forced swimming test in mice in a dose‐dependent manner.
Neither IFN‐β nor ‐γ possessed any effect under the same experimental conditions.
Pre‐treatment with an opioid receptor antagonist, naloxone (1 mg kg−1, s.c.) inhibited the prolonged immobility time induced by IFN‐α (60 KIU kg−1, i.v. or 50 IU per mouse. i.cist.).
Peripheral administration of naloxone methiodide (1 mg kg−1, s.c.), which does not pass the blood–brain barrier, failed to block the effect of IFN‐α, while intracisternal administration of naloxone methiodide (1 nmol per mouse) completely blocked.
The effect of IFN‐α was inhibited by a μ1‐specific opioid receptor antagonist, naloxonazine (35 mg kg−1, s.c.) and a μ1/μ2 receptor antagonist, β‐FNA (40 mg kg−1, s.c.). A selective δ‐opioid receptor antagonist, naltrindole (3 mg kg−1, s.c.) and a κ‐opioid receptor antagonist, nor‐binaltorphimine (20 mg kg−1, s.c.), both failed to inhibit the increasing effect of IFN‐α.
These results suggest that the activator of the central opioid receptors of the μ1‐subtype might be related to the prolonged immobility time of IFN‐α, but δ and κ‐opioid receptors most likely are not involved.

British Journal of Pharmacology (2000) 130, 1269–1274; doi:10.1038/sj.bjp.0703432
Cytokine‐mediated inflammatory hyperalgesia limited by interleukin‐1 receptor antagonist
Authors: Cunha J M , Cunha F Q , Poole S , Ferreira S H 
Published: January 2005

The effect of IL‐1ra on response to intraplantar (i.pl.) injection of LPS, carrageenin, bradykinin, TNFα, IL‐1β, IL‐8, PGE2 and dopamine was investigated in a model of mechanical hyperalgesia in rats.
IL‐1ra inhibited hyperalgesic response to LPS, carrageenin, bradykinin, TNFα, and IL‐1β, but not responses to IL‐8, PGE2 and dopamine.
A sheep anti‐rat IL‐1ra serum potentiated response to LPS, carrageenin, bradykinin, TNFα and IL‐1β but not IL‐8.
Carrageenin and LPS stimulated and production of immunoreactive TNFα, IL‐1β and IL‐1ra in the skin of injected paws.
The inhibition by IL‐1ra of the hyperalgesic response to carrageenin was not affected by antibodies neutralizing IL‐4 and IL‐10.
In mice, IL‐1ra inhibited the nociceptive response to i.p. injection of acetic acid.
These data suggest that IL‐1ra, released at sites of inflammation, limits inflammatory hyperalgesia. This effect is independent of (IL‐1ra‐induced) IL‐4 and IL‐10 and appears to be the result of antagonism by IL‐1ra of IL‐1β‐stimulated eicosanoid production.

British Journal of Pharmacology (2000) 130, 1418–1424; doi:10.1038/sj.bjp.0703434
Inotropic response to endothelin‐1, isoprenaline and calcium in cardiomyocytes isolated from endotoxin treated rats: effects of ethyl‐isothiourea and dexamethasone
Authors: Spiers J P , Kelso E J , Allen J D , Silke B , McDermott B J 
Published: January 2005

The contractile effects of endothelin‐1, isoprenaline and extracellular calcium were assessed on ventricular cardiomyocytes isolated from lipopolysaccharide‐treated rats. The involvement of nitric oxide was investigated using dexamethasone (in vivo) and ethyl isothiourea (in vitro).
Male Wistar rats (n=70) were injected with either saline (1 ml kg−1) or lipopolysaccharide (LPS; 5 mg kg−1) alone, or following pre‐treatment with dexamethasone (DEX+LPS; 5 mg kg−1). Ventricular cell shortening was recorded using a video edge detection system, and concentration‐response relationships were established for endothelin‐1, isoprenaline and calcium, in the absence or presence of ethyl isothiourea (ETU; 10 μM). iNOS expression was assessed using reverse transcription‐polymerase chain reaction.
iNOS mRNA expression was greater (P<0.001) in the LPS (iNOS/GAPDH ratio: 0.90±0.09) treated group compared to saline (iNOS/GAPDH ratio: 0.36±0.02). Baseline contractile amplitude was reduced (P<0.05) in the LPS (7.3±0.2 μm) and DEX+LPS groups (6.7±0.3 μm) compared to saline (8.0±0.2 μm).
The concentration‐dependent contractile response to endothelin‐1 was attenuated (P<0.05) in the LPS group compared to saline (maximum change: 0.45±0.2 vs 1.8±0.2 μm). Neither ETU nor dexamethasone improved contractile function in the LPS‐treated animals.
The concentration‐dependent increase in the contractile response to isoprenaline was attenuated in the LPS‐treated group compared to saline (P<0.05; maximum change: 1.7±0.4 vs 3.1±0.4 μm). This effect was reversed by ETU (maximum change: 3.7±0.6 μm). Pre‐treatment with dexamethasone prevented a significant fall in contraction amplitude (maximum change: 2.4±0.4 μm).
The contractile response to calcium was reduced (P<0.05) in the LPS group compared to saline (maximum change: 8.7±0.6 vs 10.7±0.8 μm). Neither ETU nor dexamethasone restored contractile function in the LPS‐treated group.
In conclusion, a nitric oxide‐mediated inhibitory pathway is not responsible for the diminished contractile response to either endothelin‐1 or extracellular calcium, but contributes to the hyporesponsiveness to isoprenaline in lipopolysaccharide treated rats.

British Journal of Pharmacology (2000) 130, 1275–1282; doi:10.1038/sj.bjp.0703435
Role of central glutamate receptors, nitric oxide and soluble guanylyl cyclase in the inhibition by endotoxin of rat gastric acid secretion
Authors: García‐Zaragozá Eugenia , Barrachina M Dolores , Moreno Lucrecia , Esplugues Juan V 
Published: January 2005

This study examines the role of a central pathway involving glutamate receptors, nitric oxide (NO) and cyclic GMP in the acute inhibitory effects of low doses of peripheral endotoxin on pentagastrin‐stimulated acid production.
Vagotomy or intracisternal (i.c.) microinjections of the NO‐inhibitor, NG‐nitro‐L‐arginine methyl esther (L‐NAME; 200 μg rat−1) restored acid secretory responses in endotoxin (10 μg kg−1, i.v.)‐treated rats.
The acid‐inhibitory effect of i.v. endotoxin (10 μg kg−1, i.v.) was prevented by prior i.c. administration of the NMDA receptor antagonists, dizocilpine maleate (MK‐801; 10 nmol rat−1) and D‐2‐amino‐5‐phosphono‐valeric acid (AP‐5; 20 nmol rat−1), or the AMPA/kainate antagonist 6,7‐dinitroquinoxaline‐2,3‐dione (DNQX; 10 nmol rat−1). However, the competitive metabotropic glutamate receptor antagonist (+)‐α‐methyl‐4‐carboxyphenylglycine (MCPG; 20–1000 nmol rat−1) did not antagonize the effects of endotoxin.
I.c. administration of L‐glutamate (0.1 nmol rat−1) inhibited pentagastrin‐stimulated gastric acid secretion. Coadministration with L‐NAME (200 μg rat−1) prevented the inhibition of gastric acid secretion by the aminoacid.
I.c. administration of 1H‐[1,2,4]Oxazodiolo[4,3‐a]quinoxalin‐1‐one (ODQ; 100 nmol rat−1), a soluble guanylyl cyclase (sGC) blocker, reversed the hyposecretory effect of endotoxin.
I.c. administration of the cyclic GMP analogue 8‐Bromoguanosine‐3,5‐cyclic monophosphate (8‐Br‐cGMP; 100–300 nmol rat−1) reduced gastric acid production in a dose‐dependent manner.
We conclude that central NMDA and AMPA/kainate receptors are involved in the acid inhibitory effect of peripherally administered endotoxin. This central pathway involves synthesis of NO, which acts on the enzyme sGC.

British Journal of Pharmacology (2000) 130, 1283–1288; doi:10.1038/sj.bjp.0703436
YD‐3, a novel inhibitor of protease‐induced platelet activation
Authors: Wu Chin‐Chung , Huang Shiow‐Wen , Hwang Tsong‐Long , Kuo Sheng‐Chu , Lee Fang‐Yu , Teng Che‐Ming 
Published: January 2005

In the present study, the antiplatelet effects and mechanisms of a new synthetic compound YD‐3 [1‐benzyl‐3(ethoxycarbonylphenyl)‐indazole] were examined.
YD‐3 inhibited the aggregation of washed rabbit platelets caused by thrombin (IC50=28.3 μM), but had no or little inhibitory effect on that induced by arachidonic acid, collagen, platelet‐activating factor (PAF) or U46619. YD‐3 also suppressed generation of inositol phosphates caused by thrombin. On the other hand, thrombin‐induced fibrin formation was not affected by YD‐3, indicating YD‐3 does not inhibit the proteolytic activity of thrombin.
In washed human platelets, however, YD‐3 had only mild inhibitory effect on the low concentration (0.05 u ml−1) of thrombin‐induced human platelet aggregation, and did not affect that induced by higher concentrations (0.1 u ml−1) of thrombin or SFLLRN, the protease‐activated receptor 1 (PAR1) agonist peptide. By contrast, YD‐3 inhibited both human and rabbit platelet aggregation elicited by trypsin with IC50 values of 38.1 μM and 5.7 μM, respectively.
YD‐3, at 100 μM, had no effect on ristocetin‐induced glycoprotein Ib (GPIb)‐dependent aggregation of human platelets. In addition, platelets treated with chymotrypsin, which cleaves GPIb, enhanced rather than attenuated the inhibition of YD‐3 on thrombin‐induced human platelet aggregation. These data indicate that GPIb plays no role in the antiplatelet effect of YD‐3.
In SFLLRN‐desensitized human platelets, high concentration of thrombin (1 u ml−1) could still elicit intracellular Ca2+ mobilization, and the rise of [Ca2+]i was prevented by either leupeptin or YD‐3.
Our results suggest that YD‐3 inhibits a non‐PAR1 thrombin receptor which mediates the major effect of thrombin in rabbit platelets, but in human platelets, this receptor function becomes significant only when the function of PAR1 has been blocked or attenuated.

British Journal of Pharmacology (2000) 130, 1289–1296; doi:10.1038/sj.bjp.0703437
Novel proline endopeptidase inhibitors do not modify Aβ40/42 formation and degradation by human cells expressing wild‐type and Swedish mutated β‐amyloid precursor protein
Authors: Petit Agnès , Barelli Hélène , Morain Philippe , Checler Frédéric 
Published: January 2005

Previous studies have suggested that proline endopeptidase (PE) could participate to the catabolism of the β‐amyloid peptide (Aβ) or to the physiopathological maturation of the β‐amyloid protein precursor (βAPP). We have examined the putative ability of human purified PE to catabolize Aβ40 and Aβ42 and the possible contribution of this enzyme to the generation of Aβ40 and Aβ42 in human HEK293 cells.
We show first that purified human PE does not degrade synthetic Aβ40 and Aβ42, in vitro.
We establish that HEK293 cell homogenates exhibit a Z‐Gly‐Pro‐7AMC‐cleaving enzyme, the activity of which is inhibited by Z‐Pro‐Prolinal and S17092 and S19825, two novel PE inhibitors, with affinities similar to those displayed on the purified human PE. These inhibitors also penetrate cells and achieve a full inhibition of endogenous proline endopeptidase in human cells.
By means of selective antibodies directed towards the C‐terminal of Aβ40 and Aβ42, we assessed the effect of PE inhibitors on the recovery of both Aβ species. This was examined in HEK293 cells stably overexpressing the wild‐type and the familial Alzheimer' disease‐related Swedish mutated β‐APP. We establish that none of these inhibitors affected Aβ40 or Aβ42 production in these transfected cells.
Overall, our study indicates that human PE does not degrade Aβ40 and Aβ42. Furthermore, PE does not contribute to Aβ40 and Aβ42 formation in HEK293 cells. Therefore, PE does not appear to contribute to the Aβ‐related aetiology of Alzheimer' disease.

British Journal of Pharmacology (2000) 130, 1613–1617; doi:10.1038/sj.bjp.0703440
[Ca2+]i‐ and insulin‐stimulating effect of the non‐membranepermeable phosphatase‐inhibitor microcystin‐LR in intact insulin‐secreting cells (RINm5F)
Authors: Leiers T , Bihlmayer A , Ammon H P T , Wahl M A 
Published: January 2005

Microcystin‐LR, a specific and effective inhibitor of serine/threonine phosphatases type 1/2A which does not permeate cells, was used to distinguish intracellular and extracellular effects of phosphatase inhibitors on insulin secretion by RINm5F cells.
Incubation of intact RINm5F cells with microcystin‐LR (0.1–2 μM) almost doubled basal insulin release at 3 mM glucose but left maximal insulin release induced by KCl (30 mM) unaffected.
In parallel, there was an increase in cytosolic Ca2+ by up to half maximum, which could be suppressed by the Ca2+‐channel blocker D600.
In contrast, microcystin‐LR incubation of intact cells did not affect phosphatase activity but significantly reduced phosphatase activity when used in cellular fractions.
From these data we conclude that microcystin‐LR could affect Ca2+‐channels and insulin release by inhibiting an extracellular phosphatase‐like activity.

British Journal of Pharmacology (2000) 130, 1406–1410; doi:10.1038/sj.bjp.0703441
Low dose carvedilol inhibits progression of heart failure in rats with dilated cardiomyopathy
Authors: Watanabe Kenichi , Ohta Yoshimi , Nakazawa Mikio , Higuchi Hiroshi , Hasegawa Go , Naito Makoto , Fuse Koichi , Ito Masahiro , Hirono Satoru , Tanabe Naohito , Hanawa Haruo , Kato Kiminori , Kodama Makoto , Aizawa Yoshifusa 
Published: January 2005

The cardioprotective properties of carvedilol (a vasodilating β‐adrenoceptor blocking agent) were studied in a rat model of dilated cardiomyopathy induced by autoimmune myocarditis.
Twenty‐eight days after immunization, surviving Lewis rats (32/43=74%) were divided into three groups to be given 2 mg kg−1 day−1 (Group‐C2, n=10) or 20 mg kg−1 day−1 (Group‐C20, n=10) of carvedilol, or vehicle (0.5% methylcellulose, Group‐V, n=12).
After oral administration for 2 months, body weight, heart weight (HW), heart rate (HR), rat α‐atrial natriuretic peptide (r‐ANP) in blood, central venous pressure (CVP), mean blood pressure (mean BP), peak left ventricular pressure (LVP), left ventricular end‐diastolic pressure (LVEDP), ±dP dt−1 and area of myocardial fibrosis were measured. Values were compared with those for normal Lewis rats (Group‐N, n=10).
Two out of 12 (17%) rats in Group‐V died from day 28 to day 42 after immunization. No rat died in Groups‐C2, ‐C20 and ‐N. Although the CVP, mean BP, LVP and ±dP dt−1 did not differ among the three groups, the HW, HR and r‐ANP in Group‐C2 (1.14±0.03, 339±16 and 135±31) and Group‐C20 (1.23±0.04, 305±8 and 156±24) were significantly lower than those in Group‐V (1.36±0.04 g, 389±9 beats min−1 and 375±31 pg ml−1, respectively). The LVEDP in Group‐C2 was significantly lower than that in Group‐V (7.4±1.4 and 12.2±1.2 mmHg, respectively, P<0.05). The area of myocardial fibrosis in Group‐C2 was smaller than that in Group‐V (12±1 and 31±2%, P<0.01).
These results indicate that a low dose of carvedilol has beneficial effects on dilated cardiomyopathy.

British Journal of Pharmacology (2000) 130, 1489–1495; doi:10.1038/sj.bjp.0703450