Biomedical subjects

W Schmitz

Publications and source records attributed to W Schmitz.

At least 73 records · Page 4Linked to original sources

PubMed1998

Postnatal changes in contractile time parameters, calcium regulatory proteins, and phosphatases.

Compared with isolated electrically driven neonatal ventricular preparations, the total time of contraction, the time to peak tension, and the time of relaxation were decreased to approximately 50% in adult ventricular preparations. The expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) was increased to 133% at the protein level and to 154% at the mRNA level in adult vs. neonatal ventricular preparations, whereas phospholamban was unchanged at both the protein and mRNA levels. Moreover, Ca2+ uptake was increased to 180% in adult vs. neonatal ventricular preparations. Phospholamban phosphorylation was enhanced in adult vs. neonatal ventricular preparations. In adult ventricular preparations, phosphatase activity was reduced to 53% of neonatal preparations, the protein levels of the immunologically detectable catalytic subunits of protein phosphatase types 1 and 2A were reduced to 28 and 61% of neonatal preparations, respectively, and the mRNA levels of type 1alpha, 1beta, 1gamma, 2Aalpha, and 2Abeta phosphatase isoforms were decreased to 69, 68, 54, 67, and 63%, respectively. We conclude that in the adult rat heart, the shortened time parameters of contraction can be explained by an elevated expression of SERCA. In addition, an increased phosphorylation state of phospholamban due to reduced phosphatase activity may be involved.

Actins↗

PubMed1998

Long-term beta adrenoceptor-mediated alteration in contractility and expression of phospholamban and sarcoplasmic reticulum Ca(++)-ATPase in mammalian ventricle.

We studied the influence of prolonged administration of the beta adrenoceptor agonist isoproterenol on contractile parameters and expression of sarcoplasmic reticulum (SR) Ca(++)-ATPase and phospholamban, genes important for Ca++ uptake into the SR. Isoproterenol (Iso), 0.9% NaCl (Ctr), propranolol (Prop) or Iso plus Prop were administered to rats by subcutaneous infusion with osmotic minipumps for 1, 2, 3, 4, 8, 13 and 26 days, respectively. The positive inotropic effect of Iso was impaired in rats pretreated with Iso in vivo. Iso pretreatment shortened time to peak tension (TPT) by 28%, time of relaxation (RT) by 27% and total contraction time (TCT) by 27% compared with the appropriate controls (day 2). The shortening of time-dependent contractile indices started after 1 day of Iso pretreatment, reached a maximum after 2 days and remained reduced for 4 days. Longer treatment by Iso failed to affect time parameters, whereas the positive inotropic effect of Iso added to the isolated muscles persisted. The shortened contractile time parameters were accompanied by diminished mRNA and protein expression of phospholamban (PLB) and SR-Ca(++)-ATPase (SERCA). The mRNA levels for PLB and SERCA were maximally reduced by 31 +/- 1.3% and 41 +/- 1.4% in the Isopretreated group (2 days) respectively. The reduced mRNA levels were accompanied by reduced levels of the corresponding proteins. It is concluded that altered levels of PLB and SERCA probably account for the noted changes in contractile time parameters in the mammalian heart.

Animals↗

PubMed1997

Molecular cloning of cDNA species for rat and mouse liver alpha-methylacyl-CoA racemases.

cDNA species coding for alpha-methylacyl-CoA racemase were cloned from rat and mouse liver cDNA libraries and characterized. The rat liver lambdagt11 cDNA expression library was screened with anti-racemase IgG [Schmitz, Albers, Fingerhut and Conzelmann (1995) Eur. J. Biochem.231, 815-822]. Several full-length clones were obtained that contained an open reading frame of 1083 bp, coding for a protein of 361 amino acid residues with a predicted molecular mass of 39679 Da. The sequences of three peptides that were isolated by HPLC from a tryptic digest of purified rat liver racemase fully matched the cDNA-derived amino acid sequence. The cDNA coding for mouse racemase was cloned from a mouse liver lambdaZAP cDNA expression library and sequenced. The coding region of 1080 bp codes for a 360-residue protein (molecular mass 39558 Da) that shares 89.7% similarity with the rat protein. Expression of the rat racemase as are combinant protein in Escherichia coli with the pTrcHisB-expression vector yielded enzymically active protein. The amino acid sequences of alpha-methylacyl-CoA racemases do not resemble any known sequence of beta-oxidation or auxiliary enzymes, supporting the view of a highly diverse evolutionary origin of enzymes acting on fatty acyl-CoA S-esters.

Amino Acid Sequence↗

PubMed1997

Quantification of the cAMP response element binding protein in ventricular nuclear protein from failing and nonfailing human hearts.

Alterations in the expression of myocardial regulatory proteins (e.g. beta-adrenoceptor, inhibitory G-proteins) in human heart failure are associated with excessive stimulation of the cAMP signalling pathway by endogenous catecholamines. The transcription factor cAMP response element binding protein (CREB) mediates cAMP-dependent transcriptional activation and is expressed in the human heart. Here, CREB protein was immunologically quantified in ventricular nuclear protein preparations from nonfailing donor hearts (n = 8) and from failing hearts transplanted due to dilative (n = 10) or ischemic cardiomyopathy (n = 6). CREB expression was unchanged in ventricular nuclei from failing hearts compared to the nonfailing controls suggesting that expressional alterations in human heart failure cannot be explained by altered expression of CREB.

Cyclic AMP Response Element-Binding Protein↗

PubMed1997

Stereochemistry of peroxisomal and mitochondrial beta-oxidation of alpha-methylacyl-CoAs.

The stereochemistry of beta-oxidation of alpha-methyl-branched fatty acids was analyzed, in rat liver and in human cells, with (2R)- and (2S)-2-methyltetradecanoic acid as model substrates. In rat liver, formation of the alpha,beta-unsaturated compound was found to be concentrated in mitochondria while in human cells, this activity co-distributed mainly with peroxisomal marker enzymes. In both cases, the dehydrogenating enzymes were absolutely specific for the (2S)-enantiomer. In human liver, activation was some three times faster with the (2R)- than with the (2S)-isomer while in rat liver both were activated at about the same rate.

Acyl Coenzyme A↗

PubMed1997

Peroxisomal multifunctional enzyme of beta-oxidation metabolizing D-3-hydroxyacyl-CoA esters in rat liver: molecular cloning, expression and characterization.

In the present study we have cloned and characterized a novel rat peroxisomal multifunctional enzyme (MFE) named perMFE-II. The purified 2-enoyl-CoA hydratase 2 with an M(r) of 31500 from rat liver [Malila, Siivari, Mäkelä, Jalonen, Latipää, Kunau and Hiltunen (1993) J. Biol. Chem. 268, 21578-21585] was subjected to tryptic fragmentation and the resulting peptides were isolated and sequenced. Surprisingly, the full-length cDNA, amplified by PCR, had an open reading frame of 2205 bp encoding a polypeptide with a predicted M(r) of 79,331 and contained a potential peroxisomal targeting signal in the C-terminus (Ala-Lys-Leu). The sequenced peptide fragments of hydratase 2 gave a full match in the middle portion of the cDNA-derived amino acid sequence. The predicted amino acid sequence showed a high degree of similarity with pig 17 beta-hydroxysteroid dehydrogenase type IV and MFE of yeast peroxisomal beta-oxidation. Recombinant perMFE-II (produced in Pichia pastoris) had 2-enoyl-CoA hydratase 2 and D-specific 3-hydroxyacyl-CoA dehydrogenase activities and was catalytically active with several straight-chain trans-2-enoyl-CoA, 2-methyltetradecenoyl-CoA and pristenoyl-CoA esters. The results showed that in addition to an earlier described multifunctional isomerase-hydratase-dehydrogenase enzyme from rat liver peroxisomes (perMFE-I), another MFE exists in rat liver peroxisomes. They both catalyse sequential hydratase and dehydrogenase reactions of beta-oxidation but through reciprocal stereochemical courses.

Amino Acid Sequence↗

PubMed1997

Increased expression of cardiac phosphatases in patients with end-stage heart failure.

Type 1 phosphatase activity was increased in membrane vesicles from failing human ventricles compared with non-failing controls. Likewise, expression of the mRNA encoding for type 1 phosphatase was enhanced by 37%. The present study provides evidence that alterations of phosphatase activity coincide with end-stage heart failure. Thus, enhanced activity of phosphatases may be causally related to heart failure and/or may aggravate the well known decreased cardiac responsiveness to positive inotropic agents in end-stage heart failure.

Adenylyl Cyclases↗

PubMed1997

Functional evidence against the existence of beta 2-adrenoceptors mediating positive intropic effects in guinea-pig right ventricular myocardium.

In guinea-pig isolated papillary muscles we studied the positive inotropic effects of the beta-adrenoceptor agonists isoprenaline, fenoterol and noradrenaline in the presence and absence of the beta 1-selective antagonist atenolol and the beta 2-adrenoceptor antagonist ICI 118.551. In Schild regression analysis pA2 values, for either atenolol (7.14-7.16) and ICI 118.551 (6.79-6.84) were independent of the agonists used. These results support the view that the inotropic response in guinea-pig ventricular myocardium is mediated by beta 1-adrenoceptors only.

Animals↗

PubMed1997

The effect of the protein phosphatases inhibitor cantharidin on beta-adrenoceptor-mediated vasorelaxation.

1. Cantharidin, an inhibitor of protein phosphatase types 1 (PP1) and 2A (PP2A), increased basal tone of bovine isolated coronary artery rings (CARs) with and without endothelium in a time- and concentration-dependent manner with pEC50 values of about 5.1 and 5.2, respectively, for both preparations. 2. Beta-Adrenoceptor stimulation with isoprenaline (Iso; 0.03-100 microM) or inhibition of phosphodiesterase activity by 3-isobutyl-1-methylxanthine (IBMX; 10-1000 microM), respectively, relaxed CARs precontracted with KCl (75 mM). CARs with and without endothelium showed no difference in the relaxing response to Iso and IBMX, respectively. 3. Cantharidin (3 microM) attenuated vasorelaxation induced by Iso (0.03-100 microM) in CARs with and without endothelium in a time-dependent manner, whereas vasorelaxation induced by IBMX (10-1000 microM) was not attenuated by 3 microM cantharidin. 4. Cantharidin (3 microM) did not affect cyclic AMP content in bovine cultured vascular cells, i.e. coronary artery smooth muscle cells (BCs), aortic endothelial cells (BAECs) and aortic smooth muscle cells (BASMCs), either under basal conditions, after beta-adrenoceptor stimulation (Iso) or inhibition of phosphodiesterase activity (IBMX), respectively. 5. Cantharidin inhibited protein phosphatase activity in homogenates from bovine coronary artery rings with a pIC50 of about 6.0. In homogenates of bovine cultured vascular cells pIC50 values of cantharidin amounted to about 6.5 for BCs, 6.7 for BAECs and 6.7 for BASMCs, respectively. 6. It was concluded that cantharidin differently affects vasorelaxation due to stimulation of beta-adrenoceptors (Iso) or inhibition of phosphodiesterase activity (IBMX), respectively. The attenuation of beta-adrenoceptor-mediated vasorelaxation by phosphatase inhibition is not due to diminished adenosine 3':5'-cyclic monophosphate (cyclic AMP) generation but could be evidence for different subcellular compartments of cyclic AMP.

1-Methyl-3-isobutylxanthine↗

PubMed1997

Characterization of biochemical effects of CGS 21680C, an A2-adenosine receptor agonist, in the mammalian ventricle.

Effects of a putative A2-adenosine receptor agonist 2-[(p-2-carboxyethyl)-phenethylamino]-5'-N-ethyl-carboxamide-adeno sine (CGS 21680C) on force of contraction, protein phosphorylation, cyclic adenosine monophosphate (cAMP) content, and the activity of phosphodiesterase (PDE) isoenzymes in guinea pig ventricular (GPV) preparations were studied. CGS 21680C (1-100 microM) did not affect force of contraction in isolated electrically driven papillary muscles and was ineffective in increasing phosphorylation of phospholamban (PLB) and the inhibitory subunit of troponin (TnI) in [32P]-labeled GPV cardiomyocytes. However, under the same conditions, CGS 21680C (10 microM) increased cAMP content from 4.3 +/- 0.2 to 13.0 +/- 0.6 pmol/mg protein, and this effect was completely abolished by A2-adenosine receptor antagonist 9-chloro-2-(2-furanyl)-5,6-dihydro-1,2,4-triazolo-(1,5-c)quinazolin++ +-5-imine (CGS 15943A). CGS 21680C (10 microM) inhibited PDE isoenzymes I, II, III, IV by 7.0, 8.3, 4.7, and 23.2%, respectively. Similarly, rolipram (100 microM), a selective PDE IV inhibitor, increased cAMP content from 4.4 +/- 0.3 to 7.2 +/- 0.3 pmol/mg protein without affecting the phosphorylation state of PLB and TnI. We conclude that CGS 21680C increases cAMP content in GPV cardiomyocytes by activation of adenylyl cyclase or in part by inhibition of PDE IV activity. The increase in cAMP content by CGS 21680C or rolipram is ineffective in increasing phosphorylation of PLB and TnI. These results support the concept of compartments for cAMP or protein kinase A or both in cardiomyocytes that are not coupled to phosphorylation and contractility.

Adenosine↗

PubMed1997

Urethral relaxation after electrostimulation in the guinea pig is independent of nitric oxide.

PURPOSE: To investigate whether the relaxation of the striated urethral sphincter in guinea pigs is mediated by nitric oxide. MATERIALS AND METHODS: After sacrifice, urethral rings were cut between the bladder neck and the penile crura and mounted in an in vitro bath. Maximal isometric tension obtained at 1, 3, 10 and 25 Hz electrical stimulation (Tmax) for 5 to 30 sec was measured. RESULTS: Tmax at 25 Hz was not changed by pretreatment with 10(-4)M nitroprusside or 10(-4)M NG-nitro-L-arginine. In urethral tissue precontracted with 10(-4)M noradrenaline, a significant relaxation of 16-25% was found at 10 Hz. This relaxation could not be prevented by pretreatment with 10(-4)M NG-nitro-L-arginine and was not enhanced by the presence of 10(-3)M L-arginine. CONCLUSION: Noradrenaline-precontracted urethral rings of male guinea pigs exhibit a maximal relaxation at 10 Hz, which does not depend on nitric oxide.

Animals↗

PubMed1997

Mechanisms of the contractile effects of levosimendan in the mammalian heart.

In spontaneously beating guinea pig right atria, levosimendan (LS, or R-[[-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)- phenyl]-hydrazono]propanedinitrile) exerted a positive chronotropic effect starting at 0.1 microM. In electrically driven guinea pig left atria, LS (0.1-10 microM) increased force of contraction without changing time parameters of contraction. In electrically driven right papillary muscles, LS (0.1-10 microM) enhanced force of contraction without affecting time parameters of contraction. The maximal effect on force of contraction at 10 microM amounted to 130 +/- 8.6% of predrug value. The positive inotropic effect of LS in papillary muscles was greatly diminished by additionally applied carbachol. In [32P]-labeled guinea pig ventricular cardiomyocytes, LS increased the phosphorylation state of phospholamban, the inhibitory subunit of troponin and C-protein. The maximal effect at 1 microM amounted to 134 +/- 8.6%, 124 +/- 4.2% and 121 +/- 8% of control for phospholamben, the inhibitory subunit of troponin and C-protein, respectively. LS (1 microM) increased cAMP content from 6.3 +/- 0.3 to 8.1 +/- 0.3 pmol/mg protein in guinea pig ventricular cardiomyocytes. Furthermore, whole-cell patch-clamp studies were performed in guinea pig ventricular cardiomyocytes. In this setup, 10 microM LS increased the amplitude of L-type Ca++ current to 402 +/- 86% of predrug value.

Animals↗

PubMed1996

Interleukin-6 correlates with hemodynamic impairment during dobutamine administration in chronic heart failure.

Proinflammatory cytokines have been implicated in the pathophysiology of chronic heart failure. We determined mixed venous levels of interleukin-6 (IL6) in 18 heart transplant candidates before, 1, 4, and 24 h after initiation of dobutamine infusion (3 micrograms/kg/min) during hemodynamic evaluation. During the first 4 h of dobutamine, systemic vascular resistance decreased (1358 to 1024 dyn x s x cm-5, P = 0.01) while cardiac index (2.3 to 2.9 l/min/m2, P = 0.008) increased. Both returned to baseline after 24 h. IL6 was elevated at baseline compared to age-matched controls (1.5 (0/4.3) vs. 0 (0/0.5) P = 0.003). There was an increase in IL6 from 1.5 (0/4.3) to 3.6 (0.3/5.3) pg/ml after 24 h (P = 0.04). We found higher IL6 levels in the sicker half of patients as defined by pulmonary capillary wedge pressure > 24 mmHg (P = 0.005), mean pulmonary arterial pressure > or = 35 mmHg (P = 0.01), right atrial pressure > 13 mmHg (P = 0.02), and heart rate > or = 87/min (P = 0.02) as well as mean arterial pressure < 82 mmHg (P = 0.005). In conclusion, in this pilot study IL6 correlates with the severity of chronic heart failure during low dose dobutamine infusion.

Adult↗

PubMed1996

Chronic treatment with carbachol sensitizes the myocardium to cAMP-induced arrhythmia.

BACKGROUND: The present study investigated biochemical and functional consequences of chronic activation of the inhibitory Gi alpha-coupled adenylyl cyclase pathway in the heart. METHODS AND RESULTS: Rats (220 to 260 g) were treated with 4-day infusions of the M-cholinoceptor agonist carbachol (9.6 mg/kg per day) or vehicle. An additional group that received the beta-adrenoceptor agonist isoprenaline (2.4 mg/kg per day) served as control. The main finding was that chronic infusion of carbachol led to a marked increase in isoprenaline- or forskolin-induced arrhythmia in electrically driven papillary muscles (in vitro). Compared with control, the potency of isoprenaline and forskolin to induce arrhythmia in cardiac preparations from carbachol-treated rats was increased 36- and 2.2-fold and the efficacy was increased 7.3- and 2.3-fold, respectively. The potency of carbachol to antagonize the isoprenaline- and forskolin-induced arrhythmia was decreased 30-fold. These changes were accompanied by a decrease in left ventricular M-cholinoceptor density by 15% (P < .05) and a decrease in pertussis toxin-sensitive G proteins (Gi alpha) by 26% (P < .05) without a decrease in the corresponding mRNAs. beta-Adrenoceptor density and basal and stimulated adenylyl cyclase activity remained unchanged. In contrast, isoprenaline infusion induced a decrease in arrhythmogenic potency of forskolin (P = NS), which was accompanied by a decrease in beta-adrenoceptor density, an increase in Gi alpha protein and mRNA levels, and a decrease in basal and stimulated adenylyl cyclase activity. CONCLUSIONS: Chronic parasympathetic activation sensitizes the myocardium to cAMP-induced arrhythmia. These changes may be due to quantitative alterations in functional Gi alpha.

Adenylate Cyclase Toxin↗

PubMed1996

Differential regulation of mRNA specific for beta 1- and beta 2-adrenergic receptors in human failing hearts. Evaluation of the absolute cardiac mRNA levels by two independent methods.

In human heart failure beta-adrenergic receptors are downregulated which contributes to the reduced responsiveness to positive inotropic beta-agonists in the diseased heart. The present study addressed the question whether the number of beta-adrenergic receptors in the failing human heart is regulated at the level of the mRNA and whether the absolute steady-state levels of subtype-specific mRNAs mirror the expression of receptor-subtype proteins in human heart. In a collaborative effort, two different and independent methods, performed in two independent laboratories, reverse transcription followed by polymerase chain reaction (RT-PCR) and RNase protection assays, were used to determine the absolute steady-state levels of beta 1- and beta 2-adrenergic receptor mRNAs in control (NF) and in failing human hearts. As determined by quantitative RT-PCR the beta 1-mRNA was significantly reduced from 0.98 +/- 0.12 (n = 10) to 0.49 +/- 0.11 pg/microgram total RNA in dilated cardiomyopathy (dCMP, n = 7) and to 0.40 +/- 0.11 pg/microgram total RNA in ischemic cardiomyopathy (iCMP, n = 8). The steady-state levels of mRNA specific for beta 2-adrenergic receptors also tended to be decreased but without reaching significance (NF: 0.16 +/- 0.05, dCMP: 0.11 +/- 0.03, iCMP: 0.13 +/- 0.04 pg/microgram total RNA). RNase protection assays revealed similar values. beta 1-mRNA was found to be significantly reduced from 1.22 +/- 0.22 in NF (n = 10) to 0.63 +/- 0.14 pg/microgram total RNA in dCMP (n = 5) and to 0.52 +/- 0.1 pg/microgram total RNA in iCMP (n = 8). The beta 2-mRNA also tended to be lower in dCMP and in iCMP as compared to NF but again without reaching significance (NF: 0.14 +/- 0.02, dCMP: 0.099 +/- 0.02, iCMP 0.107 +/- 0.02 pg/microgram total RNA). This is the first study to demonstrate in parallel by two different methods performed independently in two laboratories that the ratio of beta 1- and beta 2-adrenergic receptor densities in the left ventricle of the normal human heart of about 80/20 is closely related to the absolute steady state concentrations of their specific mRNA. In addition, the magnitude of the decrease in mRNA-levels of beta 1- and beta 2-adrenergic receptors in the failing human heart closely correlates with the decrease of the respective receptor proteins. These data suggest that the predominant regulation of beta-adrenergic receptors occurs at the mRNA level.

Adult↗

PubMed1996

Endotoxin and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase.

In patients with septic shock or inflammatory cardiac diseases like myocarditis myocardial contractility is depressed. These patients have elevated circulating levels of bacterial endotoxins (lipopolysaccharides, LPS) and pro-inflammatory cytokines like interleukin-1 beta (IL-alpha 1 beta) or tumor necrosis factor-alpha (TNF-alpha). It is not clear, whether LPS and/or cytokines have direct inotropic effects on cardiomyocytes and whether these effects are mediated via the L-arginine-nitric oxide synthase (NOS) pathway as demonstrated in vascular smooth muscle cells. Therefore, we examined the direct effects of LPS. IL-1 beta and TNF-alpha on contractility and cGMP content in isolated guinea-pig ventricular cardiomyocytes. Furthermore, the influence of the NOS inhibitor NG-nitro-L-arginine (L-NNA) and dexamethasone on these effects was studied as well as inducible NOS (iNOS) protein expression. LPS (1000 ng/ml), IL-1 beta (25 ng/ml) and TNF-alpha (100 ng/ml) decreased contractility by 48%, 55% and 65% and augmented cGMP content by 135%, 88% or 70% after long-term treatment (18 h) in cardiomyocytes, without altering contractility or cGMP content after short-term treatment (30 min). These effects were blocked by L-NNA (100 microM) and dexamethasone (3 microM). Furthermore iNOS protein was expressed in LPS- and cytokine-treated cardiomyocytes. These findings demonstrate that LPS. IL-1 beta and TNF-alpha have direct negative inotropic effects on cardiomyocytes, which are accompanied by an increase in cGMP content. These effects are mediated via de novo synthesis of a myocardial iNOS. The direct negative inotropic effects of endotoxins and cytokines on cardiomyocytes may in part contribute to the contractile dysfunction observed in patients with septic shock or inflammatory cardiac diseases.

Animals↗

PubMed1996

Effects of metoprolol on myocardial beta-adrenoceptors and Gi alpha-proteins in patients with congestive heart failure.

OBJECTIVE: In human heart failure downregulation of beta-adrenoceptors and upregulation of Gi-protein alpha-subunits (Gi alpha) results desensitization of the myocardial beta-adrenergic signal transduction pathway and reduced positive inotropic effects of catecholamines. Metoprolol treatment has been shown to restore the reduced beta-adrenoceptor density in dilated cardiomyopathy. The main objective of the present study was to investigate whether metoprolol also decreases the elevated inhibitory Gi alpha levels in patients suffering from congestive heart failure. METHODS: Total Gi alpha was determined by pertussis toxin-catalysed ADP ribosylation and beta 1- and beta 2-adrenoceptor densities by radioligand binding in right ventricular myocardial biopsies of 18 patients with dilated or ischaemic cardiomyopathy (NYHA II-IV) before and after 3 months of therapy. Nine controls were treated with conventional therapy only [diuretics, digitalis, nitrates, angiotensin-converting enzyme (ACE) inhibitors], and nine received the beta 1-selective blocker metoprolol in addition (mean 98 +/- 12 mg daily). RESULTS: In biopsies from patients treated with metoprolol, Gi alpha significantly decreased to 74% of predrug value and total beta-adrenoceptor increased by a selective increase in beta 1-adrenoceptors (44.7 vs 34.0 fmol mg-1 protein). These effects were accompanied by significantly increased oxygen uptake at the anaerobic threshold (8.65 vs 6.95 ml . kg-1 . min-1). In the control group no significant changes in biochemical and clinical parameters occurred. CONCLUSION: Metoprolol partly reverses Gi alpha-upregulation and beta-adrenoceptor downregulation in heart failure, which might contribute to the clinical improvement of patients treated with beta-blockers.

Adrenergic beta-Antagonists↗

PubMed1996

Effects of cantharidin on force of contraction and phosphatase activity in nonfailing and failing human hearts.

1. The effect of the phosphatase inhibitor, cantharidin (3-300 microM) on force of contraction was studied in isolated electrically driven right ventricular trabeculae carneae from human myocardium. 2. The positive inotropic effect of cantharidin started at a concentration of 100 microM with a positive inotropic effect to 199% and to 276% of the predrug value in nonfailing and failing human hearts, respectively. 3. Under basal conditions the contraction time parameters were prolonged in human heart failure vs. nonfailing preparations. However, the positive inotropic effect of cantharidin did not affect contraction time parameters. Thus, time to peak tension, time of relaxation and total contraction time were not shortened by cantharidin in nonfailing and failing preparations. 4. The phosphatase activity was unchanged in preparations from failing hearts compared to nonfailing hearts. 5. Cantharidin inhibited phosphatase activity in a concentration-dependent manner. The IC50 value of cantharidin was about 3 microM in both nonfailing and failing human myocardium. 6. The positive inotropic effect of cantharidin was similar in nonfailing and failing human hearts, accompanied by a similar inhibitory effect of cantharidin on the phosphatase activity. The positive inotropic effect of cantharidin in failing hearts was as strong as the effect of isoprenaline in nonfailing hearts. 7. It is concluded that the treatment with a phosphatase inhibitor may offer a new positive inotropic modality for the treatment of human heart failure.

Analysis of Variance↗