Increased myocardial cAMP in patients with transplant coronary vasculopathy.
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Adult↗
Biomedical subjects
W Schmitz
Publications and source records attributed to W Schmitz.
Regulation and possible functional implications of G-protein mRNA expression in nonfailing and failing ventricular myocardium.
In human end-stage heart failure an increased amount of inhibitory G-protein alpha-subunits (Gi alpha) is assumed to play a role in desensitization of the adenylyl cyclase signaling pathway. In the present study, northern blot experiments with 32P-labeled cDNA probes in ventricular tissue samples from explanted human hearts revealed that Gi alpha-2- and Gi alpha-3- mRNA are the predominant Gi alpha-mRNA subtypes in human ventricles, whereas Gi alpha-1-mRNA was not detectable. The mRNA for the stimulatory G-protein alpha-subunit (GS alpha) consisted of two mRNA sizes. Quantification of mRNA levels revealed a 103 +/- 38% increase in Gi alpha-2-mRNA levels in hearts with idiopathic dilative cardiomyopathy (IDC; n = 8), and a 77 +/- 25% increase in hearts with ischemic cardiomyopathy (ICM; n = 6) as compared to nonfailing controls (NF, n = 8). In contrast, Gi alpha-3- and GS alpha-mRNA levels were similar in failing and nonfailing hearts. To investigate whether or not the increased expression of Gi alpha-2-mRNA might be due to chronically elevated catecholamine levels, we determined the influence of a 4-day infusion of isoprenaline (Iso; 2.4 mg/kg.d), propranolol (Prop; 9.9 mg/kg.d), Iso + Prop or 0.9% NaCl as control (Ctr) on myocardial Gi alpha-mRNA and Gi alpha-protein levels in rats. In Iso-treated rats, hybridization experiments revealed a 49 +/- 18% (n = 7) and 27 +/- 7% (n = 8) increase in Gi alpha-2 and Gi alpha-3-mRNA, respectively. Pertussis toxin-catalyzed ADP-ribosylation revealed a 22 +/- 7% (n = 8) increase in Gi-protein as compared to Ctr (n = 8). These alterations were accompanied by an increased potency for the negative inotropic effect (NIE) of carbachol (mean EC50: 0.04 microM vs. 0.28 microM) in the presence of Iso in isolated electrically driven (1 Hz) papillary muscles. Prop itself had no effect, but it antagonized all Iso-induced effects. We conclude that, in human heart failure due to IDC or ICM, increased Gi alpha-2-, but not Gi alpha-3- mRNA levels accompany the increased amount of Gi alpha-protein, suggesting that this increase is at least in part due to increased de novo synthesis. The experiments in rats demonstrated that chronic beta-adrenergic stimulation leads to an increased expression of Gi alpha-mRNA and -protein, and to an enhanced potency of the negative inotropic effect of muscarinic agonists.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Phosphodiesterase inhibition and positive inotropy in failing human myocardium.
Positive inotropic effects of phosphodiesterase inhibitors like 3-isobutyl-1-methylxanthine (IBMX), pimobendan, adibendan, milrinone, saterinone, and enoximone are greatly diminished in isolated heart muscle preparations from human failing myocardium as compared to nonfailing myocardium. This is accompanied by a reduced increase in cAMP content in intact isometrically contracting human trabeculae. With anion exchange chromatography four peaks of phosphodiesterase activities (PDE I-IV) could be separated from both nonfailing and failing human myocardium. Substrate specificity, Km, and Vmax were similar in nonfailing and failing myocardium. Furthermore, the PDE inhibitors investigated exhibited similar IC50-values in both tissues, indicating that the sensitivity of the enzymes from nonfailing and failing tissue was unchanged. Thus, changes in PDE are probably not responsible for the reduced positive inotropic and cAMP-increasing effects of PDE inhibitors in human failing heart muscle preparations. Instead, an increase in signal transducing inhibitory G-proteins may keep the adenylyl cyclase at reduced activity, resulting in an attenuated formation of cAMP, even in the presence of PDE inhibitors.
Benzimidazoles↗
Isoprenaline-induced increase in the 40/41 kDa pertussis toxin substrates and functional consequences on contractile response in rat heart.
Chronic beta-adrenoceptor stimulation leads to desensitization of the myocardial adenylyl cyclase signalling pathway which includes beta-adrenoceptor downregulation and upregulation of Gi-protein alpha-subunits. However, these investigations have mainly been done in cellular preparations. In this study we report that isoprenaline infusion in vivo leads to an increase in myocardial Gi alpha and present evidence for functional consequences of this increase. Rats were treated by a 4-day subcutaneous infusion with isoprenaline (2.4 mg/kg.d), propranolol (9.9 mg/kg.d) and triiodothyronine (T3, 0.5 mg/kg.d) for comparison. Isoprenaline treatment increased the pertussis toxin-sensitive amount of Gi alpha by 22 +/- 6% and decreased beta 1- and beta 2-adrenoceptor density from 35 +/- 4 to 23 +/- 6 fmol/mg protein and 24 +/- 4 to 8 +/- 6 fmol/mg protein, respectively. Contraction experiments on electrically driven papillary muscles revealed that the negative inotropic potency of the M-cholinoceptor agonist carbachol in the presence of isoprenaline was increased as compared to control (mean EC50-values: 0.04 mumol/l vs. 0.28 mumol/l). All isoprenaline-induced effects were antagonized by simultaneously administered propranolol. T3 treatment had no influence on the parameters investigated. The results suggest that chronic beta-adrenoceptor stimulation desensitizes myocardial adenylyl cyclase by at least two mechanisms: beta-adrenoceptor downregulation leading to diminished signal transduction in the stimulatory pathway and Gi alpha upregulation leading to sensitization of the inhibitory pathway. Such adaptation might protect the heart from chronic exposure to catecholamines in heart diseases with elevated plasma catecholamine levels.
Adenosine Diphosphate Ribose↗
Regional distribution of beta 1- and beta 2-adrenoceptors in the failing and nonfailing human heart.
Total beta-adrenoceptor density and beta 1- and beta 2-subtype distribution in right and left atria and in different ventricular regions from 14 failing and seven nonfailing human hearts have been compared. End-stage heart failure was due to idiopathic dilated cardiomyopathy (n = 8) or ischaemic cardiomyopathy (n = 6). In nonfailing hearts the total beta-adrenoceptor density was similar in the right and left atria and in all the ventricular regions studied (about 70 to 80 fmol/mg protein). The beta 1:beta 2-adrenoceptor ratio in both nonfailing atria was similar (about 70:30%) and was significantly smaller than in the different regions of both ventricles (about 80:20%). The beta 1-subtype density was similar in nonfailing atria and ventricles (about 55 fmol/mg protein). The beta 2-subtype density was significantly higher in the right and left atrium (about 25 fmol/mg protein) than in both ventricles (about 15 fmol/mg protein). In patients with end-stage heart failure due to idiopathic dilated cardiomyopathy or ischaemic cardiomyopathy the total beta-adrenoceptor density was reduced by 50-60% in all regions. On the other hand, the beta 1- and beta 2-subtype distribution differed with the cause of heart failure. In patients with idiopathic dilated cardiomyopathy, the beta 1-adrenoceptor density was not significantly reduced. In patients with ischaemic cardiomyopathy both beta 1- and beta 2-adrenoceptors were reduced in all regions. It is concluded that downregulation of beta-adrenoceptors in patients with end-stage idiopathic dilated cardiomyopathy or ischaemic cardiomyopathy occurs uniformly throughout the heart. The results support the hypothesis that changes in beta-adrenoceptor subtypes may be related to the cause of heart failure.
Adult↗
Changes in cardiac beta 1- and beta 2-adrenoceptor densities after human cardiac transplantation: relation to transplant coronary vasculopathy and pretransplantation disease.
In 100 patients 12 to 60 months after cardiac transplantation, the influence of transplant coronary vasculopathy and of the pretransplantation disease (end-stage heart failure caused by coronary artery disease or dilated cardiomyopathy) on the beta-adrenergic receptor (AR) numbers and beta 1/beta 2-AR ratio of right ventricular biopsies was determined. Patients with coronary vasculopathy (CVP) after cardiac transplantation had lower absolute numbers of beta 1-AR compared with patients without CVP. Since patients with CVP had increased left ventricular (LV) end-diastolic pressure and LV muscle mass, it is suggested that decreased beta 1-AR may be the result of an altered hemodynamic situation of the transplanted heart after development of CVP. Patients with dilated cardiomyopathy (DCM) before cardiac transplantation showed a decrease in total beta-AR and of the beta 1/beta 2-AR ratio as a result of an increase in beta 2-AR and a decrease in beta 1-AR numbers. The decreased beta 1/beta 2-AR ratio in patients with previous DCM may indicate that the beta-AR system of the transplanted heart might be influenced (at least in part) by pathophysiologic factors that are characteristic of the pretransplantation disease ultimately leading to cardiac transplantation and persisting after cardiac transplantation.
Adult↗
Decrease in beta 1- and increase in beta 2-adrenoceptors in long-term follow-up after orthotopic cardiac transplantation.
Total beta 1- and beta 2- subtype distribution were examined in right ventricular biopsies taken from 100 patients 1-60 months after orthotopic cardiac transplantation and from eight prospective transplant donor hearts serving as controls. The patients were classified into eight groups depending on the time after transplantation that the biopsies were taken: 1-3 (n = 15), 4-7 (n = 15), 8-11 (n = 6), 12 (n = 15), 24 (n = 15), 36 (n = 12), 48 (n = 12) and 60 months (n = 10). The non-selective beta-adrenoceptor antagonist (-)-[125I]-iodocyanopindolol (ICYP) was used as a radioligand to assess total beta-adrenoceptor density. The beta 1- and beta 2-subtype distribution was determined with a beta 1-adrenoceptor saturating concentration of the selective beta 1-adrenoceptor antagonist CGP 20712A (300 nmol/l). In transplant donor hearts the total beta-adrenoceptor density was found to be 70.8 +/- 7.1 fmol/mg protein including a beta 1:beta 2-adrenoceptor ratio of about 80:20%. Until 36 months after cardiac transplantation the total number of beta-adrenoceptors showed no significant change. A slight but insignificant decrease was observed after 48 (16.2%) and 60 (21.2%) months. In contrast, from 12 to 60 months after cardiac transplantation the beta 1:beta 2-adrenoceptor ratio was shifted significantly (66:33% to 61:39%) as compared with transplant donor hearts which was due to an increase in beta 2- and a decrease in beta 1-adrenoceptor number. Thus, the surgically denervated, transplanted human heart exhibits a beta 2-adrenoceptor up-regulation during long-term follow-up. It is suggested that this up-regulation of the beta 2-adrenoceptor subtype could be owing to an increased importance of circulating catecholamines in modulating positive chronotropic and inotropic effects.
Adult↗
Beta-adrenergic receptor number in surgically denervated, transplanted human hearts.
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Adult↗
Rearrangements of the upstream regulatory region of human papillomavirus type 6 can be found in both Buschke-Löwenstein tumours and in condylomata acuminata.
Clinically malignant Buschke-Löwenstein tumours and benign condylomata acuminata are caused by human papillomaviruses (HPVs), predominantly HPV-6 and -11. In some cases, the HPV-6 genomes found in Buschke-Löwenstein tumours and in verrucous carcinomas differ from HPV-6b isolated from a benign genital wart, by rearrangements of the upstream regulatory region (URR). To evaluate the frequency and role of mutations of the URR of HPV-6 we analysed 42 condylomata acuminata and four Buschke-Löwenstein tumours by the polymerase chain reaction and restriction enzyme cleavage. Using only four different restriction enzymes we could demonstrate four distinct restriction patterns, indicating that naturally occurring HPV-6 isolates display a high degree of DNA polymorphism within the URR. One Buschke-Löwenstein tumour and two condylomata acuminata yielded rearranged URRs with DNA duplications. All three lesions harboured multiple HPV-6 variants, suggesting that cellular or environmental factors facilitate the development of rearrangements. Therefore, rearrangements of the URR may represent only secondary events in condylomata acuminata and Buschke-Löwenstein tumours which do not necessarily confer a higher malignant potential to the infected cell.
Base Sequence↗
Reduced alpha 1- and beta 2-adrenoceptor-mediated positive inotropic effects in human end-stage heart failure.
1. alpha 1-Adrenoceptor (phenylephrine in the presence of propranolol) and beta 2-adrenoceptor (fenoterol)-mediated positive inotropic effects were investigated in human ventricular preparations isolated from five non-failing (prospective organ donors) and from eight explanted failing hearts with end-stage idiopathic dilative cardiomyopathy (NYHA IV). 2. For comparison, the nonselective beta-adrenoceptor agonist isoprenaline, the phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX), the cardiac glycoside dihydroouabain, and calcium were studied. 3. Furthermore, the influence of IBMX on adenosine 3':5'-cyclic monophosphate (cyclic AMP) PDE activity as well as total beta-adrenoceptor density, beta 1- and beta 2-adrenoceptor subtype distribution, and alpha 1-adrenoceptor density were compared in nonfailing and failing human heart preparations. The radioligands (-)-[125I]-iodocyanopindolol for beta-adrenoceptor binding and [3H]-prazosin for alpha 1-adrenoceptor binding were used. 4. The inotropic responses to calcium and dihydroouabain in failing human hearts were unchanged, whereas the maximal alpha 1- and beta 2-adrenoceptor-mediated positive inotropic effects were greatly reduced. The inotropic effects of the other cyclic AMP increasing compounds, i.e. isoprenaline and IBMX, were also reduced to about 60% of the effects observed in nonfailing controls. The potency of these compounds was decreased by factors 4-10. 5. The basal PDE activity and the PDE inhibition by IBMX were similar in nonfailing and failing preparations. 6. The total beta-adrenoceptor density in nonfailing hearts was about 70 fmol mg-1 protein. In failing hearts the total number of beta-adrenoceptors was markedly reduced by about 60%. The betal/beta2-adrenoceptor ratio was shifted from about 80/20% in nonfailing to approximately 60/40% in failing hearts which was due to a selective reduction of beta1-adrenoceptors. The beta2-adrenoceptor population remaining unchanged. alpha-Adrenoceptor density was increased from about 4 fmol mg-' protein in nonfailing to 10 fmol mgprotein in failing hearts.7. Changes in PDE activity and adrenoceptor downregulation cannot completely explain the reduced positive inotropic effects of alpha 1- and beta 2-adrenoceptor agonists in failing human hearts. This supports the hypothesis that impairment of other processes such as the coupling between receptor and effector system, i.e. the respective G-proteins, are equally important in end-stage heart failure.
3',5'-Cyclic-AMP Phosphodiesterases↗
Phosphodiesterase inhibition in ventricular cardiomyocytes from guinea-pig hearts.
1. The present study compared the cyclic nucleotide phosphodiesterase (PDE) activities in cardiomyocytes and ventricular cardiac tissue from guinea-pigs. The aim of the study was to determine whether PDE activities in ventricular tissue accurately reflect the isoenzymes present in cardiomyocytes. 2. In homogenates of cardiomyocytes and multicellular ventricular tissue, four distinct soluble PDE activities could be separated by DEAE-sepharose chromatography. 3. In multicellular cardiac tissue as well as in cardiomyocyte preparations, adenosine 3':5'-cyclic monophosphate (cyclic AMP) PDE isoenzymes I-IV were comparable in terms of substrate affinities, and inhibition or stimulation by guanosine 3':5'-cyclic monophosphate (cyclic GMP). However, in cardiomyocytes the Vmax values of PDE I-IV were lower by a factor of about 2 to 7 and the basal activities were lower by a factor of about 3 to 5 as compared to multicellular cardiac tissue. 4. To investigate whether the PDE I-IV activities were similarly inhibited by PDE inhibitors in both preparations, we studied the effects of 3-isobutyl-1-methylxanthine (IBMX), UD-CG 212 Cl (2-(4-hydroxy-phenyl)-5-(5-methyl-3-oxo-4, 5-dihydro-2H-6-pyridazinyl)benzimidazole HCl) and rolipram. UD-CG 212 Cl was a selective PDE III inhibitor in cardiomyocytes (IC50 0.3 mumol l-1) and in ventricular tissue (IC50 value 0.1 mumol l-1). Rolipram selectively inhibited PDE IV in cardiomyocytes (IC50 1.4 mumol ml-1) and in ventricular tissue (IC50 1.1 mumol l-1) whereas IBMX was a nonselective PDE inhibitor in both preparations.5. It is concluded that the PDE isoenzymes I-IV from multicellular ventricular tissue can be used as a representative system for investigating PDE inhibiting properties of PDE inhibitors in the myocardium since comparable PDE isoenzymes I-IV exist in guinea-pig ventricular cardiomyocytes and multicellular ventricular tissue.
1-Methyl-3-isobutylxanthine↗
Cardiac alpha 1-adrenoceptor densities in different mammalian species.
1. alpha 1-Adrenoceptor densities were studied in cardiac membrane preparations from several mammalian species including human failing hearts under identical experiment conditions; the alpha 1-adrenoceptor antagonist, [3H]-prazosin, was used as radioligand. End-stage heart failure (NYHA IV) in human hearts was due to idiopathic dilated cardiomyopathy. 2. The ventricular alpha 1-adrenoceptor densities were not significantly different in guinea-pig, mouse, pig, calf, and man (11 to 18 fmol mg-1 protein) but about 5 to 8 fold smaller than in rat (about 90 fmol mg-1 protein). Right and left ventricular receptor densities were similar in these species. 3. A sufficient amount of right and left atrial tissue was obtained from rabbit, pig, calf, and man only. The alpha 1-adrenoceptor densities in both atria of these species were found to be at the detection limit of the method used (less than 8 fmol mg-1 protein). 4. The equilibrium dissociation constant (KD) was similar in all species studied ranging from 0.047 +/- 0.006 to 0.063 +/- 0.007 nmol l-1. 5. It is concluded that differences in alpha 1-adrenoceptor density between atria and ventricles may exist in mammalian species. The exceptionally high density of these receptors in rat ventricles seem to be a particular feature in these animals.
Animals↗
Increased messenger RNA level of the inhibitory G protein alpha subunit Gi alpha-2 in human end-stage heart failure.
In human heart failure the positive inotropic and cAMP-elevating effects of both beta-adrenoceptor agonists and phosphodiesterase inhibitors are diminished. This has been explained at least in part by an increase in the inhibitory signal-transducing G protein (Gi) and unchanged stimulatory G protein (Gs). In the present study we determined the mRNA expression pattern of the alpha subunits of Gi-1, Gi-2, Gi-3, and Gs in myocardial tissue samples of patients undergoing heart transplantation. Northern blot analysis of total RNA extracted from left ventricles with 32P-labeled cDNAs demonstrated expression of Gi alpha-2, Gi alpha-3, and Gs alpha mRNA. In contrast, Gi alpha-1 mRNA was not detectable. To investigate whether the increased ratio of Gi/Gs might be due to altered gene expression, we compared mRNA levels of Gi alpha-2, Gi alpha-3, and Gs alpha in left ventricular myocardium from failing hearts with idiopathic dilated cardiomyopathy (n = 8) and ischemic cardiomyopathy (n = 6) and from nonfailing hearts from transplant donors (n = 8). Compared with nonfailing control hearts, the Gi alpha-2 mRNA was increased by 75 +/- 26% (p less than 0.05) in idiopathic dilated cardiomyopathy hearts and 90 +/- 26% (p less than 0.05) in ischemic cardiomyopathy hearts. Gi alpha-3 and Gs alpha mRNA levels were similar in the three groups. The results suggest that as in other mammalian species, Gi alpha-2 and Gi alpha-3 mRNA are the predominant Gi alpha mRNA subtypes in human ventricular myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
[Changes in gene expression in terminal myocardial failure].
End-stage human heart failure is the common final manifestation of a group of heterogeneous diseases, and it is usually accompanied by myocardial hypertrophy. Studies on animal models have shown that myocardial hypertrophy is an adaptational process accompanied by characteristic changes in the expression of cardiac genes: reinduction of fetal isoforms of the myofilaments actin and myosin, downregulation of SR Ca(2+)-ATPase and phospholamban, downregulation of beta-adrenoceptors and increased expression of inhibitory G proteins (Gi). These alterations lead to reduced shortening velocity, slowed relaxation, and to desensitization of adenylyl cyclase, thereby probably increasing myocardial economy and lowering energy demand. Gene expression in human end-stage heart failure due to dilated cardiomyopathy exhibits some clear differences, but also significant parallels to gene expression in experimental hypertrophy: there is no isoform shift because fetal isoforms of the myofilaments are already predominant in the adult ventricle. However, like in animal models expression of SR Ca(2+)-ATPase and phospholamban is decreased, correlating with slowed relaxation of the diseased myocardium, beta-adrenoceptors are downregulated, and the expression of Gi is increased, leading to desensitization of the adenylyl cyclase pathway. These results suggest that alterations of gene expression in human end-stage myocardial failure, known so far, are secondary to chronic overload and are not a primary cause in the pathogenetic process. They are probably initially favorable adaptive processes to chronic overload, but finally cause a further deterioration of contractile performance of the myocardium.
Animals↗
Existence and alpha 1-adrenergic stimulation of inositol polyphosphates in mammalian heart.
The concentration-response curves and the time course of the effects of phenylephrine (0.01-100 microM) on force of contraction and on inositol polyphosphates in isolated electrically stimulated perfused rat hearts (Langendorff technique) were studied. A nonradiometric high performance liquid chromatography metal dye detection technique was used to determine absolute concentration masses/changes of inositol polyphosphates in heart. Products measured after separation with high performance liquid chromatography were inositol 1,4,5-trisphosphate (1,4,5-IP3), inositol 1,3,4,5-tetrakisphosphate (1,3,4,5-IP4) and its isomer 1,3,4,6-IP4, inositol 1,3,4,5,6-pentakisphosphate (1,3,4,5,6-IP5), and inositol hexakisphosphate (IP6). 1,4,5-IP3 (significant at 10 microM) and both IP4 isomers (significant at 1 microM) increased after alpha-adrenoceptor stimulation, whereas 1,3,4,5,6-IP5 and IP6 remained unaffected. Phenylephrine had a concentration-dependent positive inotropic effect (significant at 1 microM). All effects were antagonized by the alpha 1-adrenoceptor antagonist prazosin (0.1 microM), indicating receptor-mediated effects. In a time course study 1,4,5-IP3 was the first compound to increase significantly, within 1 min after stimulation; this rise was followed by an increase in 1,3,4,5-IP4 beginning within 2 min. The increase in all other inositol polyphosphates was slower (5-10 min). The increase in the force of contraction started at 2 min. For comparison, the effects of the beta-adrenoceptor agonist isoprenaline were studied. Isoprenaline produced a positive inotropic effect similar to that of phenylephrine, but all inositol polyphosphates remained unaffected. In conclusion, for the first time the existence of 1,3,4,5,6-IP5 and IP6 was observed in the heart. However, the physiological role of these inositol polyphosphate isomers in the heart remains to be elucidated, because, from the time course, they appear to have no acute intracellular second messenger function. Increased inositol polyphosphate turnover may be involved in the mechanism(s) whereby alpha 1-adrenoceptor stimulation produces an increase in myocardial force of contraction. Because the increase in 1,4,5-IP3 precedes and that in 1,3,4,5-IP4 coincides with the increase in the force of contraction, 1,4,5-IP3 may initiate and 1,3,4,5-IP4 may maintain the positive inotropic effect of alpha 1-adrenoceptor agonists.
Animals↗
Long term beta-adrenoceptor-mediated up-regulation of Gi alpha and G(o) alpha mRNA levels and pertussis toxin-sensitive guanine nucleotide-binding proteins in rat heart.
Chronic stimulation of beta-adrenoceptors leads to increased mRNA and protein levels of pertussis toxin (PTX)-sensitive guanine nucleotide-binding proteins (G proteins) in the heart. In the present study the time course is reported of the effect of isoprenaline infusions on myocardial mRNA levels of Gi alpha-2, Gi alpha-3, G(o) alpha, Gs alpha, and G beta and myocardial levels of PTX-sensitive G proteins. Rats were treated by subcutaneous infusions, with osmotic minipumps, of 0.9% NaCl, isoprenaline (2.4 mg/kg/day), propranolol (9.9 mg/kg/day), or a combination thereof for 1, 2, 3, 4, or 8 days, and two groups were treated with NaCl or isoprenaline for 13 or 26 days. Additional groups of rats were treated with 0.24 or 0.07 mg/kg/day for 4 days to determine the dose dependency of the effects of isoprenaline. mRNA concentrations were determined by standardized slot blotting with 32P-labeled cDNA or cRNA probes. In isoprenaline-treated rats, mRNA levels of all members of the Gi alpha/G(o) alpha family increased gradually in parallel. The increase in Gi alpha-2, Gi alpha-3, and G(o) alpha mRNA levels reached significance on days 2-3, reached maximal values on days 3-4, and remained stable over the total time of treatment of up to 26 days. Compared with NaCl, maximal increases were 77% (Gi alpha-2; 16.4 versus 9.3 pg/micrograms), 58% (Gi alpha-3; 4.65 versus 2.95 pg/micrograms), and 78% (G(o) alpha; 0.40 versus 0.22 pg/microgram). Gs alpha mRNA levels (about 30 pg/micrograms) and G beta mRNA levels remained unchanged. In isoprenaline-treated rats myocardial levels of PTX-sensitive G proteins increased by maximally 54%, compared with control. The time course differed slightly from the time course of mRNA up-regulation in the first 3 days of treatment and paralleled the increase in mRNA levels from day 4 on. Propranolol had no effect on G alpha mRNA or protein levels when given alone but abolished all effects of isoprenaline when given in combination. Isoprenaline at a dose of 0.24 mg/kg/day still induced an increase in Gi alpha-2 mRNA levels of 24%, without any effects on histopathology of the myocardium.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Inositol-1,4,5-trisphosphate and malignant hyperthermia.
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Humans↗
Mechanism underlying the reduced positive inotropic effects of the phosphodiesterase III inhibitors pimobendan, adibendan and saterinone in failing as compared to nonfailing human cardiac muscle preparations.
The present study was performed to compare the effects of the new positive inotropic phosphodiesterase III inhibitors pimobendan, adibendan, and saterinone on the isometric force of contraction in electrically driven ventricular trabeculae carneae isolated from explanted failing (end-stage myocardial failure) with those from nonfailing (prospective organ donors) human hearts. In preparations from nonfailing hearts the phosphodiesterase inhibitors, as well as the beta-adrenoceptor agonist isoprenaline, the cardiac glycoside dihydro-ouabain, and calcium, which were studied for comparison, revealed pronounced positive inotropic effects. The maximal effects of pimobendan, adibendan, and saterinone amounted to 56%, 36% and 45%, respectively, of the maximal effect of calcium. In contrast, in preparations from failing hearts the phosphodiesterase III inhibitors failed to significantly increase the force of contraction and the effect of isoprenaline was markedly reduced. The effects of dihydroouabain and calcium were almost unaltered. The diminished effects of isoprenaline were restored by the concomitant application of phosphodiesterase inhibitors. To elucidate the underlying mechanism of the lack of effect of the phosphodiesterase III inhibitors in the failing heart we also investigated the inhibitory effects of these compounds on the activities of the phosphodiesterase isoenzymes I-III separated by DEAE-cellulose chromatography from both kinds of myocardial tissue. Furthermore, the effects of pimobendan and isoprenaline on the content of cyclic adenosine monophosphate (determined by radioimmunoassays) of intact contracting trabeculae were studied. The lack of effect of the phosphodiesterase inhibitors in failing human hearts could not be explained by an altered phosphodiesterase inhibition, since the properties of the phosphodiesterase isoenzymes I-III and also the inhibitory effects of the phosphodiesterase inhibitors on these isoenzymes did not differ between failing and nonfailing human myocardial tissue. Instead, it may be due to a diminished formation of cyclic adenosine monophosphate in failing hearts, presumably caused mainly by a defect in receptor-adenylate cyclase coupling at least in idiopathic dilated cardiomyopathy. Both the basal and the pimobendan-stimulated or isoprenaline-stimulated contents of cyclic adenosine monophosphate of intact contracting trabeculae from failing hearts were decreased compared with the levels in nonfailing hearts. However, under the combined action of isoprenaline and pimobendan the cyclic adenosine monophosphate level reached values as high as with each compound alone in nonfailing preparations, and in addition the positive inotropic effect of isoprenaline was restored. These findings may have important clinical implications. Along with the elevated levels of circulating catecholamines the positive inotropic effects of the phosphodiesterase inhibitors may be maintained in patients with heart failure.(ABSTRACT TRUNCATED AT 400 WORDS)
1-Methyl-3-isobutylxanthine↗