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H von der Leyen

Publications and source records attributed to H von der Leyen.

At least 19 recordsLinked to original sources
PubMed1996

Induction of nitric oxide synthase in the human cardiac allograft is associated with contractile dysfunction of the left ventricle.

BACKGROUND: The mechanisms underlying cardiac contractile dysfunction after transplantation remain poorly defined. Previous work has revealed that inducible nitric oxide synthase (iNOS) is expressed in the rat heterotopic cardiac allograft during rejection; resultant overproduction of nitric oxide (NO) might cause cardiac contractile dysfunction via the negative inotropic and cytotoxic actions of NO. In this investigation, we tested the hypothesis that induction of iNOS may occur and be associated with cardiac allograft contractile dysfunction in humans. METHODS AND RESULTS: We prospectively studied 16 patients in the first year after cardiac transplantation at the time of serial surveillance endomyocardial biopsy. Clinical data, the results of biopsy histology, and echocardiographic and Doppler evaluation of left ventricular systolic and diastolic function were recorded. Total RNA was extracted from biopsy specimens, and mRNA for beta-actin, detected by reverse transcription-polymerase chain reaction (RT-PCR) using human specific primers, was used as a constitutive gene control; iNOS mRNA was similarly detected by RT-PCR using human specific primers. iNOS protein was detected in biopsy frozen sections by immunofluorescence. Myocardial cGMP was measured by radioimmunoassay, and serum nitrogen oxide levels (NOx = NO2 + NO3) were measured by chemiluminescence. iNOS mRNA was detected in allograft myocardium at some point in each patient and in 59 of 123 biopsies (48%) overall. In individual patients, iNOS mRNA expression was episodic and time dependent; the frequency of expression was highest during the first 180 days after transplant (P = .0006). iNOS protein associated with iNOS mRNA was detected by immunofluorescence in cardiac myocytes. iNOS mRNA expression was not related to the ISHLT histological grade of rejection or to serum levels of NOx but was associated with increased levels of myocardial cGMP (P = .01) and with both systolic (P = .024) and diastolic (P = .006) left ventricular contractile dysfunction measured by echocardiography and Doppler. CONCLUSIONS: These data support a relation between iNOS mRNA expression and contractile dysfunction in the human cardiac allograft.

Adolescent↗
PubMed1995

Usefulness of increased myocardial cyclic adenosine 3',5'-monophosphate content as a sign of rejection after cardiac transplantation.

Cardiac allograft rejection represents a series of cellular and molecular events triggered by the recognition of the graft by the host immune system. One of the second messenger systems involved in mitogenic mechanisms is the cyclic adenosine 3',5'-monophosphate (cAMP)-coupled signaling system. The aim of this preliminary study was to evaluate whether rejection after cardiac transplantation is accompanied by changes in the expression of cAMP. Myocardial cAMP content was determined by radioimmunoassay in endomyocardial biopsy specimens taken during routine follow-up after cardiac transplantation with or without cellular and/or vascular (i.e., coronary vasculopathy) rejection, respectively. Analysis of the different subgroups of patients showed that patients without any signs of rejection (no vasculopathy, no cellular rejection) had the lowest myocardial cAMP content (1.41 +/- 0.12 pmol/mg wet weight). Patients with either cellular or vascular rejection had significantly higher myocardial cAMP levels (2.25 +/- 0.29 and 2.24 +/- 0.59 pmol/mg wet weight, respectively, p < 0.05). Patients with both cellular rejection and coronary vasculopathy had the highest cAMP levels (5.95 +/- 1.6 pmol/mg wet weight; p < 0.001). We speculate that cAMP may play a functional role in mediating rejection induced by mitogenic factors activated after cardiac transplantation, suggesting a possible "cross-talk" between different cellular signaling pathways.

Adult↗
PubMed1994

Intimal hyperplasia after vascular injury is inhibited by antisense cdk 2 kinase oligonucleotides.

The cell cycle regulatory enzyme, cdk (cyclin-dependent kinase) 2 kinase, is activated in the rat carotid artery after balloon angioplasty injury, and may mediate smooth muscle proliferation. To test the hypothesis that inhibition of the expression of this key enzyme can inhibit intimal hyperplasia, we studied the effect of antisense phosphorothioate oligodeoxynucleotides (ODN) against cdk 2 kinase administered by intraluminal delivery using hemagglutinating virus of Japan (HVJ)-liposome-mediated transfer. The specificity of antisense cdk 2 ODN was confirmed by the observation that mRNA level of cdk 2 kinase in injured vessels was markedly diminished by the antisense ODN treatment. At 2 wk after transfection, antisense cdk 2 ODN treatment (15 microM) resulted in a significant inhibition (60%) in neointima formation, compared with sense ODN-treated and untreated vessels. Since we have previously observed that cell division cycle 2 kinase mRNA was also activated after vascular injury, we administered the combination of antisense cdc 2 and cdk 2 ODN in this study. Antisense cdc 2 ODN alone (15 microM) only reduced intimal formation by 40%. Combined antisense treatment resulted in near complete inhibition of neointima formation. To understand the mechanism of the sustained effect of a single antisense ODN administration, we examined kinetics of ODN in the vessel wall. Using phosphorothioate FITC-labeled ODN, we transfected carotid artery using the HVJ-liposome method. Fluorescence localized immediately to the medial layer, and persisted up to 2 wk after transfection. These results demonstrate that a single intraluminal administration of antisense ODN directed to cell cycle regulatory genes (e.g., cdk 2 kinase) using the HVJ method can result in a sustained inhibition of neointima formation after balloon angioplasty in rat carotid injury model.

Angioplasty, Balloon↗
PubMed1993

[Multivariate analysis of prognostically significant parameters in acute transmural myocardial infarct].

The clinical data of 722 patients admitted for acute myocardial infarction to the coronary care unit of the Hannover Medical School were retrospectively analyzed. Six hundred patients survived through the fifth day of their hospital stay. We evaluated 142 variables from each patient, i.e., previous cardiac manifestations, drug-history, acute complications, laboratory data, intensive care treatment and the 1-year outcome. One-hundred-sixty-nine patients underwent cardiac catheterization before being discharged from the hospital. Thirty-two variables showed to be predictive of 1-year survival in the univariate analysis, although performance of logistic regression analysis revealed only seven parameters to be independent predictors: age (p < 0.0001), glycoside intake before infarction (p = 0.0317), acute heart failure (p = 0.0005), late (occurring after 48 h) ventricular tachycardia or fibrillation (p = 0.0003), maximum of serum creatine phosphokinase (p = 0.0129), new onset of atrial fibrillation (p = 0.0116), and use of dobutamine during intensive care stay (p = 0.0014). With this combination of clinical variables alone, using a survival probability partition value of 50%, the model had a sensitivity of 39% and a specificity of 96%, respectively, 84% overall correct classification. Predictive accuracy for death was 71%, compared to a predictive accuracy for survival of 85%. Diagnostic procedures performed after infarction were highly predictive in the individual case, but they could not improve accuracy of the statistical model. These data emphasize the importance of multivariate methods to find suitable predictors for outcome after acute myocardial infarction.

Adult↗
PubMed1992

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↗
PubMed1992

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↗
PubMed1992

Enoximone, a post-operative inodilator in patients following mitral valve operation: a prospective and controlled study.

Inotropic support is often required for post-operative management of patients following mitral valve operation. The use of positive inotropes is limited by tolerance development and increase in myocardial oxygen demand. We have compared i.v. enoximone (E) (group E, n = 13), a recently developed phosphodiesterase (PDE) inhibitor, to the conventional i.v. therapeutics dopamine (D) and glyceroltrinitrate (G) in patients following mitral valve operation. The two groups were comparable in terms of physical and pre-operative haemodynamic data. Haemodynamic measurements including cardiac index (CI) determinations were recorded for the first 18 h post surgery in both groups. Group E received a bolus of 1 mg.kg-1 E followed by 4-20 micrograms.kg-1.min-1 (mean = 5 +/- 2 micrograms.kg-1.min-1) for 14 h according to therapeutic requirements, while group D received dopamine (4-10 micrograms.kg-1.min-1, mean = 3.8 +/- 1.9 micrograms.kg-1.min-1) and glyceroltrinitrate (0.5-5 micrograms.kg-1.min-1; mean = 4 +/- 2 micrograms.kg-1.min-1). Adrenaline was added if the MAP was below 60 mmHg or the CI was below 2.5 in both groups (range 50-500 ng.kg-1.min-1; mean E = 0.7 +/- 2 ng.kg-1.min-1; mean D = 2 +/- 2.8 ng.kg-1.min-1). Bolus injection of E resulted in a rise in CI from 2.6 to 3.21.min-1.m-2 (P less than 0.05) within 30 min, followed by a further rise to a maximum of 3.51.min-1.m-2 6 h post bolus. Termination of the E drip resulted in a drop of CI to baseline values (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Comparison of enoximone and piroximone in patients after mitral valve operation: a prospective and controlled clinical study.

Phosphodiesterase III (PDEII) inhibitors as so-called inodilators have previously proven a valuable alternative to positive inotropes in patients with cardiac insufficiency. In this study we compared patients receiving piroximone (P, n = 14, 0.5-mg/kg bolus in 30 min and then 3-6 micrograms/kg/min) with enoximone patients (E, n = 13, 1-mg/kg bolus and then 4-20 micrograms/kg/min) and with a third group (D, n = 14) receiving a combination of dopamine (4-10 micrograms/kg/min) and glyceroltrinitrate (0.5-5 micrograms/kg/min) for hemodynamic support. All three groups were comparable in terms of age, body surface area, and preoperative cardiac function [cardiac index (CI) less than or equal to 2.5 L/min/m2, LAP greater than 15 mm Hg]. Hemodynamic measurements (10) and Holter monitoring were performed until 18 h post MVR. In all groups, epinephrine was used for additional inotropic therapy if mean arterial pressure (MAP) was less than 60 mm Hg and/or CI was less than 2.5 L/min/m2. There was no early or late postoperative mortality in either group. Continuous support with epinephrine was necessary in 8 patients in group D, whereas initially 8 patients in group E and 6 patients in group P required epinephrine support. After PDE III inhibitor infusion, 2 patients in group E and 2 patients in group P remained epinephrine dependent (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

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↗
PubMed1992

Phosphodiesterase inhibition by enoximone in preparations from nonfailing and failing human hearts.

The effects of enoximone (MDL 17043, Perfan, CAS 77671-31-9) on the activities of the phosphodiesterase (PDE) isoenzymes I-IV and on force of contraction were investigated in ventricular preparations isolated from failing (end-stage myocardial failure, NYHA IV) and non-failing human hearts. In both tissues four PDE isoenzymes (PDE I-IV) with similar properties were separated by DEAE-sepharose chromatography. The effects of enoximone on PDE I-IV activities did not differ between non-failing and failing human hearts. As compared to PDE I (IC50 2100 mumol/l) and II (IC50 2900 mumol/l) enoximone is a selective PDE III (cGMP-inhibited PDE, IC50 5.9 mumol/l) and PDE IV (cGMP-insensitive PDE, IC50 21.1 mumol/l) inhibitor. Milrinone, 3-isobutyl-1-methylxanthine (IBMX) and UD-CG 212 Cl, a derivative of pimobendan, were studied in the failing heart for comparison. Milrinone inhibited PDE I-IV activities similar to enoximone, revealing IC50 values for inhibition of PDE III and IV (1.2 and 3.3 mumol/l) which were about two orders of magnitude lower than that of PDE I and II (173 and 306 mumol/l). UD-CG 212 Cl was the most potent (IC50 0.05 mumol/l) and most selective PDE III inhibitor tested (IC50 for PDE I, II and IV were 175, 181 and 40.8 mumol/l, resp.), whereas IBMX inhibited PDE I-IV nonselectively (IC50 15.3, 26.2, 5.6, 5.8 mumol/l, respectively). In trabeculae carneae from nonfailing and failing human hearts enoximone increased force of contraction only marginally by 18.0 +/- 9.1% (n = 8) and 24.5 +/- 8.7% (n = 9) of the predrug value.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

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↗
PubMed1991

Effects of isomazole on force of contraction and phosphodiesterase isoenzymes I-IV in nonfailing and failing human hearts.

The phosphodiesterase (PDE) inhibitor isomazole increased the force of contraction to 278.3 +/- 89.1% (n = 7) of the predrug value in ventricular trabeculae carneae isolated from nonfailing human hearts. This effect can be attributed mainly to a PDE III or a combined PDE III/IV inhibition since at the concentration of the maximal positive inotropic effect of isomazole, PDE III and PDE IV were completely inhibited. In explanted failing human hearts (end-stage myocardial failure, NYHA IV), isomazole increased the force of contraction only marginally to 110.1 +/- 10.7% of the predrug value. The lack of a distinct positive inotropic efficacy of isomazole in failing human hearts could not be explained by an impairment of PDE inhibition since the properties of the PDE I-IV isoenzymes separated by DEAE-Sepharose chromatography and the inhibitory effects of isomazole did not differ in both preparations. The positive inotropic effect of the beta-adrenoceptor agonist isoprenaline was also reduced in failing hearts. However, in the presence of isomazole, the diminished positive inotropic effect of isoprenaline was restored to values obtained with isoprenaline alone in nonfailing hearts. Thus, the decreased effect of inotropic drugs like isoprenaline or isomazole in preparations from failing human heart might be explained mainly by a diminished cAMP formation due to a defect in receptor-adenylate cyclase coupling.

Adult↗
PubMed1990

[Acute anterior wall infarct with intractable ventricular fibrillation: successful therapy by recanalization of a left anterior descending coronary artery occlusion].

A 35-year-old male patient was admitted to the intensive care unit of a community hospital with an acute anterior myocardial infarction complicated by initial recurrent episodes of ventricular fibrillation and successful resuscitation. Persistent malignant ventricular arrhythmias during the following days necessitated external defibrillation approximately 250 times. The patient was transferred to the Hannover Medical School, where the occluded left anterior descending coronary artery was successfully recanalized. Eight days later, the malignant ventricular tachyarrhythmias ceased and after 59 days of hospitalization the patient could be discharged in stable condition.

Adult↗
PubMed1989

Phosphodiesterase inhibition by new cardiotonic agents: mechanism of action and possible clinical relevance in the therapy of congestive heart failure.

Cyclic AMP is known as a secondary messenger regulating the myocardial force of contraction. For the degradation of cAMP multiple forms of PDE within the cell are described, which vary according to substrate specificity, kinetic characterization, and cellular localization. One of these isoenzymes, the low Km cAMP-specific PDE (PDE III), which seems to be closely related to cardiotonic effects of PDE inhibitors, exists either in a particulate form (in dogs), probably associated with the sarcoplasmic reticulum, or in soluble form (in guinea pig). The existence of different forms of PDE III possibly reflects a different pooling or compartmentalization of cAMP. Many agents selectively inhibiting PDE III are described which potently increase the force of contraction and which exert vasodilatory effects. Besides PDE inhibition some of these agents possess additional cAMP-independent actions, e.g., sensitization of the contractile proteins to Ca2+, prolongation of the action potential, or prolongation of the open state of the Na+-channel. Since agents which nonselectively inhibit PDE are known as potent positive inotropic agents (e.g., IBMX), PDE III inhibition itself, but not a selectivity for PDE III inhibition, seems to be a prerequisite for this mechanism of action of cardiotonic drugs. Investigations with preparations from diseased human myocardium show that the beta-adrenoceptor agonist isoprenaline as well as the PDE inhibitor IBMX increase the force of contraction to only about one-third of the maximal effect of the cardiac glycoside dihydro-ouabain or Ca2+. In nonfailing human heart preparations all agents had equal activity. Possible reasons for these differences may be a decreased responsiveness to beta-adrenoceptor stimulation (beta-receptor down-regulation) or an inappropriate increase in cAMP levels due to increased activity of inhibitory Gi-proteins with resulting decrease of adenylate cyclase activity in the failing heart. Besides a short-term clinical and hemodynamic improvement of congestive heart failure, uncontrolled long-term administration of PDE III-inhibitor agents failed to produce sustained clinical benefit and had no effect on survival. Controlled long-term studies with new cardiotonic agents in patients with severe CHF are still lacking.

Cardiotonic Agents↗
PubMed1989

Effects of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a highly selective adenosine receptor antagonist, on force of contraction in guinea-pig atrial and ventricular cardiac preparations.

The effects of the A1 adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) on force of contraction were examined in isolated electrically driven auricles and papillary muscles from guinea-pigs in the absence and presence of (-)-N6-phenylisopropyladenosine (PIA) and 5'-N-ethylcarboxamidadenosine (NECA). In auricles DPCPX (30-1000 mmol/l) alone increased force of contraction. DPCPX produced only a minor inhibition of phosphodiesterase I-III activity. PIA and NECA alone exerted concentration-dependent negative inotropic effects and the concentration-response curves for PIA and NECA were shifted competitively to the right by the adenosine receptor antagonist DPCPX with similar potency and efficacy. The pA2-value for the inhibition of the effects of PIA and NECA were 9.1 and 8.8, respectively. In papillary muscles DPCPX alone had no inotropic effect. In the presence of isoprenaline PIA and NECA alone exerted concentration-dependent negative inotropic effects and again DPCPX shifted the concentration-response curves for PIA and NECA competitively to the right with similar potency and efficacy. The pA2-value for the inhibition of the effects of PIA and NECA were 9.3 and 9.0, respectively. It is concluded that DPCPX is a potent competitive A1 adenosine receptor antagonist in guinea-pig atrial and ventricular cardiac preparations. Since PIA and NECA were equally potent the cardiac adenosine receptor may constitute a subtype of A1 adenosine receptors differing from the receptor in other tissues such as fat cells. Furthermore, DPCPX has a positive inotropic effect in atrial tissue which cannot be attributed to the A1 receptor antagonism.

Adenosine↗