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Biomedical subjects

E Scholtens

Publications and source records attributed to E Scholtens.

At least 19 recordsLinked to original sources
PubMed2000

Beta-adrenoceptor density in chronic infarcted myocardium: a subtype specific decrease of beta1-adrenoceptor density.

UNLABELLED: Beta-adrenoceptor density is altered in different cardiac diseases. In heart failure beta-adrenoceptor density is down regulated but in acute myocardial ischemia beta-adrenoceptor density is up regulated. In hearts with myocardial infarction total beta-adrenoceptor density is decreased shortly after myocardial infarction. AIMS AND METHODS: To investigate whether total beta-adrenoceptor number is altered in the chronic phase after myocardial infarction, and to identify the specificity of alteration, we studied male Wistar rats (n = 18) which underwent a ligation of the left coronary artery or a sham operation. Twelve weeks after coronary ligation, rats were sacrificed and hearts were excised, perfused to obtain blood-free myocardium and frozen in liquid nitrogen. Infarcted myocardium was identified visually and separated from non-infarcted myocardium. Total beta-adrenoceptor number was calculated in fmol (-)-[125I]iodocyanopindolol specifically bound/mg protein and the relative amount of beta1- and beta2-adrenoceptor density was measured by inhibition of (-)-[125I]iodocyanopindolol binding with CGP 20712 A. RESULTS: Total beta-adrenoceptor number in infarcted myocardium was significantly decreased (25.7+/-1.4 vs. 24.9+/-2.2 vs. 20.1+/-3.2 fmol/mg protein (P=0.03) resp. Sham vs. Non-infarcted vs. Infarcted myocardium), due to a decrease of only beta1-adrenoceptor density (14.7+/-0.61 vs. 12.7+/-1.09 vs. 4.84+/-0.96 fmol/mg protein (P=0.004) resp.), whereas the beta2-adrenoceptor density and the dissociation constant (Kd) were not significantly decreased. CONCLUSION: In the infarcted myocardium total beta-adrenoceptor density is decreased due to a decreased beta1-adrenoceptor density at 12 weeks after myocardial infarction.

Animals↗
PubMed2000

Direct interaction between the sympathetic and renin-angiotensin system in myocardial tissue: a microdialysis study in anaesthetised rats.

It has been suggested that local activation of the renin-angiotensin system is involved in early stages of myocardial pathophysiology. To date, there is increasing evidence for interactions between the renin-angiotensin system and the sympathetic nervous system; consequently, local sympathetic activation may also be involved in this. Microdialysis has great potential in the direct investigation of neurohormonal interactions. Therefore, the present study employs microdialysis to study the local effects of exogenous angiotensin II on the interstitial norepinephrine concentration of the normally innervated left ventricle of the anaesthetised rat. The present study investigates the effect of increasing dosages of exogenous angiotensin II on local interstitial norepinephrine. Furthermore, a single dose of losartan was infused on top of the highest dose of angiotensin II, in order to study possible involvement of angiotensin II type 1 (AT1) receptors. Both infusion and sampling were carried out locally, via the microdialysis probes. Concomitantly, circulating norepinephrine levels, heart rate and respiratory rate were monitored to evaluate physiologic stability of the preparation throughout the experiment. Time controls consisted of rats that were perfused with only a Ringer's solution. Angiotensin II induced a dose dependent increase in norepinephrine that was significantly reduced by losartan. Norepinephrine levels in both plasma (infusion experiment and time controls) and the left ventricular wall (time controls) remained stable throughout the experiment, just as heart rate and respiratory rate did. This study for the first time employs microdialysis to demonstrate direct interaction between the sympathetic nervous system and the renin-angiotensin system in the rat left ventricle. The data strongly suggest that AT1 receptors are involved in this interaction, since selective AT1 receptor blockade with losartan significantly reduced the angiotensin II induced norepinephrine concentration.

Angiotensin II↗
PubMed2000

Increased kallikrein expression protects against cardiac ischemia.

Multiple indirect lines of evidence point at a cardioprotective role for enhanced bradykinin formation. In particular, the inhibition of angiotensin-converting enzyme, also known as kininase II, can protect against cardiac ischemia, putatively via accumulation of bradykinin. To address whether an increase in kinin formation is sufficient to protect against cardiac ischemia, we studied transgenic rats harboring the human tissue kallikrein gene TGR(hKLK1) under the control of the metallothionein promoter, which drives expression of the transgene in various organs including the heart. We subjected the isolated hearts from transgenic rats and their transgene negative littermates to ex vivo regional cardiac ischemia and reperfusion. During the experiment, the hearts were treated with either vehicle or the specific bradykinin type 2 receptor antagonist HOE 140 (10-9 M). In the transgenic rats, overflow of nucleotide breakdown products upon reperfusion was significantly less (455 +-54 nmol/min/g in transgene negative rats vs. 270+-57 nmol/min/g in the transgenic rats, P.

Animals↗
PubMed1997

Cardiovascular end-organ damage in Ren-2 transgenic rats compared to spontaneously hypertensive rats.

To compare hypertensive end-organ damage in two genetic forms of hypertension we assessed cardiovascular function in two rat strains of genetic hypertension: transgenic rats overexpressing the mouse Ren-2 gene [(TGR(mREN2)27]) and blood pressure matched spontaneously hypertensive rats (SHR). Despite similarly elevated blood pressure, systolic dp/dt (mmHg/s) was more impaired in transgenic rats (3099 +/- 446) than in SHR (3571 +/- 272) and normals (4342 +/- 119; P < 0.05). Left ventricular weight (mg/g body weight) increased more in the transgenic rats (40 +/- 3) than in SHR (31 +/- 2) and normals (26 +/- 2). Endothelium-dependent relaxation was significantly decreased only in the transgenic rats. This study shows significantly more cardiac and endothelial dysfunction in transgenic, hypertensive TGR (mREN2)27 than in age and blood pressure matched SHR. This supports the hypothesis that chronic activation of the renin-angiotensin system significantly contributes to hypertensive end-organ damage.

Animals↗
PubMed1997

Effects of selective dopaminergic receptor stimulation on ventricular remodeling after experimental myocardial infarction in rats.

BACKGROUND: The disappointing results of the nonselective dopaminergic agonist ibopamine in the treatment of heart failure may be caused by nonselective receptor stimulation. Therefore, a search for more selective dopaminergic agonists remains important. Z1046 is such a compound. METHODS AND RESULTS: Forty-two normotensive rats with a myocardial infarction (MI) and 18 sham-operated rats were studied. Rats with MI were treated for 6 weeks with Z1046 (n = 12) or ibopamine (n = 12) or were not treated (n = 18). Sham-operated control rats were not treated (n = 18). Assessments during the trial included those of plasma catecholamine levels, cardiac function, and morphology. Z1046 significantly decreased heart rate and blood pressure in rats with MI. Ibopamine affected only blood pressure. Compared with control rats with MI (736 +/- 66 pg/mL), plasma norepinephrine was significantly lower both after Z1046 (508 +/- 44 pg/mL) and after ibopamine (561 +/- 28 pg/mL). Infarct size was significantly reduced both by Z1046 and by ibopamine (P < .05). Z1046, but not ibopamine, normalized baseline left ventricular pressure (P < .05, treated rats vs MI control rats). CONCLUSIONS: The new (relatively selective) dopaminergic agonist Z1046 appears to have a more pronounced effect in protection against remodeling than ibopamine; this results in preservation of cardiac function. The effects appear to be mediated by both a reduced sympathetic drive and an improved hemodynamic profile.

Animals↗
PubMed1997

Effects of amlodipine on endothelial function in rats with chronic heart failure after experimental myocardial infarction.

In chronic heart failure, the role of endothelial dysfunction is not yet well established. As calcium metabolism plays an important role in the endothelium, it might be suggested that calcium channel blockers influence endothelial function. Although calcium channel blockers are generally contraindicated in chronic heart failure, because they are believed to stimulate neurohumoral mechanisms and to exert negative inotropic effects, recently it has been suggested that amlodipine might have a favorable affect on mortality in patients with heart failure. The mechanism of amlodipine that contributes to this beneficial effect is not known. Therefore we investigated whether 10 weeks of amlodipine treatment could influence endothelial function in rats with congestive heart failure induced by myocardial infarction. The main finding of our study was that amlodipine, when administered for 10 weeks to rats after a myocardial infarction had been induced, had no significant effects on in vitro and in vivo hemodynamics or neurohormones. The effect of amlodipine on endothelium-intact, norepinephrine-precontracted aortic rings appears to differ from the placebo treatment with respect to the endothelium-dependent relaxation, whereas no differences are seen in endothelium-independent relaxation. We conclude that our data do not support a beneficial role of amlodipine on endothelial function in chronic heart failure.

Amlodipine↗
PubMed1997

Myocardial infarction with aortic banding. A combined rat model of heart failure.

The effect of additional abdominal aortic banding on parameters of heart failure was studied in male Wistar rats with myocardial infarction. Contractile function was studied 8-9 weeks after operation, with an isoprenaline dose response protocol, in a retrograde Langendorff perfusion. Also, plasma noradrenaline concentration, infarct size and morphology were determined. Compared with controls, myocardial infarction/aortic banding animals showed a decreased contractile function, both at baseline and after maximal isoprenaline stimulation, and elevated noradrenaline levels (1316 +/- 94) vs 1909 +/- 174 pg/ml, both p < 0.05). In myocardial infarction rats, baseline values, but not those after inotropic stimulation were decreased, when compared with controls, while the calculated Emax was significantly decreased. In aortic banding rats, contractile parameters were not significantly impaired, compared with controls. Both myocardial infarction and the myocardial infarction/aortic banding animals, but not aortic banding rats, had a significantly increased heart weight (1.4 +/- 0.04 g for controls vs 1.7 +/- 0.08 g for myocardial infarction and 2.0 +/- 0.12 g for myocardial infarction/aortic banding), and left ventricular cavity volume (19 +/- 1.4 mm3 for controls vs 49 +/- 5.5 mm3 for myocardial infarction and 48 +/- 4.3 mm3 for myocardial infarction/aortic banding) compared to control animals. Infarct size was 36.0% and 39.4% for the myocardial infarction and myocardial infarction/aortic banding animals, respectively. We conclude that myocardial infarction/aortic banding provides a new experimental model, which may yield important information and pathophysiology which allow evaluation of changes that may mimic clinical myocardial infarction with concomitant hypertension.

Animals↗
PubMed1995

Relation between myocardial beta-adrenoceptor density and hemodynamic and neurohumoral changes in a rat model of chronic myocardial infarction: effects of ibopamine and captopril.

OBJECTIVES: The purpose of this study was to investigate the changes in beta-adrenoceptor density (Bmax) and distribution in a model of chronic myocardial infarction in rats, and to relate possible changes to hemodynamic and neurohumoral abnormalities. In addition, we examined the effects of 8 weeks treatment with ibopamine and captopril. METHODS: There were 3 experiments: (1) Bmax and plasma catecholamines were examined (n = 46), (2) Bmax was compared in infarcted and non-infarcted tissue (n = 13), and (3) contractile function was evaluated by isolated heart perfusion (n = 40). Of rats in Expts. (1) and (3), 50% had myocardial infarction induced by coronary ligation and 50% were controls. Each group was divided between ibopamine, ibopamine and captopril, or standard (no drug) treatment. RESULTS: Bmax was not decreased in rats with myocardial infarction (10.8 +/- 0.8 fmol/mg protein), compared to normal rats (11.4 +/- 0.6 fmol/mg protein), and the ratio beta 1/beta 2 was also unaffected. In infarcted tissue, Bmax was significantly (P = 0.03) lower than in non-infarcted tissue. Baseline left ventricular pressure, systolic and diastolic dP/dT were all impaired (P < 0.001), and plasma norepinephrine levels were elevated in rats with myocardial infarction (16.03 +/- 230 vs. 1287 +/- 83 pg/ml; P < 0.05), compared to normals. Both ibopamine alone and in combination with captopril reduced the elevated plasma norepinephrine levels in infarcted rats (P < 0.001), but only the combination of the 2 drugs significantly increased Bmax in infarcted rats (14.7 +/- 0.8 fmol/mg protein; P = 0.03 vs. untreated myocardial infarction), while ibopamine alone had no significant effect (13.1 +/- 1.1 fmol/mg protein; p = ns). Also, active drug treatment had no significant effect on the hemodynamic changes. CONCLUSIONS: In this coronary artery ligation model of myocardial infarction in rats, no beta-adrenoceptor down-regulation is observed, despite marked abnormalities in baseline left ventricular function and plasma norepinephrine levels. The combination of ibopamine and captopril significantly increases Bmax in infarcted rats, which is accompanied by a reduction in plasma norepinephrine levels, but not by an improvement in hemodynamic parameters.

Adrenergic beta-Agonists↗
PubMed1994

Neurohumoral and hemodynamic effects of ibopamine in a rat model of chronic myocardial infarction and heart failure.

There is increasing evidence that both neurohumoral and hemodynamic factors play a role in disease progression in chronic heart failure (CHF). To examine the influence of the oral dopamine agonist ibopamine on these factors, we studied 20 rats with chronic myocardial infarction and CHF, and compared them with 20 normal rats. After 6 weeks, rats were randomly divided between control treatment (50%) or ibopamine (50%) for 3 weeks. At the end of the study, plasma and tissue neurohumoral parameters, as well as hemodynamics, were determined. In infarcted rats, the elevated plasma norepinephrine (PNE) levels were reduced by ibopamine (251 +/- 19 vs. 138 +/- 32 pg/ml; p < 0.05). Other plasma neurohormones measured (epinephrine, renin, aldosterone, and angiotensin converting enzyme [ACE]) were not significantly increased in rats with myocardial infarction and were not affected by ibopamine. Cardiac (tissue) ACE was increased in infarcted rats (12.1 +/- 1.9 U/l/min) and was significantly lowered by ibopamine (9.6 +/- 1.0 U/l/min; p < 0.05); renal ACE was unaffected. Blood pressure and heart rate were similar in the two groups and were not influenced by ibopamine treatment. In conclusion, in chronic myocardial infarction and CHF in rats, ibopamine reduces the elevated levels of PNE and cardiac ACE. Further research will be needed to determine whether this effect may lead to a favorable influence on disease progression in CHF.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Effect of ibopamine on ventricular remodeling after experimental myocardial infarction: a comparison with captopril.

Remodeling after myocardial infarction (MI) is influenced not only by hemodynamic but possibly by neurohumoral factors as well. Ibopamine is an orally active dopamine agonist (DA) with both hemodynamic and neurohumoral properties in humans. The latter property prevails in rats. To study the dose-dependent effect of ibopamine on myocardial remodeling and compare it with the effect of captopril, we randomized rats with (n = 27) or without (n = 27) experimental MI to captopril (25 mg/kg/day), low-dose ibopamine (10 mg/kg/day), high-dose ibopamine (30 mg/kg/day), or no treatment. After 8-week treatment, hearts were isolated and left ventricular (LV) function, LV cavity volume, and infarct size (IS) were evaluated. Both ibopamine and captopril significantly reduced plasma norepinephrine (NE) levels in rats with MI. In untreated but not in treated infarcted rats, LV function was significantly reduced as compared with that of controls. IS was reduced in all three active treatment groups as compared with untreated rats. LV cavity volume was significantly increased in untreated rats with MI as compared with controls. This dilatation was attenuated by both ibopamine and captopril. Ibopamine, comparable to captopril, administered early after coronary ligation reduced IS and subsequent ventricular dilatation, resulting in preservation of cardiac function in this rat model. This observation suggests a major role for neurohumoral activation in the process of remodeling.

Animals↗
PubMed1993

Selective and time related activation of the cardiac renin-angiotensin system after experimental heart failure: relation to ventricular function and morphology.

OBJECTIVE: The cardiac renin-angiotensin system is activated in experimental heart failure, but it is unknown at what stage of heart failure it becomes activated, and whether activation is related to ventricular dysfunction and dilatation. Changes in activity of cardiac, renal, and plasma angiotensin converting enzyme (ACE) were therefore examined at different stages of experimental heart failure, with simultaneous measurements of left ventricular pressure, systolic dP/dt, and inner ventricular radius. METHODS: Heart failure was induced by experimental infarction in 17 normotensive male Wistar rats; 14 rats were sham operated. Rats were killed 3, 5, or 80 d after infarction. In an isolated heart perfusion, left ventricular pressure and systolic dP/dT were measured. ACE activity was determined in samples of the left and right cardiac ventricle, kidney, and plasma. Radius of the ventricular cavity was planimetrically determined in transverse sections of the left ventricle. RESULTS: At the different stages both left ventricular pressure and systolic dP/dT progressively decreased and inner radius of the left ventricle increased in all heart failure groups. ACE activity in the left ventricle increased significantly in all heart failure groups and correlated inversely with left ventricular pressure (R = -0.81; p < 0.001) and dP/dt (R = -0.85; p < 0.001). ACE activity in the kidney was only increased 80 d after the induction of heart failure [17(SEM 1) v 11.2(0.5) nM His-Leu generated per min.mg-1, p < 0.01], while plasma ACE activity was not increased in any heart failure group. CONCLUSIONS: Cardiac ACE is activated in the early stage after induction of heart failure and is related to the amount of dysfunction. ACE in the kidney is activated only in the chronic stage. The cardiac renin-angiotensin system therefore already appears to be an important neurohumoral adjustment in the early stage of heart failure and is thereby a suitable target for early intervention by ACE inhibitors.

Acute Disease↗
PubMed1993

Endothelium dependent relaxation in two different models of chronic heart failure and the effect of ibopamine.

OBJECTIVES: The purpose was to relate endothelium dependent relaxation to neurohumoral and haemodynamic changes in rats with chronic heart failure. METHODS: Rats were submitted to either coronary ligation causing myocardial infarction or banding of the abdominal aorta (aortic stenosis), and comparisons were made with normal rats (n = 20 per group). Starting six weeks after surgery, half of the experimental animals received ibopamine and the other half served as controls and were given saline for another three weeks. After this, haemodynamic and neurohumoral variables were determined and the rats were killed. Rings of both the thoracic and abdominal aorta were studied in organ baths to measure their response to vasoactive agents. RESULTS: Increased plasma noradrenaline concentrations in rats with myocardial infarction and aortic stenosis were reduced by ibopamine. Blood pressure and heart rate, which were higher in rats with aortic stenosis than in rats with myocardial infarction and in normal rats, were unaffected by ibopamine. The maximal relaxation to sodium nitrite was depressed in the thoracic aorta from rats with myocardial infarction. The pIC50 of metacholine induced relaxation was smaller in the thoracic aorta from rats with myocardial infarction and aortic stenosis. By contrast, both pIC50 and the maximal relaxation (Emax) were increased in the abdominal aorta from rats with aortic stenosis, whereas Emax was smaller in rats with myocardial infarction. Ibopamine had no significant effects on these responses. CONCLUSIONS: Endothelium dependent relaxation to metacholine was selectively altered in rats with chronic heart failure due to aortic stenosis, probably because of differences in regional haemodynamics. In rats with myocardial infarction, however, endothelium dependent relaxation was impaired in both the thoracic and abdominal aorta. Ibopamine acted as a neurohumoral modulator by reducing increased noradrenaline concentrations but had no significant effect on either endothelium dependent or independent relaxation.

Animals↗
PubMed1991

Converting enzyme inhibitors and the role of the sulfhydryl group in the potentiation of exo- and endogenous nitrovasodilators.

In this study, the effect of bradykinin on coronary flow in the isolated rat heart was significantly potentiated when cysteine or the sulfhydryl-containing converting enzyme inhibitors captopril and zofenoprilat were administered simultaneously. In contrast, the effect of concomitant administration of enalaprilat only slightly increased the effect of bradykinin on coronary flow. In nitrate-tolerant hearts of rats pretreated with isosorbide dinitrate (15 mg daily), the increase in coronary flow by nitroglycerin and bradykinin was significantly less when compared to control hearts. The effect of captopril was not affected by pretreatment. The involvement of endothelium-derived relaxing factor (EDRF) in the effect of captopril was apparent from experiments with L-arginine, the precursor of EDRF, and L-NMMA, the "false" precursor of EDRF. L-Arginine increased the effect of captopril, whereas L-NMMA showed a competitive antagonism for the effect of captopril on coronary flow in the isolated rat heart. Clinically, the effect of captopril was studied in 10 patients with stable, exercise-induced angina pectoris that had been treated for 3 weeks with slow-release isosorbide dinitrate (20 mg four times daily). At day 7, a baseline exercise test was obtained. Subsequently, patients with chest pain and at least 1-mm ST-segment depression on the ECG during exercise were included. They received on day 14 and 21 either captopril (25 mg) or placebo 1 h before exercise testing in a randomized, double-blind, crossover design. Captopril significantly improved the combined score of maximal ST-segment depression, maximal workload, and time to angina when compared to placebo. No differences in the pressure-rate index at rest and during exercise were seen. These results indicate that the sulfhydryl group of certain angiotensin converting enzyme inhibitors can potentiate their effect on the endogenous nitrovasodilator EDRF. In the clinical situation, this may lead to an improved exercise performance in patients with stable angina pectoris during chronic nitrate treatment, independent of its systemic vascular effects.

Aged↗
PubMed1988

Protective effects of captopril against ischemia/reperfusion-induced ventricular arrhythmias in vitro and in vivo.

The effects of the converting enzyme inhibitor captopril on the susceptibility of the heart to ventricular arrhythmias following ischemia, both in vitro and in vivo, were studied. In isolated rat hearts, captopril, administered either before or at the end of ischemia, reduced ventricular fibrillation upon reperfusion after 15 minutes of local ischemia. Reduction of purine overflow, improvement in contractility, and increase in coronary blood flow occurred concomitantly. In vivo, a closed-chest pig model was used to determine the effects of captopril, administered at the end of ischemia and continued orally, on the susceptibility to ventricular arrhythmias during the chronic phase of myocardial infarction. Myocardial ischemia was induced by 60-minute inflation of a balloon catheter in the left anterior descending coronary artery. Upon reperfusion, an accelerated idioventricular rhythm occurred, both in 10 untreated and in 10 captopril-treated animals. Creatine kinase levels during the reperfusion period were significantly lower after captopril treatment. Two weeks after the short-term experiments, monomorphic ventricular tachycardia could be induced with programmed electrical stimulation in six of eight surviving untreated pigs. In contrast, in none of the six surviving captopril-treated animals was ventricular tachycardia inducible. Thus, early intervention with captopril during the development phase of myocardial infarction may have beneficial effects on the subsequent development of ventricular arrhythmias. Salvage of ischemic myocardium, improvement in ventricular function, beneficial effects on coronary flow, and decreased activity of the sympathetic nervous system may all contribute.

Animals↗
PubMed1988

Differential influences of angiotensin converting-enzyme inhibitors on the coronary circulation.

The effects of captopril and zofenoprilate (the active form of the prodrug zofenopril and also a sulfhydryl-containing angiotension converting-enzyme inhibitor) on coronary flow in the isolated rat heart were compared with the effects of a nonsulfhydryl converting-enzyme inhibitor, ramiprilate (the active form of the prodrug ramipril) and of sulfhydryl-containing compounds with no converting-enzyme inhibiting properties such as glutathione, cysteine, and the (R,S)-isomer of captopril. Drug concentrations of the angiotensin converting-enzyme inhibitors were equipotent in their effect on angiotensin I pressor response. Concentrations of the other compounds were equimolar with respect to the sulfhydryl group. Hearts treated with captopril, its isomer, zofenoprilate, cysteine, and glutathione showed significant increases in coronary flow by 5 min of perfusion. In contrast, ramiprilate treatment resulted in a slower increase in coronary flow that was only significant after 20 min of perfusion. The effect of ramiprilate was associated with a significant increase in 6-keto-prostaglandin (PG) F1 alpha overflow in the coronary effluent compared with that in saline-treated hearts, whereas captopril and glutathione had no significant effect on overflow of the measured cyclooxygenase products 6-keto-PGF1 alpha, thromboxane B2, and PGE2. The effects of captopril, zofenoprilate, and glutathione on coronary flow were dose dependent. These results corroborate the view that ramiprilate enhances coronary flow by affecting prostacyclin synthesis, mediated by an increase of endogenous bradykinin.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗