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1.
Am Heart J ; 145(3): E14, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12660683

ABSTRACT

BACKGROUND: This study evaluated the short-term and long-term effects of the angiotensin II type 1 receptor antagonist candesartan cilexetil on hemodynamics, neurohormones, and clinical symptoms in patients with congestive heart failure (CHF). METHODS: In this multicenter, double-blind, parallel-group study, 218 patients with CHF (New York Heart Association class II or III) with impaired left ventricular function (ejection fraction < or =40%) and pulmonary capillary wedge pressure > or =13 mm Hg were randomly assigned to 12 weeks of treatment with placebo (n = 44) or candesartan cilexetil (2 mg [n = 45], 4 mg [n = 46], 8 mg [n = 39], or 16 mg [n = 44]) once daily after a 2-week placebo run-in period. Hemodynamic measurements were performed by right heart catheterization over a 24-hour period after single (day 1) and repeated (3-month) treatment with the study drug. RESULTS: On regression analysis of the time-response curves, single and multiple doses of candesartan cilexetil produced sustained, significant, and dose-dependent reductions in pulmonary capillary wedge pressure (short-term effect P =.036, long-term effect P =.035) and mean pulmonary arterial pressure (short-term effect P =.031, long-term effect P =.042). Systemic vascular resistance showed a trend toward decreasing with dose on short-term and long-term treatments. No consistent changes were seen in cardiac index. Compensatory increases in plasma renin activity and angiotensin II levels with decreases in aldosterone and atrial natriuretic peptide were dose-dependent and significant. Candesartan cilexetil improved clinical symptoms, stabilized patient New York Heart Association status compared with placebo, and was judged to be an efficacious treatment by the investigators. More patients receiving placebo stopped the trial prematurely because of an adverse event than in any candesartan cilexetil group, and there was no excess of deaths in any treatment group. Candesartan was safe and well tolerated at all dosages. CONCLUSIONS: Candesartan cilexetil demonstrated significant short-term and long-term improvements in hemodynamic, neurohormonal, and symptomatic status and was well tolerated in patients with CHF.


Subject(s)
Benzimidazoles/therapeutic use , Biphenyl Compounds/therapeutic use , Heart Failure/drug therapy , Hemodynamics/drug effects , Hormones/blood , Tetrazoles , Adolescent , Adult , Aged , Aldosterone/blood , Angiotensin II/blood , Angiotensin Receptor Antagonists , Atrial Natriuretic Factor/blood , Benzimidazoles/pharmacology , Biphenyl Compounds/pharmacology , Double-Blind Method , Female , Follow-Up Studies , Heart Failure/blood , Heart Failure/diagnosis , Humans , Male , Middle Aged , Placebos , Prodrugs/pharmacology , Prodrugs/therapeutic use , Regression Analysis , Renin/blood , Treatment Outcome
2.
J Mol Med (Berl) ; 79(10): 601-8, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11692158

ABSTRACT

Angiotensin II is known to stimulate cardiac hypertrophy and contractility. Most angiotensin II effects are mediated via membrane bound AT1 receptors. However, the role of myocardial AT1 receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that increased myocardial AT1 receptor density causes cardiac hypertrophy apart from high blood pressure we developed a transgenic rat model which expresses the human AT1 receptor under the control of the alpha-myosin heavy-chain promoter specifically in the myocardium. Expression was identified and quantified by northern blot analysis and radioligand binding assays, demonstrating overexpression of angiotensin II receptors in the transgenic rats up to 46 times the amount seen in nontransgenic rats. Coupling of the human AT1 receptor to rat G proteins and signal transduction cascade was verified by sensitivity to GTP-gamma-S and increased sensitivity of intracellular Ca2+ [Ca2+]i to angiotensin II in fluo-3 loaded transgenic cardiomyocytes. Transgenic rats exhibited normal cardiac growth and function under baseline conditions. Pronounced hypertrophic growth and contractile responses to angiotensin II, however, were noted in transgenic rats challenged by volume and pressure overload. In summary, we generated a new transgenic rat model that exhibits an upregulated myocardial AT1 receptor density and demonstrates augmented cardiac hypertrophy and contractile response to angiotensin II after volume and pressure overload, but not under baseline conditions.


Subject(s)
Cardiomegaly/genetics , Myocardium/metabolism , Receptors, Angiotensin/genetics , Angiotensin II/pharmacology , Animals , Animals, Genetically Modified , Animals, Newborn , Binding, Competitive , Blood Pressure/drug effects , Calcium/metabolism , Cardiomegaly/pathology , Cardiomegaly/physiopathology , Disease Models, Animal , Dose-Response Relationship, Drug , Gene Expression Regulation , Heart Ventricles/drug effects , Heart Ventricles/physiopathology , Hemodynamics/drug effects , Humans , Membranes/metabolism , Myocardium/pathology , Organ Size/drug effects , Perfusion , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptor, Angiotensin, Type 1 , Time Factors , Transgenes/genetics
3.
Eur J Heart Fail ; 3(5): 535-43, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11595601

ABSTRACT

OBJECTIVE: Recently, deletion of specific genes by so called knock-out techniques has become important for investigating the pathogenesis of various diseases. This form of genetic engineering is widely performed in murine models. There are, however, only a limited number of mouse models available in cardiovascular pathology. The objective of this study, therefore, was to develop a new model of overt congestive heart failure associated with myocardial hypertrophy in the mouse. METHODS: Female C57/BL6 mice weighing 19-20 g were anesthetized with ether. After abdominal incision, the aorta was temporarily clamped proximal to the renal arteries. The aorta was then punctured with a needle (outer diameter 0.6 mm) and the needle was further advanced into the adjacent vena cava. After withdrawal of the needle, the aortic puncture site was sealed with cyanoacrylate glue. The clamp was removed, and the patency of the shunt was visually verified as swelling and mixing of venous and arterial blood in the vena cava. Sham-operated mice served as controls. RESULTS: Perioperative mortality of mice with aortocaval shunt was 42%. Four weeks after shunt induction, mice showed a significant cardiac hypertrophy with a relative heart weight of 7.5+/-0.2 mg/100 g body weight (vs. 5.1+/-0.7 mg/100 g in control mice, P<0.001). While no changes in blood pressure and heart rate occurred, left ventricular enddiastolic pressure was significantly increased in mice with shunt, and left ventricular contractility was impaired from 6331+/-412 to 4170+/-296 mmHg/s (P<0.05). Plasma concentrations of atrial natriuretic peptide (ANP) and its second messenger cGMP as humoral markers of heart failure as well as ventricular expression of ANP- and brain natriuretic peptide (BNP)-mRNA were significantly increased in mice with shunt compared to control mice. CONCLUSIONS: The aortocaval shunt in the mouse constitutes a new model of overt congestive heart failure with impaired hemodynamic parameters and may be a useful tool to investigate the role of particular genes in the development of heart failure.


Subject(s)
Disease Models, Animal , Heart Failure/physiopathology , Animals , Arteriovenous Shunt, Surgical , Atrial Natriuretic Factor/blood , Atrial Natriuretic Factor/metabolism , Blood Pressure/physiology , Cardiac Volume/physiology , Cardiomegaly/etiology , Cardiomegaly/physiopathology , Female , Heart Failure/etiology , Heart Rate/physiology , Mice , Mice, Inbred C57BL , Natriuretic Peptide, Brain/metabolism
4.
Am J Physiol Heart Circ Physiol ; 278(5): H1500-6, 2000 May.
Article in English | MEDLINE | ID: mdl-10775127

ABSTRACT

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones that are involved in water and electrolyte homeostasis in heart failure. Although both hormones exert almost identical biological actions, the differential regulation of cardiac ANP and BNP mRNA in compensated and overt heart failure is not known. To study the hypothesis that cardiac BNP is more specifically induced in overt heart failure, a large aortocaval shunt of 30 days duration was produced in rats and compared with compensated heart failure. Compensated heart failure was induced either by a small shunt of 30 days duration or by a large shunt of 3 days duration. Both heart failure models were characterized by increased cardiac weight, which was significantly higher in the large-shunt model, and central venous pressure. Left ventricular end-diastolic pressure was elevated only in the overt heart failure group (control: 5.7 +/- 0. 7; small shunt: 8.6 +/- 0.9; large shunt 3 days: 8.5 +/- 1.7; large shunt 30 days: 15.9 +/- 2.6 mmHg; P < 0.01). ANP and BNP plasma concentrations were elevated in both heart failure models. In compensated heart failure, ANP mRNA expression was induced in both ventricles. In contrast, ventricular BNP mRNA expression was not upregulated in any of the compensated heart failure models, whereas it increased in overt heart failure (left ventricle: 359 +/- 104% of control, P < 0.001; right ventricle: 237 +/- 33%, P < 0.01). A similar pattern of mRNA regulation was observed in the atria. These data indicate that, in contrast to ANP, cardiac BNP mRNA expression might be induced specifically in overt heart failure, pointing toward the possible role of BNP as a marker of the transition from compensated to overt heart failure.


Subject(s)
Atrial Natriuretic Factor/metabolism , Heart Failure/metabolism , Natriuretic Peptide, Brain/metabolism , RNA, Messenger/biosynthesis , Animals , Arteriovenous Shunt, Surgical , Atrial Natriuretic Factor/genetics , Central Venous Pressure/physiology , Glyceraldehyde-3-Phosphate Dehydrogenases/genetics , Glyceraldehyde-3-Phosphate Dehydrogenases/metabolism , Heart Atria/metabolism , Heart Atria/pathology , Heart Ventricles/metabolism , Heart Ventricles/pathology , Hemodynamics , Lung/physiology , Male , Myocardial Contraction/physiology , Myocardium/metabolism , Natriuretic Peptide, Brain/genetics , Organ Size , Rats , Rats, Wistar , Ventricular Function, Left/physiology
5.
Basic Res Cardiol ; 95 Suppl 1: I84-9, 2000.
Article in English | MEDLINE | ID: mdl-11192360

ABSTRACT

In the not so distant past, the idea of using beta-blockers as a primary therapy for congestive heart failure to improve symptoms and prognosis seemed paradoxical. The cardiac community reacted with skepticism when, in 1975, the pioneering report of Waagstein et al. appeared in the British Heart Journal. Since then numerous groups have investigated the effects of beta-adrenoceptor antagonists in patients with congestive heart failure. Unfortunately, the results of these trials have sometimes contradicted one another. Exercise tolerance and left ventricular ejection fraction improved in the trials with a duration of treatment of longer than 3 months, but no benefit was observed when beta-blockers were administered for only 1 month. Now, in the year 2000 we have proof for the concept that beta-blockade improves symptoms and prolongs life in heart failure. Three large placebo-controlled clinical trials with more than 9000 patients have shown that carvedilol, bisoprolol and metoprolol significantly reduce morbidity and mortality in heart failure. These agents, therefore, are clearly indicated in the majority of patients with mild to moderate heart failure.


Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Heart Failure/drug therapy , Animals , Cardiology/trends , Catecholamines/blood , Heart Failure/blood , Heart Failure/physiopathology , Humans , Randomized Controlled Trials as Topic , Sympathetic Nervous System/physiopathology
6.
J Renin Angiotensin Aldosterone Syst ; 1 Suppl 1: 24-30, 2000 Sep.
Article in English | MEDLINE | ID: mdl-11967792

ABSTRACT

Is heart failure an endocrine disease? Historically, congestive heart failure (CHF) has often been regarded as a mechanical and haemodynamic condition. However, there is now strong evidence that the activation of neuroendocrine systems, like the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, as well as the activation of natriuretic peptides, endothelin and vasopressin, play key roles in the progression of CHF. In this context, agents targeting neurohormones offer a highly rational approach to CHF management, with ACE inhibitors, aldosterone antagonists and beta-adrenergic blockade improving the prognosis for many patients. Although relevant improvements in clinical status and survival can be achieved with these drug classes, mortality rates for patients with CHF are still very high. Moreover, most patients do not receive these proven life-prolonging drugs, partially due to fear of adverse events, such as hypotension (with ACE inhibitors), gynaecomastia (with spironolactone) and fatigue (with beta-blockers). New agents that combine efficacy with better tolerability are therefore needed. The angiotensin II type 1 (AT(1))-receptor blockers have the potential to fulfil both these requirements, by blocking the deleterious cardiovascular and haemodynamic effects of angiotensin II while offering placebo-like tolerability. As shown with candesartan, AT(1)-receptor blockers also modulate the levels of other neurohormones, including aldosterone and atrial natriuretic peptide (ANP). Combined with its tight, long-lasting binding to AT(1)-receptors, this characteristic gives candesartan the potential for complete blockade of the RAAS-neurohormonal axis, along with the great potential to improve clinical outcomes.


Subject(s)
Heart Failure/drug therapy , Hormone Antagonists/therapeutic use , Neurotransmitter Agents/antagonists & inhibitors , Aldosterone/physiology , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Benzimidazoles/therapeutic use , Biphenyl Compounds , Heart Failure/physiopathology , Humans , Mineralocorticoid Receptor Antagonists/therapeutic use , Neurotransmitter Agents/physiology , Receptor, Angiotensin, Type 1 , Renin-Angiotensin System/physiology , Tetrazoles/therapeutic use
7.
Life Sci ; 65(21): 2241-9, 1999.
Article in English | MEDLINE | ID: mdl-10576596

ABSTRACT

Adrenomedullin (AM) is a peptide hormone with vasodilating and natriuretic properties. AM plasma concentrations are elevated in heart failure. Whether cardiac AM-mRNA synthesis is increased in heart failure is not known. We measured AM-mRNA/GAPDH-mRNA in all four heart chambers in compensated and overt heart failure in rats with two different sizes of aortocaval shunt. Left and right atrial AM-mRNA expressions were unchanged in both heart failure models. Similarly, left and right ventricular AM-mRNA expressions were unchanged in compensated heart failure. In overt heart failure, however, the AM-mRNA expression was significantly increased in the left ventricle (145+/-20 vs. 100+/-3% of control, p<0.05). The right ventricular AM-mRNA expression was significantly increased only in a subgroup of animals with pulmonary congestion (lung weight >2.0 g, 141+/-16 vs. 100+/-11% of control, p<0.05). Ventricular AM concentrations were elevated in both ventricles in overt heart failure. AM plasma concentrations were significantly higher in the subgroup with pulmonary congestion than in rats with compensated heart failure (496+/-95 vs. 143+/-7 pmol/l, p<0.01). These data indicate that ventricular AM-mRNA expression and AM concentrations were upregulated only in advanced stages of heart failure. However, the exact contribution of cardiac AM synthesis to the increased AM plasma levels remains to be established.


Subject(s)
Heart Failure/metabolism , Myocardium/metabolism , Peptides/metabolism , RNA, Messenger/biosynthesis , Adrenomedullin , Animals , Glyceraldehyde-3-Phosphate Dehydrogenases/metabolism , Heart Atria/metabolism , Heart Failure/pathology , Heart Failure/physiopathology , Heart Ventricles/metabolism , Hemodynamics , Lung/pathology , Male , Myocardium/pathology , Organ Size , Peptides/blood , RNA, Messenger/analysis , Rats , Rats, Wistar
8.
Herz ; 24(5): 389-97, 1999 Aug.
Article in German | MEDLINE | ID: mdl-10505289

ABSTRACT

This review article summarizes the long-term standard therapy for patients with myocardial infarction. The chronic therapy is able to significantly improve quality of life and survival of affected patients. Previous studies showed that in most western countries, the established standard therapy is not given to all patients who would benefit from chronic treatment. The essential parts of today's myocardial infarction treatment consists of effective beta-blockade, inhibition of the angiotensin-conversion enzyme, inhibition of platelet aggregation and lipid lowering agents. This article reviews the clinical benefits which may be expected from each of these therapeutic approaches. Newer, but not yet proven strategies, like blockade of the angiotensin receptor subtype 1 and treatment with antioxidative agents will be discussed.


Subject(s)
Cardiovascular Agents/therapeutic use , Myocardial Infarction/drug therapy , Adrenergic beta-Antagonists/adverse effects , Adrenergic beta-Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Aspirin/adverse effects , Aspirin/therapeutic use , Cardiovascular Agents/adverse effects , Humans , Myocardial Infarction/mortality , Prognosis , Randomized Controlled Trials as Topic , Survival Rate
9.
Clin Chem Lab Med ; 37(8): 805-12, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10536929

ABSTRACT

Natriuretic peptides are important regulators of vascular resistance and volume and electrolyte homeostasis. The quantification of natriuretic peptide receptor (NPR) mRNA is important for the understanding of the regulation of this humoral system, but is difficult due to low expression of the NPR mRNA. We report here on the evaluation of a polymerase chain reaction (PCR)-aided transcript titration assay for quantification of all three NPR subtypes (NPR-A, NPR-B, and NPR-C) mRNA. A multispecific internal standard RNA with parts of NPR-A, NPR-B, NPR-C and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) nucleotide sequences was constructed and reverse transcription of standard and sample RNA (400 ng) was performed in parallel for all three NPRs and GAPDH. The specific PCR yielded differently sized products, which were quantified by high performance liquid chromatography (HPLC). The determination of specific mRNA concentrations was not influenced by cDNA input and did not depend on the PCR cycle number. Linearity between sample RNA input and mRNA concentration was demonstrated. Application of the evaluated method showed that the NPR-A mRNA expression was the most abundant of the three natriuretic peptide receptor mRNAs in rat lungs, glomeruli and left ventricles, followed by the NPR-C mRNA and the NPR-B mRNA expression. Thus, the described method allows the reliable quantification of the specific mRNA expression of all three NPRs with small amounts of RNA. The presented method might foster future research on the regulation of this humoral system in cardiovascular and kidney diseases.


Subject(s)
RNA, Messenger/metabolism , Receptors, Atrial Natriuretic Factor/genetics , Animals , Base Sequence , Chromatography, High Pressure Liquid , DNA, Complementary , Glyceraldehyde-3-Phosphate Dehydrogenases/genetics , Male , RNA, Messenger/genetics , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction
10.
Cardiovasc Res ; 42(3): 733-42, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10533614

ABSTRACT

OBJECTIVE: In heart failure atrial natriuretic peptide (ANP) release in response to volume expansion is impaired while the renin-angiotensin system is activated. This study was designed to test the hypothesis that ANP release in heart failure is dependent on an activated angiotensin system. METHODS: We studied the ANP and renin-angiotensin systems in a rat model of shunt-induced high-output heart failure, in which we rapidly increased circulating fluid volume with a 5 ml, hyperoncotic infusion, and evaluated the effects of acute inhibition of the angiotensin converting enzyme as well as of the blockade of the angiotensin II type 1 receptors on the ANP release and on renal excretory function. RESULTS: ANP and angiotensin II plasma concentrations prior to volume expansion were elevated (p < 0.05) in rats with aortocaval shunt compared to controls. The diuretic response to acute volume expansion (18.5 +/- 1.5 vs. 48.2 +/- 2.4 microliters/min, p < 0.001) was markedly blunted. ANP release was attenuated in rats with aortocaval shunt, as was the increase of its second messenger cGMP in plasma and urine. The blunted increase in ANP plasma levels was not due to depleted cardiac stores as cardiac ANP content, as well as ANP synthesis, were increased (p < 0.05). Acute inhibition of the angiotensin converting enzyme as well as blockade of the angiotensin II type 1 receptors restored ANP release in response to volume expansion (p < 0.01). Moreover, acute inhibition of the renin-angiotensin system completely normalized the diuretic response. CONCLUSIONS: Our data suggest that the ANP system is impaired in rats with aortocaval shunt. The activation of the angiotensin system contributes to the impairment of the ANP system. Acute inhibition of the angiotensin II system significantly improved the ability of the ANP system to respond to acute volume expansion. Our findings indicate a hitherto fore unappreciated interaction between both systems and suggest additional mechanisms for the beneficial effects of angiotensin converting enzyme inhibition or angiotensin II type 1 receptor antagonists in heart failure.


Subject(s)
Angiotensin II/blood , Atrial Natriuretic Factor/blood , Heart Failure/physiopathology , Renin-Angiotensin System , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Atrial Natriuretic Factor/biosynthesis , Blood Volume , Cyclic GMP/blood , Cyclic GMP/urine , Diuresis , Heart Failure/blood , Heart Failure/urine , Male , Myocardium/metabolism , Ramipril/analogs & derivatives , Ramipril/pharmacology , Rats , Rats, Wistar , Statistics, Nonparametric , Tetrazoles/pharmacology , Valine/analogs & derivatives , Valine/pharmacology , Valsartan
11.
Eur J Pharmacol ; 369(2): 195-203, 1999 Mar 19.
Article in English | MEDLINE | ID: mdl-10206179

ABSTRACT

Heart failure is characterized by increased vascular resistance and water retention. Adrenomedullin is a peptide hormone with vasodilating and diuretic properties whose efficacy in heart failure has not been well established. We used an aortocaval shunt model of moderate heart failure in rats and infused increasing doses of adrenomedullin, both as bolus injections and 20-min infusions. In controls, a clear dose-dependent 4.8+/-1.0 to 13.6+/-2.3 mm Hg decrease in arterial blood pressure was observed after injection of 1 microg to 30 microg of adrenomedullin. In rats with aortocaval shunt, the hypotensive responses were significantly diminished. The urine flow rate, which was diminished at baseline in rats with aortocaval shunt, was increased and normalized by adrenomedullin administration. The glomerular filtration rate increased after infusion of adrenomedullin (0.5 microg/kg min(-1)) from 2.37+/-0.25 to 3.47+/-0.43 ml/min (P<0.01) in controls and from 1.79+/-0.33 to 2.58+/-0.49 (P<0.05) in rats with aortocaval shunt. Similarly, renal blood flow was significantly increased by adrenomedullin in both groups. Our results indicate a beneficial effect of adrenomedullin on renal function in rats with aortocaval shunt. These data suggest that adrenomedullin might be of potential therapeutic value in heart failure, without inordinately decreasing blood pressure.


Subject(s)
Cardiotonic Agents/pharmacology , Heart Failure/physiopathology , Hemodynamics/drug effects , Kidney/drug effects , Peptides/pharmacology , Adrenomedullin , Animals , Arteriovenous Shunt, Surgical , Cyclic AMP/urine , Cyclic GMP/urine , Disease Models, Animal , Diuresis/drug effects , Glomerular Filtration Rate/drug effects , Male , Natriuresis/drug effects , Peptides/administration & dosage , Rats , Rats, Wistar , Renal Circulation/drug effects
12.
J Am Soc Nephrol ; 10(3): 572-80, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10073608

ABSTRACT

The physiologic and pathophysiologic importance of natriuretic peptides (NP) has been imperfectly defined. The diminished renal responses to exogenous atrial NP in heart failure have led to the perception that the endogenous NP system might be less effective and thus contribute to renal sodium retention in heart failure. This study tests the hypothesis that in experimental heart failure, the renal responses to an acute volume load are still dependent on the NP system. The specific antagonist HS-142-1 was used to block the effects of NP in a model of high-output heart failure induced by an aortocaval shunt. Plasma cGMP levels and renal cGMP excretion were significantly lower in shunted and sham-operated rats receiving HS-142-1, compared with vehicle-treated controls, indicating effective blockade of guanylate cyclase-coupled receptors. Baseline sodium excretion and urine flow rate were lower in HS-142-1-treated sham-operated rats (15.2+/-1.1 microl/min versus 27.5+/-3.1 microl/min with vehicle, P < 0.001) and in HS-142-1-treated shunted rats (8.1+/-1.3 microl/min versus 19.9+/-2.3 microl/min with vehicle, P < 0.001). After an acute volume load, the diuretic and natriuretic responses were attenuated by HS-142-1 in control and shunted rats. The renal responses were reduced by HS-142-1 to a significantly greater extent in shunted rats than in control rats. HS-142-1 did not induce any significant systemic hemodynamic changes in either group, nor did it alter renal blood flow. However, the GFR in HS-142-1-treated shunted rats was lower than that in vehicle-treated shunted rats, both at baseline (0.6+/-0.3 ml/min versus 2.1+/-0.4 ml/min with vehicle, P < 0.05) and after an acute volume load (1.2+/-0.4 ml/min versus 2.6+/-0.4 ml/min with vehicle, P = 0.01), whereas no such effect was observed in control rats. These data indicate that the maintenance of basal renal function and the responses to acute volume loading are dependent on the NP system. The NP seem to be of particular importance for the maintenance of GFR in this model of experimental heart failure. These observations provide new insights into the importance of the renal NP system in heart failure.


Subject(s)
Atrial Natriuretic Factor/biosynthesis , Heart Failure/physiopathology , Urodynamics , Analysis of Variance , Angiotensin II/blood , Angiotensin II/urine , Animals , Atrial Natriuretic Factor/analysis , Atrial Natriuretic Factor/drug effects , Cyclic GMP/blood , Cyclic GMP/urine , Disease Models, Animal , Glomerular Filtration Rate/drug effects , Kidney Function Tests , Male , Polysaccharides/pharmacology , Rats , Rats, Wistar , Reference Values , Renal Circulation/drug effects , Statistics, Nonparametric
13.
Thromb Haemost ; 82 Suppl 1: 73-5, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10695491

ABSTRACT

The term ventricular remodeling has been coined to describe the geometrical changes in size and shape of the left ventricle occurring after large myocardial infarcts. We do not exactly know what initiates this process. Slipping of myofilaments following destruction of connective tissue--probably due to metalloproteinase activation--could be the initial event. As a consequence, wall stress is increased triggering deleterious adaptation processes, such as: - intracardiac angiotensin II generation; - cardiac endothelin formation and release; - pro-apoptotic signals for cardiomyocytes; - hypertrophic signals for fibroblasts and cardiomyocytes. This cascade of events is not only observed in the process of remodeling following myocardial infarction but is also operating during the progression of heart failure. Therapeutic principles therefore are similar in both conditions: - reduction of wall stress (pharmacological or mechanical unloading of the heart); - blockade of angiotensin II generation or of AT1-receptors (ACE-inhibitors or AT1 antagonists); - blockade of endothelin receptors (ET(A)-blockers); - blockade of adrenergic receptors (preferably beta1-adrenergic receptor blockers). Better understanding of the molecular mechanisms of the remodeling process already has fueled the search for new therapeutic interventions (such as endothelin receptor blockers, aldosterone antagonists and growth hormone application). Continuous research in this field may be especially rewarding if we will succeed in identifying the very first step in the cascade.


Subject(s)
Myocardial Infarction/physiopathology , Ventricular Remodeling , Animals , Humans , Myocardial Infarction/pathology
14.
Basic Res Cardiol ; 93 Suppl 2: 101-8, 1998.
Article in English | MEDLINE | ID: mdl-9833171

ABSTRACT

An activated renin-angiotensin system is a major risk factor for cardiovascular events. Angiotensin II acts on AT1 and AT2 receptors. Stimulation of AT1 receptors is associated with endothelial dysfunction, mainly as the consequence of an increased vascular production of superoxide radicals, vasoconstriction, platelet activation, enhanced release of plasminogen activator inhibitor-1, activation of immediate early genes c-fos and c-jun, myocyte hypertrophy, connective tissue formation, endothelin-1 synthesis, and activation of growth factors like PDGF and TGF-beta 1. Stimulation of AT2 receptors can mitigate or abolish the growth promoting effects of AT1 receptor stimulation. The contribution of these effects--single or in combination--on the progression of atherosclerotic lesions, the phenomenon of restenosis and the process of remodeling in heart failure is being progressively elucidated. With increasing knowledge about these relationships the inhibition of AT1 receptors appears as a main target in preventive and reparative strategies in cardiovascular diseases.


Subject(s)
Angiotensin II/physiology , Coronary Disease/physiopathology , Death, Sudden, Cardiac , Heart Failure/physiopathology , Humans , Models, Cardiovascular
15.
Am J Physiol ; 275(5): H1818-25, 1998 11.
Article in English | MEDLINE | ID: mdl-9815090

ABSTRACT

The atrial natriuretic peptide (ANP)-C receptor is generally believed to clear ANP; however, the ANP-C receptor may serve to reduce cAMP by inhibiting adenylate cyclase. ANP decreases endothelial permeability in coronary endothelial cell monolayers. We tested the hypothesis that part of this effect might be mediated by the ANP-C receptor. We used an endothelial cell monolayer from rat coronary endothelium and measured albumin flux. We applied either ANP or a ring-deleted ANP (C-ANP), which only stimulates the ANP-C receptor. ANP and C-ANP both decreased permeability from 100 pM to 100 nM by 60 and 30%, respectively. ANP increased endothelial cGMP contents 5.5-fold, whereas C-ANP had no effect. ANP reduced endothelial cAMP contents by 75%, which was only partly blocked by pertussis toxin. C-ANP also reduced cAMP; however, this effect was completely blocked by pertussis toxin. Protein kinase G inhibition blocked the ANP-mediated decrease in permeability by 50%. In contrast, pretreatment with pertussis toxin, in the face of protein kinase G inhibition, blocked the effect completely. C-ANP decreased permeability by half the amount of ANP. This C-ANP effect was completely blocked by pertussis toxin but not by protein kinase G inhibition. Isoproterenol (10 microM) increased permeability by almost 50%, which was completely blocked by ANP but only partially blocked by C-ANP. The C-ANP effect was blocked completely by pertussis toxin. Isoproterenol increased cAMP threefold, which was abolished by ANP. C-ANP reduced the isoproterenol-induced increase in cAMP by 50%. Isoproterenol had no effect on cGMP. We conclude that agonist binding to the ANP-C receptor inhibits cAMP production via a Gi protein-coupled signaling system. This inhibition may contribute to the decreased endothelial permeability evoked by ANP in this system.


Subject(s)
Atrial Natriuretic Factor/physiology , Capillary Permeability/physiology , Endothelium, Vascular/physiology , Guanylate Cyclase/physiology , Receptors, Atrial Natriuretic Factor/physiology , Animals , Atrial Natriuretic Factor/pharmacology , Coronary Vessels/physiology , Cyclic AMP/physiology , Cyclic GMP/physiology , Male , Rats , Rats, Wistar , Receptors, Atrial Natriuretic Factor/agonists , Signal Transduction/physiology
16.
Eur J Pharmacol ; 347(2-3): 245-52, 1998 Apr 24.
Article in English | MEDLINE | ID: mdl-9653889

ABSTRACT

Neutral endopeptidase inhibition (NEPI) provides a potential avenue to modulate the actions of atrial natriuretic peptide (ANP). We tested the hypothesis that acute and chronic NEPI increased the renal responses at baseline and after acute volume expansion in rats. ANP plasma levels and cGMP excretion were significantly increased with acute NEPI by SQ 28.603, whereas chronic inhibition with SCH 34826 did not lead to any changes. The ratio of cGMP excretion per plasma ANP, however, was significantly increased (6.2 +/- 0.9) by chronic treatment with SCH 34826 compared to chronic vehicle treatment (4.2 +/- 0.7) indicating an activated renal ANP receptor system. Baseline diuresis and natriuresis were enhanced with acute but not with chronic treatment. After acute volume expansion, ANP increased five-fold with acute NEPI, whereas it only increased about 70% in chronically inhibited rats. The natriuretic (497 +/- 62 vs. 329 +/- 42 micromol/60 min with vehicle, P < 0.05) and diuretic responses were significantly enhanced with chronic treatment. Together with an increased cGMP/ANP ratio, these data suggest that chronic activation of the renal ANP system after long-term NEPI facilitated the excretion of an acute volume load. These findings may have therapeutic implications in patients with chronic sodium retention.


Subject(s)
Atrial Natriuretic Factor/blood , Cyclic GMP/blood , Natriuresis , Neprilysin/antagonists & inhibitors , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Blood Pressure/drug effects , Body Weight/drug effects , Diuresis/drug effects , Enzyme Inhibitors/pharmacology , Heart Rate/drug effects , Hemodynamics , Kidney/drug effects , Male , Rats , Rats, Wistar
17.
Lancet ; 351(9111): 1233-7, 1998 Apr 25.
Article in English | MEDLINE | ID: mdl-9643742

ABSTRACT

BACKGROUND: Some studies have suggested that treatment with recombinant human growth hormone (rhGH) increases left-ventricular mass and improves haemodynamic and functional status in patients with heart failure due to dilated cardiomyopathy. We did a double-blind, randomised, placebo-controlled study of rhGH in patients with chronic heart failure due to dilated cardiomyopathy. METHODS: 50 patients (43 men) were randomly allocated treatment with subcutaneous rhGH (2 IU daily) or placebo for a minimum of 12 weeks. The primary endpoints were the effects on left-ventricular mass and systolic wall stress. The secondary endpoints were the effects on left-ventricular size and function. Data were analysed by intention to treat. FINDINGS: Patients in the rhGH group had an increase in left-ventricular mass compared with those in the placebo group (27%, p=0.0001). There was no significant difference in left-ventricular systolic wall stress, mean blood pressure, or systemic vascular resistance between the two groups. New York Heart Association functional class, left-ventricular ejection fraction, and distance on the 6 min walking test were unchanged. The change in serum insulin-like growth factor (IGF)-I concentrations (rhGH 77 ng/mL; placebo -19 ng/mL, GH vs placebo p=0.0001) was significantly related to the change in left-ventricular mass (r=0.55, p=0.0001). One patient in the rhGH group was withdrawn at 6 weeks because of worsening heart failure. INTERPRETATION: There is a significant increase in left-ventricular mass in patients with dilated cardiomyopathy given rhGH but this is not accompanied by an improvement in clinical status. Changes in left-ventricular mass are related to changes in serum IGF-I concentrations. Whether a longer treatment period would provide clinical benefits and decrease mortality is unknown.


Subject(s)
Cardiomyopathy, Dilated/complications , Growth Hormone/therapeutic use , Heart Failure/drug therapy , Adult , Aged , Double-Blind Method , Female , Growth Hormone/adverse effects , Heart Failure/etiology , Heart Failure/pathology , Heart Failure/physiopathology , Heart Ventricles/drug effects , Humans , Hypertrophy, Left Ventricular/chemically induced , Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor I/metabolism , Male , Middle Aged , Stroke Volume , Ventricular Function, Left
18.
Z Kardiol ; 86(10): 803-11, 1997 Oct.
Article in German | MEDLINE | ID: mdl-9454447

ABSTRACT

Dilated cardiomyopathy is a disease of the myocardium which is characterized by predominant enlargement of the left ventricle, decreased systolic function, and reduced myocardial wall thickness. The reduction in the number and function of myocardial fibers induces hypertrophy and leads to interstitial fibrosis. Ventricular dilatation and reduced wall thickness contributes to a further increase of the already elevated myocardial wall stress and triggers the continuous decrease of myocardial function. The initial myocyte injury by different and mostly unknown causes leads to progressive myocyte damage resulting in a similar uniform clinical picture independent from the initial myocellular derangement. One of the common pathways may be an inadequate response of the heart to human growth hormone (GH). Several studies support this hypothesis: GH deficiency results in a significant reduction of ventricular wall thickness and myocardial function, and GH-substitution is able to normalize the depressed left ventricular function. In addition, Sacca et al. reported in an uncontrolled study that GH-therapy reduced left ventricular wall stress by 40% in 7 patients with dilated cardiomyopathy. There was a parallel increase of the ejection fraction from 34% to 47%. This improvement was accompanied by a decrease of the functional classification of heart failure from NYHA 2.7 to 1.6. This therapeutic approach to alter the myocyte function directly by growth factors may open a new therapeutic concept in dilated cardiomyopathy. If double blind, randomized studies confirm the results of Sacca's study, a new era of therapeutic options may be available for the treatment of dilated cardiomyopathy.


Subject(s)
Cardiomyopathy, Dilated/therapy , Growth Hormone/therapeutic use , Animals , Cardiomyopathy, Dilated/physiopathology , Growth Hormone/adverse effects , Heart Failure/physiopathology , Heart Failure/therapy , Hemodynamics/drug effects , Hemodynamics/physiology , Human Growth Hormone/physiology , Humans , Treatment Outcome , Ventricular Dysfunction, Left/physiopathology , Ventricular Dysfunction, Left/therapy , Ventricular Function, Left/drug effects , Ventricular Function, Left/physiology
19.
Am J Physiol ; 273(6): H2580-5, 1997 12.
Article in English | MEDLINE | ID: mdl-9435590

ABSTRACT

Baroreceptor-heart rate reflex sensitivity is decreased in congestive heart failure. The reflex control of heart rate and sympathetic nerve activity in rats with chronic volume overload, an established model for moderate heart failure, is still unknown. Therefore, we investigated the regulation of humoral and neuronal sympathetic activity and the baroreflex control of heart rate and sympathetic nerve activity in conscious, unrestrained rats with aortocaval shunt. Rats with aortocaval shunts had larger hearts (388 +/- 11 vs. 277 +/- 4 mg/100 g body wt), elevated central venous pressures (14 +/- 4 vs. 4 +/- 3 mmHg), and higher atrial natriuretic peptide plasma levels (87 +/- 16 vs. 25 +/- 3 pmol/l) than controls but had similar systemic blood pressure and heart rate values. Plasma epinephrine (0.63 +/- 0.16 vs. 0.21 +/- 0.08 pmol/l, P < 0.05) and norepinephrine concentrations (0.27 +/- 0.03 vs. 0.16 +/- 0.02 pmol/l, P < 0.05) were elevated in shunted rats compared with controls. Nitroprusside-induced hypotension led to a significantly greater increase in efferent splanchnic sympathetic nerve activity in shunted rats than in controls (0.9 +/- 0.1 vs. 2.6 +/- 0.6 microV, P < 0.05), whereas the heart rate responses were not different between the groups. These results indicate that the regulation of the autonomic nervous system is altered in chronically volume-overloaded rats. The arterial baroreflex control of efferent splanchnic sympathetic nerve activity was dissociated from the control of heart rate. Therefore, analysis of the activation of sympathetic nervous system assessed by direct measurements of efferent sympathetic nerve activity appears to be more sensitive for the detection of altered autonomic nervous system function than the analysis of baroreflex control of heart rate.


Subject(s)
Atrial Natriuretic Factor/blood , Baroreflex/physiology , Blood Pressure , Epinephrine/blood , Heart Rate , Norepinephrine/blood , Sympathetic Nervous System/physiology , Animals , Aorta, Abdominal/surgery , Baroreflex/drug effects , Body Weight , Heart/anatomy & histology , Heart/physiology , Heart Rate/drug effects , Male , Nitroprusside/pharmacology , Organ Size , Portasystemic Shunt, Surgical , Rats , Rats, Wistar , Reference Values , Splanchnic Circulation/physiology , Vena Cava, Inferior/surgery
20.
Hypertension ; 27(6): 1259-66, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8641733

ABSTRACT

In heart failure, sodium and water retention develop despite elevated plasma levels of atrial natriuretic peptide. Atrial natriuretic peptide is degraded in part by a neutral endopeptidase. Whether neutral endopeptidase inhibition improves sodium and water excretion in heart failure is unknown. We determined the effect of neutral endopeptidase inhibition on plasma levels of atrial natriuretic peptide and the renal response to acute volume expansion in rats with aortocaval shunts and in sham-operated controls. Acute endopeptidase inhibition with SQ 28,603 (30 mg/kg) elevated atrial natriuretic peptide plasma levels in both shunted rats (523 +/- 54 to 1258 +/- 330 pmol/L, P<.05) and controls (184 +/- 28 to 514 +/- 107 pmol/L, P<.05). Urinary cGMP excretion, which reflects renal action, increased in parallel. However, the diuretic and natriuretic responses to acute volume expansion were enhanced only in control rats and not in shunted rats. In contrast to the acute effects, chronic neutral endopeptidase inhibition with SCH 34826 (30 mg/kg twice daily) in shunted rats did not change atrial natriuretic peptide plasma levels or cGMP excretion. Nevertheless, the diuretic and natriuretic responses to acute volume load were increased by chronic endopeptidase inhibition in shunted rats (1789 +/- 154 to 2674 +/- 577 microL/80 min and 99 +/- 31 to 352 +/- 96 micromol/80 min, respectively; P<.05). Chronic endopeptidase inhibition attenuated the cardiac hypertrophic response to aortocaval shunt without changing arterial blood pressure. Our data show that the renal effects of neutral endopeptidase inhibition are not necessarily dependent on changes in atrial natriuretic peptide plasma levels but instead may be mediated by local inhibition of the neutral endopeptidase in the kidney. In addition, chronic endopeptidase inhibition may attenuate heart failure-induced cardiac hypertrophy independent of hemodynamic effects.


Subject(s)
Alanine/analogs & derivatives , Atrial Natriuretic Factor/blood , Diuresis/drug effects , Enzyme Inhibitors/pharmacology , Heart Failure/metabolism , Neprilysin/antagonists & inhibitors , Alanine/pharmacology , Angiotensin II/blood , Animals , Aorta, Abdominal/surgery , Arteriovenous Shunt, Surgical , Cyclic GMP/urine , Hemodynamics/drug effects , Male , Natriuresis/drug effects , Neprilysin/physiology , Rats , Rats, Wistar , Renin/blood , Vena Cava, Inferior/surgery
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