cyclic-gmp and Cardiomyopathy--Dilated

An important hallmark of cardiac failure is abnormal second messenger signaling due to impaired synthesis and catabolism of cyclic adenosine 3',5'- monophosphate (cAMP) and cyclic guanosine 3',5'- monophosphate (cGMP). Their dysregulation, altered intracellular targeting, and blunted responsiveness to stimulating pathways all contribute to pathological remodeling, muscle dysfunction, reduced cell survival and metabolism, and other abnormalities. Therapeutic enhancement of either cyclic nucleotides can be achieved by stimulating their synthesis and/or by suppressing members of the family of cyclic nucleotide phosphodiesterases (PDEs). The heart expresses seven of the eleven major PDE subtypes - PDE1, 2, 3, 4, 5, 8, and 9. Their differential control over cAMP and cGMP signaling in various cell types, including cardiomyocytes, provides intriguing therapeutic opportunities to counter heart disease. This review examines the roles of these PDEs in the failing and hypertrophied heart and summarizes experimental and clinical data that have explored the utility of targeted PDE inhibition.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cardiomyopathy, Dilated; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 1; Cyclic Nucleotide Phosphodiesterases, Type 2; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Diseases; Heart Failure; Humans; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Signal Transduction

Cyclic guanosine monophosphate (cGMP) and its primary signaling kinase, protein kinase G, play an important role in counterbalancing stress remodeling in the heart. Growing evidence supports a positive impact on a variety of cardiac disease conditions from the suppression of cGMP hydrolysis. The latter is regulated by members of the phosphodiesterase (PDE) superfamily, of which cGMP-selective PDE5 has been best studied. Inhibitors such as sildenafil and tadalafil ameliorate cardiac pressure and volume overload, ischemic injury, and cardiotoxicity. Clinical trials have begun exploring their potential to benefit dilated cardiomyopathy and heart failure with a preserved ejection fraction. This review discusses recent developments in the field, highlighting basic science and clinical studies.

Topics: Carbolines; Cardiomyopathy, Dilated; Cyclic AMP; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Fibrosis; Heart; Heart Failure; Humans; Hypertrophy; Myocardium; Phosphodiesterase 5 Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Transforming Growth Factor beta; TRPC Cation Channels; Ventricular Remodeling

Short-term infusion of carperitide (atrial natriuretic peptide) has beneficial effects on neurohumoral factors; however, it remains unclear whether the effects are sustained for long-term infusion. To evaluate the effects of long-term infusion of carperitide on neurohumoral factors in patients with chronic congestive heart failure (CHF), we measured neurohumoral factors before and 1 hour after stopping carperitide infusion in 42 CHF patients. Carperitide infusion was continued for more than 2 days until there was symptomatic improvement of CHF. Patients were divided into 2 groups by the median value of infusion duration: group 1 (less than 7 days, n=21) and group 2 (more than 7 days, n=21). In group 1, aldosterone (ALD) and endothelin-1 (ET-1) were significantly increased after stopping carperitide. In contrast, ALD and ET-1 did not change after stopping carperitide in group 2. The molar ratio of cyclic guanosine monophosphate/atrial natriuretic peptide before stopping carperitide was significantly lower in group 2 than in group 1. Suppression of ALD and ET-1 was maintained for 7 days of carperitide infusion, but the beneficial effect on neurohumoral factors was attenuated after more than 7 days, probably through down-regulation of biologic receptors coupled with guanylate cyclase in CHF patients.

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathy, Dilated; Chronic Disease; Cyclic GMP; Endothelin-1; Female; Heart Failure; Heart Rate; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Stroke Volume; Time Factors; Treatment Outcome

Dilated cardiomyopathy is characterized by elevated arterial vascular resistance and impaired nitric oxide (NO)-dependent vasodilation. Insulin-like growth factor-I (IGF-I) has been shown to stimulate endothelial NO-synthase resulting in endothelium-dependent vasodilation. Growth hormone (GH) substitution therapy leads in GH-deficient patients to significant increases of IGF-I which may alter systemic vascular resistance by stimulating NO production. This study was designed to evaluate the effects of treatment with recombinant human growth hormone (GH) on NO production and NO-dependent vascular effects in patients with dilated cardiomyopathy.. 50 patients with dilated cardiomyopathy were randomly assigned to double-blind treatment with 2 I.U. of GH or placebo for 3 months. Central hemodynamics were determined by Swan-Ganz catheter and cardiac output was obtained by the thermodilution method. Serum GH and IGF-I levels were measured and systemic NO production was determined from urinary nitrate and cyclic GMP excretion rates in 42 patients.. GH treatment caused in comparison to the placebo group a significant increase of IGF-I by 91 ng/ml (P = 0.0001). Urinary excretion rates of nitrate and cyclic GMP increased also significantly by 38 mumol/mmol creatinine (P = 0.027) and 65 nmol/mmol creatinine (P = 0.003), respectively. The parallel increase of both marker molecules indicates increased systemic NO production during GH treatment.. GH treatment induces a significant, but moderate increase of systemic NO production in patients with dilated cardiomyopathy. This effect may be mediated by IGF-I stimulating endothelial NO synthase.

Topics: Cardiomyopathy, Dilated; Chi-Square Distribution; Cyclic GMP; Double-Blind Method; Female; Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Nitrates; Nitric Oxide; Regression Analysis

In eight patients (63 +/- 8 years) with dilated cardiomyopathy, the acute effects of positive inotropic stimulation with dopexamine hydrochloride, a beta-2-agonistic and DA1-dopaminergic catecholamine, on the plasma levels of ANP and cGMP were tested. A four-point dose-response curve was prepared for dopexamine from 1 microgram/kg/min to 4 micrograms/kg/min. Each infusion stage lasted 15 min; ANP and cGMP were taken from the mixed venous blood. Hemodynamic parameters were determined by a Swan-Ganz catheter; cardiac output was determined by thermodilution. ANP dropped by 40% from 348 +/- 124 pg/ml to 208 +/- 70 pg/ml (p less than or equal to 0.01), while cGMP dropped by 25% from 4.8 +/- 1.6 pmol to 3.6 +/- 1.3 pmol/ml at the time of maximum hemodynamic effect after 1 h. Linear regression analyses revealed a significant relationship (p less than or equal to 0.01) between ANP as the independent variable and cGMP as the dependent variable. The hemodynamic determinants of the ANP concentration proved to be--independently of each other--the pulmonary capillary wedge pressure (p less than or equal to 0.01) and the mean right atrial pressure (p less than or equal to 0.01). The results show that chronically elevated ANP and cGMP levels can be strikingly reduced within a short time, whereby ANP and cGMP show similar kinetics. The results suggest a use of ANP and cGMP as humoral parameters in the therapy control of chronic heart failure.

Topics: Adrenergic beta-Agonists; Aged; Atrial Natriuretic Factor; Cardiomyopathy, Dilated; Clinical Trials as Topic; Cyclic GMP; Dopamine; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged

Ibopamine is a novel oral dopamine analogue with positive inotropy and diuretic effects. In a double-blind, randomized study, the drug was investigated in 10 patients (mean age 49 +/- 10 years, six male, four female) with mild heart failure (NYHA classes II: six patients, III: four patients). Effects of single oral doses of 200 mg ibopamine, of 40 mg furosemide, and of 200 mg ibopamine plus 40 mg furosemide were compared in each patient at 3-day-intervals. One h after application, systolic and diastolic blood pressure increased from 119 +/- 11 to 124 +/- 8, and from 75 +/- 4 to 80 +/- 6 mm Hg (p less than 0.01) in the ibopamine group, while changes in both other groups and changes of the heart rate were insignificant. During 2 h after drug ingestion urinary flow was raised from 124 +/- 81 to 227 +/- 166 ml/2 h in the ibopamine group (p less than 0.05), while the application of furosemide (with or without ibopamine) resulted in several fold increases of urinary flow. After ibopamine, the 2-h-creatinine-clearance rose from 123 +/- 73 to 130 +/- 85 ml/min (not significant). Sodium excretion remained unchanged by ibopamine, potassium excretion was increased from 2.9 +/- 1.7 to 4.0 +/- 3.3 mmol/h (p less than 0.05), while effects of furosemide were several fold of those of ibopamine. Atrial natriuretic factor concentrations in plasma increased significantly after ibopamine and after ibopamine plus furosemide (p less than 0.01), but remained constant after furosemide alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathy, Dilated; Coronary Disease; Cyclic GMP; Deoxyepinephrine; Diuretics; Dopamine; Electrolytes; Female; Furosemide; Heart Failure; Humans; Male; Middle Aged; Mitral Valve Insufficiency; Natriuresis; Urodynamics

Sodium restriction is often recommended in heart failure (HF) to block symptomatic edema, despite limited evidence for benefit. However, a low-sodium diet (LSD) activates the classical renin-angiotensin-aldosterone system (RAAS), which may adversely affect HF progression and mortality in patients with dilated cardiomyopathy (DCM). We performed a randomized, blinded pre-clinical trial to compare the effects of a normal (human-equivalent) sodium diet and a LSD on HF progression in a normotensive model of DCM in mice that has translational relevance to human HF. The LSD reduced HF progression by suppressing the development of pleural effusions (

Topics: Angiotensin I; Animals; Biological Availability; Biomarkers; Blood Pressure; Cardiomyopathy, Dilated; Cyclic GMP; Diet, Sodium-Restricted; Edema; Heart Failure; Kidney; Male; Mice, Inbred C57BL; Natriuretic Peptide, Brain; Nitric Oxide; Nitric Oxide Synthase; Peptide Fragments; Phosphoric Diester Hydrolases; Pleural Effusion; Renin-Angiotensin System; Survival Analysis; Systole

Implantation of left ventricular assist devices (LVADs) as bridge to transplant in end-stage heart failure allows for analyzing reverse remodeling processes of the supported heart. Whether this therapy influences the cGMP-PKG signaling pathway, which is currently under thorough investigation for developing new heart failure therapeutics, is unknown. In fourteen end-stage heart failure patients (8 with dilated cardiomyopathy, DCM; 6 with ischemic cardiomyopathy, ICM) tissue specimens of left ventricles were collected at LVAD implantation and afterwards at receiver heart explantation, respectively. Then the expressions of key components of the cGMP-PKG signaling pathway were determined by polymerase chain reaction (ANP; BNP; natriuretic peptide receptor A, NPR-A; natriuretic peptide receptor C, NPR-C; neprilysin; NOS3; soluble guanylyl cyclase, sGC; PDE5; cGMP-dependent protein kinase G, PKG) and enzyme-linked immunosorbent assay (cGMP), respectively. Patients were predominantly male, 52 ± 10 years old, were receiving recommended heart failure therapy, and had their donor organ implanted after 351 ± 317 days of LVAD support. Except for more DCM patients with ICD therapy, no significant differences were detected between ICM and DCM, which also applies to the expression of cGMP-PKG pathway components at baseline. After LVAD support, ANP, NPR-C, and cGMP were significantly down-regulated and neprilysin, PDE5, and PKG I expressions were reduced with borderline significance in DCM, but not in ICM patients. Multiple significant correlations were found for expression differences (i.e., expression at LVAD implantation minus expression at heart transplantation) both in DCM and ICM, even though there was a closer connection between the NO and NP side of the cGMP-PKG pathway in DCM patients. Furthermore, duration of LVAD support negatively correlated with expression differences of PKG I, PDE5, and sGC in ICM, but not in DCM. Originating from the same activation level at LVAD implantation, cardiac unloading significantly alters key components of the cGMP-PKG pathway in DCM, but not in ICM patients. This etiology-specific regulation should be considered when analyzing therapeutic interventions with effects on this signaling pathway.

Topics: Cardiomyopathy, Dilated; Cyclic GMP; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Heart-Assist Devices; Humans; Male; Middle Aged; Myocardial Ischemia; Reverse Transcriptase Polymerase Chain Reaction; RNA; Signal Transduction; Ventricular Remodeling

In heart failure (HF), ventricular myocardium expresses brain natriuretic peptide (BNP). Despite the association of elevated serum levels with poor prognosis, BNP release is considered beneficial because of its antihypertrophic, vasodilating, and diuretic properties. However, there is evidence that BNP-mediated signaling may adversely influence cardiac remodeling, with further impairment of calcium homeostasis.. We studied the effects of BNP on preload-dependent myocardial sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) expression. In rabbit isolated muscle strips stretched to high preload and shortening isotonically over 6 hours, the SERCA/glyceraldehyde phosphate dehydrogenase mRNA ratio was enhanced by 168% (n=8) compared with unloaded preparations (n=8; P<0.001). Recombinant human BNP at a concentration typically found in end-stage HF patients (350 pg/mL) abolished SERCA upregulation by stretch (n=9; P<0.0001 versus BNP free). Inhibition of cyclic guanosine 3',5' monophosphate (cGMP)-phosphodiesterase-5 mimicked this effect, whereas inhibition of cGMP-dependent protein kinase restored preload-dependent SERCA upregulation in the presence of recombinant human BNP. Furthermore, in myocardium from human end-stage HF patients undergoing cardiac transplantation (n=15), BNP expression was inversely correlated with SERCA levels. Moreover, among 23 patients treated with left ventricular assist devices, significant SERCA2a recovery occurred in those downregulating BNP.. Our data indicate that preload stimulates SERCA expression. BNP antagonizes this mechanism via guanylyl cyclase-A, cGMP, and cGMP-dependent protein kinase. This novel action of BNP to uncouple preload-dependent SERCA expression may adversely affect contractility in patients with HF.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Animals; Calcineurin; Calcium Signaling; Calcium-Transporting ATPases; Cardiomyopathy, Dilated; Cohort Studies; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Enzyme Induction; Female; Guanylate Cyclase; Heart Failure; Heart-Assist Devices; Humans; In Vitro Techniques; Male; Middle Aged; Myocardial Ischemia; Myocardium; Natriuretic Peptide, Brain; NFATC Transcription Factors; Receptors, Atrial Natriuretic Factor; Recombinant Fusion Proteins; RNA, Messenger; Sarcoplasmic Reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Stress, Mechanical

Nitric oxide synthase (NOS)-derived nitric oxide (NO) production is regulated posttranslationally through enzyme's inhibitory interaction with the caveolar coat protein, caveolin and stimulatory interaction with the chaperone heat shock protein, Hsp90. However, changes in the expression of these regulators with the development of hypertrophic cardiomyopathy are unknown.. Histochemical and immunoblotted signals for the NOS isoforms, caveolin and Hsp90 were compared in left ventricle (LV) and aortic or mesenteric vessels between spontaneously hypertensive rats (SHR; 18 and 63 weeks old) and age-matched normotensive Wistar-Kyoto (WKY) rats. To assess functional impacts on downstream NO signaling, superoxide anions (O(2)(-)) and cGMP contents were measured in the same tissues by oxidative fluorescent hydroethidine staining and enzyme immunoassay, respectively.. Compared with levels in age-matched WKY rats, endothelial NOS (eNOS) proteins were increased in aorta of SHR at 18 weeks. Conversely, aortic caveolin-1 and -3 were decreased in SHR, whereas Hsp90 remained unchanged. In LV tissue of SHR at 18 weeks, caveolin-1 and -3 were similarly decreased, but Hsp90 upregulated, together with a downregulation of eNOS. However, at 63 weeks, both eNOS and neuronal NOS (nNOS) were markedly upregulated in the LV of SHR, together with an upregulation of Hsp90. No difference in cardiac and aortic cGMP contents was found between the two strains. In LV sections, O(2)(-) generation was higher in older compared with younger rats from both strains and highest in 63 weeks SHR.. Changes in NOS protein abundance in SHR rats compared with WKY controls are differentially regulated according to the age of hypertension and the tissue examined and are not necessarily correlated with cGMP contents. The coordinate expressional changes in NOS isoforms and their allosteric regulators, such as caveolin and Hsp90, may act as a compensatory mechanism to maintain the production of bioactive NO in the face of increased oxidant stress.

Topics: Allosteric Regulation; Animals; Aorta, Thoracic; Blotting, Western; Cardiomyopathy, Dilated; Caveolin 1; Caveolin 3; Caveolins; Cyclic GMP; Heart Ventricles; Hypertension; Male; Mesenteric Arteries; Nitric Oxide Synthase; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Superoxides

The multidrug resistance protein 5 (MRP5/ABCC5) has been recently identified as cellular export pump for cyclic nucleotides with 3',5'-cyclic GMP (cGMP) as a high-affinity substrate. In view of the important role of cGMP for cardiovascular function, expression of this transport protein in human heart is of relevance. We analyzed the expression and localization of MRP5 in human heart [21 auricular (AS) and 15 left ventricular samples (LV) including 5 samples of dilated and ischemic cardiomyopathy]. Quantitative real-time polymerase chain reaction normalized to beta-actin revealed expression of the MRP5 gene in all samples (LV, 38.5 +/- 12.9; AS, 12.7 +/- 5.6; P < 0.001). An MRP5-specific polyclonal antibody detected a glycoprotein of approximately 190 kd in crude cell membrane fractions from these samples. Immunohistochemistry with the affinity-purified antibody revealed localization of MRP5 in cardiomyocytes as well as in cardiovascular endothelial and smooth muscle cells. Furthermore, we could detect MRP5 and ATP-dependent transport of [(3)H]cGMP in sarcolemma vesicles of human heart. Quantitative analysis of the immunoblots indicated an interindividual variability with a higher expression of MRP5 in the ischemic (104 +/- 38% of recombinant MRP5 standard) compared to normal ventricular samples (53 +/- 36%, P < 0.05). In addition, we screened genomic DNA from our samples for 20 single-nucleotide polymorphisms in the MRP5 gene. These results indicate that MRP5 is localized in cardiac and cardiovascular myocytes as well as endothelial cells with increased expression in ischemic cardiomyopathy. Therefore, MRP5-mediated cellular export may represent a novel, disease-dependent pathway for cGMP removal from cardiac cells.

Topics: Aged; Biological Transport; Cardiomyopathy, Dilated; Cyclic GMP; Female; Heart Atria; Heart Ventricles; Humans; Immunohistochemistry; Male; Middle Aged; Multidrug Resistance-Associated Proteins; Myocardial Ischemia; Myocardium; Myocytes, Cardiac; Nucleotides, Cyclic; Polymorphism, Single Nucleotide; Sarcolemma; Tissue Distribution

Recently, a significant activity of inducible nitric oxide synthase (iNOS) has been reported in biopsies from failing hearts due to idiopathic dilated cardiomyopathy (IDC). Thus, a potential pathophysiological role of iNOS in IDC has been stated. In order to investigate, whether iNOS expression is of pathophysiological relevance in human heart failure, we measured iNOS protein expression and cGMP content in left ventricular myocardium from non-failing and failing human hearts. Immunoblot analysis revealed iNOS protein expression in four out of six failing hearts from septic patients, whereas no iNOS-protein expression was detected in either non-failing human hearts (n = 6) or failing hearts due to IDC (n = 9), ischemic heart disease (IHD, n = 7), Becker muscular dystrophy (BMD, n = 2) and mitoxantrone-induced toxic cardiomyopathy TCM, n = 1). cGMP content was increased by 130% in septic hearts, whereas there was no cGMP increase in hearts with IDC. IHD and BMD compared to non-failing hearts. We conclude, that the induction of iNOS may play a role in contractile dysfunction observed in septic shock, but is unlikely to be of major pathophysiological importance in end-stage heart failure due to IDC, IHD, BMD and TCM.

Topics: Animals; Cardiomyopathies; Cardiomyopathy, Dilated; Cell Line; Cyclic GMP; Gene Expression; Heart Failure; Heart Ventricles; Humans; Isoenzymes; Macrophages; Mice; Mitoxantrone; Muscular Dystrophies; Myocardial Ischemia; Myocardium; Nitric Oxide Synthase; Reference Values; Sepsis

Sarcoplasmic reticulum-associated cAMP phosphodiesterase activity was examined in microsomes prepared from the left ventricular myocardium of eight heart transplant recipients with end-stage idiopathic dilated cardiomyopathy and six unmatched organ donors with normal cardiac function. At cAMP concentrations less than or equal to 1.0 microM, sarcoplasmic reticulum-associated cAMP phosphodiesterase activity was functionally homogeneous. cAMP phosphodiesterase activity was inhibited competitively by cGMP (Ki = 0.031 +/- 0.008 microM) and the cilostamide derivative OPC 3911 (Ki = 0.018 +/- 0.004 microM), but was essentially insensitive to rolipram. Vmax and Km were 781.7 +/- 109.2 nmol/mg per min and 0.188 +/- 0.031 microM, respectively, in microsomes prepared from nonfailing hearts and 793.9 +/- 68.9 nmol/mg per min and 0.150 +/- 0.027 microM in microsomes prepared from failing hearts. Microsomes prepared from nonfailing and failing hearts did not differ with respect to either the ratio of cAMP phosphodiesterase activity to ATP-dependent Ca2+ accumulation activity or the sensitivity of cAMP phosphodiesterase activity to inhibition by OPC 3911. These data suggest that the diminished inotropic efficacy of phosphodiesterase inhibitors in failing human hearts does not result from changes in the level, kinetic properties, or pharmacologic sensitivity of sarcoplasmic reticulum-associated cAMP phosphodiesterase activity.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adult; Calcium; Cardiomyopathy, Dilated; Cyclic GMP; Heart Failure; Humans; Kinetics; Middle Aged; Myocardium; Sarcoplasmic Reticulum

In eight patients (63 +/- 7.9 years) with angiographically documented dilated cardiomyopathy, we studied the acute effects of a beta-adrenergic stimulation with dobutamine on the plasma levels of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP). For this purpose, a four-point dose-response curve was prepared for dobutamine starting with an initial dose of 2.5 micrograms kg-1 min-1, which was increased by 2.5 micrograms kg-1 min-1 at a time up to altogether 10 micrograms kg-1 min-1. Each stage lasted 15 min. ANP and cGMP were determined from the mixed venous blood before the start (t0), at 5 micrograms kg-1 min-1 after 30 min (t1), at 10 micrograms kg-1 min-1 after 60 min (t2) and after subsidence of the drug effect after 90 min (t3). ANP dropped from 380 +/- 151 pg ml-1 (normal range up to 55 pg ml-1) by 38% to 235 +/- 90 pg ml-1 after 30 min and by another 17% to 171 +/- 45 pg ml-1 after 60 min. After the effect of dobutamine had subsided, an increase by 41% to 325 +/- 139 was reached. There was a parallel drop of the mean cGMP level from 5.4 +/- 1.4 pmol.ml-1 by 28% to 3.89 +/- 1.4 pmol.ml-1 (30 min) and by another 14% to 3.2 +/- 0.7 pmol.ml-1 (60 min). After 90 min it was 18% below the initial value, being 4.4 +/- 1.3 pmol.ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Atrial Natriuretic Factor; Cardiomyopathy, Dilated; Chronic Disease; Cyclic GMP; Dobutamine; Dose-Response Relationship, Drug; Heart Failure; Hemodynamics; Humans; Male; Middle Aged

A total of 43 patients were examined: 21 patients with large myocardial infarction (MI) and 22 donors. In MI patients without signs of left ventricular failure, the level of atrial natriuretic factor was higher than that in the controls, which resulted in inhibition of aldosterone production; whereas in those with the signs, it was slightly lower than that in healthy individuals. All the patients with MI were found to have elevated blood plasma levels of cyclic nucleotides and beta 2-microglobulin. Ultrasound application to the heart was demonstrated to normalize secretion of atrial natriuretic factor, to increase plasma cyclic nucleotide levels and to produce no effects on beta 2-microglobulin quantities.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; beta 2-Microglobulin; Cardiomyopathy, Dilated; Cyclic AMP; Cyclic GMP; Humans; Middle Aged; Myocardial Infarction; Ultrasonic Therapy

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathy, Dilated; Cyclic GMP; Endothelins; Heart Failure; Hematocrit; Humans; Renin

The aim of the present investigation was to evaluate a possible down-regulation of atrial natriuretic peptide (ANP) binding sites on platelets in patients with chronically elevated ANP plasma levels. The assay procedure was proved to be able to measure the total number of binding sites even in the presence of high ANP plasma levels. We studied 15 adult patients with congestive cardiomyopathy in comparison to 18 healthy volunteers. In the patients the median ANP plasma level (median = 375, range: 155-900 pg ml-1) was about six-fold higher than in the healthy volunteers (median: 55.5, range: 20-90 pg ml-1). The median cyclic guanosine monophosphate (cGMP) plasma level (median: 6.2, range: 2.5-21.4 pmol ml-1) was about three-fold higher than in the healthy volunteers (median: 1.8 range: 1-2.8 pmol ml-1). Despite these markedly elevated ANP and cGMP plasma levels we did not find significantly less receptors per platelet in the patients (median: 19, range: 7.2-60.2) than in the healthy volunteers (median: 24.5, range: 14.8-41.1). Furthermore, there was no difference in the dissociation constants between the patients (median: 10.5, range: 7.9-27.4 pmol l-1) and the control subjects (median: 8.9, range: 5.4-17 pmol l-1).

Topics: Aged; Atrial Natriuretic Factor; Binding Sites; Blood Platelets; Cardiomyopathy, Dilated; Cyclic GMP; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Radioimmunoassay; Time Factors