guanosine-monophosphate and Disease-Models--Animal

Catalytic hydrolysis of cyclic guanosine monophosphate (cGMP) by phosphodiesterase 6 (PDE6) is critical in phototransduction signalling in photoreceptors. Mutations in the genes encoding any of the three PDE6 subunits are associated with retinitis pigmentosa, the most common form of inherited retinal diseases. The RD1 mouse carries a naturally occurring nonsense mutation in the Pde6b gene. The RD1 mouse retina rapidly degenerates and fails to form rod photoreceptor outer segments due to the elevated cGMP level and subsequent excessive Ca2+ influx. In this study, we aim to test whether the PDE5 expression, a non-photoreceptor-specific member of the PDE superfamily, rescues photoreceptors in the RD1 retina.. Electroporation used the PDE5 expression plasmid to transfect neonatal RD1 mice. The mouse retina degeneration was assessed by retinal sections' stains with DAPI. The expression and localization of phototransduction proteins in photoreceptors were analysed by immunostaining. The expression of proteins in cultured cells was analysed by immunoblotting.. The exogenous PDE5 expression, a non-photoreceptor-specific member of the PDE superfamily, prevents photoreceptor degeneration in RD1 mice. Unlike endogenous photoreceptor-specific PDE6 localised in the outer segments of photoreceptors, ectopically- expressed PDE5 was distributed in inner segments and synaptic terminals. PDE5 also promoted the development of the outer segments in RD1 mice. PDE5 co-expression with rhodopsin in cultured cells showed enhanced rhodopsin expression.. Lowering the cGMP level in photoreceptors by PDE5 is sufficient to rescue photoreceptors in RD1 retinas. cGMP may also play a role in rhodopsin expression regulation in photoreceptors.

Topics: Animals; Calcium; Codon, Nonsense; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Cyclic Nucleotide Phosphodiesterases, Type 6; Disease Models, Animal; Guanosine Monophosphate; Mice; Mice, Inbred C57BL; Retina; Retinal Degeneration; Rhodopsin

Phosphodiesterase 5 inhibitors (PDE5is) inhibit the hydrolysis of cyclic guanosine 5'-monophosphate in smooth muscle cells and are a widely known treatment for erectile dysfunction. Accumulating evidence also suggests that PDE5is exhibit potential benefits in cardiovascular and chronic kidney diseases. In this study, we examined the therapeutic effects of a PDE5i, vardenafil (VAR), in a focal segmental glomerulosclerosis (FSGS) mouse model.. FSGS was induced in BALB/c mice by the intravenous administration of Adriamycin (AD, 11 mg/kg of body weight). After 24 h, VAR (at 12.5 μg/ml) was given in drinking water ad libitum until the animals were sacrificed. At the end of the experiment, plasma and kidney samples were harvested to evaluate clinical parameters, histopathological changes, and alterations in transcriptome and protein expressions.. In this study, VAR treatment attenuated the deterioration of proteinuria, renal dysfunction, and hypercholesterolemia in AD-induced FSGS. Treatment with VAR exhibited reductions in the severity of both glomerulosclerosis and tubulointerstitial injury in the histological analysis. In addition to relieving AD-induced podocyte loss, VAR also preserved endothelial cells in glomerular capillaries and ameliorated the accumulation of collagen fibers in the mesangial area and Bowman's capsule basement membrane. In addition, VAR showed an ability to suppress transforming growth factor-β-induced fibroblast-to-myofibroblast transdifferentiation.. Our data suggest that VAR exhibited reno-therapeutic effects via attenuating podocyte loss, preserving the integrity of the glomerular vasculature, and ameliorating fibrotic changes. These findings suggest that PDE5is might be a promising treatment modality for nephrotic syndrome.

Topics: Animals; Collagen; Disease Models, Animal; Doxorubicin; Drinking Water; Endothelial Cells; Glomerulosclerosis, Focal Segmental; Guanosine Monophosphate; Male; Mice; Mice, Inbred BALB C; Phosphodiesterase 5 Inhibitors; Podocytes; Transforming Growth Factors; Vardenafil Dihydrochloride

Impaired angiogenesis function in pulmonary artery endothelial cells (PAEC) contributes to persistent pulmonary hypertension of the newborn (PPHN). Decreased nitric oxide (NO) amounts in PPHN lead to impaired mitochondrial biogenesis and angiogenesis in the lung; the mechanisms remain unclear. We hypothesized that decreased cyclic guanosine monophosphate (cGMP)-PKG (protein kinase G) signaling downstream of NO leads to decreased mitochondrial biogenesis and angiogenesis in PPHN. PPHN was induced by ductus arteriosus constriction from 128-136 days' gestation in fetal lambs. Control animals were gestation-matched lambs that did not undergo ductal constriction. PAEC isolated from PPHN lambs were treated with the sGC (soluble guanylate cyclase) activator cinaciguat, the PKG activator 8-bromo-cGMP, or the PDE-V (PDE type V) inhibitor sildenafil. Lysates were immunoblotted for mitochondrial transcription factors and electron transport chain C-I (complex I), C-II, C-III, C-IV, and C-V proteins. The

Topics: Animals; Animals, Newborn; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Endothelial Cells; Female; Guanosine Monophosphate; Humans; Hypertension, Pulmonary; Infant, Newborn; Mitochondria; Neovascularization, Pathologic; Nitric Oxide Synthase Type III; Pregnancy; Pulmonary Artery; Sheep; Signal Transduction; Sildenafil Citrate

The present study was performed to elucidate the role of nitric oxide (NO) and connexin 40 (Cx40) in the induction of cerebral vasospasm after subarachnoid hemorrhage (SAH) in vivo.. A SAH rat model was established using the double-bleed method. A total of 108 Sprague-Dawley rats weighing 250-300 g were randomly divided into 6 groups: SAH; SAH plus diethylenetriamine (DETA)/NO (exogenous NO donor); SAH plus 8-bromoadenosine (8-Br)-cyclic guanosine monophosphate (cGMP; protein kinase G [PKG] activator); SAH plus DETA/NO plus KT5823 (PKG inhibitor); SAH plus DETA/NO plus 40Gap27 (Cx40 inhibitor); and sham. The changes in the diameter of the branch microvessels in the middle cerebral artery were recorded. The neurological score was evaluated using the Garcia scoring system. Basilar artery (BA) tension was measured using the Danish Myo Technology myograph system. Cx40 protein expression was analyzed using immunofluorescence and Western blotting. Endothelial NO synthase, soluble guanylate cyclase, and PKG protein expression were measured by Western blotting.. A considerable narrowing of the cerebral vessels was detected in the SAH group compared with that in the sham group. Moreover, compared with the sham group, the SAH group showed a marked decrease in Cx40, endothelial NO synthase, soluble guanylate cyclase, and PKG expression. The expression of Cx40 and PKG were obviously higher in the SAH plus DETA/NO and SAH plus 8-Br-cGMP groups than in the SAH group. However, Cx40 was lower in the SAH plus DETA/NO plus KT5823 and SAH plus DETA/NO plus 40Gap27 groups than in the SAH plus ETA/NO group. The BAs showed significant vasodilation in the SAH plus DETA/NO and SAH plus 8-Br-cGMP groups. However, the vasodilation response of BAs was inhibited in the SAH plus DETA/NO plus KT5823 and SAH plus DETA-NO plus 40Gap27 groups.. The NO-cGMP-PKG pathway alleviated cerebral vasospasm via Cx40 upregulation.

Topics: Animals; Connexins; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Gap Junction alpha-5 Protein; Guanosine Monophosphate; Nitric Oxide; Nitric Oxide Synthase; Rats, Sprague-Dawley; Signal Transduction; Soluble Guanylyl Cyclase; Subarachnoid Hemorrhage; Up-Regulation; Vasospasm, Intracranial

Phosphodiesterase-9 (PDE9) reduces natriuretic peptide (NP) signaling and may be involved in the pathophysiology of heart failure (HF).. This study investigated for the first time the integrated hemodynamic, endocrine, and renal effects of phosphodiesterase-9 inhibition (PDE9-I).. A total of 8 normal sheep and 8 sheep with pacing-induced HF received incremental intravenous boluses of PDE9-I (30, 100, and 300 mg PF-04749982 at 1-h intervals).. PDE9-I dose-dependently increased plasma cyclic guanosine monophosphate (cGMP) in normal sheep (p < 0.05) while concurrently reducing circulating atrial natriuretic peptide levels (p < 0.01). Similar trends were evident in HF, resulting in significant elevations in the cGMP/NP ratio in both states (p < 0.001 and p < 0.05, respectively). PDE9-I also produced progressive falls in arterial pressure (HF: p < 0.001), atrial pressure (Normal: p < 0.001; HF: p < 0.001), and peripheral resistance (HF: p < 0.001), and transiently increased cardiac output at the top dose (Normal: p < 0.05; HF: p < 0.001). Inhibition of PDE9 had a negligible effect on circulating hormones at the lower doses, but post-high dose, acutely increased renin activity (Normal: p < 0.001; HF: p < 0.05), vasopressin (Normal: p < 0.001; HF: p < 0.01), and cyclic adenosine monophosphate (HF: p < 0.001). Plasma aldosterone increased briefly after high-dose PDE9-I in normal sheep, and fell following the top dose in HF. PDE9-I dose-dependently increased urinary cGMP in both states (both p < 0.001). In HF, this was associated with increases in urine volume (p < 0.01), sodium excretion (p < 0.01), and creatinine clearance (p < 0.001).. PDE9-I improves NP efficacy in conjunction with beneficial hemodynamic and renal effects in experimental HF. These results support a role for PDE9 in HF pathophysiology and suggest its inhibition may constitute a novel therapeutic approach to this disease.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adenosine Monophosphate; Aldosterone; Animals; Atrial Natriuretic Factor; Atrial Pressure; Blood Pressure; Cardiac Output; Creatinine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Guanosine Monophosphate; Heart Failure; Phosphodiesterase Inhibitors; Renin; Sheep; Sodium; Urine; Vascular Resistance; Vasopressins

BACKGROUND Depression is a major mood disorder. Some patients have been reported to improve following acupuncture. This study aimed to investigate the effects of acupuncture on behaviors associated with depression in the chronic unpredictable mild stress (CUMS) rat model. The expression of signaling pathway components of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) in the rat hippocampus and plasma were also measured. MATERIAL AND METHODS Male Sprague-Dawley rats (N=40) were divided into the control group (N=10), the model group (N=10), the acupuncture group (N=10), and the non-acupuncture group (N=10). The rat model was established by orphaning combined with chronic unpredictable mild stress (CUMS) for six weeks. The acupuncture group was given 21 days of treatment using acupoints (AP) or non-acupoints (NP). Rat behaviors associated with depression were tested using the sucrose preference test (SPT), the open field test (OFT), and the elevated plus maze (EPM) test. Enzyme-linked immunoassay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) were used to detect the expression of inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor subunits, NR1, NR2A, and NR2B in the rat plasma and hippocampus. RESULTS Acupuncture reversed the behaviors associated with depression in the CUMS rat model and reduced the expression of components of the NO and cGMP pathway in the rat hippocampus and plasma. CONCLUSIONS In the CUMS rat model, treatment with acupuncture reduced behaviors associated with depression, and these effects were associated with changes in the NO and cGMP signaling pathway.

Topics: Acupuncture Points; Acupuncture Therapy; Animals; Antidepressive Agents; Behavior, Animal; Cyclic GMP; Depression; Depressive Disorder, Major; Disease Models, Animal; Guanosine Monophosphate; Hippocampus; Male; Nitric Oxide; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Stress, Psychological

Hirschsprung disease (HSCR) is a partially penetrant oligogenic birth defect that occurs when enteric nervous system (ENS) precursors fail to colonize the distal bowel during early pregnancy. Genetic defects underlie HSCR, but much of the variability in the occurrence and severity of the birth defect remain unexplained. We hypothesized that nongenetic factors might contribute to disease development. Here we found that mycophenolate, an inhibitor of de novo guanine nucleotide biosynthesis, and 8 other drugs identified in a zebrafish screen impaired ENS development. In mice, mycophenolate treatment selectively impaired ENS precursor proliferation, delayed precursor migration, and induced bowel aganglionosis. In 2 different mouse models of HSCR, addition of mycophenolate increased the penetrance and severity of Hirschsprung-like pathology. Mycophenolate treatment also reduced ENS precursor migration as well as lamellipodia formation, proliferation, and survival in cultured enteric neural crest–derived cells. Using X-inactivation mosaicism for the purine salvage gene Hprt, we found that reduced ENS precursor proliferation most likely causes mycophenolate-induced migration defects and aganglionosis. To the best of our knowledge, mycophenolate is the first medicine identified that causes major ENS malformations and Hirschsprung-like pathology in a mammalian model. These studies demonstrate a critical role for de novo guanine nucleotide biosynthesis in ENS development and suggest that some cases of HSCR may be preventable.

Topics: Animals; Cell Movement; Cell Proliferation; Cells, Cultured; Disease Models, Animal; DNA; Drug Evaluation, Preclinical; Enteric Nervous System; Female; Guanosine Monophosphate; Hirschsprung Disease; Humans; Male; Mice; Mice, 129 Strain; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mycophenolic Acid; Pregnancy; Zebrafish

Feeding high fructose (Frc) to rats induces a moderate increase in blood pressure, which is associated with insulin resistance. The present study was designed to evaluate the effect of the methanol extract of Sorbus commixta cortex (MSC) on vascular inflammation in a rat model of the metabolic syndrome induced by a high Frc-diet. Male Sprague-Dawley rats were divided into 4 groups and treated for 7 weeks as follows: 1) control, 2) high Frc-diet group, 3) Frc/MSC1 group; high Frc-diet group treated with MSC (100 mg/kg/day), and 4) Frc/MSC2 group; high Frc-diet group treated with MSC (200 mg/kg/day). High Frc-induced decreases of the expression level of aortic endothelial nitric oxide synthase (ecNOS) while the production of cyclic GMP (cGMP) was restored by treatment with MSC. On the contrary, increases of the expression level of endothelin-1 (ET-1) in the aorta, the transcription factor, the cytokine related with vascular inflammation, and the adhesion molecules were suppressed by MSC treatment. Moreover, MSC treatment was shown to lessen the thickening noted in the aortic intima and media of the high Frc-diet group. Our findings suggest that MSC may have an anti-vascular inflammatory effect on rats with a high Frc-induced metabolic syndrome.

Topics: Animals; Aorta, Thoracic; Cell Adhesion Molecules; Cyclic GMP; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Fructose; Guanosine Monophosphate; Inflammation; Male; Metabolic Syndrome; Methanol; NF-kappa B; Nitrites; Plant Extracts; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sorbus; Sweetening Agents; Triglycerides; Tunica Intima; Tunica Media

Hypercholesterolemia is one of the most important risk factors for the development of erectile dysfunction (ED) in men.. We employed an established mouse model of hypercholesterolemia.. We test for abnormalities in vasoreactivity in corporal tissue and temporally correlated changes in vasoreactivity with alterations in histology and protein expression.. A total of 150 mice were studied. A total of 100 apolipoprotein-E knockout (ApoE(-/-)) mice were fed a 1.25% cholesterol diet for 2, 4, 8, and 12 weeks (N = 25/group), while a group of ApoE(-/-) and wild-type Bl-6 mice were fed a normal diet. The study was terminated, and all mice were harvested at 22 weeks of age for vasoreactivity, histology, and protein studies from corporal tissues. Dose-response curves were generated to evaluate endothelium-dependent and endothelium-independent vasoreactivity, ex vivo. The contents of endothelial cells, smooth muscle cells, and smooth muscle/collagen ratio were assessed by immunohistochemistry staining or Masson staining. Level of cyclic guanosine monophosphate (cGMP) was detected by enzyme immunoassay assay. Levels of phosphorylated endothelial nitric oxide synthase (p-eNOS)/total eNOS, neuronal nitric oxide synthase (nNOS), and cyclic GMP-dependent kinase (cGK-1) protein were assessed by Western analysis.. Abnormalities in endothelium-dependent and endothelium-independent vasoreactivities, endothelial content, smooth muscle/collagen ratio, p-eNOS phosphorylation at Ser1177 only, nNOS, cGMP, and cGK-1 changed with the different durations of the high-cholesterol diet.. These data demonstrate that this mouse model is suitable for investigating aspects of hypercholesterolemic ED.

Topics: Animals; Blotting, Western; Cholesterol; Cyclic AMP; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Erectile Dysfunction; Guanosine Monophosphate; Hypercholesterolemia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Penis

Superoxide anion may contribute to erectile dysfunction (ED) in diabetes mellitus by reducing cavernosal nitric oxide (NO) bioavailability. The purpose of this study was to determine if gene transfer of extracellular superoxide dismutase (EC-SOD) can reduce superoxide anion formation and determine if this reactive oxygen species may contribute to diabetes-related ED in an experimental model of diabetes.. Three groups of animals were utilized: (1) control; (2) streptozotocin (STZ)-diabetic rats [60 mg/kg intraperitoneally (ip)] intracavernosally injected with AdCMVbetagal (negative control); and (3) STZ-rats intracavernosally injected with AdCMVEC-SOD. Two months after ip injection of STZ, groups 2 and 3 were transfected with the adenoviruses and 2 days after transfection, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Confocal microscopy for superoxide anion and von Willebrand Factor (vWF) was performed in the STZ-diabetic rat. Superoxide anion production, total SOD activity, and cyclic guanosine monophosphate (cGMP) levels were measured in each experimental group of rats.. Confocal microscopy demonstrated superoxide in smooth muscle and endothelial cells of the STZ-rat cavernosum and colocalized with vWF in the endothelium. Higher superoxide anion levels and decreased cGMP levels were found in the penis of STZ-rats at a time when erectile function was reduced. Two days after administration of AdCMVEC-SOD, superoxide anion levels were significantly lower in the penis of STZ-rats. Total SOD activity and cavernosal cGMP was increased in the penis of EC-SOD-transfected rats. STZ-rats transfected with AdCMVEC-SOD had a peak intracavernosal pressure (ICP) and total ICP to CNS that was similar to control rats.. These data demonstrate that in vivo adenoviral gene transfer of EC-SOD can reduce corporal superoxide anion levels and raise cavernosal cGMP levels by increasing NO bioavailability thus restoring erectile function in the STZ-diabetic rat.

Topics: Adenoviridae; Animals; Diabetes Mellitus, Experimental; Disease Models, Animal; Electric Stimulation; Endothelium, Vascular; Erectile Dysfunction; Genetic Therapy; Guanosine Monophosphate; Male; Microscopy, Confocal; Muscle, Smooth, Vascular; Penis; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Streptozocin; Superoxide Dismutase; Superoxides; Transfection

1. Guanosine-5'-monophosphate (GMP) was evaluated as a neuroprotective agent against the damage observed in rat hippocampal slices submitted to an in vitro model of ischemia with or without the presence of the ionotropic glutamate receptor agonist, Kainic acid (KA). 2. Cellular injury was evaluated by MTT reduction, lactate dehydrogenase(LDH) release assay, and measurement of intracellular ATP levels. 3. In slices submitted to ischemic conditions, 1 mM GMP partially prevented the decrease in cell viability induced by glucose and oxygen deprivation and the addition of KA. 4. KA or N-methyl-D-aspartate (NMDA) receptor antagonists, gamma-D-glutamylamino-methylsulfonate (GAMS) or (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801, 20 microM) also prevented toxicity in hippocampal slices under ischemic conditions, respectively. 5. The association of GMP with GAMS or MK-801 did not induce additional protection than that observed with GMP or that classical glutamate receptor antagonists alone. 6. GMP, probably by interacting with ionotropic glutamate receptors, attenuated the damage caused by glucose and oxygen deprivation in hippocampal slices. This neuroprotective action of GMP in this model of excitotoxicity is of outstanding interest in the search for effective therapies against ischemic injury.

Topics: Adenosine Triphosphate; Animals; Animals, Newborn; Cell Survival; Disease Models, Animal; Energy Metabolism; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Guanosine Monophosphate; Hippocampus; Hypoxia-Ischemia, Brain; Kainic Acid; Male; Neurons; Neuroprotective Agents; Rats; Rats, Wistar; Receptors, Glutamate; Synaptic Transmission

Increased expression of inducible nitric oxide synthase (iNOS) has been found in inflammatory myocardial disease and increased production of nitric oxide (NO) has both an inhibitory effect on virus replication and a cytotoxic effect on host cells. To investigate the relationship between severity of enteroviral myocarditis and iNOS expression, a characterised murine model was infected with either cardiovirulent or an attenuated Coxsackievirus B3 and myocardial samples were collected on Day 7. The ability of these viruses to induce NOS expression was compared by measurement of iNOS enzyme activity and localisation of iNOS protein or peroxynitrite, a product of excessive NO production. In accordance with previous reports, high expression of iNOS was detected in mice infected with the cardiovirulent virus. The iNOS protein was located mainly in infiltrating macrophages in and around foci of necrotic myofibres where viral genomic RNA was detected. In contrast, the level of iNOS expression was significantly lower in mice infected with the attenuated virus. This correlates with fewer and smaller myocarditic lesions and less infiltrating cells in the heart. iNOS was not detected in mock-infected mice by the above assays. These findings suggest that one mechanism of attenuation may be associated with the reduced ability of the variant to induce NOS expression in the heart. This also confirms a cytotoxic role for NO in the pathogenesis of Coxsackievirus B3-induced myocarditis.

Topics: Animals; Disease Models, Animal; Enterovirus; Guanosine Monophosphate; Heart; Immunohistochemistry; Male; Mice; Myocarditis; Myocardium; Nitrates; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nucleic Acid Hybridization; RNA, Viral; Tyrosine

This study was done to examine the protective effects of cyclic guanosine monophosphate (cGMP), a second messenger of nitric oxide, for ischemia/reperfusion injury of the liver, since it is known to induce vasodilatation and to inhibit platelet aggregation. Using an experimental model of porcine liver ischemia, 8-bromoguanosine 3',5' monophosphate, a cGMP analog, was continuously administered into the portal vein before ischemia and after reperfusion 30 min for each in the cGMP group (n = 6). Saline water was administered in the same way in the control group (n = 6). The cardiac output (CO), mean arterial blood pressure (MAP), portal venous flow (PVF), hepatic arterial flow (HAF), hepatic tissue blood flow (HTBF), and hepatic tissue cGMP level were determined. Hepatic enzymes and the bile discharge were also assessed as indicators of hepatic function. The hepatic tissue cGMP level was significantly higher, and PVF, HTBF, and the bile discharge were significantly greater in the cGMP group, while there were no remarkable differences between the groups with CO, MAP, HAF, and hepatic enzymes. In conclusion, the continuous supplementation of cGMP into the portal vein was found to be beneficial for preserving both the hepatic circulation and, consequently, the hepatic function after warm ischemia of porcine liver.

Topics: Analysis of Variance; Animals; Cyclic GMP; Disease Models, Animal; Guanosine Monophosphate; Hemodynamics; Injections, Intravenous; Liver Circulation; Liver Function Tests; Nitric Oxide; Portal Vein; Reference Values; Reperfusion Injury; Swine

Cardiac hypertrophy develops to compensate for hemodynamic overload of the myocardium. However, cardiac hypertrophy itself poses a serious risk to patients with heart failure. Whether natriuretic peptides enhanced by ecadotril, a neutral endopeptidase inhibitor, suppress the increase of left ventricular mass in the rat aortic insufficiency model was investigated. Ecadotril suppressed the increase of the left ventricular mass without affecting blood pressure (710.9 +/- 15.6 mg in the group treated with ecadotril and 865.0 +/- 27.3 mg in the control group, P < 0.01). Although the increase of atrial natriuretic peptide in the left ventricle was trivial and did not reach statistical significance (406.5 +/- 62.2 pg/mg in the ecadotril-treated group versus 269.8 +/- 35.7 pg/mg in the control group), urinary cGMP excretion was greater in the group given ecadotril than in the control group (10.6 +/- 2.5 pmol/mL and 1.7 +/- 0.6 pmol/mL, respectively, P < 0.01). Plasma angiotensin II concentration also decreased in the group treated with ecadotril compared with the control group (116.6 +/- 25.4 pg/mL versus 358.7 +/- 98.7 pg/mL, P < 0.05). In conclusion, ecadotril suppressed the increase of left ventricular mass in the overloaded heart. In ecadotril-treated rats, cGMP synthesis was augmented and angiotensin II concentration was reduced.

Topics: Angiotensin II; Animals; Aortic Diseases; Blood Pressure; Cardiomegaly; Disease Models, Animal; Guanosine Monophosphate; Male; Protease Inhibitors; Rats; Rats, Wistar; Thiorphan