cyclic-gmp and Chronic-Disease

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive and debilitating diseases characterized by gradual obstruction of the pulmonary vasculature, leading to elevated pulmonary artery pressure (PAP) and increased pulmonary vascular resistance (PVR). If untreated, they can result in death due to right-sided heart failure. Riociguat is a novel soluble guanylate cyclase (sGC) stimulator that is approved for the treatment of PAH and CTEPH. We describe in detail the role of the nitric oxide-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway in the pathogenesis of PAH and CTEPH and the mode of action of riociguat. We also review the preclinical data associated with the development of riociguat, along with the efficacy and safety data of riociguat from initial clinical trials and pivotal phase III randomized clinical trials in PAH and CTEPH.

Topics: Chronic Disease; Cyclic GMP; Humans; Hypertension, Pulmonary; Nitric Oxide; Pulmonary Embolism; Pyrazoles; Pyrimidines; Signal Transduction; Treatment Outcome; Walk Test

Nitric oxide (NO) activates soluble guanylate cyclase (sGC) by binding its prosthetic heme group, thereby catalyzing cyclic guanosine monophosphate (cGMP) synthesis. cGMP causes vasodilation and may inhibit smooth muscle cell proliferation and platelet aggregation. The NO-sGC-cGMP pathway is disordered in pulmonary arterial hypertension (PAH), a syndrome in which pulmonary vascular obstruction, inflammation, thrombosis, and constriction ultimately lead to death from right heart failure. Expression of sGC is increased in PAH but its function is reduced by decreased NO bioavailability, sGC oxidation and the related loss of sGC's heme group. Two classes of sGC modulators offer promise in PAH. sGC stimulators (e.g., riociguat) require heme-containing sGC to catalyze cGMP production, whereas sGC activators (e.g., cinaciguat) activate heme-free sGC. Riociguat is approved for PAH and yields functional and hemodynamic benefits similar to other therapies. Its main serious adverse effect is dose-dependent hypotension. Riociguat is also approved for inoperable chronic thromboembolic pulmonary hypertension.

Topics: Animals; Benzoates; Chronic Disease; Cyclic GMP; Drug Design; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Nitric Oxide; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Thromboembolism

Pseudomonas aeruginosa is the most common pathogen that colonizes the lungs of patients with cystic fibrosis. Isolates from sputum are typically all derived from the same strain of bacterium but show extensive phenotypic heterogeneity. One of these variants is the so-called small colony variant, which also shows increased ability to form a biofilm and is frequently resistant to multiple antibiotics. The presence of small colony variants in the sputum of patients with cystic fibrosis is associated with a worse clinical condition. The underlying mechanism responsible for generation of the small colony phenotype remains unclear, but a final common pathway would appear to be elevation of intracellular levels of cyclic di-GMP. This phenotypic variant is thus not just a laboratory curiosity, but a significant bacterial adaptation that favors survival within the lung of patients with cystic fibrosis and contributes to the pulmonary damage caused by P. aeruginosa.

Topics: Anti-Bacterial Agents; Biofilms; Chronic Disease; Cyclic GMP; Cystic Fibrosis; Drug Resistance, Bacterial; Humans; Lung; Phenotype; Pseudomonas aeruginosa; Pseudomonas Infections

Natriuretic peptides such as brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are commonly used in the diagnosis and evaluation of heart failure. However, their utility in patients with chronic kidney disease (CKD) is less clear as renal dysfunction itself can be associated with elevated concentrations of these biomarkers. Given the high prevalence of left ventricular hypertrophy and left ventricular systolic dysfunction in patients with CKD, diagnosis or exclusion of heart failure becomes important in this population. Most studies to date indicate that upward adjustment of diagnostic cut points preserves the usefulness of both BNP and NT-proBNP in the CKD patient, with similar clinical performance of each biomarker. We review the role of natriuretic peptide in heart failure in the setting of chronic renal disease.

Topics: Biomarkers; Chronic Disease; Cyclic GMP; Heart Failure; Humans; Kidney Diseases; Natriuretic Peptides; Renal Dialysis

Natriuretic peptides (NPs) secreted by the heart in response to volume overload are pleiotropic molecules with vasodilating, diuretic, natriuretic, antiproliferative, and antifibrotic actions. Functioning of the NP system is altered in congestive heart failure (CHF), suggesting that support of the NP system might be beneficial in treatment of acute and chronic CHF. Several approaches alone or in combination with other pharmacologic therapies have been shown to enhance function of the NP system: direct administration of native and designer NPs, inhibition of degradation of NPs and their second messenger (cyclic guanosine monophosphate ), and stimulation of cGMP generation. Despite increasing numbers of studies using NPs in therapy of acute and chronic CHF, several controversies regarding safety, efficacy, and dosing of NPs need to be addressed. Moreover, further research is warranted to identify the stages and etiologies of CHF that may profit from NP therapy.

Topics: Acute Disease; Chronic Disease; Cyclic GMP; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Prognosis; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Treatment Outcome

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Cardiopulmonary Bypass; Chronic Disease; Cyclic GMP; Glomerular Filtration Rate; Heart Failure; Humans; Intraoperative Care; Myocardial Infarction; Natriuresis; Renin-Angiotensin System; Urination; Vasodilation

Activating PKG-1α induces a long-term hyperexcitability (LTH) in nociceptive neurons. Since the LTH correlates directly with chronic pain in many animal models, we tested the hypothesis that inhibiting PKG-1α would attenuate LTH-mediated pain. We first synthesized and characterized compound N46 (N-((3R,4R)-4-(4-(2-fluoro-3-methoxy-6-propoxybenzoyl)benzamido)pyrrolidin-3-yl)-1H-indazole-5-carboxamide). N46 inhibits PKG-1α with an IC50 of 7.5 nmol, was highly selective when tested against a panel of 274 kinases, and tissue distribution studies indicate that it does not enter the CNS. To evaluate its antinociceptive potential, we used 2 animal models in which the pain involves both activated PKG-1α and LTH. Injecting complete Freund's adjuvant (CFA) into the rat hind paw causes a thermal hyperalgesia that was significantly attenuated 24 hours after a single intravenous injection of N46. Next, we used a rat model of osteoarthritic knee joint pain and found that a single intra-articular injection of N46 alleviated the pain 14 days after the pain was established and the relief lasted for 7 days. Thermal hyperalgesia and osteoarthritic pain are also associated with the activation of the capsaicin-activated transient receptor protein vanilloid-1 (TRPV1) channel. We show that capsaicin activates PKG-1α in nerves and that a subcutaneous delivery of N46 attenuated the mechanical and thermal hypersensitivity elicited by exposure to capsaicin. Thus, PKG-1α appears to be downstream of the transient receptor protein vanilloid-1. Our studies provide proof of concept in animal models that a PKG-1α antagonist has a powerful antinociceptive effect on persistent, already existing inflammatory pain. They further suggest that N46 is a valid chemotype for the further development of such antagonists.

Topics: Adenosine Triphosphate; Animals; Biphenyl Compounds; Chronic Disease; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Double-Blind Method; Enzyme Inhibitors; Freund's Adjuvant; Gene Expression Regulation, Enzymologic; Hyperalgesia; Inflammation; Male; Models, Molecular; Osteoarthritis; Pain; Pain Threshold; Pyridines; Rats; Rats, Sprague-Dawley; Thionucleotides; Time Factors

Carperitide is used to treat acute decompensated heart failure (ADHF), but its effects on long-term prognosis have not been studied.. A multicenter randomized controlled study of 49 patients with ADHF was performed to clarify the drug's effects on long-term prognosis. Low-dose carperitide (0.01-0.05 microg x kg(-1 ) x min(-1)) was infused for 72 h as the initial treatment (n=26), whereas in the control group (n=23), standard medical treatment other than carperitide was given without limitation. Anti-aldosterone drugs were prohibited in both groups. During carperitide infusion, significant increases of the atrial natriuretic peptide and cyclic GMP levels and a significant decrease in the heart-type fatty acid-binding protein/serum creatinine ratio were observed, suggesting inhibition of myocyte cell membrane damage. On the other hand, no significant differences in the plasma brain natriuretic peptide, troponin T, and creatinine levels were noted in either group. During 18-month follow-up, significant reductions of death and rehospitalization occurred in the carperitide vs control group (11.5% vs 34.8%; p=0.0359). Cox regression analysis revealed that randomization to carperitide (p=0.020), pretreatment systolic blood pressure >or=140 mmHg (p=0.043), and beta-blocker therapy (p=0.016) were independent predictors for freedom from cardiac events.. Acute-phase low-dose carperitide infusion improved the long-term prognosis of patients with ADHF.

Topics: Aged; Atrial Natriuretic Factor; Blood Pressure; Chronic Disease; Creatinine; Cyclic GMP; Fatty Acid-Binding Proteins; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Prognosis; Remission Induction; Troponin T

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

Three specific receptors for the cardiac natriuretic peptide system have been identified to date. Down-regulation of the biologically active binding sites (i.e. NPR-A and NPR-B) could explain the blunted response to cardiac natriuretic hormones observed in heart failure (HF), but not the increased metabolic clearance rate. Variations in the ratio between biological and clearance (NPR-C) receptors in target tissue may explain this increase.. The aim of this study was to investigate the regulation of NPR-C receptors on platelets, in patients with HF.. Eighteen patients with HF (NYHA class: I-II, n=8; III-IV, n=10) and 18 age-matched healthy subjects were studied. The affinity constant (K(d)) and density (B(max)) of binding sites were derived by saturation assays on platelet suspensions using 125I-ANP as radioligand.. B(max) increased as a function of the severity of disease: 21.3+/-3.3 fmol/10(9) cells in class III-IV, 11.7+/-2.2 in class I-II, and 11.6+/-1.1 in controls, respectively (P=0.0179 for class III-IV vs. controls and P=0.0451 vs. NYHA I-II).. The increase in density of 'clearance' receptors in severe HF is theoretically consistent with the reduction in cardiac natriuretic peptide biological activity, as well as the increase in metabolic clearance rate. This suggests that clearance receptor blockade may be of potential therapeutic value in HF.

Topics: Adult; Aged; Analysis of Variance; Atrial Natriuretic Factor; Biomarkers; Blood Platelets; Chronic Disease; Cyclic GMP; Female; Heart Failure; Humans; Male; Middle Aged; Receptors, Atrial Natriuretic Factor; Reference Values; Sensitivity and Specificity; Severity of Illness Index; Up-Regulation

B-type natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) are secreted from the heart and are thought to be equally important factors in the regulation of vascular tone in health and in congestive heart failure (CHF). However, no studies directly compare vasodilator effects of these peptides in healthy subjects and in patients with CHF.. Plethysmography was used to determine the vasodilatory effects of BNP and to compare these to the effects of ANP in patients with CHF (n = 15) and age-matched healthy subjects (n = 16). Graded doses of ANP and BNP (8, 16, 32, and 48 pmol/min per 100 ml of tissue volume for both) were administered randomly into the brachial artery. Forearm blood flow (FBF) was measured, and cyclic GMP (cGMP) spillover was calculated.. Responses in FBF to both peptides in CHF were significantly lower than those of healthy subjects (BNP p < 0.05; ANP p < 0.01). Similarly, forearm spillover of cGMP was significantly lower in CHF than in healthy subjects (BNP p < 0.05; ANP p < 0.01). When vascular responses in healthy subjects were compared between BNP and ANP, BNP-induced changes in FBF (p < 0.05) and forearm cGMP spillover (p < 0.01) were significantly less than changes induced by ANP. In CHF, though, FBF change and cGMP spillover induced by the two peptides were not significantly different.. These results suggest that the metabolism and action of these natriuretic peptides in CHF may differ from the healthy state.

Topics: Aged; Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Female; Forearm; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Plethysmography; Regional Blood Flow; Vasodilation

This study was designed to investigate the effect of angiotensin-converting enzyme (ACE) inhibitors with and without a sulfhydryl group on intracellular production of cGMP, forearm blood flow, and neurohormonal factors during continuous transdermal application of nitroglycerin in patients with chronic heart failure. Platelet cGMP level and forearm blood flow were measured before and 5 min after sublingual administration of nitroglycerin (NTG) in 20 patients with chronic heart failure during the following 4 phases: (1) baseline phase; (2) NTG phase (1 week after NTG tape 10 mg/day); (3) CPT phase (1 week after both captopril 37.5 mg/day and NTG tape 10 mg/day); and (4) ENL phase (1 week after both enalapril 5 mg/day and NTG tape 10 mg/day). The platelet GMP level before sublingual NTG and forearm blood flow were significantly higher during the 3 phases with NTG tape than during the control phase. The percent increases in platelet cGMP level and forearm blood flow after sublingual NTG were significantly lower during the NTG phase than during the baseline phase. In contrast, concomitant application of ACE inhibitors maintained the percent increase in platelet cGMP level and forearm blood flow. These results indicate that concomitant therapy with ACE inhibitors may be helpful in preventing the attenuation of intracellular cGMP production in patients with chronic heart failure during continuous transdermal application of NTG.

Topics: Administration, Cutaneous; Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Platelets; Blood Pressure; Body Weight; Chronic Disease; Cyclic GMP; Drug Tolerance; Female; Forearm; Heart Failure; Heart Rate; Hematocrit; Humans; Male; Middle Aged; Nitrates; Nitroglycerin; Norepinephrine; Regional Blood Flow; Renin; Systole; Vasodilator Agents

This study was designed to evaluate the effect of carvedilol on nitrate tolerance in patients with chronic heart failure.. The attenuation of cyclic guanosine 5'-monophosphate (cGMP) production due to inactivation of guanylate cyclase by increased superoxide has been reported as a mechanism of nitrate tolerance. Carvedilol has been known to combine alpha/beta-blockade with antioxidant properties.. To evaluate the effect of carvedilol on nitrate tolerance, 40 patients with chronic heart failure were randomized to four groups that received either carvedilol (2.5 mg once a day [carvedilol group, n=10]), metoprolol (30 mg once a day [metoprolol group, n=10]), doxazosin (0.5 mg once a day [doxazosin group, n=10]) or placebo (placebo group, n=10). Vasodilatory response to nitroglycerin (NTG) was assessed with forearm plethysmography by measuring the change in forearm blood flow (FBF) before and 5 min after sublingual administration of 0.3 mg NTG, and at the same time blood samples were taken from veins on the opposite side to measure platelet cGMP. Plethysmography and blood sampling were obtained serially at baseline (day 0); 3 days after carvedilol, metoprolol, doxazosin or placebo administration (day 3); and 3 days after application of a 10-mg/24-h NTG tape concomitantly with carvedilol, metoprolol, doxazosin or placebo (day 6).. There was no significant difference in the response of FBF (%FBF) and cGMP (%cGMP) to sublingual NTG on day 0 and day 3 among the four groups. On day 6, %FBF and %cGMP were significantly lower in the metoprolol, doxazosin and placebo groups than on day 0 and day 3, but these parameters in the carvedilol group were maintained.. These results indicated that carvedilol may prevent nitrate tolerance in patients with chronic heart failure during continuous therapy with NTG.

Topics: Adrenergic Antagonists; Aged; Blood Flow Velocity; Blood Platelets; Blood Pressure; Carbazoles; Carvedilol; Chronic Disease; Cyclic GMP; Double-Blind Method; Doxazosin; Drug Hypersensitivity; Drug Therapy, Combination; Female; Follow-Up Studies; Forearm; Heart Failure; Heart Rate; Humans; Male; Metoprolol; Middle Aged; Nitroglycerin; Propanolamines; Vasodilator Agents

Administration of L-arginine improves nitric oxide (NO) formation and endothelium-dependent vasodilation in atherosclerotic patients.. We investigated in this double-blind, controlled study whether prolonged intermittent infusion therapy with L-arginine improves the clinical symptoms of patients with intermittent claudication, as compared with the endothelium-independent vasodilator prostaglandin E1, and control patients.. Thirty-nine patients with intermittent claudication were randomly assigned to receive 2 x 8 g L-arginine/day, or 2 x 40 microg prostaglandin E1 (PGE1)/day or no hemodynamically active treatment, for 3 weeks. The pain-free and absolute walking distances were assessed on a walking treadmill at 3 km/h, 12% slope, and NO-mediated, flow-induced vasodilation of the femoral artery was assessed by ultrasonography at baseline, at 1, 2 and 3 weeks of therapy and 6 weeks after the end of treatment. Urinary nitrate and cyclic guanosine-3', 5'-monophosphate (GMP) were assessed as indices of endogenous NO production.. L-Arginine improved the pain-free walking distance by 230+/-63% and the absolute walking distance by 155+/-48% (each p < 0.05). Prostaglandin E1 improved both parameters by 209+/-63% and 144+/-28%, respectively (each p < 0.05), whereas control patients experienced no significant change. L-Arginine therapy also improved endothelium-dependent vasodilation in the femoral artery, whereas PGE1 had no such effect. There was a significant linear correlation between the L-arginine/asymmetric dimethylarginine (ADMA) ratio and the pain-free walking distance at baseline (r=0.359, p < 0.03). L-Arginine treatment elevated the plasma L-arginine/ADMA ratio and increased urinary nitrate and cyclic GMP excretion rates, indicating normalized endogenous NO formation. Prostaglandin E1 therapy had no significant effect on any of these parameters. Symptom scores assessed on a visual analog scale increased from 3.51+/-0.18 to 83+/-0.4 (L-arginine) and 7.0+/-0.5 (PGE1; each p < 0.05), but did not significantly change in the control group (4.3+/-0.4).. Restoring NO formation and endothelium-dependent vasodilation by L-arginine improves the clinical symptoms of intermittent claudication in patients with peripheral arterial occlusive disease.

Topics: Aged; Aged, 80 and over; Alprostadil; Arginine; Arterial Occlusive Diseases; Blood Flow Velocity; Chronic Disease; Cyclic GMP; Double-Blind Method; Exercise Test; Female; Femoral Artery; Follow-Up Studies; Humans; Infusions, Intravenous; Intermittent Claudication; Leg; Male; Middle Aged; Nitrates; Nitric Oxide; Peripheral Vascular Diseases; Treatment Outcome; Ultrasonography, Doppler, Duplex; Vasodilation; Vasodilator Agents

C-type natriuretic peptide (CNP) is a newly identified peptide that is structurally related to atrial natriuretic peptide (ANP). Although it has been suggested that CNP is released from the endothelium for the regulation of local vascular tone, no data are available concerning the vasodilatory response to CNP in humans.. Strain-gauge plethysmography was used to determine the vasodilatory effects of intra-arterially infused CNP compared with the effects of ANP infusion in 11 patients with chronic heart failure (CHF) and 11 age-matched healthy controls. Graded doses of CNP and ANP (8, 16, 32, and 48 pmol.min-1.dL-1 tissue volume) were administered randomly into the nondominant brachial artery, and forearm blood flow (FBF) was measured. No significant changes in systemic blood pressure and heart rate were found during the study. Both the absolute and percent FBF responses to ANP relative to the baseline value were significantly lower in CHF patients than in healthy controls (P < .01), whereas the responses to CNP were similar. The calculated forearm spillover of cyclic GMP (cGMP) was significantly lower in CHF patients receiving the highest dose of ANP (P < .02), whereas changes in cGMP spillover after the equimolar dose of CNP were significantly higher (P < .02), despite the lesser potency of CNP.. In patients with CHF the peripheral vasodilatory effect of ANP is attenuated, but CNP-induced peripheral vasorelaxation is preserved, with CNP being less potent for equimolar doses.

Topics: Atrial Natriuretic Factor; Blood Vessels; Cardiac Output, Low; Chronic Disease; Cyclic GMP; Female; Forearm; Humans; Injections, Intra-Arterial; Male; Middle Aged; Natriuretic Peptide, C-Type; Plethysmography; Proteins; Regional Blood Flow; Vascular Resistance; Vasodilation

This study evaluated the relation between plasma cyclic guanosine monophosphate (cGMP) and hemodynamic and neurohormonal parameters in patients with chronic congestive heart failure and assessed the effect of organic nitrate on plasma cGMP levels. Plasma cGMP was fourfold higher in 18 patients with congestive heart failure compared with 15 control subjects (16.7 +/- 9.7 versus 4.0 +/- 1.0 pmol/ml; p < 0.0001) but did not correlate with plasma levels of catecholamines, renin, atrial natriuretic peptide, or with baseline hemodynamic values. The administration of a hemodynamically effective dose of oral isosorbide dinitrate (40 mg) resulted in a transient reduction in plasma cGMP from 16.7 +/- 9.7 pmol/ml at baseline to 13.0 +/- 6.6 pmol/ml at 1 hour (p < 0.05). This change was associated with small and statistically insignificant changes in neurohormonal values and had no relation to any of the hemodynamic changes. We concluded that (1) elevated plasma cGMP in congestive heart failure does not correlate with other neurohormonal or hemodynamic parameters and may be an independent parameter of heart failure, (2) in contrast to previously documented nitrate-mediated increases in intracellular cGMP, nitrate therapy results in a reduction in plasma cGMP, and (3) changes in plasma cGMP cannot serve as a surrogate measurement of changes in intracellular cGMP.

Topics: Administration, Oral; Adult; Aged; Chronic Disease; Cyclic GMP; Female; Heart Failure; Hemodynamics; Humans; Isosorbide Dinitrate; Male; Middle Aged; Neurotransmitter Agents

Pg E, F2 alpha and F1 alpha, protein-bound plasmic oxyproline (PBPO) as well as 24-h oxyprolinuria (OPU) were measured in 119 patients suffering from various forms of chronic hepatic diseases. Composition of cellular infiltrates in histological specimens was assessed quantitatively for chronic hepatitis patients. Hepatic levels of Pg E, OPU and PBPO were elevated in all the patients, whereas PgF2 alpha and 6-keto-PgF1 alpha values were similar to controls. There were relationships between PBPO and OPU, PgE and 6-keto-PgF1 alpha. Unlike patients with active hepatitis and hepatic cirrhosis, those with chronic persistent hepatitis demonstrated a direct correlation between cellular infiltrate fibroblasts and PgE, PgF2 alpha; between PgF2 alpha and Kupffer's cells content. Inverse relationship occurred between PgE and free hepatic macrophages. In response to prostenon (PGE2) moderate PBPO decline went in line with elevation of cAMP/cGMP. A significant increase of PBPO during introduction of ensaprost-F (PgF2 alpha) did not result in changes in cyclic nucleotides. Prostenon treatment decreased PBPO under no shifts in OPU. A regulatory role of PgE is suggested in collagen metabolism stabilization. Prostenon is proposed for therapeutic use to inhibit sclerotic processes in liver impairment.

Topics: Adolescent; Adult; Aged; Chronic Disease; Collagen; Cyclic AMP; Cyclic GMP; Female; Hepatitis, Chronic; Humans; Liver Diseases; Male; Middle Aged; Prostaglandins

1. To examine whether or not atrial natriuretic peptide-induced proteinuria simply results from increases in urine flow or glomerular filtration rate, we infused dopamine (1 microgram min-1 kg-1) and alpha-human atrial natriuretic peptide (0.025 microgram min-1 kg-1) into nine patients with chronic glomerulonephritis and nine essential hypertensive patients without renal damage, and compared the effects of the two agents on renal function and urinary protein excretion. 2. In patients with chronic glomerulonephritis, dopamine infusion significantly increased urinary sodium excretion (+59%), renal blood flow (+20%) and creatinine clearance (+14%). However, urinary protein excretion was not changed. Addition of atrial natriuretic peptide to the dopamine infusion further increased urinary sodium excretion and maintained creatinine clearance at the same level. In contrast to the infusion of dopamine alone, atrial natriuretic peptide markedly increased urinary protein excretion (77 versus 229 mg min-1 m2, P less than 0.02). Furthermore, the addition of atrial natriuretic peptide elevated the urinary protein/creatinine ratio (1.55 versus 5.35, P less than 0.05), while dopamine alone did not (1.55 versus 1.45, not significant). 3. In essential hypertensive patients, dopamine and dopamine plus ANP showed renal effects similar to those of chronic glomerulonephritis; however, the urinary excretion of protein was not changed significantly. 4. These results suggest that atrial natriuretic peptide may increase urinary protein excretion mainly by increasing the permeability of the damaged glomeruli to protein rather than by simply increasing urine flow or glomerular filtration. Possible mechanisms underlying the proteinuria-increasing effects of atrial natriuretic peptide are discussed.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Chronic Disease; Cyclic GMP; Dopamine; Glomerular Filtration Rate; Glomerulonephritis; Heart Rate; Humans; Hypertension; Kidney; Middle Aged; Proteinuria; Urination

Chronic stress and neuronal vulnerability have recently been recognized as factors contributing to cognitive disorders. One way to modify neuronal vulnerability is through mediation of phosphodiesterase 2 (PDE2), an enzyme that exerts its action on cognitive processes via the control of intracellular second messengers, cGMP and, to a lesser extent, cAMP. This study explored the effects of a PDE2 inhibitor, Bay 60-7550, on stress-induced learning and memory dysfunction in terms of its ramification on behavioral, morphologic, and molecular changes. Bay 60-7550 reversed stress-induced cognitive impairment in the Morris water maze, novel object recognition, and location tasks (object recognition test and/or object location test), effects prevented by treatment with 7-NI, a selective inhibitor of neuronal nitric oxide synthase; MK801, a glutamate receptor (NMDAR) inhibitor; myr-AIP, a CaMKII inhibitor; and KT5823, a protein kinase G inhibitor. Bay 60-7550 also ameliorated stress-induced structural remodeling in the CA1 of the hippocampus, leading to increases in dendritic branching, length, and spine density. However, the neuroplasticity initiated by Bay 60-7550 was not seen in the presence of 7-NI, MK801, myr-AIP, or KT5823. PDE2 inhibition reduced stress-induced extracellular-regulated protein kinase activation and attenuated stress-induced decreases in transcription factors (e.g., Elk-1, TORC1, and CREB phosphorylation) and plasticity-related proteins (e.g., Egr-1 and brain-derived neurotrophic factor). Pretreatment with inhibitors of NMDA, CaMKII, neuronal nitric oxide synthase, and protein kinase G (or protein kinase A) blocked the effects of Bay 60-7550 on cGMP or cAMP signaling. These findings indicate that the effect of PDE2 inhibition on stress-induced memory impairment is potentially mediated via modulation of neuroplasticity-related NMDAR-CaMKII-cGMP/cAMP signaling.

Topics: Animals; Chronic Disease; Cognition; Cognition Disorders; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Hippocampus; Imidazoles; Male; Mice, Inbred ICR; Nerve Regeneration; Neuronal Plasticity; Neurons; Phosphodiesterase Inhibitors; Signal Transduction; Stress, Psychological; Triazines

The β1-adrenergic antagonist metoprolol improves cardiac function in animals and patients with chronic heart failure, isolated mitral regurgitation (MR), and ischemic heart disease, though the molecular mechanisms remain incompletely understood. Metoprolol has been reported to upregulate cardiac expression of β3-adrenergic receptors (β3AR) in animal models. Myocardial β3AR signaling via neuronal nitric oxide synthase (nNOS) activation has recently emerged as a cardioprotective pathway. We tested whether chronic β1-adrenergic blockade with metoprolol enhances myocardial β3AR coupling with nitric oxide-stimulated cyclic guanosine monophosphate (β3AR/NO-cGMP) signaling in the MR-induced, volume-overloaded heart. We compared the expression, distribution, and inducible activation of β3AR/NO-cGMP signaling proteins within myocardial membrane microdomains in dogs (canines) with surgically induced MR, those also treated with metoprolol succinate (MR+βB), and unoperated controls. β3AR mRNA transcripts, normalized to housekeeping gene RPLP1, increased 4.4 × 10(3)- and 3.2 × 10(2)-fold in MR and MR+βB hearts, respectively, compared to Control. Cardiac β3AR expression was increased 1.4- and nearly twofold in MR and MR+βB, respectively, compared to Control. β3AR was detected within caveolae-enriched lipid rafts (Cav3(+)LR) and heavy density, non-lipid raft membrane (NLR) across all groups. However, in vitro selective β3AR stimulation with BRL37344 (BRL) triggered cGMP production within only NLR of MR+βB. BRL induced Ser (1412) phosphorylation of nNOS within NLR of MR+βB, but not Control or MR, consistent with detection of NLR-specific β3AR/NO-cGMP coupling. Treatment with metoprolol prevented MR-associated oxidation of NO biosensor soluble guanylyl cyclase (sGC) within NLR. Metoprolol therapy also prevented MR-induced relocalization of sGCβ1 subunit away from caveolae, suggesting preserved NO-sGC-cGMP signaling, albeit without coupling to β3AR, within MR+βB caveolae. Chronic β1-blockade is associated with myocardial β3AR/NO-cGMP coupling in a microdomain-specific fashion. Our canine study suggests that microdomain-targeted enhancement of myocardial β3AR/NO-cGMP signaling may explain, in part, β1-adrenergic antagonist-mediated preservation of cardiac function in the volume-overloaded heart.

Topics: Adrenergic beta-1 Receptor Antagonists; Animals; Chronic Disease; Cyclic GMP; Dogs; Ethanolamines; Guanylate Cyclase; Membrane Microdomains; Metoprolol; Mitral Valve Insufficiency; Nitric Oxide; Nitric Oxide Synthase Type I; Receptors, Adrenergic, beta-3; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase; Ventricular Function, Left

It has been suggested that increase in acute nitric oxide (NO) or cyclic guanosine monophosphate production may be involved in cardioprotection induced by chronic hypoxia (CH). We studied the effect of NO donor molsidomine and phosphodiesterase type 5 inhibitor sildenafil on myocardial ischemia/reperfusion (I/R) injury in rats adapted to CH. Male Wistar rats were exposed to continuous hypoxia in a normobaric chamber (10 % O(2), 4 weeks). Rats received either saline, molsidomine (10 mg/kg body weight, i.v.) or sildenafil (0.7 mg/kg body weight, i.v.) 30 min before ischemia. Control rats were kept under normoxia and treated in a corresponding manner. Adaptation to CH increased the myocardial ischemic tolerance. Acute treatment with either molsidomine or sildenafil significantly reduced infarct size in normoxic rats and further enhanced cardioprotection induced by CH. However, the cardioprotective effect of CH on I/R injury was not additive to the cardioprotection provided by the drugs.

Topics: Animals; Chronic Disease; Cyclic GMP; Hypoxia; Male; Myocardial Ischemia; Nitric Oxide; Rats; Rats, Wistar; Signal Transduction

When pulmonary hypertension results in marked limitation in activities of daily living (functional class III), the first-choice vasodilator is bosentan, despite its limitations. There is no proven advantage of adding another vasodilator. The adverse effects of vasodilators outweigh their uncertain efficacy in patients with only a slight limitation of physical activity (class II). When surgery is not feasible or when chronic thromboembolic pulmonary hypertension persists despite surgery, there are no vasodilators with a favourable harm-benefit balance. Riociguat (Adempas, Bayer) is a vasodilator that acts by enhancing the synthesis of cyclic guanosine monophosphate (cGMP), a mediator of vasodilation. This mechanism of action is similar to that of sildenafil, which inhibits cGMP catabolism. Riociguat has been authorised in the European Union in adult patients with class II or III pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Riociguat monotherapy has not been compared with another vasodilator in patients with pulmonary arterial hypertension. In a 12-week randomised, double-blind, placebo-controlled trial in 380 patients, riociguat had modest symptomatic efficacy, improving the functional class in 21% of patients (versus 14% in the placebo arm). There was no statistically significant difference in mortality. The symptomatic benefit appeared to be similar in patients who continued to take bosentan and in those who were not taking a vasodilator other than riociguat. In a 16-week, double-blind trial in 261 patients with chronic thromboembolic pulmonary hypertension in whom surgery was not feasible or had failed, riociguat was more effective than placebo on symptoms; there was improvement in functional class in respectively 33% and 15% of patients. There was no statistically significant change in mortality. In these two clinical situations, subgroup analyses showed no benefit of riociguat in patients who had only slight limitation of physical activity (class II). The main adverse effects of riociguat are related to its vasodilatory properties, and include headache, arterial hypotension, dizziness and peripheral oedema. Riociguat can also cause bleeding, including potentially severe pulmonary haemorrhage. More data are needed on its cardiac, renal and osseous adverse effects. Riociguat is subject to pharmacodynamic interactions with many other drugs. In particular, riociguat coadministration with a phosphodiesterase type 5 inhi

Topics: Activities of Daily Living; Adult; Animals; Chronic Disease; Cyclic GMP; Humans; Hypertension, Pulmonary; Motor Activity; Pyrazoles; Pyrimidines; Thromboembolism; Vasodilator Agents

Inhaled nitric oxide (NO) and other cGMP- or cAMP-dependent pulmonary vasodilators are often used in combination for the treatment of the persistent pulmonary hypertension of the newborn syndrome. There is in vitro evidence to indicate that NO downregulate the pulmonary vascular response to cGMP-dependent agonists raising concern as to whether a synergistic effect is observed when employing a combined strategy in newborns. Hypothesizing that a synergistic effect is absent, we evaluated newborn and juvenile rat pulmonary arteries to determine the individual and combined vasodilatory effect of cGMP- and cAMP-dependent agonists. In precontracted near-resistance pulmonary arteries, the addition of sildenafil reduced vasorelaxation response to NO donor S-nitroso-N-acetyl penicillamine (SNAP). A similar decrease in SNAP-induced vasodilation was observed in arteries pretreated with BAY 41-2272 (10(-9) M), a soluble guanylate cyclase stimulator cGMP, and its downstream protein kinase activator. cGMP also reduced the vasorelaxant response to the cAMP-dependent forskolin. Inhibition of endogenous vascular NO generation enhanced SNAP-induced relaxation. The present data suggest that the mechanism involved in the cGMP desensitization to other relaxant agonists involves downregulation of the small heat shock protein HSP20 and is evident in rat pulmonary and systemic vascular smooth muscle cells. In newborn rats with chronic hypoxia-induced pulmonary hypertension, the combination of sildenafil and inhaled NO resulted in a lesser reduction in pulmonary vascular resistance compared with their individual effect. These data suggest that clinical exposure to one cGMP-dependent pulmonary vasodilator may affect the response to other cGMP- or cAMP-mediated agonists.

Topics: Animals; Animals, Newborn; Chronic Disease; Cyclic GMP; Female; HSP20 Heat-Shock Proteins; HSP27 Heat-Shock Proteins; Hypoxia; Male; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Donors; Phosphorylation; Piperazines; Primary Cell Culture; Protein Kinase Inhibitors; Pulmonary Circulation; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

Exposing mice to a chronic hypoxic treatment (10% oxygen, 21 days) that promotes pulmonary hypertension was observed to attenuate the pulmonary vasoconstriction response to acute hypoxia (HPV) both in vivo and in isolated pulmonary arteries. Since catalase restored the HPV response in isolated arteries, it appeared to be attenuated by extracellular hydrogen peroxide. Chronic hypoxia promoted the detection of elevated lung superoxide, extracellular peroxide, extracellular SOD expression, and protein kinase G (PKG) activation [based on PKG dimerization and vasodilator-stimulated phosphoprotein (VASP) phosphorylation], suggesting increased generation of extracellular peroxide and PKG activation may contribute to the suppression of HPV. Aorta from mice exposed to 21 days of hypoxia also showed evidence for extracellular hydrogen peroxide, suppressing the relaxation response to acute hypoxia. Peroxide appeared to partially suppress contractions to phenylephrine used in the study of in vitro hypoxic responses. Treatment of mice with the heme precursor δ-aminolevulinic acid (ALA; 50 mg·kg(-1)·day(-1)) during exposure to chronic hypoxia was examined as a pulmonary hypertension therapy because it could potentially activate beneficial cGMP-mediated effects through promoting a prolonged protoporphyrin IX (PpIX)-elicited activation of soluble guanylate cyclase. ALA attenuated pulmonary hypertension, increases in both superoxide and peroxide, and the suppression of in vitro and in vivo HPV responses. ALA generated prolonged detectible increases in PpIX and PKG-associated phosphorylation of VASP, suggesting PKG activation may contribute to suppression of pulmonary hypertension and prevention of alterations in extracellular peroxide that appear to be attenuating HPV responses caused by chronic hypoxia.

Topics: Acute Disease; Aminolevulinic Acid; Animals; Antihypertensive Agents; Aorta; Cell Adhesion Molecules; Chronic Disease; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Enzyme Activation; Familial Primary Pulmonary Hypertension; Hydrogen Peroxide; Hypertension, Pulmonary; Hypoxia; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins; Phosphoproteins; Phosphorylation; Protoporphyrins; Pulmonary Artery; Superoxide Dismutase; Superoxides; Time Factors; Up-Regulation; Vasoconstriction

Obesity-associated nonalcoholic fatty liver disease (NAFLD), covering from simple steatosis to nonalcoholic steatohepatitis (NASH), is a common cause of chronic liver disease. Aberrant production of adipocytokines seems to play a main role in most obesity-associated disorders. Changes in adipocytokines in obesity could be mediated by alterations in cyclic GMP (cGMP) homeostasis. The aims of this work were: (1) to study the role of altered cGMP homeostasis in altered adipocytokines in morbid obesity, (2) to assess whether these alterations are different in simple steatosis or NASH, and (3) to assess whether these changes reverse in obese patients after bariatric surgery.. In 47 patients with morbid obesity and 45 control subjects, the levels in blood of adipocytokines, cGMP, nitric oxide (NO) metabolites, and atrial natriuretic peptide (ANP) were studied. Whether weight loss after a bariatric surgery reverses the changes in these parameters was evaluated.. NO metabolites and leptin increase (and adiponectin decreases) similarly in patients with steatosis or NASH, suggesting that these changes are due to morbid obesity and not to liver disease. Inflammation and cGMP homeostasis are affected both by morbid obesity and by liver disease. The increases in interleukin 6 (IL-6), interleukin 18 (IL-18), plasma cGMP, ANP, and the decrease in cGMP in lymphocytes are stronger in patients with NASH than with steatosis. All these changes reverse completely after bariatric surgery and weight loss, except IL-18.. Altered cGMP homeostasis seems to contribute more than inflammation to changes in leptin and adiponectin in morbid obesity.

Topics: Adipokines; Adult; Bariatric Surgery; Body Mass Index; Case-Control Studies; Chronic Disease; Cyclic GMP; Fatty Liver; Female; Homeostasis; Humans; Inflammation; Interleukin-18; Interleukin-6; Leptin; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity, Morbid

Chronic hypoxia attenuates soluble guanylate cyclase-induced vasorelaxation in serotonin (5-HT)-contracted ovine carotid arteries. Because protein kinase G (PKG) mediates many effects of soluble guanylate cyclase activation through phosphorylation of multiple kinase targets in vascular smooth muscle, we tested the hypothesis that chronic hypoxia reduces the ability of PKG to phosphorylate its target proteins, which attenuates the ability of PKG to induce vasorelaxation. We also tested the hypothesis that hypoxia attenuates PKG expression and/or activity. Arteries from normoxic and chronically hypoxic (altitude of 3,820 m for 110 days) fetal and adult sheep were denuded of endothelium and equilibrated with 95% O2-5% CO2 in the presence of nitro-l-arginine methyl ester (l-NAME) and N(G)-nitro-l-arginine (l-NNA) to inhibit residual endothelial nitric oxide synthase. Concentration-response relations for 5-HT were determined in the presence of prazosin to minimize activation of α-adrenergic receptors. The PKG activator 8-(p-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate (8-pCTP-cGMP) reduced agonist binding affinity of the 5-HT receptor in a concentration-dependent manner that was attenuated by hypoxia. Expression and activity of PKG-I was not significantly affected by chronic hypoxia in either fetal or adult arteries, although PKG-I abundance was greater in fetal arteries. Pretreatment with the large conductance calcium-sensitive potassium channel (BK) inhibitor iberiotoxin attenuated the vasorelaxation induced by 8-pCPT-cGMP in normoxic but not chronically hypoxic arteries. These results support the hypothesis that hypoxia attenuates the vasorelaxant effects of PKG through suppression of the ability of PKG to activate large conductance calcium-sensitive potassium channels in arterial smooth muscle. The results also reveal that this hypoxic effect is greater in fetal than adult arteries and that chronic maternal hypoxia can profoundly affect fetal vascular function.

Topics: Aging; Animals; Blotting, Western; Carotid Arteries; Chronic Disease; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Endpoint Determination; Female; Fetus; Hypoxia; Large-Conductance Calcium-Activated Potassium Channels; Muscle, Smooth, Vascular; Phosphorylation; Pregnancy; Receptor, Serotonin, 5-HT2A; Serotonin; Serotonin Receptor Agonists; Sheep; Thionucleotides

Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are highly prevalent gastrointestinal disorders. Traditional symptoms based therapies had somewhat limited success and efficacy in addressing the disorders. Recently, linaclotide emerged as novel peptide capable of improving abdominal symptoms in patients suffering from IBS-C and CIC. Guanylate cyclase C (GC-C) receptor a multi domain protein, found to be molecular target for linaclotide which acts by activating GC-C receptor on the apical surface of intestinal epithelial cells. Binding of linaclotide to GC-C receptor triggers the elevation of second messenger cGMP that elicits fluid secretion into intestinal cells which play a critical role in maintaining homeostasis through cystic fibrosis transmembrane conductance regulator (CFTR). Data from Phase II and III clinical trials demonstrated that linaclotide seems to produce a statistically significant increase in stool frequency, improved straining, decreased abdominal pain and discomfort.

Topics: Chronic Disease; Clinical Trials as Topic; Constipation; Cyclic GMP; Cystic Fibrosis Transmembrane Conductance Regulator; Half-Life; Humans; Irritable Bowel Syndrome; Peptides; Receptors, Guanylate Cyclase-Coupled

How diversity evolves and persists in biofilms is essential for understanding much of microbial life, including the uncertain dynamics of chronic infections. We developed a biofilm model enabling long-term selection for daily adherence to and dispersal from a plastic bead in a test tube. Focusing on a pathogen of the cystic fibrosis lung, Burkholderia cenocepacia, we sequenced clones and metagenomes to unravel the mutations and evolutionary forces responsible for adaptation and diversification of a single biofilm community during 1,050 generations of selection. The mutational patterns revealed recurrent evolution of biofilm specialists from generalist types and multiple adaptive alleles at relatively few loci. Fitness assays also demonstrated strong interference competition among contending mutants that preserved genetic diversity. Metagenomes from five other independently evolved biofilm lineages revealed extraordinary mutational parallelism that outlined common routes of adaptation, a subset of which was found, surprisingly, in a planktonic population. These mutations in turn were surprisingly well represented among mutations that evolved in cystic fibrosis isolates of both Burkholderia and Pseudomonas. These convergent pathways included altered metabolism of cyclic diguanosine monophosphate, polysaccharide production, tricarboxylic acid cycle enzymes, global transcription, and iron scavenging. Evolution in chronic infections therefore may be driven by mutations in relatively few pathways also favored during laboratory selection, creating hope that experimental evolution may illuminate the ecology and selective dynamics of chronic infections and improve treatment strategies.

Topics: Bacterial Adhesion; Base Sequence; Biofilms; Burkholderia cenocepacia; Burkholderia Infections; Chronic Disease; Cyclic GMP; Cystic Fibrosis; Directed Molecular Evolution; DNA, Bacterial; Ecosystem; Genome, Bacterial; Humans; Lung Diseases; Mannose; Metagenome; Mutation; Opportunistic Infections; Phylogeny; Selection, Genetic

Familial diarrhea disorders are, in most cases, severe and caused by recessive mutations. We describe the cause of a novel dominant disease in 32 members of a Norwegian family. The affected members have chronic diarrhea that is of early onset, is relatively mild, and is associated with increased susceptibility to inflammatory bowel disease, small-bowel obstruction, and esophagitis.. We used linkage analysis, based on arrays with single-nucleotide polymorphisms, to identify a candidate region on chromosome 12 and then sequenced GUCY2C, encoding guanylate cyclase C (GC-C), an intestinal receptor for bacterial heat-stable enterotoxins. We performed exome sequencing of the entire candidate region from three affected family members, to exclude the possibility that mutations in genes other than GUCY2C could cause or contribute to susceptibility to the disease. We carried out functional studies of mutant GC-C using HEK293T cells.. We identified a heterozygous missense mutation (c.2519G→T) in GUCY2C in all affected family members and observed no other rare variants in the exons of genes in the candidate region. Exposure of the mutant receptor to its ligands resulted in markedly increased production of cyclic guanosine monophosphate (cGMP). This may cause hyperactivation of the cystic fibrosis transmembrane regulator (CFTR), leading to increased chloride and water secretion from the enterocytes, and may thus explain the chronic diarrhea in the affected family members.. Increased GC-C signaling disturbs normal bowel function and appears to have a proinflammatory effect, either through increased chloride secretion or additional effects of elevated cellular cGMP. Further investigation of the relevance of genetic variants affecting the GC-C-CFTR pathway to conditions such as Crohn's disease is warranted. (Funded by Helse Vest [Western Norway Regional Health Authority] and the Department of Science and Technology, Government of India.).

Topics: Chronic Disease; Cyclic GMP; Diarrhea; Female; Genetic Linkage; Heterozygote; Humans; Male; Mutation, Missense; Pedigree; Polymorphism, Single Nucleotide; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Signal Transduction

Previous studies show that chronic hyperammonemia impairs learning ability of rats by impairing the glutamate-nitric oxide (NO)-cyclic guanosine mono-phosphate (cGMP) pathway in cerebellum. Three types of glutamate receptors cooperate in modulating the NO-cGMP pathway: metabotropic glutamate receptor 5 (mGluR5), (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptors. The aim of this work was to assess whether hyperammonemia alters the modulation of this pathway by mGluR5 and AMPA receptors in cerebellum in vivo. The results support that in control rats: (1) low AMPA concentrations (0.1mM) activate nearly completely Ca(2+)-permeable (glutamate receptor subunit 2 (GluR2)-lacking) AMPA receptors and the NO-cGMP pathway; (2) higher AMPA concentrations (0.3 mM) also activate Ca(2+)-impermeable (GluR2-containing) AMPA receptors, leading to activation of NMDA receptors and of NO-cGMP pathway. Moreover, the data support that chronic hyperammonemia: (1) reduces glutamate release and activation of the glutamate-NO-cGMP pathway by activation of mGluR5; (2) strongly reduces the direct activation by AMPA receptors of the NO-cGMP pathway, likely due to reduced entry of Ca(2+) through GluR2-lacking, high affinity AMPA receptors; (3) strongly increases the indirect activation of the NO-cGMP pathway by high affinity AMPA receptors, likely due to increased entry of Na(+) through GluR2-lacking AMPA receptors and NMDA receptors activation; (4) reduces the indirect activation of the NO-cGMP pathway by low affinity AMPA receptors, likely due to reduced activation of NMDA receptors.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Blotting, Western; Chronic Disease; Citrulline; Cyclic GMP; Glutamic Acid; Hyperammonemia; Male; Nitric Oxide; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, AMPA; Receptors, Metabotropic Glutamate

Revascularization is an adaptive repair mechanism that restores blood flow to undersupplied ischemic tissue. Nitric oxide plays an important role in this process. Whether dietary nitrate, serially reduced to nitrite by commensal bacteria in the oral cavity and subsequently to nitric oxide and other nitrogen oxides, enhances ischemia-induced remodeling of the vascular network is not known.. Mice were treated with either nitrate (1 g/L sodium nitrate in drinking water) or sodium chloride (control) for 14 days. At day 7, unilateral hind-limb surgery with excision of the left femoral artery was conducted. Blood flow was determined by laser Doppler. Capillary density, myoblast apoptosis, mobilization of CD34(+)/Flk-1(+), migration of bone marrow-derived CD31(+)/CD45(-), plasma S-nitrosothiols, nitrite, and skeletal tissue cGMP levels were assessed. Enhanced green fluorescence protein transgenic mice were used for bone marrow transplantation. Dietary nitrate increased plasma S-nitrosothiols and nitrite, enhanced revascularization, increased mobilization of CD34(+)/Flk-1(+) and migration of bone marrow-derived CD31(+)/CD45(-) cells to the site of ischemia, and attenuated apoptosis of potentially regenerative myoblasts in chronically ischemic tissue. The regenerative effects of nitrate treatment were abolished by eradication of the nitrate-reducing bacteria in the oral cavity through the use of an antiseptic mouthwash.. Long-term dietary nitrate supplementation may represent a novel nutrition-based strategy to enhance ischemia-induced revascularization.

Topics: Animal Feed; Animals; Bone Marrow Transplantation; Cell Movement; Chronic Disease; Cyclic GMP; Dietary Supplements; Disease Models, Animal; Femoral Artery; Green Fluorescent Proteins; Hindlimb; Ischemia; Laser-Doppler Flowmetry; Ligation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myoblasts; Nitrates; Nitric Oxide; Nitrites; Regeneration; Regional Blood Flow; S-Nitrosothiols

Biofilms contribute to Pseudomonas aeruginosa persistence in a variety of diseases, including cystic fibrosis, burn wounds, and chronic suppurative otitis media. However, few studies have directly addressed P. aeruginosa biofilms in vivo. We used a chinchilla model of otitis media, which has previously been used to study persistent Streptococcus pneumoniae and Haemophilus influenzae infections, to show that structures formed in vivo are biofilms of bacterial and host origin within a matrix that includes Psl, a P. aeruginosa biofilm polysaccharide. We evaluated three biofilm and/or virulence mediators of P. aeruginosa known to affect biofilm formation in vitro and pathogenesis in vivo--bis-(3',5')-cyclic dimeric GMP (c-di-GMP), flagella, and quorum sensing--in a chinchilla model. We show that c-di-GMP overproduction has a positive impact on bacterial persistence, while quorum sensing increases virulence. We found no difference in persistence attributed to flagella. We conclude from these studies that a chinchilla otitis media model provides a means to evaluate pathogenic mediators of P. aeruginosa and that in vitro phenotypes should be examined in multiple infection systems to fully understand their role in disease.

Topics: Animals; Biofilms; Chinchilla; Chronic Disease; Cyclic GMP; Disease Models, Animal; Gene Expression Regulation, Bacterial; Humans; Otitis Media; Pseudomonas aeruginosa; Pseudomonas Infections; Quorum Sensing; Rodent Diseases; Virulence

Whether chronic hypoxia attenuates myocardial ischemia-reperfusion injury remains controversial because conflicting data have been reported probably due to the existence of many factors influencing the functional recovery of hearts. These factors include the differences of species, the time at which hypoxia begins, the degree of hypoxia, and so on. Regarding chronic hypoxia from birth, so far the only available data are based on findings in rabbit hearts. The purpose of this study was to describe the effect of chronic hypoxia from birth on myocardial reperfusion injury in the rat heart.. Normoxic hearts were obtained from rats housed in ambient air for 6 weeks (normoxic group); hypoxic hearts were obtained from rats housed in a hypoxic chamber (13%-14% oxygen) from birth for 6 weeks (hypoxic group). Isolated, crystalloid perfused working hearts were subjected to 30 min of global normothermic ischemia followed by 15 min of reperfusion; functional recovery was then measured in the two groups. The excretion of cyclic guanosine monophosphate (cGMP) in the coronary drainage was measured at the end of the preischemia and reperfusion periods.. The percent recovery of the left ventricular developed pressure and the first derivative of left ventricular pressure were significantly better in the hypoxic group than in the normoxic group. cGMP excretion in the coronary drainage was significantly increased during both the preischemia and reperfusion periods.. Chronic hypoxia from birth increased myocardial tolerance to ischemia-reperfusion injury with increased cGMP synthesis in the isolated heart model in rats.

Topics: Animals; Chronic Disease; Cyanosis; Cyclic GMP; Disease Models, Animal; Heart; Hypoxia; KATP Channels; Male; Myocardial Contraction; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Sprague-Dawley; Recovery of Function; Up-Regulation; Ventricular Function, Left; Ventricular Pressure

Attenuation of the effects of natriuretic peptides has been demonstrated in animal models but studies in humans are scarce, particularly concerning renal attenuation. We investigated the attenuation of B-type natriuretic peptide (BNP) in chronic advanced heart failure (HF).. We included 62 outpatients with HF and severe left ventricular systolic dysfunction. Cases had at least one hospital admission or emergency department visit for acute HF in the previous year and were in NYHA class III/IV despite optimized therapy. The individual age- and sex-matched controls were symptomatically controlled (NYHA I and II). We collected 24 h urine and a blood sample from all patients. Plasma BNP and plasma (pcGMP) and urine cyclic guanosine monophosphate (ucGMP) were measured. Patients were followed for 3 months for hospital admission or all-cause death. ucGMP to plasma BNP (ucGMP/BNP) ratio was attenuated in cases vs. controls [median (IQR): 8354 (4293-16,456) vs. 12,693 (6896-22,851)]. There were no differences in pcGMP to BNP (pcGMP/BNP) ratio or urine cGMP excretion. Patients with worse outcome had lower pcGMP/BNP [260 (86-344) vs. 381 (244-728) in patients without adverse outcome events] and lower ucGMP/BNP [4146 (2207-9363) vs. 10,922 (7495-19,971)].. Renal NP's second messenger production is attenuated in advanced HF. Patients with worse outcome have lower ucGMP/BNP and pcGMP/BNP ratios.

Topics: Aged; Chronic Disease; Creatinine; Cyclic GMP; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Second Messenger Systems; Ventricular Dysfunction, Left

A broad variety of evidence obtained largely in pulmonary vasculature suggests that chronic hypoxia modulates vasoreactivity to nitric oxide (NO). The present study explores the general hypothesis that chronic hypoxia also modulates cerebrovascular reactivity to NO, and does so by modulating the activity of soluble guanylate cyclase (sGC), the primary target for NO in vascular smooth muscle. Pregnant and nonpregnant ewes were maintained at either sea level or at 3,820 m for the final 110 days of gestation, at which time middle cerebral arteries from term fetal lambs and nonpregnant adults were harvested. In both fetal and adult arteries, NO-induced vasodilatation was attenuated by chronic hypoxia and completely inhibited by 10 microM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of sGC. sGC abundance (in ng sGC/mg protein) measured via Western immunoblots was approximately 10-fold greater in fetal (17.6 +/- 1.6) than adult (1.7 +/- 0.3) arteries but was not affected by chronic hypoxia. The specific activity of sGC (in pmol cGMP.microg sGC(-1).min(-1)) was similar in fetal (255 +/- 64) and adult (280 +/- 75) arteries and was inhibited by chronic hypoxia in both fetal (120 +/- 10) and adult (132 +/- 26) arteries. Rates of cGMP degradation (in pmol cGMP.mg protein(-1).min(-1)) were similar in fetal (159 +/- 59) and adult (134 +/- 36) arteries but were not significantly depressed by chronic hypoxia in either fetal (115 +/- 25) or adult (108 +/- 25) arteries. The cGMP analog 8-(p-chlorophenylthio)-cGMP was a more potent vasorelaxant in fetal (pD(2) = 4.7 +/- 0.1) than adult (pD(2) = 4.3 +/- 0.1) arteries, but its ability to promote vasodilatation was not affected by chronic hypoxia in either age group. Together, these results reveal that hypoxic inhibition of NO-induced vasodilatation is attributable largely to attenuation of the specific activity of sGC and does not involve significant changes in sGC abundance, cGMP-phosphodiesterase activity, or the vasorelaxant activity of protein kinase G.

Topics: Altitude Sickness; Animals; Cerebral Arteries; Chronic Disease; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Endothelium-Dependent Relaxing Factors; Enzyme Inhibitors; Female; Fetus; Guanylate Cyclase; Hypoxia; Muscle, Smooth, Vascular; Nitric Oxide; Oxadiazoles; Pregnancy; Quinoxalines; Receptors, Cytoplasmic and Nuclear; Sheep; Soluble Guanylyl Cyclase; Vasodilation

The roles of Rho kinase (ROCK) and cGMP-dependent protein kinase (PKG) in cGMP-mediated relaxation of fetal pulmonary veins exposed to chronic hypoxia (CH) were investigated. Fourth generation pulmonary veins were dissected from near-term fetuses ( approximately 140 days of gestation) delivered from ewes exposed to chronic high altitude hypoxia for approximately 110 days (CH) and from control ewes. After constriction with endothelin-1, 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) caused a similar relaxation of both control and CH vessels. Rp-8-Br-PET-cGMPS (a PKG inhibitor) inhibited whereas Y-27632 (a ROCK inhibitor) augmented relaxation of control veins to 8-Br-cGMP. These effects were significantly diminished in CH veins. PKG protein expression and activity were greater whereas ROCK protein expression and activity were less in CH vessels compared with controls. Phosphorylation of threonine 696 (ROCK substrate) and serine 695 (PKG substrate) of the regulatory myosin phosphatase targeting subunit MYPT1 of myosin light chain (MLC) phosphatase was stimulated to a lesser extent in CH than in control veins by endothelin-1 (ROCK stimulant) and 8-Br-cGMP (PKG stimulant), respectively. The phosphorylation and dephosphorylation of MLC caused by endothelin-1 and 8-Br-cGMP, respectively, were less in CH veins than in controls. These results suggest that CH in utero upregulates PKG activity but attenuates PKG action in fetal pulmonary veins. These effects are offset by the diminished ROCK action on MYPT1 and MLC and thus lead to an unaltered response to cGMP.

Topics: Altitude; Animals; Chronic Disease; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Female; Fetus; Hypoxia; In Vitro Techniques; Models, Biological; Myosin Light Chains; Myosin-Light-Chain Kinase; Phosphorylation; Phosphoserine; Phosphothreonine; Pulmonary Veins; rho-Associated Kinases; Sheep; Vasodilation

The cGMP/cGMP-dependent protein kinase I (cGKI) signaling pathway plays an important role in spinal nociceptive processing. However, downstream targets of cGKI in this context have not been identified to date. Using a yeast two-hybrid screen, we isolated cysteine-rich protein 2 (CRP2) as a novel cGKI interactor in the spinal cord. CRP2 is expressed in laminas I and II of the mouse spinal cord and is colocalized with cGKI, calcitonin gene-related peptide, and isolectin B4. Moreover, the majority of CRP2 mRNA-positive dorsal root ganglion (DRG) neurons express cGKI and peripherin. CRP2 is phosphorylated in a cGMP-dependent manner, and its expression increases in the spinal cord and in DRGs after noxious stimulation of a hindpaw. To elucidate the functional role of CRP2 in nociception, we analyzed mice with a targeted deletion of CRP2. CRP2-deficient (CRP2-/-) mice demonstrate normal behavioral responses to acute nociception and after axonal injury of the sciatic nerve, but increased nociceptive behavior in models of inflammatory hyperalgesia compared with wild-type mice. Intrathecal administration of cGMP analogs increases the nociceptive behavior in wild-type but not in CRP2-/- mice, indicating that the presence of CRP2 is important for cGMP-mediated nociception. These data suggest that CRP2 is a new downstream effector of cGKI-mediated spinal nociceptive processing and point to an inhibitory role of CRP2 in the generation of inflammatory pain.

Topics: Animals; Chronic Disease; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Cyclic GMP-Dependent Protein Kinases; Ganglia, Spinal; Inflammation Mediators; LIM Domain Proteins; Mice; Mice, Knockout; Muscle Proteins; Nuclear Proteins; Pain; Peripheral Nervous System Diseases; Rats; Signal Transduction; Spinal Cord

It has been proposed that impairment of the glutamate-nitric oxide-cyclic guanosine monophosphate (cGMP) pathway in brain contributes to cognitive impairment in hepatic encephalopathy. The aims of this work were to assess whether the function of this pathway and of nitric oxide synthase (NOS) are altered in cerebral cortex in vivo in rats with chronic liver failure due to portacaval shunt (PCS) and whether these alterations are due to hyperammonemia. The glutamate-nitric oxide-cGMP pathway function and NOS activation by NMDA was analysed by in vivo microdialysis in cerebral cortex of PCS and control rats and in rats with hyperammonemia without liver failure. Similar studies were done in cortical slices from these rats and in cultured cortical neurons exposed to ammonia. Basal NOS activity, nitrites and cGMP are increased in cortex of rats with hyperammonemia or liver failure. These increases seem due to increased inducible nitric oxide synthase expression. NOS activation by NMDA is impaired in cerebral cortex in both animal models and in neurons exposed to ammonia. Chronic liver failure increases basal NOS activity, nitric oxide and cGMP but reduces activation of NOS induced by NMDA receptors activation. Hyperammonemia is responsible for both effects which will lead, independently, to alterations contributing to neurological alterations in hepatic encephalopathy.

Topics: Ammonia; Animals; Blotting, Western; Cerebral Cortex; Chronic Disease; Cyclic GMP; Enzyme Activation; Fluorescent Antibody Technique, Indirect; Glutamic Acid; Immunohistochemistry; In Vitro Techniques; Liver Failure; Male; N-Methylaspartate; Nitrates; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitrites; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction

On the basis of limited experimental and clinical studies, increased activity of the vasodilatory nitric oxide-cyclic guanosine monophosphate pathway is considered to play a key role in the pathogenesis of hepatopulmonary syndrome. We report a 46-year-old woman with Child-Pugh class C cirrhosis and progressive dyspnoea for 12 months. Investigations revealed elevated circulating concentrations of nitric oxide metabolites and exhaled nitric oxide levels, an hyperdynamic circulation with low systemic vascular resistance and mean arterial pressure, a large right to left intrapulmonary shunt fraction on radiolabelled macroaggregated albumin perfusion scanning, positive contrast-enhanced echocardiography, reduced diffusion capacity of carbon monoxide, hypoxaemia and orthodeoxyia, all in keeping with severe hepatopulmonary syndrome. Sequential inhibition of the nitric oxide-cyclic guanosine monophosphate pathway using curcumin (diferuloylmethane), terlipressin and methylene blue was associated with substantial improvements in vascular tone and the hyperdynamic circulation. No improvement, however, in the intrapulmonary shunt was demonstrated. Both hypoxaemia and orthodeoxia were substantially, reproducibly and reversibly worsened with all three treatments. Our findings argue against the contention that intrapulmonary shunting and impairment in arterial oxygenation in hepatopulmonary syndrome are necessarily the consequence of on-going, nitric oxide-cyclic guanosine monophosphate-mediated vasodilatation, at least in the chronic stage, and, given the possibility of substantial worsening of pulmonary oxygen exchange, suggest that inhibition of the nitric oxide-cyclic guanosine monophosphate pathway should be avoided in this setting.

Topics: Antihypertensive Agents; Blood Pressure; Chronic Disease; Curcumin; Cyclic GMP; Echocardiography; Female; Hepatopulmonary Syndrome; Humans; Lypressin; Methylene Blue; Middle Aged; Nitric Oxide; Terlipressin; Treatment Failure; Vascular Resistance

Nitric oxide (NO) activates soluble guanylate cyclase (sGC), a heterodimer composed of alpha- and beta-subunits, to produce cGMP. NO reduces pulmonary vascular remodeling, but the role of sGC in vascular responses to acute and chronic hypoxia remains incompletely elucidated. We therefore studied pulmonary vascular responses to acute and chronic hypoxia in wild-type (WT) mice and mice with a nonfunctional alpha1-subunit (sGCalpha1-/-).. sGCalpha1-/- mice had significantly reduced lung sGC activity and vasodilator-stimulated phosphoprotein phosphorylation. Right ventricular systolic pressure did not differ between genotypes at baseline and increased similarly in WT (22+/-2 to 34+/-2 mm Hg) and sGCalpha1-/- (23+/-2 to 34+/-1 mm Hg) mice in response to acute hypoxia. Inhaled NO (40 ppm) blunted the increase in right ventricular systolic pressure in WT mice (22+/-2 to 24+/-2 mm Hg, P<0.01 versus hypoxia without NO) but not in sGCalpha1-/- mice (22+/-1 to 33+/-1 mm Hg) and was accompanied by a significant rise in lung cGMP content only in WT mice. In contrast, the NO-donor sodium nitroprusside (1.5 mg/kg) decreased systemic blood pressure similarly in awake WT and sGCalpha1-/- mice as measured by telemetry (-37+/-2 versus -42+/-4 mm Hg). After 3 weeks of hypoxia, the increases in right ventricular systolic pressure, right ventricular hypertrophy, and muscularization of intra-acinar pulmonary vessels were 43%, 135%, and 46% greater, respectively, in sGCalpha1-/- than in WT mice (P<0.01). Increased remodeling in sGCalpha1-/- mice was associated with an increased frequency of 5'-bromo-deoxyuridine-positive vessels after 1 and 3 weeks (P<0.01 versus WT).. Deficiency of sGCalpha1 does not alter hypoxic pulmonary vasoconstriction. sGCalpha1 is essential for NO-mediated pulmonary vasodilation and limits chronic hypoxia-induced pulmonary vascular remodeling.

Topics: Acute Disease; Animals; Antimetabolites; Blood Pressure; Bromodeoxyuridine; Chronic Disease; Cyclic GMP; Dimerization; Female; Guanylate Cyclase; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Male; Mice; Mice, Mutant Strains; Nitric Oxide; Pulmonary Artery; Pulmonary Circulation; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Vasodilation; Ventricular Function, Right

Persistent stimulation of nociceptors and C-fibers by tissue injury causes hyperalgesia and allodynia by sensitization of nociceptors and facilitation of synaptic transmission in the spinal cord. The important participant in the inflammatory response of injured peripheral nerve may be nitric oxide (NO). The aim of the present study was to test the sensitivity of PDE5 inhibitor sildenafil in chronic constriction injury (CCI) model a rat model of neuropathic pain. Sciatic nerve injury is associated with development of hyperalgesia 14 days after the nerve ligation. Sildenafil (100 and 200 microg/rat, i.t.) produced a significant decrease in pain threshold, which in lower dose did not alter the nociceptive threshold. The hyperalgesic effect of sildenafil was blocked by L-NAME and methylene blue (MB), which on per se treatment showed antinociceptive effect in nerve ligated rats. The results from the present study indicated that the major activation of NO-cGMP pathway in the chronic constriction injury model of neuropathic pain. The aggravation of hyperalgesic response might be due to the increased cGMP levels resulting in PKG-I activation and its upregulation.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Chronic Disease; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hyperalgesia; Injections, Spinal; Male; Methylene Blue; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pain; Pain Threshold; Piperazines; Purines; Rats; Rats, Wistar; Sciatic Neuropathy; Signal Transduction; Sildenafil Citrate; Sulfones

Type V phosphodiesterase (PDE V) metabolizes cyclic guanosine monophosphate (cGMP) and is abundant in the kidney and vasculature and was found recently in the heart. Sildenafil is a PDE V inhibitor that is used clinically for erectile dysfunction. Brain natriuretic peptide (BNP) is a cardiac peptide with vasodilating, lusitropic, and natriuretic properties that are mediated via cGMP. It was hypothesized that chronic inhibition of PDE V (PDE VI) will enhance the renal actions of exogenous BNP by potentiating the renal cGMP. The cardiorenal and humoral function was determined at baseline in two groups of dogs with pacing-induced overt chronic heart failure (CHF; 240 bpm for 10 d): Group 1 (n = 6) received Sildenafil 50 mg orally three times daily during the 10 d of pacing, and group 2 (n = 5) received no PDE V inhibitor. The response to acute subcutaneous BNP (5 microg/kg) administration also was compared in both groups on day 11. The GFR was assessed by inulin clearance (P < 0.05). There was no improvement of renal function in group 1 after 10 d of PDE VI as compared with group 2, despite having higher cardiac output (P < 0.05). Group 1 had significantly higher plasma (44 +/- 2 versus 21 +/- 3 pmol/ml; P < 0.05) and urinary cGMP (4219 +/- 900 versus 1954 +/- 300 pmol/min; P < 0.05) as compared with group 2. With acute subcutaneous BNP administration, group 1 had a natriuretic and diuretic response that was associated with an increase in GFR (30 +/- 6 to 45 +/- 6 ml/min; P < 0.05) and that was not observed in group 2 (25 +/- 6 to 29 +/- 4 ml/min). Plasma BNP increased to a similar extent in both groups with subcutaneous BNP. In contrast, group 1 had a much greater urinary cGMP excretion (4219 +/- 900 to 8600 +/- 1600 pmol/min; P < 0.05) as compared with group 2 (1954 +/- 300 to 3580 +/- 351 pmol/min; P < 0.05). In experimental overt CHF, chronic administration of PDE V inhibitor did not enhance renal function despite an improvement in cardiac output. However, chronic PDE VI significantly enhanced the renal hemodynamic and excretory responses to exogenous BNP. This study supports a role for PDE V as contributing to renal maladaptation in a model of experimental overt CHF and the strategy of maximizing the renal cGMP system by combined PDE VI and natriuretic peptides in CHF to improve renal function.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Chronic Disease; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Heart Failure; Kidney; Male; Natriuretic Peptide, Brain; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Devising therapies that might prevent the onset or progression of pulmonary hypertension in newborns has received little attention. Our major objective was to determine whether sildenafil, a selective phosphodiesterase inhibitor, prevents the development of an early stage of chronic hypoxia-induced pulmonary hypertension in newborn pigs. Another objective was to determine whether sildenafil causes pulmonary vasodilation without systemic vasodilation in piglets with chronic pulmonary hypertension. Piglets were raised in room air (control, n = 5) or 10-11% O(2) (hypoxic, n = 17) for 3 days. Some piglets (n = 4) received oral sildenafil, 12 mg/kg/day, throughout exposure to hypoxia. All piglets were anesthetized and catheterized, and pulmonary arterial pressure (Ppa), pulmonary wedge pressure (Pw), aortic pressure (Ao), and cardiac output (CO) were measured. Then for some piglets raised in hypoxia for 3 days, a single oral sildenafil dose (3 mg/kg, n = 6) or placebo (n = 5) was given, and hemodynamic measurements were repeated. For piglets raised in hypoxia for 3 days, mean Ppa and calculated PVR were elevated above respective values in control piglets. Mean Ppa and PVR did not differ between piglets that received sildenafil throughout exposure to hypoxia and those that did not. For piglets with chronic hypoxia-induced pulmonary hypertension that received a single oral dose of sildenafil, mean Ppa and PVR decreased, while mean Pw, CO, mean Ao, and systemic vascular resistance remained the same. All hemodynamic measurements were unchanged after placebo. Oral sildenafil did not influence the early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. However, a single oral dose of sildenafil caused pulmonary vasodilation, without systemic vasodilation, in piglets with chronic hypoxia-induced pulmonary hypertension, which may have therapeutic implications.

Topics: Administration, Oral; Animals; Animals, Newborn; Chronic Disease; Cyclic GMP; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Infant, Newborn; Infant, Newborn, Diseases; Lung; Piperazines; Pulmonary Artery; Purines; Reference Values; Sildenafil Citrate; Sulfones; Swine; Treatment Outcome; Vasodilator Agents

Long-term potentiation (LTP) is impaired in the CA1 area of hippocampal slices from rats with chronic moderate hyperammonemia. We studied the mechanisms by which hyperammonemia in vivo impairs LTP. This process requires sequential activation of soluble guanylate cyclase, cyclic GMP-dependent protein kinase (PKG) and cyclic GMP-degrading phosphodiesterase. Application of the tetanus induced a rapid increase of cyclic GMP in slices from control or hyperammonemic rats, which is followed in control slices by a sustained decrease in cyclic GMP due to sustained activation of cyclic GMP-degrading phosphodiesterase, which in turn is due to sustained activation of PKG. In slices from rats with chronic hyperammonemia tetanus-induced decrease in cyclic GMP was delayed and transient due to lower and transient activation of PKG and of the phosphodiesterase. Hyperammonemia-induced impairment of LTP may be involved in the alterations of cognitive function in patients with hepatic encephalopathy.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Chronic Disease; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Electric Stimulation; Enzyme Activation; Hippocampus; Hyperammonemia; In Vitro Techniques; Long-Term Potentiation; Male; Phosphoric Diester Hydrolases; Rats; Rats, Wistar

We investigated the effects of fluvastatin on hypoxia-induced (1 to 3 weeks, 10% O2) pulmonary hypertension with focus on endothelial nitric oxide synthase (eNOS) activity.. Oral fluvastatin treatment (1 mg/kg daily) prevented the causing and progression of pulmonary hypertension as determined by the right ventricular pressure, right ventricular hypertrophy, and muscularization of pulmonary artery. We also revealed that fluvastatin treatments prevented the hypoxia-induced decrease in cGMP production in the rat lung and restored the endothelium-dependent relaxation in the pulmonary artery. We revealed that this beneficial effect was not dependent on the increase in eNOS mRNA or protein expression, but was dependent on the inhibition of the eNOS-tight coupling with caveolin-1, the eNOS dissociation from heat shock protein 90, and the decrease in eNOS Ser1177-phosphorylation induced by hypoxia. Furthermore, in a whole-mount immunostaining the hypoxia-induced eNOS protein condensation with caveolin-1 of pulmonary endothelial cells was restored by the fluvastatin-treatment.. These results suggest that the fluvastatin exerts beneficial effects on chronic hypoxia-induced pulmonary hypertension by protecting against the eNOS activity at the post-transcriptional level.

Topics: Animals; Blood Pressure; Caveolin 1; Chronic Disease; Cyclic GMP; Electrocardiography; Endothelium, Vascular; Fatty Acids, Monounsaturated; Fluvastatin; HSP90 Heat-Shock Proteins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Pulmonary; Hypoxia; Indoles; Myocardium; Nitric Oxide Synthase Type III; Organ Size; Phosphorylation; Proto-Oncogene Proteins c-akt; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Vasodilation; Ventricular Function, Right

Topics: Adult; Arginine; Chronic Disease; Citrulline; Cyclic GMP; Endothelium, Vascular; Erectile Dysfunction; Humans; Hypertension, Pulmonary; Infant; Male; Marketing; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

To characterize effects of interferon alpha (If-a) on functional activity of platelets in patients with chronic viral hepatitis (CVH) and viral hepatic cirrhosis (VHC).. Induced platelet aggregation (PA), spontaneous PA, levels of cAMP, cGMP and glycogen in platelets, plasm beta-thromboglobulin (bTG) and activity of thrombocytic factor 4 (TF4) were measured in 95 patients before, 4.5 h after the first If-a introduction, after 12 and 24 weeks of If-a treatment.. The patients demonstrated low induced PA, intracellular glycogen and high cAMP, b-TG and TF4. The initial administration of If-a led to normalization of most of functional platelet indices. A 24-h course of If-a therapy normalized platelet functions irrespective of stability of the virusological response.. If-a preparations in single and multiple administrations normalize platelet function.

Topics: Adolescent; Adult; Blood Coagulation; Blood Platelets; Chronic Disease; Cyclic AMP; Cyclic GMP; Female; Glycogen; Hepatitis, Viral, Human; Humans; Interferon-alpha; Liver Cirrhosis; Male; Middle Aged; Platelet Aggregation

The role of nitric oxide (NO) in the antinociceptive effect of indomethacin was assessed in the pain-induced functional impairment model in the rat (PIFIR model), a model of inflammatory and chronic pain similar to that observed in clinical gout. Oral administration of indomethacin (5.6 mg/kg), a nonselective cyclooxygenase inhibitor, significantly decreased the nociceptive response elicited by uric acid injected into the knee joint of the right hind limb (2.0+/-3.0 and 149.7+/-18.0 area units [au], in the absence and the presence of indomethacin, respectively). This effect of indomethacin was reduced in nearly 50% by local pretreatment with the nonselective inhibitor of NO synthase, N G-L-nitro-arginine methyl ester (L-NAME) (72.9+/-10.7 vs. 149.7+/-18.0 au, P<0.05). On the other hand, local administration of L-arginine (a NO synthase substrate) or sodium nitroprusside (a non-enzymatic NO donor) each increased in almost 40% the antinociceptive effect of indomethacin (230.9+/-12.6 and 226.6+/-9.7 vs. 149.7+/-18.0 au, P<0.05), whereas D-arginine (the inactive isomer of arginine) had no effect on the indomethacin antinociceptive response (208.0+/-34.9 vs. 149.7+/-18.0 au). These results suggest that, the antinociceptive effect of indomethacin involves, at least in part, the NO-cyclic GMP pathway at peripheral level.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arginine; Chronic Disease; Cyclic GMP; Disease Models, Animal; Enzyme Inhibitors; Female; Gout; Indomethacin; Nerve Tissue Proteins; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitroprusside; Pain; Pain Measurement; Peripheral Nervous System; Rats; Rats, Wistar; Signal Transduction; Uric Acid

To investigate the effects of long-term nitric oxide (NO) inhalation on the recovery process of right ventricular hypertrophy (RVH) and functional alterations in the NO-cyclic guanosine monophosphate (cGMP) relaxation pathway in rat conduit pulmonary arteries (PAs) in established chronic hypoxic pulmonary hypertension.. A total of 35 rats were exposed to chronic hypobaric hypoxia (380 mm Hg, 10% oxygen), and 39 rats were exposed to air for 10 days. Both groups were then exposed to 3 or 10 days of NO 10 ppm, NO 40 ppm, or air (control groups for each NO concentration), resulting in a total of 16 groups. Acetylcholine- and sodium nitroprusside (SNP)-induced relaxation were evaluated in precontracted PA rings. RVH was assessed by heart weight ratio of right ventricle to left ventricle plus septum.. NO inhalation had no effect on either the regression of RVH or the recovery process of impaired relaxation induced by acetylcholine or SNP in a endothelium-intact hypertensive conduit extrapulmonary artery or intrapulmonary artery (IPA). In a normal endothelium-intact conduit IPA, 40 ppm NO inhalation for 10 days partially augmented SNP-induced relaxation, but not that induced by acetylcholine.. Continuous NO inhalation did not affect the regression process of either established RVH or the impaired endogenous NO-cGMP relaxation cascade in a conduit PA in rats during the recovery period after chronic hypoxia.

Topics: Acetylcholine; Administration, Inhalation; Animals; Chronic Disease; Cyclic GMP; Endothelium-Dependent Relaxing Factors; Endothelium, Vascular; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Male; Nitric Oxide; Nitroprusside; Pulmonary Artery; Rats; Rats, Wistar; Vasodilation; Vasodilator Agents

The impaired ability to excrete sodium is a key feature of established congestive heart failure and is also apparent in asymptomatic left ventricular (LV) impairment. However, few studies have examined responses to chronic volume loading immediately post-myocardial infarction (MI). Experimental MI was induced in six sheep by thrombogenic coil coronary artery occlusion, and resulted in significant LV dysfunction with reduced LV ejection fraction ( P =0.001) and subsequent remodelling (increased LV volumes, P =0.015). Chronic volume loading with 2, 3 and 4 litres/day intravenous saline (each for 7 days) showed no evidence of renal sodium or volume retention in sheep with experimental MI compared with six normal control sheep. Plasma levels of brain natriuretic peptide (BNP), N-terminal pro-BNP and cGMP (all P <0.05) were higher in the MI group compared with normal control sheep. There were no differences in haemodynamics, body mass or renin-aldosterone levels between groups. This study provides evidence that natriuretic peptides play a pivotal role in preserving volume/electrolyte balance in the early stages of post-MI cardiac dysfunction.

Topics: Animals; Chronic Disease; Cyclic GMP; Female; Homeostasis; Models, Animal; Myocardial Infarction; Natriuretic Peptide, Brain; Sheep; Sodium; Sodium Chloride; Ventricular Dysfunction, Left

Recent studies from our laboratory indicate that pulmonary vasodilatory responses to exogenous nitric oxide (NO) are attenuated following chronic hypoxia (CH) and that this NO-dependent vasodilation is mediated by cGMP. Similarly, we have demonstrated that CH attenuates vasodilatory responses to the cGMP analog 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP). We hypothesized that attenuated pulmonary vasodilation to 8-BrcGMP following CH is mediated by decreased protein kinase G-1 (PKG-1) expression/activity. Therefore, we examined vasodilatory responses to 8-BrcGMP (1 microM) in isolated, saline-perfused lungs from control and CH (4 wk at barometric pressure of 380 mmHg) rats in the presence of the competitive PKG inhibitor Rp-beta-phenyl-1, N2-etheno-8-bromoguanosine 3',5'-cyclic monophosphorothionate (30 microM) or the highly specific PKG inhibitor KT-5823 (10 microM). PKG-1 expression and activity were determined in whole lung homogenates from each group, and vascular PKG-1 levels were assessed by quantitative immunohistochemistry. PKG inhibition with either Rp-8-Br-PET-cGMPS or KT-5823 diminished vasodilatory responses to 8-BrcGMP in lungs from both control and CH rats, thus indicating a role for PKG in mediating reactivity to 8-BrcGMP in each group. However, in contrast to our hypothesis, PKG-1 levels were approximately twofold greater in lungs from CH rats vs. controls, and furthermore, this upregulation was localized to the vasculature. This correlates with an increase in PKG activity following CH. We conclude that PKG-1 is involved in 8-BrcGMP-mediated vasodilation; however, attenuated pulmonary vasodilation following CH is not associated with decreased expression/activity of PKG-1.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Alkaloids; Animals; Carbazoles; Chronic Disease; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Enzyme Inhibitors; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Immunohistochemistry; Indoles; Lung; Nitric Oxide; Platelet Aggregation Inhibitors; Polycythemia; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Thionucleotides; Up-Regulation; Vascular Resistance; Vasodilation

Stimulation of cardiomyocyte guanosine 3',5'-cyclic monophosphate (cyclic GMP) via endothelial-derived nitric oxide (NO) is an important mechanism by which bradykinin and ACE inhibitors prevent hypertrophy. Endothelial NO dysfunction and cardiac hypertrophy are morbid features of diabetes not entirely prevented by ACE inhibitors. In cardiomyocyte/endothelial cell cocultures, bradykinin efficacy is abolished by high-glucose-induced endothelial NO dysfunction. We now demonstrate that antihypertrophic actions of natriuretic peptides, which stimulate cyclic GMP independently of NO, are preserved in cardiomyocytes despite high-glucose-induced endothelial dysfunction. Further, streptozotocin-induced diabetes significantly impairs the effectiveness of acute antihypertrophic strategies in isolated rat hearts. In hearts from citrate-treated control rats, angiotensin II-stimulated [(3)H]phenylalanine incorporation and atrial natriuretic peptide and beta-myosin heavy chain mRNA expression were prevented by B-type natriuretic peptide (BNP), bradykinin, the ACE inhibitor ramiprilat, and the neutral endopeptidase inhibitor candoxatrilat. These antihypertrophic effects were accompanied by increased left ventricular cyclic GMP. In age-matched diabetic hearts, the antihypertrophic and cyclic GMP stimulatory actions of bradykinin, ramiprilat, and candoxatrilat were absent. However, the blunting of hypertrophic markers and accompanying increases in cyclic GMP stimulated by BNP were preserved in diabetes. Thus BNP, which increases cyclic GMP independently of NO, is an important approach to prevent growth in the diabetic myocardium, where endothelium-dependent mechanisms are compromised.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Cardiomegaly; Cells, Cultured; Chronic Disease; Cyclic GMP; Diabetes Mellitus, Experimental; Gene Expression; Heart Ventricles; Male; Myocytes, Cardiac; Natriuretic Peptide, Brain; Phenylalanine; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tritium

Cyclic GMP (cGMP) serves as an intracellular second messenger of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and nitric oxide (NO) and its peripheral blood concentration is an index of its biological activity. It has been reported that the plasma concentration of cGMP is correlated with the concentrations of ANP and BNP and is related to the prognosis of chronic heart failure patients, but the relation with NO has not been studied. Therefore, we investigated the roles of ANP, BNP, and NO in relation to cGMP in the blood during worsening and improvement of chronic heart failure. The subjects were 25 patients who were hospitalized in our hospital for acute worsening of chronic heart failure. Plasma concentrations of NO, norepinephrine (NE), ANP, BNP, and cGMP were measured on acute worsening (admission) and improvement (discharge) of heart failure. The cGMP concentration on worsening showed a positive correlation with the NO concentration (r = (0.57, P < 0.01), but no correlations with ANP or BNP were observed. The cGMP concentration on improvement showed no correlation with the NO concentration, but a positive correlation with ANP (r = 0.69, P < 0.001) and BNP (r = 0.67, P < 0.001). No correlation was observed between the NO and NE concentrations. We also studied serious cases of NYHA IV and mild cases of NYHA II to III. The cGMP concentration in the serious group showed a positive correlation with the NO concentration but no correlations with ANP or BNP concentrations on worsening. However, in the mild group, the cGMP concentration during worsening showed positive correlations with both the NO and BNP concentrations. On improvement, the cGMP concentration showed no correlation with the NO concentration but positive correlations with both the ANP and BNP concentrations in both the severe and mild groups. The results suggest the possibility that cGMP is produced mainly by NO during worsening, and by ANP and BNP rather than NO during improvement of chronic heart failure.

Topics: Aged; Analysis of Variance; Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Nitric Oxide; Norepinephrine; Tropanes

Reduced endothelium-dependent vasorelaxation partly due to loss of nitric oxide (NO) bioavailability occurs in most cases of chronic hypertension. Intrauterine nutritional deprivation has been associated with increased risk for hypertension and stroke, associated with relaxant dysfunction and decreased vascular compliance, but the underlying mechanisms are not known. The present studies were undertaken to investigate whether endothelial dysfunction associated with altered NO-dependent vasodilatation pathways is also observed in a model of in utero programming of hypertension.. Pregnant Wistar rats were fed a normal (18%), low (9%), or very low (6%) protein isocaloric diet during gestation. Vasomotor response of resistance cerebral microvessels (<50 micro m) was studied in adult offspring of dams fed the 18% and 9% protein diets by a video imaging technique. Endothelial NOS (eNOS), soluble guanylate cyclase (sGC), and K(Ca) channel expression were measured by Western blot. NO synthase (NOS) activity was measured enzymatically as well as in situ by NADPH diaphorase staining.. Litter size and survival to adulthood were not affected by the diets. Birth weights of offspring of dams fed the 6% diet were markedly lower than those of dams fed the 9% diet, which were marginally lower than those of controls. Systolic blood pressures of adult offspring of mothers in the 6% and 9% groups were comparably greater (156+/-2 and 155+/-1 mm Hg, respectively) than that of control offspring (137+/-1 mm Hg); we therefore focused on the 9% and 18% groups. Cerebral microvessel constriction to thromboxane A(2) mimetic and dilation to carba-prostaglandin I(2) did not differ between diet groups. In contrast, vasorelaxation to the NO-dependent agents substance P and acetylcholine was diminished by 50% in low protein-exposed offspring, but eNOS expression and activity were similar between the 2 diet groups. Vasorelaxant response to the NO donor sodium nitroprusside was also decreased and was associated with reduced (by 50% to 65%) cGMP levels and sGC expression. cGMP analogues caused comparable vasorelaxation in the 2 groups. Expression of K(Ca) (another important mediator of NO action) and relaxation to the K(Ca) opener NS1619 were unchanged by antenatal diet.. Maternal protein deprivation, which leads to hypertension in the offspring, is associated with diminished NO-dependent relaxation of major organ (cerebral) microvasculature, which seems to be largely attributed to decreased sGC expression and cGMP levels. The study provides an additional explanation for abnormal vasorelaxation in nutrient-deprived subjects in utero.

Topics: Animals; Chronic Disease; Cyclic GMP; Dietary Proteins; Disease Models, Animal; Endothelium, Vascular; Enzyme Inhibitors; Female; Guanylate Cyclase; Hypertension; In Vitro Techniques; Microcirculation; Neurotransmitter Agents; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Pia Mater; Pregnancy; Prenatal Exposure Delayed Effects; Protein Deficiency; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase; Vasodilation; Vasodilator Agents; Vasomotor System

Chronic hypoxia (CH) augments endothelium-derived nitric oxide (NO)-dependent pulmonary vasodilation; however, responses to exogenous NO are reduced following CH in female rats. We hypothesized that CH-induced attenuation of NO-dependent pulmonary vasodilation is mediated by downregulation of vascular smooth muscle (VSM) soluble guanylyl cyclase (sGC) expression and/or activity, increased cGMP degradation by phosphodiesterase type 5 (PDE5), or decreased VSM sensitivity to cGMP. Experiments demonstrated attenuated vasodilatory responsiveness to the NO donors S-nitroso-N-acetylpenicillamine and spermine NONOate and to arterial boluses of dissolved NO solutions in isolated, saline-perfused lungs from CH vs. normoxic female rats. In additional experiments, the sGC inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, blocked vasodilation to NO donors in lungs from each group. However, CH was not associated with decreased pulmonary sGC expression or activity as assessed by Western blotting and cGMP radioimmunoassay, respectively. Consistent with our hypothesis, the selective PDE5 inhibitors dipyridamole and T-1032 augmented NO-dependent reactivity in lungs from CH rats, while having little effect in lungs from normoxic rats. However, the attenuated vasodilatory response to NO in CH lungs persisted after PDE5 inhibition. Furthermore, CH similarly inhibited vasodilatory responses to 8-bromoguanosine 3'5'-cyclic monophosphate. We conclude that attenuated NO-dependent pulmonary vasodilation after CH is not likely mediated by decreased sGC expression, but rather by increased cGMP degradation by PDE5 and decreased pulmonary VSM reactivity to cGMP.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Blotting, Western; Chronic Disease; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Enzyme Inhibitors; Female; Guanylate Cyclase; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Lung; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Donors; Nitroarginine; Polycythemia; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Vasodilation

Previous research of our group demonstrated an increase in L-arginine/nitric oxide (NO) pathway activity in patients with chronic daily headache (CDH) with a previous history of migraine, which was associated with a reduced platelet serotonin content and increased Ca(2+) levels. In the present work, we assessed the variations in L-arginine/NO pathway activity and platelet cyclic guanosine 3',5'-monophosphate (cGMP) levels in 25 patients affected by chronic tension-type headache (CTTH) (8 M, 17 F; age range: 34-54 years). The NO production, shown spectrophotometrically by stoichiometric transformation of oxyhemoglobin to methemoglobin due to NO synthase (NOS) activity, and inter platelet cGMP concentration, assessed with a RIA method, were determined in parallel to variations of aggregation response to 0.3 microg/ml collagen. The intracellular platelet calcium concentrations were also determined using fluorescence polarisation spectrometry. Platelet serotonin content and collagen-induced secretion as well as glutamate content were also determined with high-performance liquid chromatography (HPLC). The above parameters were compared with those of an age-matched control group. A reduction in aggregation platelet response was found. The reduction in platelet aggregation was coupled with an increased NO and cGMP production (p<0.0002 and p<0.001, respectively). A significant increase in cytosolic Ca(2+) concentration was also detected compared to control individuals (p<0.001). This was accompanied by a reduced platelet content and collagen-induced secretion of serotonin and increased content of glutamate (p<0.0001, p<0.0001 and p<0.001, respectively). The above findings were more evident in patients with analgesic abuse. It can be hypothesized that the increased NOS activity shown in platelets of CTTH patients reflects an analogous central up-regulation of NOS activity in the spinal horn/trigeminal nucleus and supraspinal structures involved in the modulation of nociceptive input from myofascial cranial structures contributing to central sensitization. The increase in NOS activity seems to be associated with a hyposerotonergic status, particularly in patients with analgesic abuse, and this can contribute to central sensitization in CTTH patients. The increase in platelet glutamate content in the same patients suggests the implication of the above excitatory amino acid in spinal and supraspinal structures involved in head pain induction and maintenance.

Topics: Adult; Arginine; Blood Platelets; Calcium; Chronic Disease; Collagen; Cyclic GMP; Cytosol; Female; Glutamic Acid; Humans; Male; Middle Aged; Nitric Oxide; Platelet Aggregation; Reference Values; Serotonin; Tension-Type Headache

We studied beta-adrenergic and muscarinic cholinergic receptor (MR) expression and proliferative response in lymphocytes from animals under chronic mild stress (CMS) model of depression (CMS animals). Animals were subjected to CMS (periods of food or water deprivation, changes in lighting conditions, tilted cage, etc.) for 12 weeks. CMS lymphocytes showed an altered mitogen-induced proliferation. CMS-B and -T lymphocytes showed an increment on beta-adrenoceptor number and on intracellular responses to a beta-agonist. CMS-T cells showed higher MR expression and lower cGMP responses than normal lymphocytes. MR were not detectable in normal B cells while CMS-B cells showed both MR expression and cGMP response. Beta and muscarinic stimulation influenced lymphocyte proliferative responses, in accordance with cAMP and cGMP responses. After 12 weeks of the CMS procedure, animals were treated with fluoxetine while the CMS procedure continued. Fluoxetine treatment reverted the alterations induced by CMS. These findings suggest a possible mechanism for the immune alterations found in depressive disorders and for the effect of fluoxetine treatment on immune response.

Topics: Adrenergic beta-Antagonists; Animals; Antidepressive Agents, Second-Generation; Autonomic Nervous System; B-Lymphocytes; CD4-CD8 Ratio; Cell Division; Chronic Disease; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Female; Fluoxetine; Iodine Radioisotopes; Mice; Mice, Inbred BALB C; Mitogens; Muscarinic Antagonists; Pindolol; Quinuclidinyl Benzilate; Radioligand Assay; Receptors, Adrenergic, beta; Receptors, Muscarinic; Stress, Psychological; T-Lymphocytes; Tritium

We tested the hypothesis that chronic high-altitude (3,820 m) hypoxia during pregnancy was associated with the upregulation of endothelial nitric oxide (NO) synthase (eNOS) protein and mRNA in ovine uterine artery endothelium and enhanced endothelium-dependent relaxation. In pregnant sheep, norepinephrine-induced dose-dependent contractions were increased by removal of the endothelium in both control and hypoxic uterine arteries. The increment was significantly higher in hypoxic tissues. The calcium ionophore A23187-induced relaxation of the uterine artery was significantly enhanced in hypoxic compared with control tissues. However, sodium nitroprusside- and 8-bromoguanosine 3',5'-cyclic monophosphate-induced relaxations were not changed. Accordingly, chronic hypoxia significantly increased basal and A23187-induced NO release. Chronic hypoxia increased eNOS protein and mRNA levels in the endothelium from uterine but not femoral or renal arteries. In nonpregnant animals, chronic hypoxia increased eNOS mRNA in uterine artery endothelium but had no effects on eNOS protein, NO release, or endothelium-dependent relaxation. Chronic hypoxia selectively augments pregnancy-associated upregulation of eNOS gene expression and endothelium-dependent relaxation of the uterine artery.

Topics: Altitude Sickness; Animals; Calcimycin; Chronic Disease; Cyclic GMP; Endothelium, Vascular; Female; Femoral Artery; Gene Expression Regulation, Enzymologic; Hypoxia; Ionophores; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitroprusside; Norepinephrine; Pregnancy; Pregnancy, Animal; Renal Artery; RNA, Messenger; Sheep; Umbilical Arteries; Uterus; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Nitric oxide (NO) is a potent vasodilator and inhibitor of vascular remodeling. Reduced NO production has been implicated in the pathophysiology of pulmonary hypertension, with endothelial NO synthase (NOS) knockout mice showing an increased risk for pulmonary hypertension. Because molecular oxygen (O2) is an essential substrate for NO synthesis by the NOSs and biochemical studies using purified NOS isoforms have estimated the Michaelis-Menten constant values for O2 to be in the physiological range, it has been suggested that O2 substrate limitation may limit NO production in various pathophysiological conditions including hypoxia. This review summarizes numerous studies of the effects of acute and chronic hypoxia on NO production in the lungs of humans and animals as well as in cultured vascular cells. In addition, the effects of hypoxia on NOS expression and posttranslational regulation of NOS activity by other proteins are also discussed. Most studies found that hypoxia limits NO synthesis even when NOS expression is increased.

Topics: Acute Disease; Animals; Chronic Disease; Cyclic GMP; Humans; Hypoxia; Lung; Nitric Oxide; Nitric Oxide Synthase; Oxygen

Low intrathecal (i.t.) doses of the nitric oxide (NO)-donor 3-morpholinosydnonimine (SIN-1) (0.1-2.0 microg/10 microl) reduced, while higher doses had no effect (5 or 100 microg/10 microl) or increased (10 and 20 microg/10 microl) the mechanical allodynia induced by chronic ligature of the sciatic nerve in rats. SIN-1 (0.1-100 microg/10 microl; i.t.) produced only antinociceptive effect in the rat tail flick test. The inhibitor of guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (4 microg/10 microl; i.t.), abolished the antinociceptive effects of SIN-1 in both tests and reduced the effect of high doses of SIN-1 in neuropathic rats. Hemoglobin (100 microg/10 microl; i.t.), a NO scavenger, inhibited the effect of low dose of SIN-1 and reduced the effect of high dose of SIN-1 in neuropathic rats. 8-Bromo-cGMP (125-500 microg/10 microl; i.t.), reduced the mechanical allodynia in neuropathic rats. The NO-synthase inhibitors, NG-nitro-L-arginine (L-NOARG) and NG-monomethyl-L-arginine (L-NMMA) (75-300 microg/10 microl; i.t.) reduced the mechanical allodynia evoked by nerve injury and increased the tail-flick latency, respectively. These effects were reduced and inhibited, respectively, by previous i.t. ODQ. The effect of L-NOARG was enhanced in a non-significant manner by hemoglobin. These results indicate that SIN-1 and NO-synthase inhibitors reduce pain through a spinal mechanism that involves activation of guanylate cyclase. The effects of SIN-1 vary depending on the dose and pain model utilized, but its most sensitive effect seems to be antinociception. However, high doses of the NO-donor can intensify ongoing pain.

Topics: Animals; Chronic Disease; Cyclic GMP; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hemoglobins; Injections, Spinal; Ligation; Male; Molsidomine; Nerve Compression Syndromes; Neuralgia; Nitric Oxide; Nitric Oxide Donors; Nitroarginine; Nociceptors; omega-N-Methylarginine; Oxadiazoles; Pain Measurement; Quinoxalines; Rats; Rats, Wistar; Sciatic Nerve

We investigated whether impaired platelet-derived nitric oxide (PDNO) bioactivity and augmented platelet aggregability in chronic smokers are related to the imbalance of the intraplatelet redox state through increased oxidative stress.. Chronic smoking impairs PDNO release and augments platelet aggregability. However, their mechanisms are unknown.. Collagen-induced PDNO release, platelet aggregation, plasma and intraplatelet vitamin C and reduced glutathione (GSH), intraplatelet cyclic guanosine 3',5'-monophosphate (cGMP) and intraplatelet nitrotyrosine production, which is a marker of the peroxynitrite formation, were measured in 11 chronic smokers and 10 age-matched nonsmokers.. Release of PDNO and levels of intraplatelet cGMP were lower, and platelet aggregation was greater, in smokers than in nonsmokers. Intraplatelet vitamin C and GSH levels were lower in smokers than in nonsmokers. Intraplatelet nitrotyrosine production was greater in smokers than in nonsmokers. Next, we investigated the effects of oral vitamin C administration (2 g). After vitamin C administration, intraplatelet vitamin C levels were increased and not different at 2 h between the two groups. Then, PDNO release, intraplatelet cGMP levels and platelet aggregation in smokers were restored to the levels of nonsmokers. In smokers, PDNO release and consumption of GSH during platelet aggregation were inversely correlated, and consumption was much less after vitamin C administration. Vitamin C administration decreased intraplatelet nitrotyrosine production in smokers.. Impaired PDNO bioactivity and augmented platelet aggregability may be caused by an imbalance of the intraplatelet redox state through increased oxidative stress in smokers.

Topics: Administration, Oral; Adult; Antioxidants; Ascorbic Acid; Biological Availability; Blood Platelets; Case-Control Studies; Chronic Disease; Cyclic GMP; Free Radical Scavengers; Glutathione; Humans; Male; Nitric Oxide; Oxidation-Reduction; Oxidative Stress; Peroxynitrous Acid; Platelet Aggregation; Smoking; Time Factors; Tyrosine

On chronic hyperimmunocomplex process (CHIP) model in rats of Wistar line (Cochrane C., Koffen D., 1973) we determined cAMP and cGMP concentration, nitrogen oxide (NO), urine, urine acid,--in muscle and clearance organs, and also in plasma. In result of carried out investigations there was determined the increase of large and middle CIC in blood plasma, their fixation on endothelium of aorta bifurcation and glomerula basal membrane, partially on liver cells. There was revealed considerable disbalance of cyclic nucleotides concentration in kidneys homogenates, spleen and plasma, with guanils fall (adenil index, what is interconnected with NO level lowering in all cases and urine increase in plasma, simultaneously with its decrease in number--in kidneys and spleen. Urinic acid increased in number in kidneys, spleen, plasma. These changes create favourable background for damaging of endothelium-neutrophil-thrombocyte cooperation through hemokinin, moleculo-adhesive, fermentative mechanism with further development of proliferative-remodulating processes in vessel wall.

Topics: Animals; Antigen-Antibody Complex; Chronic Disease; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Free Radicals; Immune Complex Diseases; Male; Nitric Oxide; Rats; Rats, Wistar; Urea; Uric Acid

Endothelin-converting enzyme-1 (ECE-1) processes big endothelin-1 (ET-1) to ET-1, a peptide implicated in atheroma formation. ECE-1 exists in 2 isoforms (ECE-1alpha and ECE-1beta), the result of alternative splicing of a common gene. Neutral endopeptidase (NEP) is a genetically distinct metallopeptidase that degrades the natriuretic peptides. These peptides mediate antiproliferative and vasodilating actions. We sought to demonstrate the distribution of the 2 ECE-1 isoforms in experimental atherosclerosis, to determine the effects of chronic NEP-I on plasma cGMP concentrations, vascular wall ECE-1 activity, and ET-1 concentration, and to correlate these actions with atheroma formation. Our hypothesis was that chronic NEP-I, in association with augmented cGMP, would inhibit ECE-1 conversion of big ET-1 to active ET-1, thus reducing tissue ET-1 concentrations and associated atheroma formation.. Cholesterol-fed New Zealand White rabbits (n=8, 1% cholesterol diet) and NEP-I-treated cholesterol-fed New Zealand White rabbits (n=8; candoxatril, 30 mg/kg per day, Pfizer) were euthanized after 8 weeks of feeding. ECE-1alpha and ECE-1beta immunoreactivity was present in the aortas of both groups. Compared with control values, plasma cGMP concentrations were increased (2.8+/-0.6 versus 8.4+/-1.2 pmol/mL, P<0.05), ECE-1 activity was attenuated (68+/-3% versus 32+/-8%, P<0. 05), aortic tissue ET-1 concentrations were reduced (4.6+/-0.5 versus 3.2+/-0.3 pg/mg protein, P<0.05), and atheroma formation was attenuated (62+/-6% versus 34+/-5%, P<0.01) by NEP-I.. These studies suggest that ECE-1 is present and functionally active in the vascular wall in atherosclerosis. Inhibition of ECE-1 by NEP-I represents a novel approach to interruption of the endothelin system in this cardiovascular disease state.

Topics: Animals; Aorta; Arteriosclerosis; Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Diet, Atherogenic; Disease Models, Animal; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; In Vitro Techniques; Isoenzymes; Male; Metalloendopeptidases; Neprilysin; Protein Precursors; Rabbits; Time Factors; Vasoconstriction

In chronically hypertensive (CH), preeclamptic (PE), and normotensive pregnant women (N), we investigated ex vivo platelet aggregation in response to L-arginine (L-Arg) and sodium nitroprusside (SN), which are respectively the substrate and donor of nitric oxide (NO).. Platelet aggregation was determined with a dual-channel aggregometer by measuring transmittance of light through the sample in comparison to platelet poor plasma, as a reference. Aggregation induced by adenosine diphosphate was continuously recorded for 3 min and measured before and after preincubation with L-Arg and SN.. Preincubation with L-Arg significantly reduced platelet aggregation in N and CH patients (p < 0.05) but not in PE women. Preincubation with SN affected aggregation in PE women also (p < 0.001). No correlation was found between platelet response to L-Arg or SN stimuli and the severity of hypertensive disorders expressed as week of gestation at delivery or birth weight.. The present study demonstrates that a decreased platelet sensitivity to L-Arg characterizes PE women, whereas SN maintains its antithrombotic power. This impairment seems to be specific for PE, because platelets of CH patients utilize L-Arg normally. This finding supports the involvement of the L-Arg-NO pathway in the pathogenesis of the procoagulative features of PE and probably in the onset of the disease. The maintained response to SN in PE patients suggests a possible therapeutical use of NO donors in the disease.

Topics: Adult; Analysis of Variance; Antihypertensive Agents; Arginine; Birth Weight; Blood Pressure; Case-Control Studies; Cesarean Section; Chronic Disease; Cross-Sectional Studies; Cyclic GMP; Female; Gestational Age; Humans; Hypertension; Nitric Oxide Donors; Nitroprusside; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Statistics, Nonparametric

Haloperidol persists in brain tissue long after discontinuation while haloperidol-induced tardive dyskinesia often worsens after withdrawal of the drug. The mechanism of haloperidol-associated tardive dyskinesia is unknown, although neurotoxic pathways are suspected. Nitric oxide (NO) synthase (NOS) inhibitors exacerbate haloperidol-induced catalepsy, while haloperidol itself is a potent neuronal NOS inhibitor in vitro. Since NO and cGMP are involved in striatal neural plasticity, this study investigates a possible relation between cGMP and extrapyramidal symptoms as early predictors of haloperidol-associated tardive dyskinesia. Sprague-Dawley rats were administered either water or oral haloperidol (0.25 mg/kg/d p.o.) for 17 weeks, followed by 3 weeks withdrawal. Saline (i.p.) or the nNOS/guanylate cyclase inhibitor, methylene blue (5 mg/kg/d i.p.), were co-administered with haloperidol for the first three weeks of treatment. Vacous chewing movements (VCM's) were continuously monitored, followed by the determination of striatal cGMP and peripheral serum nitrogen oxide (NOx) levels. Chronic haloperidol engendered significant VCM's, with acute withdrawal associated with significantly reduced striatal cGMP levels as well as reduced serum NOx. Furthermore, suppressed cGMP levels were maintained and VCM's were significantly worse after early administration of methylene blue to the chronic haloperidol group. However, serum NOx was unchanged from control. We conclude that the central effects of chronic haloperidol on striatal NO-cGMP function persist for up to 3 weeks post-withdrawal. Moreover, suppression of striatal cGMP constitutes an early neuronal insult that determines the presence and intensity of haloperidol-associated motor dysfunction.

Topics: Animals; Chronic Disease; Corpus Striatum; Cyclic GMP; Dopamine Antagonists; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Extrapyramidal Tracts; Haloperidol; Male; Mastication; Methylene Blue; Motor Activity; Nitric Oxide; Rats; Rats, Sprague-Dawley

Chronic hyperammonemia impairs the glutamate-nitric oxide-cGMP pathway in rat brain in vivo. The aims of this work were to assess whether hyperammonemia impairs modulation of soluble guanylate cyclase, and to look for a peripheral marker for impairment of this pathway in brain. We activated the pathway at different steps using glutamate, SNAP, or YC-1. In control neurons these compounds increased cGMP by 7.4-, 9.7- and 7.2-fold, respectively. In ammonia-treated neurons formation of cGMP induced by glutamate, SNAP, and YC-1 was reduced by 50%, 56%, and 52%, respectively, indicating that hyperammonemia impairs activation of guanylate cyclase. This enzyme is also present in lymphocytes. Activation of guanylate cyclase by SNAP or YC-1 was impaired in lymphocytes from hyperammonemic rats. These results suggest that determination of the activation of soluble guanylate cyclase in lymphocytes could serve as a peripheral marker for impairment of the neuronal glutamate-nitric oxide-cGMP pathway in brain.

Topics: Ammonia; Animals; Biomarkers; Cells, Cultured; Chronic Disease; Cyclic GMP; Enzyme Activation; Excitatory Amino Acid Antagonists; Glutamic Acid; Guanylate Cyclase; Hepatic Encephalopathy; Indazoles; Lymphocytes; Neurons; Penicillamine; Rats; Rats, Wistar; S-Nitroso-N-Acetylpenicillamine; Time Factors

These studies tested whether fetal artery reactivity is sensitive to both acute changes in oxygen levels (in vitro) and chronic changes (in utero).. Pregnant guinea pigs near term were exposed to either normoxia or hypoxia (12% oxygen) for 4 or 7 days. The effect of decreasing PO (2 ) in vitro (acute hypoxia) on relaxation in response to acetylcholine, A23187, sodium nitroprusside, and 8-bromo-cyclic guanosine monophosphate was measured in isolated carotid arteries from normoxic fetuses. In separate experiments relaxation in response to acetylcholine and sodium nitroprusside of endothelially intact and denuded fetal arteries from fetuses exposed to normoxic conditions and long-term (4 and 7 days) hypoxic conditions was measured in the presence and absence of nitro-L -arginine (10(-4) mol/L).. Acute hypoxia inhibited endothelium-dependent relaxation in response to acetylcholine and A23187, increased sensitivity to sodium nitroprusside, but had no effect on relaxation in response to 8-bromo-cyclic guanosine monophosphate. Chronic hypoxia (4 but not 7 days) inhibited maximal relaxation of arteries in response to acetylcholine but not relaxation of arteries in response to sodium nitroprusside with respect to relaxation seen in arteries from normoxic fetuses. Nitro-L -arginine attenuated the differences between normoxic and hypoxic fetuses in acetylcholine response.. Hypoxia may alter relaxation of fetal arteries by decreasing the availability of oxygen for nitric oxide production and causing vascular adaptations related to altered nitric oxide release.

Topics: Acetylcholine; Acute Disease; Animals; Arteries; Calcimycin; Chronic Disease; Cyclic GMP; Disease Models, Animal; Female; Guinea Pigs; Hypoxia; Muscle, Smooth, Vascular; Nitric Oxide; Nitroprusside; Pregnancy; Vasodilator Agents

Chronic exposure to hypoxia from birth increased the tolerance of the rabbit heart to subsequent ischemia compared with age-matched normoxic controls. The nitric oxide donor GSNO increased recovery of post-ischemic function in normoxic hearts to values not different from hypoxic controls, but had no effect on hypoxic hearts. The nitric oxide synthase inhibitors L-NAME and L-NMA abolished the cardioprotective effect of hypoxia. Message and catalytic activity for constitutive nitric oxide synthase as well as nitrite, nitrate, and cGMP levels were elevated in hypoxic hearts. Inducible nitric oxide synthase was not detected in normoxic or chronically hypoxic hearts. Increased tolerance to ischemia in rabbit hearts adapted to chronic hypoxia is associated with increased expression of constitutive nitric oxide synthase.

Topics: Adaptation, Physiological; Animals; Chronic Disease; Cyclic GMP; Hypoxia; Myocardial Ischemia; Myocardium; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitrites; Rabbits; RNA, Messenger

Lung function is often impaired after cardiac surgery and cardiopulmonary bypass (CPB), particularly in chronically cyanotic patients. This study aimed to evaluate lung function in a surgically created chronic cyanotic neonatal lamb model after CPB and deep hypothermic circulatory arrest (DHCA) and to assess the role of nitric oxide (NO) in the pathogenesis of increased pulmonary vascular resistance.. A chronic cyanosis model was surgically created in 7 lambs (4.7+/-0.8 days old) by anastomosing the pulmonary artery (PA) to the left atrium (LA). Another 7 lambs underwent a sham operation (control). One week later, the animals underwent shunt takedown and CPB with 90 minutes of DHCA at 18 degrees C. Cardiac index (CI), pulmonary vascular resistance index (PVRI), lung dynamic compliance (Cdyn), alveolar-arterial oxygen difference (AaDO2), left atrial plasma nitrate/nitrite (NO metabolites) levels, and pulmonary cGMP production (concentration difference between LA and PA) were measured before CPB and at 1 and 2 hours after reperfusion.. The cyanosis model consistently produced significantly lower arterial oxygen tension (34.8+/-2.3 vs 93.1+/-8.8 torr in control, p < 0.001) and Qp/Qs (0.6+/-0.1 vs 1.0+/-0.0 in control, p < 0.001) than controls. Postoperative PVRI was significantly lower in the cyanosis group than in controls, although CPB with DHCA significantly elevated PVR in both cyanotic and control animals. There were no significant differences in AaDO2 and Cdyn after CPB between groups. The level of NO metabolites did not change before or after CPB in either cyanotic or acyanotic animals. NO metabolite levels tended to be higher in the cyanotic animals (p = 0.08). There was no significant difference in pulmonary cGMP production between both groups.. These findings suggest that CPB with DHCA, per se, does not affect NO production in cyanotic or acyanotic neonatal lambs but causes increased PVR in both groups. Chronic cyanosis does not result in reduced pulmonary function after CPB with DHCA, and is associated with lower PVR. The mechanism may involve an increased NO production in cyanotic animals.

Topics: Animals; Animals, Newborn; Cardiac Output; Cardiopulmonary Bypass; Chronic Disease; Cyanosis; Cyclic GMP; Disease Models, Animal; Endothelium, Vascular; Heart Arrest, Induced; Lung; Lung Compliance; Nitrates; Nitric Oxide; Nitrites; Pulmonary Diffusing Capacity; Sheep; Vascular Resistance

A chronic partially ischemic state may alter the skeletal muscle response to acute ischemia and free radical formation.. In order to investigate this hypothesis, a chronic ischemic state was established by ligating the right femoral artery of four mongrel dogs. ABIs were decreased from 1.05 +/- 0.25 preligation to 0.54 +/- 0.14 at 6 weeks (P = 0.04). At the end of 8 weeks, the hindlimb was subjected to 3 h of acute ischemia by clamping the iliac artery. The clamp was then released for 2 h of reperfusion. Plasma samples from the right iliac vein were taken during the ischemia-reperfusion period for analysis of cGMP. Tibialis anterior biopsies for Western analysis of eNOS and iNOS were taken upon completion of reperfusion. Comparisons to control dogs subjected to the acute ischemia and reperfusion without prior femoral artery ligation were made.. cGMP levels were increased in the controls at 3 h of ischemia (3539 +/- 350) and 2 h of reperfusion (2880 +/- 269). The chronic ischemia group did not develop a corresponding increase in cGMP at 3 h of ischemia (2762 +/- 251) or after 2 h of reperfusion (2102 +/- 130). Western analysis of eNOS and iNOS revealed similar levels in both groups. Analysis of eNOS revealed 0.6429 +/- 0.086 and 0.5916 +/- 0.072 (densitometric units +/- SEM) for study and control dogs, respectively. Analysis of iNOS revealed 0.3401 +/- 0.067 and 0.2475 +/- 0.066 for study and control dogs, respectively.. Previous ligation of the femoral artery resulting in chronic partial ischemia in this model demonstrated no increase in cGMP following acute ischemia that was not accompanied by a change in eNOS or iNOS levels. Nitric oxide activity is reflected by cGMP levels, which may increase in response to free radicals in the acute setting of complete ischemia.

Topics: Acute Disease; Animals; Blotting, Western; Chronic Disease; Cyclic GMP; Densitometry; Dogs; Hindlimb; Ischemia; Muscle, Skeletal; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Reference Values; Time Factors

An alteration in serotonin concentration has been found in patients with chronic headache caused by abuse of analgesic substances as well as an up-regulation of 5HT2 platelet receptors, which has been correlated with chronicization of the headache. In a previous study we demonstrated an increase in L-arginine/nitric oxide (NO) pathway activity in platelets from patients affected by migraine with or without aura, particularly during attacks. In the present research we assessed the variations in platelet L-arginine/NO pathway and cyclic guanosine monophosphate (cGMP) levels in 32 patients affected by chronic daily headache (CDH) (8 M, 24 F, age range 34-50 years) both during and between attacks. In these same patients, the platelet aggregation to different collagen concentrations (0.3, 1, 3 micrograms/ml) was determined as well as the intracellular platelet calcium concentration using fluorescence polarization spectrometry. These parameters were compared with those of an age- and sex-matched control group (n = 25; n = 10, n = 15, age range 35-51 years). A reduction found in platelet aggregation response to each collagen concentration used (p < 0.001) was coupled with an increased NO and cGMP production (NO: p < 0.0001; cGMP: p < 0.001). This was accompanied by a significant increase in intracytosolic Ca2+ (p < 0.0001) concentration and a reduced platelet serotonin content compared to those in control individuals (p < 0.0002). Changes in the above platelet parameters were accentuated more in patients with analgesic abuse than in CDH patients with no drug abuse. These findings suggest the occurrence of an activation of cGMP-Ca2+ mediated events in CDH patients with analgesic abuse. This physiologic compensatory mechanism, which intervenes in overcoming the increase in cytosolic Ca2+ levels, is not as efficient at limiting serotonin depletion by platelet dense bodies. A similar depletion in the central serotoninergic pathway can be assumed in the same patients.

Topics: Adult; Analgesics; Blood Platelets; Calcium; Chronic Disease; Collagen; Cyclic GMP; Cytosol; Female; Headache; Humans; Male; Middle Aged; Nitric Oxide; Platelet Aggregation; Recurrence; Serotonin; Substance-Related Disorders

Topics: Adenylyl Cyclases; Cell Membrane; Chronic Disease; Cyclic AMP; Cyclic GMP; Fatty Liver; Hepatitis, Chronic; Humans; Liver; Liver Cirrhosis

Here we demonstrate that T. cruzi antigen molecule SAPA (shed acute phase antigen) with neuraminidase-trans sialidase activity triggers down-regulation of T lymphocyte proliferation by interacting with T lymphocyte muscarinic acetylcholine receptors (mAChR). SAPA attachment to mAChR from Lyt 2.2+ T cells resulted in synthesis of cyclic GMP (cGMP) and secretion of PGE2, an immunoregulator effector substance. These T suppressor cell signals were blunted by atropine and by indomethacin. Cell sorter analysis showed that the interaction of SAPA with purified T cells, affected the ratio of L3T4+/Lyt 2.2+ T cells increasing the percentage of Lyt 2.2+ T cells, effect that was inhibited by the mAChR antagonist, atropine. The interaction between SAPA and mAChR from Lyt 2.2+ T cells may result, therefore, in the down-regulation of the host immune response as consequence of T suppressor/cytotoxic cells activation and PGE2 release as they were observed. These results support the theory of an immunosuppressive state that contribute to the chronic course of Chagas' disease.

Topics: Animals; Antigens, Protozoan; Atropine; Cell Division; Chagas Disease; Chronic Disease; Concanavalin A; Cyclic GMP; Cyclooxygenase Inhibitors; Dinoprostone; Down-Regulation; Indomethacin; Mice; Mice, Inbred BALB C; Muscarinic Antagonists; Receptors, Muscarinic; T-Lymphocytes; Trypanosoma cruzi

It has been suggested that renal disease is characterized by the presence of resistance to the natriuretic effects of atrial peptide (ANP). In this study, plasma ANP (pANP) and renal function were evaluated during stepwise infusion of low ANP doses (2, 4, 8, and 16 ng/kg per min) in glomerulonephritic patients with (CRF) or without (GN) moderate renal failure, and in normal subjects (NOR), kept at low-sodium diet (LSD; 35 mEq NaCl/day). To assess the physiological ANP levels, pANP was also measured in the three groups after normal-sodium diet (NSD; 235 mEq NaCl/day). ANP did not affect systemic and renal perfusion at any of the doses tested; a significant increment of GFR was observed only in NOR and GN. The 2-, 4-, and 8-ng/kg doses increased pANP to values overlapping the physiological concentrations measured at NSD; this was associated with a dose-dependent increment of urinary excretion of sodium (UNaV) that reached analogous levels in the three groups. ANP accounted for approximately 40% of the UNaV increment evoked by NSD in patients and in normal subjects. The 16-ng/kg dose led to supraphysiological levels that induced a similar marked enhancement of UNaV (from the basal value of 0.12 +/- 0.02 to 0.42 +/- 0.08 mEq/min in CRF, from 0.13 +/- 0.02 to 0.73 +/- 0.08 in GN, and from 0.09 +/- 0.02 to 0.49 +/- 0.11 in NOR). In CRF, the normal natriuretic response to the highest dose was caused by a larger increase of fractional UNaV that was strictly dependent on the greater pANP increment, as demonstrated by similar changes in the fractional excretion of cGMP, and, in part, on the greater aldosterone decrease. In all groups, ANP also induced a dose-dependent urinary loss of phosphate, potassium, and urea, resulting in a significant 15 to 25% decrease in the plasma levels. Thus, in GN and CRF patients, ANP plays a significant role in the renal handling of sodium; moreover, the achievement of low supraphysiological pANP levels leads to a conspicuous natriuresis associated with unique extranatriuretic effects.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Diet, Sodium-Restricted; Diuresis; Dose-Response Relationship, Drug; Glomerulonephritis; Hemodynamics; Humans; Kidney Failure, Chronic; Male; Natriuresis; Reference Values; Renal Circulation

We investigated the effects of chronic hypoxia on the major outward K+ currents in early cultured human main pulmonary arterial smooth muscle cells (HPSMC). Unitary currents were measured from inside-out, outside-out, and cell-attached patches of HPSMC. Chronic hypoxia depolarized resting membrane potential (Em) and reduced the activity of a charybdotoxin (CTX)- and iberiotoxin-sensitive, Ca2+-dependent K+ channel (KCa). The 4-aminopyridine-sensitive and CTX-insensitive channel or the delayed rectifier K+ channel was unaffected by chronic hypoxia. Chronic hypoxia caused a +33- to +53-mV right shift in voltage-dependent activation of K(Ca) and a decrease in K(Ca) activity at all cytosolic Ca2+ concentrations ([Ca2+]i) in the range of 0.1-10 microM. Thus the hypoxia-induced decrease in K(Ca) activity was most likely due to a decrease in K(Ca) sensitivity to Em and [Ca2+]i. Chronic hypoxia reduced the ability of nitric oxide (NO.) and guanosine 3',5'-cyclic monophosphate (cGMP) to activate K(Ca). The cGMP-dependent protein kinase-induced activation of K(Ca) was also significantly inhibited by chronic hypoxia. In addition, inhibiting channel dephosphorylation with calyculin A caused significantly less increase in K(Ca) activity in membrane patches excised from chronically hypoxic HPSMC compared with normoxic controls. This suggests that the mechanism by which hypoxia modulates NO.-induced K(Ca) activation is by decreasing the NO./cGMP-mediated phosphorylation of the channel.

Topics: Blood Vessels; Calcium; Chronic Disease; Cyclic GMP; Electrophysiology; Humans; Hypoxia; Membrane Potentials; Muscle, Smooth, Vascular; Nitric Oxide; Potassium Channels; Protein Kinases; Pulmonary Circulation

Neonatal pulmonary hypertension is associated with increased pulmonary vascular reactivity. We studied the responses of isolated porcine intrapulmonary arteries after exposure of piglets to chronic hypobaric hypoxia (CHH) from 0 to 2.5, 3 to 6, or 14 to 17 days of age. CHH inhibited the postnatal development of endothelium-dependent vasorelaxation to acetylcholine (ACh) and the calcium ionophore A-23187. Basal accumulation of guanosine 3', 5'-cyclic monophosphate (cGMP) was unaffected, but cGMP response to ACh was inhibited. Endothelium-independent relaxation to nitric oxide (NO) and zaprinast (a phosphodiesterase inhibitor) was also inhibited, but cGMP accumulation in response to these agonists was normal. The ability of sodium nitroprusside (SNP) to cause vasorelaxation and increase cGMP accumulation was unaffected. Contractile responses to potassium chloride and prostaglandin F2 alpha (PGF2 alpha) were similar to normal after exposure from birth and 3 days and were decreased in the older group, but the ability of NG-monomethyl-L-arginine acetate to increase PGF2 alpha-induced contractions decreased. Thus exposure of newborn piglets to CHH causes 1) no increase in contractile responses and 2) impairment of endothelium-dependent and -independent relaxation by impairing signal transduction mechanisms involved in the release of NO and the effectiveness of cGMP.

Topics: Acetylcholine; Animals; Animals, Newborn; Atmospheric Pressure; Calcimycin; Chronic Disease; Cyclic GMP; Dinoprost; Endothelium, Vascular; Heart; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Nitric Oxide; omega-N-Methylarginine; Potassium Chloride; Pulmonary Artery; Purinones; Swine; Vasodilation; Vasomotor System

Plasma levels of the vasoconstrictor peptide endothelin (ET) are increased in chronic heart failure (CHF), and ET levels are a major predictor of mortality in this disease. Thus, ET may play a deleterious role in CHF. The purpose of this study was to assess the effects of chronic treatment with the ET receptor antagonist bosentan in a rat model of CHF.. Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg x kg(-1) x d(-1)). Bosentan 100 mg x kg(-1) markedly increased survival (after 9 months: untreated, 47%; bosentan, 65%; P<.01). Throughout the 9-month treatment period, bosentan significantly reduced arterial pressure and heart rate. After 2 or 9 months of treatment, the ET antagonist reduced central venous pressure and left ventricular (LV) end-diastolic pressure as well as plasma catecholamines, urinary cGMP, and LV ventricular collagen density. Bosentan also reduced LV dilatation (evidenced at 2 months by a shift in the pressure/volume relationship ex vivo). Echocardiographic studies performed after 2 months showed that the ET antagonist reduced hypertrophy and increased contractility of the noninfarcted LV wall. The lower dose of bosentan (30 mg x kg(-1)), which had no major hemodynamic or structural effects, also had no effect on survival.. Long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival is associated with decreases in both preload and afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Cardiac Volume; Chronic Disease; Collagen; Consciousness; Coronary Vessels; Cyclic GMP; Echocardiography; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Failure; Heart Ventricles; Male; Myocardial Infarction; Myocardium; Norepinephrine; Pressure; Protein Precursors; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides; Survival Analysis; Ventricular Function, Left

The aim of this study was to evaluate clinical, adrenergic and endocrine factors that could predict sinus rhythm maintenance after direct current cardioversion in chronic atrial fibrillation. Nineteen patients with chronic non-rheumatic atrial fibrillation (mean duration 6 +/- 5 months) were studied. They were exercised 24 h before cardioversion at maximum effort with the Naughton protocol. Heart rate and blood pressure at rest and exercise were recorded and blood samples were taken for the assessment of adrenergic activity, by measuring cyclic adenosine monophosphate, heart endocrine function, atrial natriuretic peptide and its second messenger, cyclic guanosine monophosphate. Fifteen of the 19 patients were initially converted to sinus rhythm (eight patients with external and seven patients with internal DC shocks). After 3 months eight patients remained in sinus rhythm and 11 had relapsed, most of them within the first month. On exercise the chronotropic response was lower in the group who remained in sinus rhythm than in the group in atrial fibrillation (peak heart rate 147 +/- 11 beats.min-1 vs 165 +/- 24 beats.min-1 P = 0.02). During exercise, the systolic blood pressure in the sinus group reached higher values than in the group who relapsed (192 +/- 17 mmHg vs 176 +/- 18 mmHg, P = 0.03). Cyclic adenosine monophosphate increased significantly from rest to peak exercise in the sinus rhythm group (from 23 +/- 9 pmol.ml-1 to 31 +/- 15 mol.ml-1, P = 0.02) while it remained unchanged in the atrial fibrillation group (25 +/- 10 pmol.ml-1 to 24 +/- 8 pmol.ml-1, P = 0.02). For all 19 patients the difference in cyclic adenosine monophosphate between rest and exercise was negatively correlated with maximum heart rate (r = 0.58, P = 0.009). Atrial natriuretic peptide increased from rest to peak exercise in the sinus rhythm group (from 129 +/- 58 fmol.ml-1 to 140 +/- 66 fmol.ml-1) while it remained unchanged in the group in which atrial fibrillation persisted or recurred (from 112 +/- 58 fmol.ml-1 to 111 +/- 53 fmol.ml-1, P = 0.002). A significant correlation between atrial natriuretic peptide and cyclic guanosine monophosphate levels at exercise before cardioversion was found for the sinus rhythm group only (r = 0.76, P = 0.02). In patients with non-rheumatic chronic atrial fibrillation evaluation of clinical parameters such as heart rate and blood pressure changes during maximal exercise can be useful in the choice of suitable therapy. An inadequate increase

Topics: Aged; Atrial Fibrillation; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Chronic Disease; Cyclic AMP; Cyclic GMP; Discriminant Analysis; Electric Countershock; Exercise Test; Female; Heart Rate; Humans; Male; Middle Aged; Prognosis; Treatment Outcome

To investigate the mechanism by which polymorphonuclear leukocytes (PMNLs) contribute to tissue injury in periodontitis, NO-activity was bioassayed by measuring its ability to increase cGMP accumulation in cultured fibroblasts in the absence or presence of PMNLs isolated from blood and gingival fluid in healthy volunteers and patients with periodontitis. Non-activated PMNLs do not NO-induced stimulation of cGMP accumulation in the detector cells. However, activated PMNLs inhibited NO-induced cGMP accumulation whereas the effects of sodium nitroprusside was unaffected. Peripheral PMNLs periodontitis impaired NO-dependent cGMP accumulation more markedly than from healthy volunteers. PMNLs from periodontal pockets in periodontal patients destroyed NO significantly higher than in venous blood of the same patients without additional activation. It is assumed that the deactivation of NO by activated PMNLs is a one of the pathomechanisms of disorders in periodontitis.

Topics: Adult; Cell Line; Cells, Cultured; Chronic Disease; Cyclic GMP; Fibroblasts; Gingival Crevicular Fluid; Humans; Middle Aged; Neutrophils; Nitric Oxide; Periodontitis

Almost all of the studies evaluating the effect of chronic hypoxia on lung nitric oxide production have been performed in adult animals. Because results of studies in adult lungs should not be extrapolated to represent the newborn lung, we performed studies to determine whether decreased nitric oxide production might be involved in the pathogenesis of chronic hypoxia-induced pulmonary hypertension in newborns. We kept newborn pigs in chambers filled with room air (control) or 11-12% O2 for either 3-5 (short) or 10-12 (long) days. Using isolated lungs, we measured pulmonary vascular responses to agents that either stimulate or inhibit the synthesis of nitric oxide. To define the vascular sites of altered production of nitric oxide, we applied the micropuncture technique and measured small venular pressures before and after treatment with a nitric oxide synthesis inhibitor. Pulmonary vascular responses to acetylcholine were blunted in chronically hypoxic piglets of both the short and long groups. The nitric oxide synthesis inhibitor had a different effect in the lungs of control piglets than in those of chronically hypoxic piglets of the long but not of the short group. For the long group, the nitric oxide synthesis inhibitors caused constriction of both arteries and veins in lungs of control but not of chronically hypoxic piglets. These findings support the idea that decreased pulmonary vascular nitric oxide production occurs with chronic hypoxia in newborn pigs and might therefore contribute to the pathogenesis of pulmonary hypertension in newborns.

Topics: Acetylcholine; Animals; Animals, Newborn; Blood Pressure; Chronic Disease; Cyclic GMP; Endothelium, Vascular; Enzyme Inhibitors; Hypoxia; In Vitro Techniques; Lung; Nitric Oxide; Nitric Oxide Synthase; Nitroprusside; Pulmonary Circulation; Swine; Vascular Resistance; Vasodilator Agents

To elucidate pathophysiological alterations in vascular relaxation in rats with chronic heart failure (CHF), guanosine 3',5'-cyclic monophosphate (cGMP)- and adenosine 3',5'-cyclic monophosphate (cAMP)-mediated vasorelaxations in pulmonary artery (PA) and thoracic aorta (TA) of rats were examined 12 wk after coronary artery ligation. Acetylcholine (ACh)-induced relaxation was attenuated in endothelium-intact segments of both arteries, whereas sodium nitroprusside-induced relaxation was attenuated only in endothelium-intact TA segments of rats with CHF. Vasorelaxations elicited by isoproterenol and NKH-477, a water-soluble forskolin analogue, were diminished mainly in PA segments of the CHF rat. NG-nitro-L-arginine methyl ester (L-NAME)-induced decrease in cGMP level was less in endothelium-intact TA segments of the rat with CHF (0.20 +/- 0.06 vs. 0.99 +/- 0.26 pmol/mg protein in control), suggesting that basal nitric oxide (NO) production is reduced in CHF. Treatment with L-NAME attenuated the isoproterenol-induced relaxation only in endothelium-intact TA segments in control rats but not in CHF rats. The results suggest that both cGMP- and cAMP-mediated relaxations are impaired in CHF, and a reduction of NO synthesis, presumably in endothelial cells, plays a significant role in pathophysiological alterations in vessels of rats with CHF.

Topics: Animals; Aorta, Thoracic; Cardiac Output, Low; Chronic Disease; Cyclic AMP; Cyclic GMP; Enzyme Inhibitors; Heart; Isoproterenol; Male; Myocardial Infarction; NG-Nitroarginine Methyl Ester; Norepinephrine; Pulmonary Artery; Rats; Rats, Wistar; Vasoconstrictor Agents; Vasodilation

Effects of intrauterine hypoxia-ischemia (HI) on brain functional development in the term rat were examined in cerebellar granule cell cultures obtained from an in utero HI model. On gestation d 17, HI conditions were achieved by complete clamping of the uterine vasculature for designated durations followed by removal of the clamps to permit reperfusion. Sham operation (surgery without vasculature clamping) was performed as the control. After surgery, the uterine horns were returned to dam's abdomen to let the pups deliver naturally. Severe HI insult from the surgical manipulation was evident in that the lactate levels of fetal brain increased, and fetal blood pH decreased with the duration of vasculature clamping up to 1 h. The experimental HI insult up to 1 h did not affect fetal survival rate, but retarded growth of fetuses or newborns was observed in the 1 h HI group. N-Methyl-D-aspartate (NMDA)- and kainate (KA)-stimulated cGMP formation and glutamate accumulation were measured in cerebellar granule cell cultures from 8-d-old pups suffering from various durations of antenatal HI insult. NMDA (100 microM)-induced elevation of cGMP was further augmented by a 10-35-min HI insult as compared with the control cells (62.4-78.2 versus 49 pmol/mg protein). In the presence of L-NG-monomethyl-arginine (L-NMMA, 150 microM), a nitric oxide synthase inhibitor, NMDA-induced cGMP formation was blocked, and the blockade of cGMP formation by L-NMMA (10 microM) could be reversed by simultaneous application of 1 mM arginine in both control and HI cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arginine; Brain Ischemia; Cells, Cultured; Cerebellar Diseases; Chronic Disease; Cyclic GMP; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Fetal Hypoxia; Gestational Age; Glutamic Acid; Hypoxia, Brain; Kainic Acid; N-Methylaspartate; Nitric Oxide Synthase; omega-N-Methylarginine; Rats; Rats, Sprague-Dawley

The response of atrial natriuretic peptide (ANP) release to haemodynamic influences after cardioversion of atrial fibrillation has not been fully examined. We measured plasma concentrations of ANP and assessed haemodynamic changes 60-120 min after DC cardioversion in 22 patients with non-valvular chronic atrial fibrillation. Passive leg elevation to enhance volume expansion was performed 60 min after DC cardioversion. Sinus rhythm was restored in 18 of the 22 patients (successful DC cardioversion group). The control group consisted of seven patients with non-valvular chronic atrial fibrillation who did not undergo DC cardioversion (atrial fibrillation control group). In the successful DC cardioversion group, the mean pulmonary artery wedge pressure decreased significantly 15 min after cardioversion (P < 0.05) and then remained unchanged. Plasma concentrations of ANP also decreased significantly 15 min after cardioversion (P < 0.05). Furthermore, there was an additional significant decrease in ANP levels for up to 60 min after cardioversion (P < 0.05 from 15 min). Passive leg elevation for 15 min led to an increase in the mean pulmonary artery wedge pressure (P < 0.01) and right atrial pressure (P < 0.05), but did not result in increased plasma concentrations of ANP (47.1 +/- 27.6 vs 43.9 +/- 34.4 pg.ml-1, mean +/- SD, P = ns). In the atrial fibrillation control group, passive leg elevation increased the mean pulmonary artery wedge pressure (P < 0.01), the mean right atrial pressure (P < 0.05) and plasma concentrations of ANP (139.9 +/- 85.8 vs 168.1 +/- 108.2, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Atrial Fibrillation; Atrial Natriuretic Factor; Cardiac Output; Chronic Disease; Cyclic GMP; Electric Countershock; Female; Hemodynamics; Humans; Male; Middle Aged; Pulmonary Wedge Pressure; Treatment Outcome

Chronic fetal anemia causes polyhydramnios and fetal hydrops and is associated with increased fetal diuresis and natriuresis. To determine the role of atrial natriuretic peptide (ANP) in the renal adaptation to chronic fetal anemia we studied the effects of HS-142-1 (HS), a specific inhibitor of the guanylate cyclase-linked ANP receptor (ANP-GC), in two groups of chronically instrumented unanesthetized sheep fetuses. Seven fetuses were made anemic by serial isovolemic hemorrhage over 1 wk, and five fetuses served as nonanemic controls. Over the 7 d of hemorrhage ANP concentrations increased (45 +/- 7 to 234 +/- 15 fmol/mL). Hematocrit and arterial blood oxygen content were significantly lower in the anemic compared with the nonanemic fetuses (13.8 +/- 0.7 versus 34.6 +/- 2.3% and 0.7 +/- 0.1 versus 2.6 +/- 0.2 mmol/L). Before HS urine flow rate, urinary sodium excretion, fractional excretion of sodium, and renal blood flow were increased in the anemic fetuses, and the extracellular fluid volume (inulin space) was increased (674 +/- 94 versus 497 +/- 71 mL/kg). However, GFR was not different between the groups. HS caused a significant increase in the central venous pressure of the anemic fetuses (0.49 +/- 0.03 to 0.70 +/- 0.05 kPa). Urinary excretion of cGMP was considered to be a marker of endogenous ANP renal effect and was measured before and after a single bolus of HS (5.2 +/- 0.30 mg/kg). HS decreased urinary cGMP excretion to 50 and 37% of baseline levels in anemic and nonanemic fetuses, respectively. Urine flow decreased in both nonanemic and anemic fetuses (0.48 +/- 0.13 to 0.25 +/- 0.06 and 1.30 +/- 0.66 +/- 0.06 mL/min). Sodium excretion decreased in both groups after HS (19 +/- 5 to 9 +/- 2 and 83 +/- 16 to 39 +/- 5 mumol/min). GFR decreased after HS (3.0 +/- 0.8 to 2.4 +/- 0.5 and 3.6 +/- 0.3 to 2.6 +/- 0.2 mL/min. Fraction excretion of sodium also decreased in both groups after HS (4.6 +/- 2.7 to 2.7 +/- 0.5 and 16.1 +/- 2.4 to 11 +/- 1.6). Percent decreases in urine flow, sodium excretion, GFR, and fractional excretion of sodium observed in the anemic fetuses were not statistically different from the nonanemic fetuses. Urine flow and sodium excretion did not decrease to control levels after HS, suggesting that factors in addition to ANP contribute to the natriuresis seen with chronic anemia. After HS a transient increase in renal blood flow was observed in the nonanemic fetuses. An immediate and sustained further increase in renal blood flow

Topics: Anemia; Animals; Atrial Natriuretic Factor; Carbon Dioxide; Cattle; Chronic Disease; Cyclic GMP; Disease Models, Animal; Fetal Diseases; Hemodynamics; Oxygen; Polysaccharides; Receptors, Atrial Natriuretic Factor; Sheep; Sodium

In the canine basilar artery during chronic vasospasm following subarachnoid hemorrhage, endothelium-dependent relaxations were diminished. Release of endothelium-derived relaxing factor (EDRF), as measured by a bioassay method, was unchanged. Relaxation to nitric oxide (NO) in preparations without endothelium was smaller in the spastic arteries. Production of cyclic GMP, measured by radioimmunoassay, was reduced in the spastic arteries; the impaired production was accompanied by decrease in GTP, the substrate for the production of cyclic nucleotide. The contents of other high-energy phosphates, such as creatine phosphate and ATP were also markedly reduced. Close temporal correlation between the metabolic failure and development of vasospasm was observed. Sarcolemmal regulation of intracellular calcium concentration was impaired in the pathological condition, suggesting a link between the metabolic failure and the pathological protracted contractions. Metabolic changes, and resultant affected viability of smooth muscle cells are likely to be an important factor in the pathogenesis of chronic vasospasm.

Topics: Adenosine Triphosphate; Animals; Basilar Artery; Calcium Channels; Cell Membrane Permeability; Chronic Disease; Cyclic GMP; Dogs; Guanosine Triphosphate; Ischemic Attack, Transient; Muscle Relaxation; Muscle, Smooth, Vascular; Nitric Oxide

Neutral endopeptidase (NEP) inhibitors have been shown to strengthen the effects of endogenous atrial natriuretic peptide (ANP). It has been well documented that angiotensin I-converting enzyme (ACE) inhibitors act beneficially in chronic congestive heart failure (CHF). In the present study, renal and hormonal effects of SCH 34826, an orally active NEP inhibitor, were studied in a coronary-ligation model of experimental CHF in the rat. The effects were compared to those of captopril. The drugs were also administered in combination. In anaesthetized rats with CHF, SCH 34826 (90 mg kg-1 sc) elevated plasma ANP from 382 +/- 85 to 658 +/- 120 ng l-1 compared with vehicle (p = 0.002). In sham-operated control rats, plasma ANP also increased slightly from 52 +/- 6 to 70 +/- 9 ng l-1 (p = 0.05). Plasma renin activity did not change in either group. When given orally for 36 h (90 mg kg-1 b.i.d.), SCH 34826 enhanced natriuresis in controls but not in rats with CHF. Captopril (0.2 mg ml-1 in drinking water) enhanced natriuresis in CHF rats and both natriuresis and kaliuresis in controls. When SCH 34826 and captopril were combined, natriuresis was potentiated in control rats as compared with captopril alone; in rats with CHF, however, a brisk kaliuresis was seen. The excretion of cyclic guanosine monophosphate was enhanced in CHF rats by 52% during treatment with SCH 34826 but not with captopril or combination of the two drugs. Moreover, captopril suppressed aldosterone excretion both in CHF rats and controls when administered alone but not when combined with SCH 34826.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Dioxolanes; Dipeptides; Drug Therapy, Combination; Heart Failure; Kidney; Male; Neprilysin; Rats; Rats, Wistar

Neutral endopeptidase (NEP) inhibition is thought to blunt hypoxic pulmonary hypertension by reducing atrial natriuretic peptide (ANP) metabolism, but this hypothesis has not been confirmed. We measured NEP activity, guanosine 3',5'-cyclic monophosphate (cGMP) production, plasma ANP levels, and cardiac ANP synthesis in rats given an orally active NEP inhibitor (SCH-34826) during 3 wk of hypoxia. Under normoxic conditions, SCH-34826 had no effect on plasma ANP levels but reduced pulmonary and renal NEP activity by 50% and increased urinary cGMP levels (60 +/- 6 vs. 22 +/- 4 pg/mg creatinine; P < 0.05). Under hypoxic conditions, SCH-34826-treated rats had lower plasma ANP levels (1,259 +/- 361 vs. 2,101 +/- 278 pg/ml; P < 0.05), lower right ventricular systolic pressure (53 +/- 5 vs. 73 +/- 2 mmHg; P < 0.05), lower right ventricle weight-to-left ventricle+septum weight ratio (0.47 +/- 0.04 vs. 0.53 +/- 0.03; P < 0.05), and less muscularization and percent medial wall thickness of peripheral pulmonary arteries (22 +/- 5 vs. 45 +/- 8% and 17 +/- 1 vs. 25 +/- 1%, respectively; P < 0.05 for all values) than did rats treated with vehicle alone. These values were not affected by SCH-34826 under normoxic conditions. SCH-34826 decreased right ventricular ANP tissue levels in hypoxic rats (27 +/- 10 vs. 8 +/- 1 ng/mg protein; P < 0.05) but did not affect steady-state ANP mRNA levels. We conclude that NEP inhibition blunts pulmonary hypertension without increasing plasma ANP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Chronic Disease; Cyclic GMP; Dioxolanes; Dipeptides; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Imidazoles; Male; Muscle, Smooth, Vascular; Myocardium; Neprilysin; Pyrazines; Rats; Rats, Sprague-Dawley; RNA, Messenger

Plasma levels of cyclic nucleotides were determined by radioimmunoassay in 196 cardiac patients and 50 normal persons. Plasma levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) increased with the deterioration of cardiac function. The level of cGMP was correlated with the cardiothoracic ratio, ratio of pre-ejection period and left ventricular ejection time, the intracardiac diameter, left ventricular ejection fraction and left ventricular short axis shortening (r = 0.55, r = 0.50, r = 0.55, r = -0.53 and r = -0.50, respectively; P < 0.001). There were only weak correlations between the level of cAMP and the cardiothoracic ratio, the ratio of pre-ejection period and the left ventricular ejection time, left ventricular ejection fraction, and left ventricular short axis shortening (r = 0.35, r = 0.38, r = -0.28 and r = -0.31, respectively; P < 0.01). The correlations between cGMP and mean pulmonary artery pressure (r = 0.48; P < 0.05) and mean left atrial pressure (r = 0.55; P < 0.01) were also significant. In patients who had received cardioversion and valve replacement the plasma cGMP level decreased significantly. During the follow-up period, 29 of 108 patients died (26.9%), the initial plasma levels of cAMP and cGMP in the dead group were significantly higher than those in the survival group (27.41 +/- 1.13 and 31.11 +/- 3.33 vs. 21.56 +/- 0.60 and 17.45 +/- 1.05 nmol/l, respectively; P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Analysis of Variance; Chronic Disease; Cyclic AMP; Cyclic GMP; Female; Heart Failure; Heart Function Tests; Humans; Least-Squares Analysis; Male; Prognosis; Severity of Illness Index; Survival Analysis

The authors have investigated the hypothesis that loss of endothelium-derived relaxing factor (EDRF) activity contributes to cerebral vasospasm after subarachnoid hemorrhage. Adventitial exposure to hemoglobin was studied angiographically by injecting purified hemoglobin solution or autologous whole blood into the cisterna magna of anesthetized pigs. Both interventions induced intra- but not extracerebral vasoconstriction, which persisted for 2 and 7 days, respectively. Cyclic guanosine monophosphate (cGMP) levels were measured in isolated buffer-perfused pig intrathecal arteries to quantify inhibition of basal EDRF activity by hemoglobin. Adventitial exposure was less effective than intimal exposure, 10 microM hemoglobin applied adventitially for 30 minutes having an effect equivalent to that of 1 microM applied intraluminally for 5 minutes. The depression of cGMP levels by hemoglobin was reversible and equivalent to the effect of endothelial denudation or incubation with NG-nitro-L-arginine methyl ester, so that the effects of hemoglobin can be attributed to a specific action on EDRF rather than interaction with a nitric oxide-like substance produced by vascular smooth muscle or adventitial nerves. Cyclic GMP levels in isolated arteries were unchanged after in vivo exposure to hemoglobin for either 2 or 7 days or to whole blood for 2 days, and were reduced by intraluminal perfusion with 1 microM hemoglobin. In contrast, after 7 days of in vivo exposure to whole blood, cGMP levels were already depressed, and not further reduced by intraluminal perfusion with 1 microM hemoglobin. The findings support the view that adventitially applied hemoglobin can inhibit basal EDRF activity and that in vivo adventitial exposure to whole blood leads to a reduction in basal cGMP levels in association with vasoconstriction of intrathecal arteries. Both mechanisms could contribute to the clinical syndrome of cerebral vasospasm after subarachnoid hemorrhage.

Topics: Animals; Cerebral Arteries; Chronic Disease; Cyclic GMP; Hemoglobins; Ischemic Attack, Transient; Nitric Oxide; Subarachnoid Hemorrhage; Subarachnoid Space; Swine; Time Factors; Vasoconstriction

To evaluate the role of endogenous atrial natriuretic peptide (ANP) in patients with congestive heart failure (CHF), the relationship between plasma ANP and cyclic guanosine monophosphate (cGMP) levels and the prognosis of patients with CHF was examined. In patients with chronic mild to moderate CHF, there was a positive correlation between plasma ANP and cGMP levels (r = 0.81, p less than 0.001). However, there was no significant correlation between these plasma levels in patients with chronic severe CHF, in whom the cGMP concentration reached a plateau in spite of high levels of ANP. The ANP extraction level and the cGMP production level in the pulmonary and systemic circulation correlated significantly in patients with mild CHF. In contrast, there was no significant correlation between the 2 parameters in patients with severe CHF, and the molar ratios of cGMP production to ANP extraction in the pulmonary and systemic circulation were significantly lower than those in patients with mild CHF. In 44 patients with chronic severe CHF who were followed up over 2 years, plasma ANP levels provided more sensitive and specific prognostic information than any other parameters. These results indicate that ANP receptors coupled to guanylate cyclase may be down-regulated in patients with chronic severe CHF, suggesting that high plasma ANP levels as a prognostic predictor may be associated with limitations of compensation by endogenous ANP.

Topics: Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Follow-Up Studies; Heart Failure; Humans; Prognosis; Pulmonary Artery; Regression Analysis; Second Messenger Systems; Sensitivity and Specificity

The initiating event in hypoxic pulmonary hypertension is felt to be sustained hypoxic vasoconstriction, ultimately leading to vascular remodeling and fixed pulmonary hypertension. During the initial vasospastic phase endogenous vasodilatory pathways may serve to ameliorate the development of pulmonary hypertension. However, various studies in the systemic and pulmonary circulations have shown that chronic hemodynamic stress alters both endothelial and smooth muscle cell function. The effect of chronic hypoxia in rats was therefore tested on three major vasodilatory pathways: 1) endothelium-dependent relaxation (using endothelium-derived relaxing factor agonists and antagonists); 2) smooth muscle cell cyclic nucleotide-mediated relaxation [using guanosine and adenosine 3',5'-cyclic monophosphate (cGMP and cAMP) agonists]; and 3) ion channel-dependent relaxation (using K+ channel agonists and Ca2+ channel antagonists). It was found that short-term exposure (72 h) to hypoxia caused augmentation of K+ and Ca2+ channel-dependent relaxation with no effect on endothelium-dependent or cyclic nucleotide-mediated relaxation. More prolonged exposure (4-5 wk) was additionally associated with inhibition of endothelium-dependent relaxation and smooth muscle cell cGMP-mediated relaxation. There was no effect on either basal modulation of tone by the endothelium, cAMP-mediated relaxation, or systemic vessel relaxation. It is concluded that an early response to hemodynamic stress in the pulmonary circulation is alteration in smooth muscle cell ion channel function and/or Ca2+ homeostasis.

Topics: Animals; Calcium; Calcium Channels; Chronic Disease; Cyclic AMP; Cyclic GMP; Endothelium, Vascular; Extracellular Space; Hypoxia; Male; Potassium Channels; Pulmonary Artery; Rats; Rats, Inbred Strains; Vasoconstriction; Vasodilator Agents

This study was designed to evaluate the role of endogenous atrial natriuretic peptide in the pulmonary circulation in patients with chronic heart failure.. Plasma atrial natriuretic peptide concentrations in patients with heart failure have been reported to be higher than those in normal subjects and to increase as the severity of heart failure progresses. Although endogenous atrial natriuretic peptide is thought to improve the condition of patients with heart failure by reducing preload and afterload, recent findings have indicated that a high plasma atrial natriuretic peptide level is a prognostic predictor in patients with heart failure.. To evaluate the pathophysiologic role of endogenous atrial natriuretic peptide in the pulmonary circulation, plasma atrial natriuretic peptide and cyclic guanosine monophosphate (cGMP) levels were determined in the main pulmonary artery and pulmonary capillary wedge region in 80 patients with chronic congestive heart failure (New York Heart Association functional classes II to IV).. The plasma atrial natriuretic peptide level decreased significantly from the main pulmonary artery to the pulmonary capillary wedge region, whereas the plasma cGMP level increased significantly from the main pulmonary artery to the pulmonary capillary wedge region. In patients with mild chronic heart failure (n = 50), the plasma atrial natriuretic peptide level correlated with the cGMP level in the main pulmonary artery (gamma = 0.71, p less than 0.001). The atrial natriuretic peptide extraction level, calculated as (Atrial natriuretic peptide in the main pulmonary artery--Atrial natriuretic peptide in the pulmonary capillary wedge region) x Cardiac output x (1-hematocrit/100) (ng/min), also correlated with the cyclic guanosine monophosphate production level, calculated as (cGMP in the pulmonary capillary wedge region--cGMP in the main pulmonary artery) x Cardiac output x (1-hematocrit/100) (nmol/min) (gamma = 0.78, p less than 0.001). In contrast, such correlations were not found in patients with severe chronic heart failure (n = 30). In these patients, the atrial natriuretic peptide extraction level was significantly higher but there was no significant difference in the cGMP production level between the two groups (mild and severe chronic heart failure). Therefore, the molar ratio of cGMP production to atrial natriuretic peptide extraction in the pulmonary circulation was significantly lower in patients with severe chronic heart failure (88 +/- 16 vs. 480 +/- 41, p less than 0.001).. These results indicate that down-regulation of atrial natriuretic peptide receptors coupled to guanylate cyclase may occur in the pulmonary vascular beds of patients with severe chronic heart failure.

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Pulmonary Artery; Pulmonary Circulation

60% of chronic caval dogs with ascites did not respond to atrial natriuretic peptide (ANP) (75 ng.kg-1.min-1) with a natriuresis (TIVC-NR; delta UNaV = 2 +/- 0.8 mu eq/min) whereas the remaining 40% responded normally (TIVC-R; delta UNaV = 216 +/- 50 mu eq/min). Since proximal tubule neutral endopeptidase 24:11 (NEP) destroys most of intrarenal luminal ANP and kinins, we attempted to convert TIVC-NR into TIVC-R by providing NEP inhibition with SQ 28603 at 30 mg/kg. This potent and specific NEP inhibitor produced a natriuresis when administered alone to nine TIVC-NR dogs (delta UNaV = 67 +/- 2 mu eq/min) and permitted a natriuresis in the presence of ANP (delta UNaV = 97 +/- 18 mu eq/min). A natriuretic response to ANP could also be induced in TIVC-NR dogs by providing renal arterial bradykinin or intravenous captopril, a kininase inhibitor. Urodilatin, a natriuretic peptide not destroyed by intrarenal NEP was without effect in TIVC-NR dogs but increased UNaV when given to TIVC-R and normal dogs. Providing bradykinin to TIVC-NR now permitted an increment in delta UNaV (62 mu eq/min) when urodilatin was reinfused. TIVC-R dogs could be converted into TIVC-NR by pretreating with a specific bradykinin antagonist before infusing ANP. We conclude that TIVC-NR dogs are deficient in intrarenal kinins but are converted to responding dogs after NEP inhibition because of increased kinin delivery to the inner medullary collecting duct.

Topics: Alanine; Animals; Ascites; Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Dogs; Female; Kidney Tubules; Kinins; Male; Neprilysin; Protease Inhibitors; Receptors, Bradykinin; Receptors, Neurotransmitter; Sodium

We have examined the effects of exposing rats to hypoxia (10% fractional inspired O2 concentration) for 2 and 7 days on endothelium-dependent and -independent vasodilation and also on the ability of guanosine 3',5'-cyclic monophosphate (cGMP) to activate cGMP-dependent protein kinase (G-kinase) in rat conduit pulmonary arteries (PA). The ability of acetylcholine (ACh) and sodium nitroprusside (SNP) to both relax PA rings and elevate tissue cGMP levels was significantly attenuated in PA from hypoxic animals. The ability of atrial natriuretic peptide to relax and generate cGMP in PA rings was unchanged by hypoxia. Relaxation and elevation of cGMP levels induced by SNP in aortic rings was unaltered by hypoxia. Similarly, hypoxia did not alter the concentration-dependent activation by exogenous cGMP of G-kinase. We conclude that chronic exposure of rats to hypoxia results in a selective impairment of soluble guanylyl cyclase in rat PA, leading to an attenuation of ACh- and SNP-induced cGMP accumulation and relaxation.

Topics: Animals; Aorta; Chronic Disease; Cyclic GMP; Endothelium, Vascular; Guanylate Cyclase; Hypoxia; Male; Nitroprusside; Phenylephrine; Pulmonary Artery; Rats; Rats, Wistar; Solubility; Vasodilation; Vasodilator Agents

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 study of the content of cyclic nucleotides in patients with chronic gastritis indicates that the level of cAMP and cGMP undergoes various changes. The cGMP/cAMP ratio was in gastritis of the A type higher than in the healthy and in the B gastritis type lower. It is concluded that chronic gastritis is accompanied not only by changes of absolute values of the level of cyclic nucleotides but also by changes of the cGMP/cAMP ratio.

Topics: Adult; Chronic Disease; Cyclic AMP; Cyclic GMP; Gastric Mucosa; Gastritis; Humans; Middle Aged; Radioimmunoassay

Fifty patients with chronic bronchitis, 30 with lingering pneumonias and 60 with lung abscesses were examined. The status of the system of cyclic nucleotides and functional properties of T lymphocytes depending on different administrations of antibiotics into the patients' body (endolymphatically or intravenously) were studied over time. The degree of the recovery to normal of the functional status of the T system immunity and cyclic nucleotides turned out significantly higher in patients receiving antibiotics endolymphatically than in those given intravenous injections. This attests to the high efficacy and advantages of endolymphatic antibiotic therapy in patients with inflammation in the lungs and bronchi.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Adolescent; Adult; Anti-Bacterial Agents; Chronic Disease; Cyclic AMP; Cyclic GMP; Female; Humans; Injections, Intralymphatic; Lung Diseases; Male; Middle Aged; T-Lymphocytes

The content of pancreatic enzymes, cyclic nucleotides and prostaglandins (PG) in the duodenal contents was measured in 77 patients with chronic pancreatitis and in 20 healthy individuals. Pancreatitis exacerbation was attended by a decrease in enzymatic activity, in bicarbonate, cAMP and cGMP production. The content of PGE in pancreatic secretion remained normal, that of PGF2 alpha was elevated. Stimulation of the exocrine part of the pancreas by means of euphylline, pentagastrin and calcium was accompanied by the rise of the content of cyclic nucleotides rather than of PG. Suppression of enzymatic secretion by contrykal was followed by the reduction in the content of the cyclic nucleotides and PGE. The data suggest that cyclic nucleotides and PG are involved in the mechanism by which the external secretion of the pancreas is impaired in patients with chronic pancreatitis.

Topics: Adult; Amylases; Chronic Disease; Cyclic AMP; Cyclic GMP; Dinoprost; Female; Humans; Lipase; Male; Middle Aged; Pancreas; Pancreatic Juice; Pancreatitis; Prostaglandins E; Trypsin

The natriuretic, diuretic, and hypotensive responses to infused atrial natriuretic peptide (ANP) were measured in rats 4 weeks after myocardial infarction induced by coronary artery ligation. Rat [1-28]-ANP was infused intravenously in doses of 0.1, 0.3, and 1.0 microgram/kg/min for 30 min each under pentobarbital anesthesia. There was a marked natriuresis, diuresis, and fall in blood pressure in rats with infarction but each response was significantly attenuated when compared with sham-operated controls (ANOVA: p less than 0.01, p less than 0.05, and p less than 0.01, respectively). Urinary cyclic guanosine monophosphate (cGMP) excretion in rats with infarction was higher than that of controls but rose to the same absolute level in both groups in response to ANP infusion (0.3 microgram/kg/min). Reduced ANP responsiveness may result from impaired postreceptor mechanisms or from physiological antagonism by angiotensin II. Reduced ANP responsiveness may partly explain impaired salt handling in heart failure.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Chronic Disease; Coronary Vessels; Cyclic GMP; Female; Heart Failure; Myocardial Infarction; Rats; Rats, Inbred Strains; Sodium; Urodynamics

Topics: Adrenal Gland Neoplasms; Adult; Chronic Disease; Cyclic AMP; Cyclic GMP; Female; Humans; Hyperaldosteronism; Hypertension; Hypertension, Renovascular; Kidney Diseases; Pheochromocytoma; Potassium; Pyelonephritis; Sodium

Topics: Chronic Disease; Cyclic AMP; Cyclic GMP; Glomerulonephritis; Humans; Immunoglobulin G; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Plant Extracts; Plants, Medicinal; Rosette Formation

Topics: Acute Disease; Adult; Aged; Bacterial Toxins; Chronic Disease; Cyclic AMP; Cyclic GMP; Female; Hepatitis, Viral, Human; Humans; Male; Middle Aged

Topics: Adult; Aged; Chronic Disease; Cyclic AMP; Cyclic GMP; Female; Gastric Mucosa; Humans; Male; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Middle Aged; Splenic Diseases; Stomach Diseases

Patients with chronic recurrent pancreatitis were examined for the blood content of insulin, glucagon, somatostatin (SS), somatotropin (STH), cAMP and cGMP. The blood content of insulin, glucagon and STH was normal, that of SS and cAMP elevated, and that of cGMP lowered. In severe pancreatitis, the endocrine part of the pancreas was activated. The relationship was established between the level of amylasemia and the activity of islet cells and the blood content of cGMP. The compensatory importance of hypersecretion of SS and glucagon for pancreatitis exacerbation is demonstrated. The role of cyclic nucleotides in the pancreatic activity is discussed.

Topics: Adult; Aged; Chronic Disease; Cyclic AMP; Cyclic GMP; Female; Glucagon; Growth Hormone; Humans; Insulin; Male; Middle Aged; Pancreatic Hormones; Pancreatitis; Recurrence; Somatostatin

Topics: Asthma; Child, Preschool; Chronic Disease; Cyclic AMP; Cyclic GMP; Humans; Leukocytes; Pneumonia

Plasma and urine levels of cyclic adenosine 3',5'-monophosphate (cAMP) and of cyclic guanosine 3',5'-monophosphate (cGMP) were measured in 35 normal subjects, in 24 patients with nonneoplastic diseases (iron deficiency anemia, peptic ulcer, and cholelithiasis), and in 50 leukemic patients. The leukemic group included patients with acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia. All patients were recently diagnosed and untreated, except for 5 patients with blastic transformation of chronic myelogenous leukemia who had been previously treated. There were no significant differences in plasma and urine cyclic nucleotide levels between normal subjects and patients with nonneoplastic diseases. In leukemic patients, plasma and urine cAMP levels were similar to those of normal subjects, whereas plasma and urine cGMP levels were markedly elevated. There were no significant differences in cGMP values between the various types of leukemia. After starting treatment, plasma cyclic nucleotide levels were periodically measured in 21 of the patients with acute leukemia; cGMP levels were normalized in all the 16 subjects who attained complete remission, whereas both cAMP and cGMP levels were apparently unaffected in the patients who did not respond to treatment. This suggests that plasma or urine cGMP could be used as an additional parameter to monitor the patient's response to treatment.

Topics: Acute Disease; Adolescent; Adult; Aged; Anemia, Hypochromic; Cholelithiasis; Chronic Disease; Cyclic GMP; Female; Humans; Leukemia; Male; Middle Aged; Nucleotides, Cyclic; Peptic Ulcer

Topics: Adolescent; Adult; Aged; Chronic Disease; Cyclic AMP; Cyclic GMP; Female; Graves Disease; Humans; Male; Middle Aged; Radioimmunoassay; Thyroiditis

c-AMP, c-GMP, HVA and 5 HIAA cerebrospinal fluid levels were investigated in 18 patients with subarachnoid haemorrhage (SAH). The main findings in the acute stage after SAH were represented by a marked increase of c-AMP and 5 HIAA values, whereas HVA levels were only slightly higher. In the chronic phase c-GMP levels turned out to be significantly increased, and were clearly related to intracranial hypertension. 5 HIAA and particularly HVA levels were decreased, probably due to the functional and anatomical lesion of the periventricular adrenergic structures, following the raised intracranial pressure.

Topics: Acute Disease; Adult; Chronic Disease; Cyclic AMP; Cyclic GMP; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Intracranial Pressure; Male; Middle Aged; Phenylacetates; Subarachnoid Hemorrhage

Topics: Acute Disease; Bacterial Infections; Catecholamines; Chronic Disease; Cyclic AMP; Cyclic GMP; Humans

Topics: Adolescent; Adult; Aged; Child; Chronic Disease; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Middle Aged; Urticaria

Lumbar CSF HVA, MHPG, 5HIAA, cAMP, and cGMP were measured in 12 chronic schizophrenics with tardive dyskinesia before and 3 weeks after sodium valproate (VPA) or cyproheptadine treatment. HVA levels significantly decreased and cAMP and cGMP levels significantly increased during the administration of VPA or cyproheptadine. There were no significant correlations between the degree of improvement in tardive dyskinesia and the changes of amine metabolities or cyclic nucleotides. None of the pretreatment values for CSF amine metabolites or cyclic nucleotides were different from those of 15 chronic schizophrenics without tardive dyskinesia as controls. Decrease of HVA and increase of cGMP during the treatment might indicate the normalization of dopaminergic-cholinergic imbalance in the brain. Furthermore, significantly low levels of 5HIAA were observed in the patients with drug-induced tremor. It is suggested that neuroleptic-induced tremor may be attributed to serotonergic dysfunction in the brain.

Topics: Adult; Chronic Disease; Cyclic AMP; Cyclic GMP; Cyproheptadine; Dyskinesia, Drug-Induced; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Middle Aged; Neurotransmitter Agents; Schizophrenia; Tremor; Valproic Acid

Topics: Animals; Atmospheric Pressure; Chronic Disease; Cyclic AMP; Cyclic GMP; Female; Histamine; Hypoxia; Lung; Methylprednisolone; Rats

Topics: Animals; Cardiomegaly; Chronic Disease; Cyclic GMP; Guanethidine; Hypertension; Lung; Myocardium; Protein Kinase Inhibitors; Protein Kinases; Rats