cyclic-gmp and Acute-Disease

Pharmacologic strategies to reduce pulmonary vascular tone and to treat pulmonary hypertension originally aimed to enrich vascular smooth muscle cyclic adenosine monophosphate levels. Alternatively, increasing cyclic guanosine monophosphate (cGMP) also reduces pulmonary vascular tone. Inhaled nitric oxide is extremely efficacious in increasing cGMP and selectively reducing mean pulmonary arterial pressure in pediatric cardiac patients. It is considered standard treatment in most centers. However, not all patients respond to inhaled nitric oxide and withdrawal is sometimes problematic. This has prompted investigation of alternative methods to increase intracellular vascular smooth muscle cGMP. Phosphodiesterase type 5 is particularly abundant in the lung vasculature of patients with severe pulmonary hypertension. Its inhibition with the sildenafil class of drugs is now commonplace. Drugs that affect cGMP metabolism in children with acute pulmonary hypertension are the subject of this review and consensus statement. Oral sildenafil is recommended in postoperative pulmonary hypertension after failed withdrawal of inhaled NO (class I, level of evidence B). The effectiveness of prolonged treatment with sildenafil in documented postoperative pulmonary hypertension is not well established (class IIb, level of evidence C). Sildenafil is indicated in idiopathic pulmonary hypertension, although data have been extrapolated mainly from adult trial (class I, level of evidence A, extrapolated). Recently, completed pediatric trials have seemed to support this recommendation. Longer-acting and intravenous forms of phosphodiesterase type 5 inhibitors, brain natriuretic peptides, and direct soluble guanylate cyclise activators all have appeal, but there is insufficient experience in children with acute pulmonary hypertensive disorders for recommendations on treatment.

Topics: Acute Disease; Administration, Inhalation; Administration, Oral; Child; Child, Preschool; Clinical Trials as Topic; Cyclic GMP; Endothelium-Dependent Relaxing Factors; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

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

A mainstay of therapy for congestive heart failure has been the use of potent diuretic agents, such as furosemide, that target the kidney to enhance sodium and water excretion. Although furosemide is widely used to treat the symptoms of acute decompensated heart failure (ADHF), the consequent activation of the renin-angiotensin-aldosterone system may limit the natriuretic response by reducing the glomerular filtration rate. In addition, excessive diuresis may reduce cardiac preload and result in systemic hypotension, which reduces renal perfusion pressure and prerenal azotemia and raises levels of blood urea nitrogen. In order to preserve and/or enhance renal function in ADHF, especially with agents such as conventional diuretics and vasodilators, an understanding of intrarenal factors that may protect the kidney may provide a direction for optimal use of current therapies and also lead to newer therapeutic strategies. Vasodilators, especially those that are linked to cGMP activation, may provide an alternative approach.

Topics: Acute Disease; Cyclic GMP; Diuretics; Furosemide; Glomerular Filtration Rate; Heart Failure; Humans; Kidney; Renin-Angiotensin System; Risk Factors; Sodium Potassium Chloride Symporter Inhibitors; Vasodilator Agents

Ischemic stroke is the third cause of death and the most common cause of neurological disability. A main target of treatment is the still salvageable tissue surrounding the core of infarction and called "ischemic penumbra". Up to now the only drug approved for the treatment of acute ischemic stroke is recombinant tissue plasminogen activator to achieve early arterial recanalization and hypoxic tissue reperfusion and improve neural function. However, thrombolytic therapy has to be administered soon after the event since its efficacy is time dependent. This intervention also carries an increased risk of hemorrhagic transformation. In the rescue of poorly perfused cerebral regions an important role is played by collateral blood supply through the circle of Willis and through small pial vessels surrounding the lesion. The extent of collateralization is variable and at least in part regulated by the modulation of arteriolar nitric oxide (NO)-dependent endothelial function. Drugs that can improve endothelial function and cerebrovascular reactivity could have a role in collateral formation and infarct volume limitation. Statins affect endothelial NO production demonstrating their potential to influence endothelial NO synthase (eNOS) and in treating stroke. Phosphodiesterase (PDE) inhibitors improve functional recovery after stroke in rats enhancing neuro and synapto genesis and increasing guanosine 3,5-cyclic monophosphate (cGMP). The aim of this review is to highlight the potential of these two classes of drugs in the treatment of acute ischemic stroke by analysing their pharmacological effects and involvement in the NO and cGMP pathways.

Topics: Acute Disease; Animals; Brain Infarction; Brain Ischemia; Cerebral Cortex; Collateral Circulation; Cyclic GMP; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Microcirculation; Nitric Oxide; Phosphodiesterase Inhibitors; Stroke

We sought to determine the influence of sildenafil on the diffusing capacity of the lungs for carbon monoxide (DLCO) and the components of DLCO (pulmonary capillary blood volume VC, and alveolar-capillary membrane conductance DM) at rest and following exercise with normoxia and hypoxia. This double-blind placebo-controlled, cross-over study included 14 healthy subjects (age = 33 +/- 11 years, ht = 181 +/- 8 cm, weight = 85 +/- 14 kg, BMI = 26 +/- 3 kg/m2, peak normoxic VO2 = 36 +/- 6 ml/kg, mean +/- SD). Subjects were randomized to placebo or 100 mg sildenafil 1 h prior to entering a hypoxic tent with an FiO2 of 12.5% for 90 min. DLCO, VC, and DM were assessed at rest, every 3 min during exercise, at peak exercise, and 10 and 30 min post exercise. Sildenafil attenuated the elevation in PAP at rest and during recovery with exposure to hypoxia, but pulmonary arterial pressure immediately post exercise was not different between sildenafil and placebo. Systemic 02 saturation and VO2peak did not differ between the two conditions. DLCO was not different between groups at any time point. VC was higher with exercise in the placebo group, and the difference in DM between sildenafil and placebo was significant only when corrected for changes in VC (DM/VC = 0.57 +/- 0.29 vs. 0.41 +/- 0.16, P = 0.04). These results suggest no effect of sildenafil on DLCO, but an improvement in DM when corrected for changes in VC during short-term hypoxic exposure with exercise.

Topics: Acute Disease; Adult; Capillaries; Cross-Over Studies; Cyclic GMP; Double-Blind Method; Endothelin-1; Exercise; Female; Heart Rate; Humans; Hypoxia; Male; Natriuretic Peptide, Brain; Oxygen; Piperazines; Pulmonary Alveoli; Pulmonary Circulation; Pulmonary Gas Exchange; Purines; Rest; Sildenafil Citrate; Stroke Volume; Sulfones; Vasodilator Agents

A clinically relevant increase of PaO subset2 or decrease of pulmonary vascular resistance (PVR) upon inhalation of NO (iNO) does occur in only 60 to 80% of patients with acute lung injury. The mechanisms for divergent responses of different patients have not yet been fully elucidated. Since NO mediates its pulmonary effects by stimulating soluble guanylate cyclase, thereby increasing levels of cyclic guanosinemonophosphate (cGMP), we hypothesized that pulmonary cGMP production upon iNO might be suppressed in patients not responding to iNO treatment.. After approval by the local ethical committee and after informed consent had been obtained, both arterial and mixed-venous cGMP levels were analyzed in 13 patients in whom iNO was administered to treat pulmonary hypertension and/or hypoxemia due to acute respiratory distress syndrome (n = 11) or reperfusion injury following lung transplantation (n = 2). Both cardiorespiratory variables and cGMP concentrations were documented simultaneously at baseline, 15 min after inhalation of 8 ppm of NO, and 15 min after withdrawal of NO, respectively.. Inhaled NO resulted in a significant increase in PaO(2)/FiO(2) and a decrease in PVR. Arterial and mixed venous concentration of cGMP (median) also increased significantly upon iNO from 2.5 to 6.5 nM (p <0.05) and from 3.0 to 5.7 nM (p <0.05), respectively. Theses effects were fully reversible after withdrawal of iNO. No gradients between arterial and mixed venous cGMP concentrations were detected (p = 0.12). Regression analysis showed no relationship between baseline arterial cGMP concentrations and changes of either PaO(2)/FiO(2) (p = 0. 62) or PVR (p = 0.91). Similarly, no relationship was found between the rise of arterial cGMP concentration subsequent to iNO and corresponding changes of PaO(2) (p = 0.40) or PVR (p = 0.74), respectively.. Inhalation of NO significantly stimulates soluble guanylate cyclase within the lungs in patients with acute lung injury. However, neither baseline cGMP nor its rise during treatment with inhaled NO can predict the clinical efficacy of iNO in humans. Furthermore, the fact that increased cGMP concentrations were detected during administration of iNO in mixed venous blood (i.e. pulmonary inflow) strongly suggest that the pharmacological effects of iNO are not fully selective for the lungs, but may also affect extrapulmonary organs.

Topics: Acute Disease; Administration, Inhalation; Adult; Bronchodilator Agents; Cyclic GMP; Female; Humans; Hypertension, Pulmonary; Lung; Male; Nitric Oxide; Pulmonary Circulation; Respiratory Insufficiency

Previous studies have shown that isopulegol has anxiolytic, anticonvulsant, gastro-protective and antioxidant activities in rodents, but until now there are no studies showing activity of isopulegol in animal models of nociception and inflammation. The objective of this study was to evaluate the antinociceptive effect of isopulegol and to propose possible mechanisms involved in its effects observed in mice. Groups of male and female Swiss mice (20-35 g, n = 5-8) were used in this test under the authorization of Ethics Committee on Animal Experimentation (CEEA/UFPI N° 82/2014). In order to evaluate the antinociceptive activity of isopulegol, nociception was induced using formalin test, capsaicin and glutamate in hind paw licking model, followed by the investigation of the involvement of opioid mechanisms, K + ATP channels, muscarinic, L arginine-nitric oxide and cGMP. The oral administration of isopulegol showed antinociceptive effect in both phases of the formalin test at doses from 0.78 to 25 mg/kg (first phase) and 1.56-25 mg/kg (second phase) and also produced significant results before capsaicin test at doses from 1.56 to 12.5 mg/kg and glutamate test at doses from 3.12 to 6.25 mg/kg with a dose-dependent effect. The antinociception activity of isopulegol was inhibited in the presence of naloxone (2 mg / kg, ip), glibenclamide (3 mg/kg, ip), atropine (1 mg/kg, ip), l-arginine (600 mg/kg, ip) and methylene blue (20 mg/kg, ip). The results suggested that acute antinociceptive action of opioid isopulegol seems to be related to the K + ATP channels system, through the involvement of muscarinic receptors, inhibiting nitric oxide and cGMP.

Topics: Acute Disease; Administration, Oral; Analgesics; Animals; Arginine; Behavior, Animal; Capsaicin; Cyclic GMP; Cyclohexane Monoterpenes; Female; Formaldehyde; Glutamic Acid; Male; Mice; Nitric Oxide; Pain; Receptors, Muscarinic; Receptors, Opioid; Signal Transduction; Terpenes

The pulmonary vasodilation induced by adrenomedullin may be beneficial in the acute pulmonary embolism (APE) setting. This study examined effects of adrenomedullin in sheep with microsphere-induced APE.. Twenty four anesthetized, mechanically ventilated sheep were randomly assigned into 3 groups (n=8 per group): animals not subjected to any intervention (Sham), animals with APE induced by microspheres (500 mg, intravenously) treated 30 min later by intravenous physiological saline (Emb group) or intravenous adrenomedullin (50 ng/kg/min) during 30 min (Emb+Adm group). Plasma concentrations of cyclic adenosine (cAMP) and guanosine monophosphate (cGMP) were determined by enzyme immunoassay.. Variables did not change over time in sham animals. In both embolized groups, microsphere injection significantly (P<0.05) increased pulmonary vascular resistance index (PVRI) and mean pulmonary artery pressure (MPAP) from baseline by 181% and 111-142%, respectively (% change in mean values). Adrenomedullin significantly decreased PVRI (18%-25%) and significantly increased cardiac index (22%-25%) from values recorded 30 min after APE (E30), without modifying MPAP. Adrenomedullin decreased mean arterial pressure (18%-24%) and systemic vascular resistance index (32%-40%). Embolization significantly increased arterial-to-end tidal CO2 gradient, alveolar-to-arterial O2 gradient, and pulmonary shunt fraction from baseline, but these variables were unaffected by adrenomedullin. While adrenomedullin significantly increased plasma cAMP, cGMP levels were unaltered.. Adrenomedullin induces systemic and pulmonary vasodilation, possibly via a cAMP mediated mechanism, without modifying the gas exchange impairment associated with APE. The pulmonary anti-hypertensive effect of adrenomedullin may be offset by increases in cardiac index.

Topics: Acute Disease; Adrenomedullin; Animals; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Hypertension, Pulmonary; Lung; Male; Pulmonary Embolism; Sheep; 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

Gene mutations that lead to decreased contraction of vascular smooth-muscle cells (SMCs) can cause inherited thoracic aortic aneurysms and dissections. Exome sequencing of distant relatives affected by thoracic aortic disease and subsequent Sanger sequencing of additional probands with familial thoracic aortic disease identified the same rare variant, PRKG1 c.530G>A (p.Arg177Gln), in four families. This mutation segregated with aortic disease in these families with a combined two-point LOD score of 7.88. The majority of affected individuals presented with acute aortic dissections (63%) at relatively young ages (mean 31 years, range 17-51 years). PRKG1 encodes type I cGMP-dependent protein kinase (PKG-1), which is activated upon binding of cGMP and controls SMC relaxation. Although the p.Arg177Gln alteration disrupts binding to the high-affinity cGMP binding site within the regulatory domain, the altered PKG-1 is constitutively active even in the absence of cGMP. The increased PKG-1 activity leads to decreased phosphorylation of the myosin regulatory light chain in fibroblasts and is predicted to cause decreased contraction of vascular SMCs. Thus, identification of a gain-of-function mutation in PRKG1 as a cause of thoracic aortic disease provides further evidence that proper SMC contractile function is critical for maintaining the integrity of the thoracic aorta throughout a lifetime.

Topics: Acute Disease; Adolescent; Adult; Amino Acid Sequence; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Exome; Female; Fibroblasts; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Molecular Sequence Data; Muscle Contraction; Muscle, Smooth, Vascular; Mutation; Myosin Light Chains; Pedigree

It is unknown if cardiac ischemia has any deleterious effect on the contractile properties of nonischemic, peripheral vascular beds. Thus, the objective of the present study was to determine whether acute myocardial ischemia results in peripheral vascular dysfunction.. This study characterized force maintenance and the sensitivity to acetylcholine (ACh)-mediated smooth muscle (SM) relaxation of tertiary (3rd) mesenteric arteries from Sprague-Dawley rats following 30 min of myocardial ischemia. Both the phosphorylation of nonmuscle (NM) light chain (LC) and SM-LCs as well as the expression of myosin phosphatase targeting subunit 1 (MYPT1) were also determined. Our data demonstrate that acute myocardial ischemia resulted in vascular dysfunction of 3rd mesenteric vessels, characterized by decreases in force maintenance, ACh- and cGMP-mediated SM relaxation, the phosphorylation of NM-LCs and SM-LCs, and MYPT1 expression. Ischemia was also associated with an increase in protein polyubiquitination, suggesting that during ischemia MYPT1 is targeted for degradation or proteolysis.. Acute myocardial ischemia produces peripheral vascular dysfunction; the changes in LC phosphorylation and MYPT1 expression result in a decrease in both tone and the sensitivity to NO-mediated SM relaxation of the peripheral vasculature.

Topics: Acetylcholine; Acute Disease; Animals; Biomechanical Phenomena; Cyclic GMP; Enzyme Induction; Male; Membrane Potentials; Mesenteric Arteries; Muscle, Smooth, Vascular; Myocardial Infarction; Myosin Light Chains; Nitric Oxide; Phosphorylation; Potassium Chloride; Protein Phosphatase 1; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Ubiquitination; Vasodilation

Obstructive jaundice and cirrhosis are associated with impaired renal function. Previously we demonstrated that increased intra-abdominal pressure (IAP, pneumoperitoneum) in normal rats induced renal dysfunction. This study investigated the renal effects of pneumoperitoneum in rats with acute jaundice and cirrhotic rats.. Following a baseline period, rats with obstructive jaundice or cirrhosis induced by acute or chronic bile duct ligation (BDL), respectively, and their sham-controls were subjected to consecutive IAPs of 10 and 14 mmHg for 45 min each. Urine flow (V), Na(+) excretion (UNaV), glomerular filtration rate (GFR), renal plasma flow (RPF), and urinary NO metabolites ([Formula: see text]) and cGMP (UcGMP) were determined.. Elevating IAP from 0 to 10 and 14 mmHg in normal rats caused IAP-dependent reductions in V, UNaV, GFR, RPF, [Formula: see text] and UcGMP. Basal renal function and hemodynamics were lower in rats with obstructive jaundice. In contrast to normal rats, application of elevated IAP of 10 and 14 mmHg significantly improved V, UNaV, GFR, RPF, and MAP along with increased [Formula: see text] and preserved UcGMP. Similarly, when identical IAP conditions were applied to cirrhotic rats, no deleterious changes in V, UNaV, GFR or RPF were observed.. Application of pneumoperitoneum to rats with acute BDL improves kidney function and renal hemodynamics. Likewise, increased IAP does not exert adverse renal effects in cirrhotic rats. These effects are distinct from the deleterious renal consequences of increased IAP in normal rats. Perturbations in the generation of NO/cGMP during IAP in normal rats but not in rats with BDL or cirrhosis may contribute to these differences.

Topics: Acute Disease; Animals; Cyclic GMP; Glomerular Filtration Rate; Jaundice, Obstructive; Liver Cirrhosis; Male; Nitrates; Nitrites; Pneumoperitoneum, Artificial; Rats; Rats, Sprague-Dawley; Renal Plasma Flow; Sodium; Urination

Inhibition of leukocyte adhesion to the vascular endothelium represents a novel and important approach for decreasing sickle cell disease (SCD) vaso-occlusion. Using a humanized SCD-mouse-model of tumor necrosis factor-α-induced acute vaso-occlusion, we herein present data demonstrating that short-term administration of either hydroxyurea or the phosphodiesterase 9 (PDE9) inhibitor, BAY73-6691, significantly altered leukocyte recruitment to the microvasculature. Notably, the administration of both agents led to marked improvements in leukocyte rolling and adhesion and decreased heterotypic red blood cell-leukocyte interactions, coupled with prolonged animal survival. Mechanistically, these rheologic benefits were associated with decreased endothelial adhesion molecule expression, as well as diminished leukocyte Mac-1-integrin activation and cyclic guanosine monophosphate (cGMP)-signaling, leading to reduced leukocyte recruitment. Our findings indicate that hydroxyurea has immediate beneficial effects on the microvasculature in acute sickle-cell crises that are independent of the drug's fetal hemoglobin-elevating properties and probably involve the formation of intravascular nitric oxide. In addition, inhibition of PDE9, an enzyme highly expressed in hematopoietic cells, amplified the cGMP-elevating effects of hydroxyurea and may represent a promising and more tissue-specific adjuvant therapy for this disease.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Acute Disease; Anemia, Sickle Cell; Animals; Antisickling Agents; Cell Adhesion; Cell Communication; Cyclic GMP; Disease Models, Animal; Endothelium, Vascular; Erythrocytes; Female; Humans; Hydroxyurea; Leukocyte Rolling; Leukocytes; Male; Mice; Mice, Inbred C57BL; Pyrazoles; Pyrimidines; Tumor Necrosis Factor-alpha; Vascular Diseases

Heme oxygenase-carbon monoxide-cGMP (HO-CO-cGMP) pathway has been reported to be involved in peripheral and spinal modulation of inflammatory pain. However, the involvement of this pathway in the modulation of acute painful stimulus in the absence of inflammation remains unknown. Thus, we evaluated the involvement of the HO-CO-cGMP pathway in nociception by means the of analgesia index (AI) in the tail flick test. Rats underwent surgery for implantation of unilateral guide cannula directed toward the lateral ventricle and after the recovery period (5-7 days) were subjected to the measures of baseline tail flick test. Animals were divided into groups to assess the effect of intracerebroventricular administration (i.c.v.) of the following compounds: ZnDPBG (HO inhibitor) or vehicle (Na(2)CO(3)), heme-lysinate (substrate overload) or vehicle (l-lysine), or the selective inhibitor of soluble guanilate cyclase ODQ or vehicle (DMSO 1%) following the administration of heme-lysinate or vehicle. Heme overload increased AI, indicating an antinociceptive role of the pathway. This response was attenuated by i.c.v. pretreatment with the HO inhibitor ZnDPBG. In addition, this effect was dependent on cGMP activity, since the pretreatment with ODQ blocked the increase in the AI. Because CO produces most of its actions via cGMP, these data strongly imply that CO is the HO product involved in the antinociceptive response. This modulation seems to be phasic rather than tonic, since i.c.v. treatment with ZnDPBG or ODQ did not alter the AI. Therefore, we provide evidence consistent with the notion that HO-CO-cGMP pathway plays a key phasic antinociceptive role modulating noninflammatory acute pain.

Topics: Acute Disease; Animals; Carbon Monoxide; Cyclic GMP; Heme Oxygenase (Decyclizing); Male; Pain; Pain Measurement; Pain Perception; Rats; Rats, Wistar; Signal Transduction

To understand the pathomechanisms of spinal cord injuries will be a prerequisite to develop efficient therapies. By investigating acute lesions of spinal cord white matter in anesthetized mice with fluorescently labeled microglia and axons using in vivo two-photon laser-scanning microscopy (2P-LSM), we identified the messenger nitric oxide (NO) as a modulator of injury-activated microglia. Local tissue damages evoked by high-power laser pulses provoked an immediate attraction of microglial processes. Spinal superfusion with NO synthase and guanylate cyclase inhibitors blocked these extensions. Furthermore, local injection of the NO-donor spermine NONOate (SPNO) or the NO-dependent second messenger cGMP induced efficient migration of microglial cells toward the injection site. High-tissue levels of NO, achieved by uniform superfusion with SPNO and mimicking extended tissue damage, resulted in a fast conversion of the microglial shape from ramified to ameboid indicating cellular activation. When the spinal white matter was preconditioned by increased, ambient ATP (known as a microglial chemoattractant) levels, the attraction of microglial processes to local NO release was augmented, whereas it was abolished at low levels of tissue ATP. Because both signaling molecules, NO and ATP, mediate acute microglial reactions, coordinated pharmacological targeting of NO and purinergic pathways will be an effective mean to influence the innate immune processes after spinal cord injury.

Topics: Acute Disease; Adenosine Triphosphate; Animals; Axons; Cell Movement; Cell Polarity; Cyclic GMP; Enzyme Inhibitors; Guanylate Cyclase; Mice; Mice, Transgenic; Microglia; Nerve Fibers, Myelinated; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Signal Transduction; Spermine; Spinal Cord; Spinal Cord Injuries

M-atrial natriuretic peptide (ANP; M-ANP) is a novel next generation 40 amino acid peptide based on ANP, which is highly resistant to enzymatic degradation and has greater and more sustained beneficial actions compared with ANP. The current study was designed to advance our understanding of the therapeutic potential of M-ANP in a canine model of acute angiotensin II-induced hypertension with elevated cardiac filling pressures and aldosterone activation. We compare M-ANP with vehicle and equimolar human B-type natriuretic peptide, which possesses the most potent in vivo actions of the native natriuretic peptides. M-ANP significantly lowered mean arterial pressure and systemic vascular resistance. Importantly, despite a reduction in blood pressure, renal function was enhanced with significant increases in renal blood flow, glomerular filtration rate, diuresis, and natriuresis after M-ANP infusion. Although angiotensin II induced an acute increase in pulmonary capillary wedge pressure, M-ANP significantly lowered pulmonary capillary wedge pressure, pulmonary artery pressure, and right atrial pressure. Further, M-ANP significantly suppressed angiotensin II-induced activation of aldosterone. These cardiovascular and renal enhancing actions of M-ANP were accompanied by significant increases in plasma and urinary cGMP, the second messenger molecule of the natriuretic peptide system. When compared with human B-type natriuretic peptide, M-ANP had comparable cardiovascular actions but resulted in a greater natriuretic effect. These results suggest that M-ANP, which is more potent than ANP in normal canines, has potent blood pressure lowering and renal enhancing properties and may, therefore, serve as an ANP based therapeutic for acute hypertension.

Topics: Acute Disease; Aldosterone; Angiotensin II; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Diuresis; Dogs; Glomerular Filtration Rate; Humans; Hypertension; Male; Natriuresis; Pulmonary Wedge Pressure; Renal Circulation; Vascular Resistance

Topics: Acute Disease; Animals; Calcium Signaling; Cyclic GMP; Endothelial Cells; Humans; Hypoxia; Metallothionein; Mice; Mice, Knockout; Models, Biological; Nitric Oxide; Nitrosation; Protein Kinase C; Protein Processing, Post-Translational; Pulmonary Artery; Rats; Signal Transduction; Vascular Resistance; Vasoconstriction; Zinc

The current therapy of acute pulmonary embolism is focused on removing the mechanical obstruction of the pulmonary vessels. However, accumulating evidence suggests that pulmonary vasoconstriction drives many of the hemodynamic changes found in this condition. We examined the effects of stimulation of soluble guanylate cyclase with BAY 41-2272 (5-Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrim idin-4-ylamine) in an anesthetized dog model of acute pulmonary embolism. Hemodynamic and arterial blood gas evaluations were performed in non-embolized dogs treated with vehicle (N=5), and in embolized dogs (intravenous injections of microspheres) that received BAY 41-2272 intravenously in doses of 0.03, 0.1, 0.3, and 1 mg/kg/h or vehicle (1 ml/kg/h of 1.13% ethanol in saline, volume/volume). Plasma cGMP and thiobarbituric acid reactive substances concentrations were determined using a commercial enzyme immunoassay and a fluorometric method, respectively. The infusion of BAY 41-2272 resulted in a decrease in pulmonary artery pressure by approximately 29%, and in pulmonary vascular resistance by approximately 46% of the respective increases induced by lung embolization (both P<0.05). While the higher doses of BAY 41-2272 produced no additional effects on the pulmonary circulation, they caused significant arterial hypotension and reduction in systemic vascular resistance (both P<0.05). Although BAY 41-2272 increased cGMP concentrations (P<0.05), it did not affect the hypoxemia and the increased oxidative stress caused by lung embolization. These results suggest that stimulation of soluble guanylate cyclase with low (but not high) doses of BAY 41-2272 produces selective pulmonary vasodilation during acute pulmonary embolism. The dose-dependent systemic effects produced by BAY 41-2272, however, may limit its usefulness in larger doses.

Topics: Acute Disease; Animals; Cyclic GMP; Dogs; Dose-Response Relationship, Drug; Female; Guanylate Cyclase; Hemodynamics; Lipid Peroxides; Male; Pulmonary Embolism; Pyrazoles; Pyridines; Respiration

To observe the changes of the levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in acutely isolated alveolar type II (ATII) cells from rats with acute respiratory distress syndrome (ARDS), and test the effects of terbutaline on the cAMP and cGMP levels.. SD rats were randomized into the control, ARDS, and terbutaline treatment groups, in which the cAMP and cGMP contents in the ATII cells were measured using radioimmunoassay, and the extravascular lung water (EVLW) content was quantified with gravimetric measurement.. The cAMP level in the ATII cells was significantly lowered whereas cGMP level and EVLW content increased in rats with oleic acid-induced ARDS. In terbutaline-treated rats with ARDS, the EVLW content were lower than that of non-treated rats, but still higher than that of the control rats. Terbutaline treatment also increased the content of cAMP but produced no significant effect on cGMP content in the ATII cells of the rats with ARDS.. Alveolar fluid clearance rate is decreased in rats with oleic acid-induced ARDS, and terbutaline can improve the capacity of alveolar fluid clearance, the mechanism of which may involve elevated cAMP content in the ATII cells. cAMP and cGMP in ATII cells might participate in the molecular pathogenesis of ARDS.

Topics: Acute Disease; Animals; Bronchodilator Agents; Cyclic AMP; Cyclic GMP; Extravascular Lung Water; Lung Diseases; Male; Oleic Acid; Pulmonary Alveoli; Random Allocation; Rats; Rats, Sprague-Dawley; Terbutaline

Sildenafil, a potent inhibitor of phosphodiesterase type 5, has recently been investigated in animal models of myocardial ischemia-reperfusion (MI/R) injury. Previous studies have suggested that the protective effects of sildenafil are mediated via activation of endothelial nitric oxide (NO) synthesis (eNOS) and inducible NOS (iNOS). To further investigate the protective mechanism of sildenafil, we subjected wild-type, eNOS, and iNOS null animals to 30 min of myocardial ischemia and 24 h of reperfusion. Treatment with 0.06 mg/kg sildenafil 5 min before reperfusion significantly reduced myocardial infarct size in wild-type, eNOS null mice (eNOS(-/-)), and iNOS(-/-) animals. Additionally, the low dose utilized in this study did not alter myocardial cGMP. These results suggest that acute low-dose sildenafil-mediated cardioprotection is independent of eNOS, iNOS, and cGMP. In a second series of experiments, we investigated sildenafil in db/db diabetic mice subjected to MI/R. We found that sildenafil failed to protect diabetic mice against MI/R. However, NO(.) donor therapy was found to significantly protect against MI/R injury in both nondiabetic and diabetic mice, suggesting that protection could be conferred in diabetic mice and that the upstream modulator of soluble guanylyl cyclase, NO(.), may mediate protection independent of cGMP signaling. The present study suggests that further research is needed to delineate the precise mechanisms by which sildenafil exerts cardioprotection.

Topics: Acute Disease; Animals; Cardiotonic Agents; Cyclic GMP; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Myocardial Reperfusion Injury; Nitric Oxide; Piperazines; Purines; Signal Transduction; Sildenafil Citrate; Sulfones; Treatment Outcome

We examined the effects of acute hypoxia on vascular tone and coronary blood flow (CBF) in rabbit coronary arteries. In the pressurized arterial preparation of small arteries (<100 mum) and the Langendorff-perfused rabbit hearts, hypoxia induced coronary vasodilation and increased CBF in the presence of glibenclamide (K(ATP) channel blocker), Rp-8-Br-PET-cGMPs [cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibitor, Rp-cGMPs], and methionyl transfer RNA synthetase (MRS) 1334 (adenosine A(3) receptor inhibitor); these increases were inhibited by the inward rectifier K(+) (Kir) channel inhibitor, Ba(2+). These effects were blocked by the adenylyl cyclase inhibitor SQ 22536 and by the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) inhibitors Rp-8-CPT-cAMPs (Rp-cAMPs) and KT 5720. However, cGMP-dependent protein kinase was not involved in the hypoxia-induced increases of the vascular diameter and CBF. In summary, our results suggest that acute hypoxia can induce the opening of Kir channels in coronary artery that has small diameter (<100 mum) by activating the cAMP and PKA signalling pathway, which could contribute to vasodilation and, therefore, increased CBF.

Topics: Acute Disease; Adenine; Animals; Blood Pressure; Carbazoles; Coronary Circulation; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Enzyme Inhibitors; Female; Glyburide; Hypoxia; In Vitro Techniques; Indoles; Male; Potassium Channel Blockers; Potassium Channels, Inwardly Rectifying; Pyrroles; Rabbits; Signal Transduction; Thionucleotides; Vasodilation

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

Activating the nitric oxide (NO)-cyclic guanosine 3',5'-monophosphate (cGMP) pathway improves haemodynamics following acute pulmonary thromboembolism (APT). However, the role of NO synthase (NOS) isoforms in the responses to APT has not been determined. We examined the effects of selective and non-selective inducible NOS (iNOS) inhibition.. Haemodynamic evaluations were performed in non-embolized dogs treated with saline (control group; n = 4), L-NAME (NAME group; n = 3), or aminoguanidine (AG group; n = 3), and in dogs that received the same drugs and were embolized with 5 mL kg(-1) of clots made with autologous blood (Emb group, n = 9; NAME + Emb group, n = 4 and AG + Emb group, n = 7). The lung concentrations of nitrite/nitrate (NOx) and cGMP were determined by chemiluminescence and ELISA respectively.. Acute pulmonary thromboembolism increased mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance index (PVRI) by 21.4 +/- 1.7 mmHg and by 843 +/- 34 dyn s cm(-5) m(-2), respectively, in Emb group. MPAP and PVRI increased to higher levels in the NAME + Emb group 15 min after APT and all dogs in this group died 15-30 min after APT. Conversely, lower MPAP and PVRI levels were found in the AG + Emb group 2 h after APT compared with the Emb group (both P < 0.05). Higher NOx concentrations were found in the Emb group compared with the other groups (all P < 0.05). Higher cGMP concentrations were found in the Emb and AG + Emb groups compared with the other groups (all P < 0.05).. These results indicate that endogenous NO protects against APT-induced cardiovascular responses. Moreover, iNOS-derived NO possibly produces unfavourable effects, which are counteracted by aminoguanidine. However, non-NO-related mechanisms may also be involved.

Topics: Acute Disease; Animals; Blood Pressure; Cyclic GMP; Dogs; Female; Guanidines; Lung; Male; Models, Animal; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type II; Pulmonary Embolism; Vascular Resistance

Phosphodiesterase 1 (PDE1) modulates vascular tone and the development of tolerance to nitric oxide (NO)-releasing drugs in the systemic circulation. Any role of PDE1 in the pulmonary circulation remains largely uncertain. We measured the expression of genes encoding PDE1 isozymes in the pulmonary vasculature and examined whether or not selective inhibition of PDE1 by vinpocetine attenuates pulmonary hypertension and augments the pulmonary vasodilator response to inhaled NO in lambs. Using RT-PCR, we detected PDE1A, PDE1B, and PDE1C mRNAs in pulmonary arteries and veins isolated from healthy lambs. In 13 lambs, the thromboxane A(2) analog U-46619 was infused intravenously to increase mean pulmonary arterial pressure to 35 mmHg. Four animals received an intravenous infusion of vinpocetine at incremental doses of 0.3, 1, and 3 mg.kg(-1).h(-1). In nine lambs, inhaled NO was administered in a random order at 2, 5, 10, and 20 ppm before and after an intravenous infusion of 1 mg.kg(-1).h(-1) vinpocetine. Administration of vinpocetine did not alter pulmonary and systemic hemodynamics or transpulmonary cGMP or cAMP release. Inhaled NO selectively reduced mean pulmonary arterial pressure, pulmonary capillary pressure, and pulmonary vascular resistance index, while increasing transpulmonary cGMP release. The addition of vinpocetine enhanced pulmonary vasodilation and transpulmonary cGMP release induced by NO breathing without causing systemic vasodilation but did not prolong the duration of pulmonary vasodilation after NO inhalation was discontinued. Our findings demonstrate that selective inhibition of PDE1 augments the therapeutic efficacy of inhaled NO in an ovine model of acute chemically induced pulmonary hypertension.

Topics: Acute Disease; Administration, Inhalation; Animals; Animals, Newborn; Blood Vessels; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 1; Dose-Response Relationship, Drug; Drug Synergism; Hemodynamics; Hypertension, Pulmonary; Lung; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pulmonary Circulation; Sheep; Vasodilation; Vinca Alkaloids

Sildenafil attenuates acute pulmonary embolism-induced pulmonary hypertension. However, the hemodynamic effects of sildenafil in combination with other vasodilators during acute pulmonary embolism have not been examined yet. In the present study, we examined the hemodynamic effects of combined sildenafil (0.25 mg/kg, i.v.) and L-arginine (100, 200, 500, and 1000 mg/kg/h, i.v.) in an anesthetized dog model of acute pulmonary embolism. Plasma nitrite/nitrate (NO(x)) and cGMP concentrations were determined using an ozone-based chemiluminescence assay and a commercial enzyme immunoassay, respectively. We found that L-arginine alone did not attenuate acute pulmonary embolism-induced pulmonary hypertension. However, significant decreases in mean pulmonary artery pressure were observed 30, 45, 60, and 75 min after the administration of sildenafil alone or after the combined administration of sildenafil and L-arginine (all P < 0.05). No significant differences among groups were observed in the respiratory parameters. While L-arginine significantly increased NO(x) concentrations, cGMP concentrations increased only when sildenafil was administered (all P < 0.05). These results suggest that while sildenafil attenuates acute pulmonary embolism-induced pulmonary hypertension, L-arginine does not enhance the beneficial hemodynamic effects of sildenafil. In addition, these findings suggest that stimulation of NO synthesis with L-arginine during acute pulmonary embolism does not produce beneficial effects.

Topics: Acute Disease; Analysis of Variance; Animals; Arginine; Blood Pressure; Cyclic GMP; Dogs; Female; Heart Rate; Hypertension, Pulmonary; Infusions, Intravenous; Male; Nitrates; Nitrites; Piperazines; Pulmonary Artery; Pulmonary Embolism; Purines; Respiration; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents

We hypothesized that the phosphodiesterase 5 inhibitor, sildenafil, and the guanosine cyclase stimulator, atrial natriuretic peptide (ANP), would act synergistically to increase cGMP levels and blunt hypoxic pulmonary hypertension in rats, because these compounds act via different mechanisms to increase the intracellular second messenger. Acute hypoxia: Adult Sprague-Dawley rats were gavaged with sildenafil (1 mg/ kg) or vehicle and exposed to acute hypoxia with and without ANP (10(-8)-10(-5) M ). Sildenafil decreased systemic blood pressure (103 +/- 10 vs. 87 +/- 6 mm Hg, P < 0.001) and blunted the hypoxia-induced increase in right ventricular systolic pressure (RVSP; percent increase 73.7% +/- 9.4% in sildenafil-treated rats vs. 117.2% +/- 21.1% in vehicle-treated rats, P = 0.03). Also, ANP and sildenafil had synergistic effects on blunting the hypoxia-induced increase in RVSP (P < 0.001) and on rising plasma cGMP levels (P < 0.05). Chronic hypoxia: Other rats were exposed to prolonged hypoxia (3 weeks, 0.5 atm) after subcutaneous implantation of a sustained-release pellet containing lower (2.5 mg), or higher (25 mg) doses of sildenafil, or placebo. Higher-dose, but not lower-dose sildenafil blunted the chronic hypoxia-induced increase in RVSP (P = 0.006). RVSP and plasma sildenafil levels were inversely correlated in hypoxic rats (r(2) = 0.68, P = 0.044). Lung cGMP levels were increased by both chronic hypoxia and sildenafil, with the greatest increase achieved by the combination. Plasma and right ventricular (RV) cGMP levels were increased by hypoxia, but sildenafil had no effect. RV hypertrophy and pulmonary artery muscularization were also unaffected by sildenafil. In conclusion, sildenafil and ANP have synergistic effects on the blunting of hypoxia-induced pulmonary vasoconstriction. During chronic hypoxia, sildenafil normalizes RVSP, but in the doses used, sildenafil has no effect on RV hypertrophy or pulmonary vascular remodeling.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Cyclic GMP; Drug Synergism; Humans; Hypertension, Pulmonary; Hypoxia; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones

To investigate the role of endogenous carbon monoxide (CO) in hypoxia.. After rats were inhaled with hypoxic gases and the heme oxygenase inhibitor ZnPPIX was administered, we measured the CO levels in plasma, liver, lung and kidney. Meanwhile plasma cGMP levels were observed. Furthermore, we recorded the change of hemodynamic and blood gases.. Acute mild hypoxia (10% O2) significantly increaed CO levels in plasma as well as liver, kidney and lung, while acute severe hypoxia (5% O2) significantly decreased CO levels in plasma as well as liver, kidney and lung. In addition, the former significantly elevated cGMP levels in plasma while the latter markedly reduced cGMP levels in plasma. The hemodynamic change occurred in accordance with the changes carbon monoxide.. Our results indicate, for the first time, that the endogenous carbon monoxide plays an important role in regulating the vessel tone during hypoxia.

Topics: Acute Disease; Animals; Blood Gas Analysis; Carbon Monoxide; Cyclic GMP; Heme Oxygenase (Decyclizing); Hemodynamics; Hypoxia; Kidney; Liver; Lung; Rats; Rats, Wistar

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

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

Using slices of the dorsal lateral geniculate nucleus, it has been shown that, in the presence of excitatory and inhibitory amino acid antagonists, brief periods of hypoxia (3-4 min of 95% N(2)/5% CO(2)) induce in thalamocortical neurons an increase in instantaneous input conductance (G(N)) accompanied by an inward shift in baseline holding current (I(BH)). These effects have been suggested to be mediated, at least in part, by a positive shift in the voltage-dependence of the hyperpolarization-activated, mixed Na(+)/K(+) current (I(h)) and a change in its activation kinetics which transforms it into an almost instantaneously activated current. In this study, using the whole-cell patch-clamp technique, the contribution of an increased Ca(2+)-dependent transmitter release to the hypoxic response of thalamocortical neurons was further investigated using (i) blockers of calcineurin, a Ca(2+)/calmodulin-activated phosphatase that selectively regulates Ca(2+)-dependent release, and (ii) antagonists of neurotransmitters that are known to modulate I(h). Thalamocortical neurons (n = 23) recorded with electrodes filled with calcineurin autoinhibitory fragment (30-250 microM), a membrane impermeable blocker of calcinuerin, showed no difference either in resting, or in the hypoxia-induced changes in, G(N), I(BH) and I(h), when compared to thalamocortical cells patched with electrodes that did not contain calcineurin autoinhibitory fragment. In contrast, in 18 of these neurons recorded with calcineurin autoinhibitory fragment-filled electrodes, bath application either of cyclosporin-A (20 microM) or tacrolimus (50-100 microM), two membrane permeable blockers of calcineurin, abolished the effects of hypoxia on G(N), I(BH), and I(h). Separate application of noradrenaline, serotonin, histamine and nitric oxide antagonists produced only a small depression of the hypoxic response, while concomitant bath application of these antagonists decreased the hypoxia-induced changes in G(N) and I(BH) by 55 and 42%, respectively (n = 12). Concomitant bath application of 8-bromo-adenosine-3'5'-cyclicmonophosphate and 8-bromo-guanosine-3'5'-cyclicmonophosphate (both 1mM), which are known to mediate the action of these transmitters on I(h), increased G(N) (40%), decreased I(h) time-constant of activation (30%) and significantly occluded (50%) the hypoxia-induced effect on G(N) and I(BH). Thalamocortical neurons (n = 6) patched with electrodes filled with 8-bromo-adenosine-3'5'-cyclicmon

Topics: Acute Disease; Animals; Calcineurin Inhibitors; Cyclic AMP; Cyclic GMP; Electrophysiology; Histamine Release; Hypoxia; Neurotransmitter Agents; Nitric Oxide; Norepinephrine; Rats; Rats, Wistar; Serotonin; Thalamic Diseases

Phosphodiesterase type 5 (PDE5) hydrolyzes cyclic guanosine monophosphate in the lung, thereby modulating nitric oxide (NO)/cyclic guanosine monophosphate-mediated pulmonary vasodilation. Inhibitors of PDE5 have been proposed for the treatment of pulmonary hypertension. In this study, we examined the pulmonary and systemic vasodilator properties of sildenafil, a novel selective PDE5 inhibitor, which has been approved for the treatment of erectile dysfunction.. In an awake lamb model of acute pulmonary hypertension induced by an intravenous infusion of the thromboxane analog U46619, we measured the effects of 12.5, 25, and 50 mg sildenafil administered via a nasogastric tube on pulmonary and systemic hemodynamics (n = 5). We also compared the effects of sildenafil (n = 7) and zaprinast (n = 5), a second PDE5 inhibitor, on the pulmonary vasodilator effects of 2.5, 10, and 40 parts per million inhaled NO. Finally, we examined the effect of infusing intravenous l-NAME (an inhibitor of endogenous NO production) on pulmonary vasodilation induced by 50 mg sildenafil (n = 6).. Cumulative doses of sildenafil (12.5, 25, and 50 mg) decreased the pulmonary artery pressure 21%, 28%, and 42%, respectively, and the pulmonary vascular resistance 19%, 23%, and 45%, respectively. Systemic arterial pressure decreased 12% only after the maximum cumulative sildenafil dose. Neither sildenafil nor zaprinast augmented the ability of inhaled NO to dilate the pulmonary vasculature. Zaprinast, but not sildenafil, markedly prolonged the duration of pulmonary vasodilation after NO inhalation was discontinued. Infusion of l-NAME abolished sildenafil-induced pulmonary vasodilation.. Sildenafil is a selective pulmonary vasodilator in an ovine model of acute pulmonary hypertension. Sildenafil induces pulmonary vasodilation via a NO-dependent mechanism. In contrast to zaprinast, sildenafil did not prolong the pulmonary vasodilator action of inhaled NO.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3',5'-Cyclic-GMP Phosphodiesterases; Acute Disease; Animals; Blood Pressure; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Enzyme Inhibitors; Hypertension, Pulmonary; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Pulmonary Artery; Pulmonary Circulation; Purines; Purinones; Sheep; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents; Wakefulness

Acute rejection and urinary tract infection (UTI) both increase nitric oxide synthase (NOS) activity in urine from renal transplant patients. Also, with rejection, a regulatory interplay between nitric oxide (NO) and cytokines has been suggested. Thus, measurement of the temporal changes of NOS products and cytokines in urine will provide a strategy for the diagnosis of acute rejection and for its differentiation from UTI.. Soluble interleukins (ILs) and NOS-related products, cyclic GMP (cGMP), nitrate, and nitrite were measured in 192 urine samples consecutively collected from 13 patients within the first three months of transplantation. Sixty-seven additional urine specimens were collected randomly from 24 patients for follow-up analysis of the nitrate test.. Among patients who experienced rejection, the percentage (%) binding of IL-2 increased within the first five days (P = 0.0004) after transplantation and one to five days prior to the clinical diagnosis (dx) of rejection (P = 0.02). Tumor necrosis factor-alpha, IL-6, and IL-8 increased at the time of rejection dx (P < or = 0.01). With UTI, IL-2 (P = 0.01) decreased one to five days prior to dx, and IL-10 (P = 0.003) increased one to five days after dx. Although cGMP and nitrate are dependent variables, cGMP increased (P < or =0.0009) with both rejection and UTI, and nitrate increased (P = 0.0001) with rejection and decreased (P = 0.0001) with UTI. Prior to formal dx (1 to 5 days), urine nitrate clearly differentiated rejection (3004 to 7451 micromol/L) from UTI (90 to 885 micromol/L) and controls (1059 to 3235 micromol/L). The additional 67 urines demonstrated that the sensitivity of the nitrate test for rejection and UTI was 100%.. In renal transplant patients, specific temporal changes in urine cytokine levels do occur with acute rejection and UTI, but urine nitrate levels are the most precise at differentiating rejection from UTI.

Topics: Acute Disease; Adult; Creatinine; Cyclic GMP; Cytokines; Female; Follow-Up Studies; Graft Rejection; Humans; Interleukin-10; Interleukin-2; Interleukin-6; Interleukin-8; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Predictive Value of Tests; Time Factors; Tumor Necrosis Factor-alpha; Urinary Tract Infections

Single intraperitoneal injection of melatonin in a dose of 1 mg/kg prevented accumulation of cGMP and intensification of lipid peroxidation in the hippocampus and habenula of rats exposed to acute hypobaric hypoxia (12,000 m). Changes in habenular content of cGMP suggest that melatonin prevents hypoxia-induced activation of heme-oxygenase.

Topics: Acute Disease; Animals; Cyclic AMP; Cyclic GMP; Enzyme Activation; Habenula; Heme Oxygenase (Decyclizing); Hippocampus; Hypoxia; Lipid Peroxidation; Male; Malondialdehyde; Melatonin; Rats

Cardiotrophin-1 (CT-1) is a recently discovered member of the gp130 cytokine family, which includes IL-6, IL-11, leukemia inhibitory factor, ciliary neurotrophic factor, and oncostatin M. Recent evidence suggests that, like other members of this family, CT-1 may possess anti-inflammatory properties. We hypothesized that in vivo CT-1 administration would attenuate endotoxin (ETX)-induced acute lung injury. We studied the effects of CT-1 (100 microgram/kg ip, 10 min prior to ETX) in a rat model of ETX-induced acute lung injury (Salmonella typhimurium lipopolysaccharide, 20 mg/kg ip). Six hours after ETX, lungs were harvested for determination of neutrophil accumulation (myeloperoxidase, MPO, assay) and lung edema (wet-to-dry weight ratio). Mechanisms of pulmonary vasorelaxation were examined in isolated pulmonary artery rings at 6 h by interrogating endothelium-dependent (response to acetylcholine) and endothelium-independent (response to sodium nitroprusside) relaxation following alpha-adrenergic (phenylephrine)-stimulated preconstriction. CT-1 abrogated the endotoxin-induced lung neutrophil accumulation: 2.3 +/- 0.2 units MPO/g wet lung (gwl) vs 6. 3 +/- 0.3 units MPO/gwl in the ETX group (P < 0.05 vs ETX, P > 0.05 vs control). Similarly, CT-1 prevented ETX-induced lung edema: wet-to-dry-weight ratio, 4.473 +/- 0.039 vs 4.747 +/- 0.039 in the ETX group (P < 0.05 vs ETX, P > 0.05 vs control). Endotoxin caused significant impairment of both endothelium-dependent and -independent pulmonary vasorelaxation, and CT-1 attenuated this injury. Thus, cardiotrophin-1 possesses significant anti-inflammatory properties in a model of endotoxin-induced acute lung injury.

Topics: Acute Disease; Animals; Cyclic GMP; Cytokines; Edema; Endotoxemia; Endotoxins; Lung; Lung Diseases; Male; Neutrophils; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Vasodilation

In the glycerol model of renal injury we describe an acute rise in systemic arterial pressure which is attended by a reduced vasodilatory response to acetylcholine in vivo; vasodilatory responses to verapamil, however, were not impaired. Neither arginine nor sodium nitroprusside diminished this rise in blood pressure; N(omega)-nitro-L-arginine methyl ester (L-NAME) elevated basal mean arterial pressure and markedly blunted the rise in mean arterial pressure following the administration of glycerol. Aortic rings from the glycerol-treated rat demonstrate an impaired vasodilatory response to acetylcholine, an effect not repaired by arginine; the vasodilatory responses to nitric oxide donors, sodium nitroprusside and SIN-1, were also impaired; 8-bromo-cGMP, at higher doses, evinced a vasodilatory response comparable to that observed in the control rings. This pattern of responses was not a nonspecific effect of aortic injury, since aortic rings treated with mercuric chloride, a potent oxidant, displayed an impaired vasodilatory response to acetylcholine but not to sodium nitroprusside. We conclude that in the glycerol model of heme protein-induced tissue injury, there is an acute elevation in mean arterial pressure attended by impaired endothelium-dependent vasodilatation in vitro and in vivo. We suggest that the acute scavenging of nitric oxide by heme proteins depletes the blood vessel wall of its endogenous vasodilator and permeation of heme proteins into the blood vessel wall may contribute to such sustained effects as observed in vitro.

Topics: Acetylcholine; Acute Disease; Animals; Blood Pressure; Cyclic GMP; Disease Models, Animal; Glycerol; Hemeproteins; Hypertension; Kidney; Male; Nitroprusside; Rats; Rats, Sprague-Dawley; Vasodilator Agents

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

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

To investigate the possible involvement of endogenous nitric oxide (NO) in acute hypotension during maintenance hemodialysis, we measured the plasma concentration of the nitrate anion NO3-, a stable metabolite of NO, in 19 patients undergoing hemodialysis. We analyzed heart rate variability to estimate the relationship between autonomic nervous activity and NO production, low-frequency/high-frequency components (L/H) as a parameter of cardiac sympathetic activity, and high-frequency power as a parameter of cardiac vagal activity. Six patients developed severe hypotension (a change in mean blood pressure during dialysis > or = 20 mm Hg), four patients developed mild hypotension (a change in mean blood pressure < or = 19 mm Hg and > or = 1 mm Hg), and nine patients did not develop hypotension. The plasma levels of NO3- before dialysis were markedly elevated in the severely hypotensive group compared with the patients who showed no hypotension (566+/-122 micromol/L v 133+/-38 micromol/L; P < 0.01), and this difference disappeared midhemodialysis and after hemodialysis. The plasma concentration of NO3- before dialysis was significantly associated with both the change in mean blood pressure during dialysis (r= -0.735; P = 0.003) and the mean blood pressure after dialysis (r = -0.675; P = 0.0015). The L/H ratio was inhibited before or after dialysis in the severely hypotensive group compared with the nonhypotensive group, and hypotension during dialysis was correlated with the inhibited L/H ratio before (r = 0.784; P = 0.001) or after (r = 0.822; P = 0.001) dialysis. Plasma NO3- concentrations were correlated with the L/H ratio before (r = -0.553; P = .014) or after (r = -0.546; P = 0.015) dialysis. These results suggest that inhibited sympathetic activity is one of the causes of acute hypotension during dialysis, and the enhanced production of NO is involved in this inhibition of the sympathetic activity in patients having a hypotensive episode during dialysis. The plasma concentration of NO3- before dialysis may be a predictor of the risk of hypotension during dialysis in patients with end-stage renal disease.

Topics: Acute Disease; Anions; Blood Pressure; Cyclic GMP; Endothelin-1; Female; Heart Rate; Humans; Hypotension; Kidney Failure, Chronic; Male; Middle Aged; Nitrates; Nitric Oxide; Renal Dialysis; Sympathetic Nervous System

Our aim was to assess the value of a single determination of plasma cyclic guanosine 3',5'-monophosphate (cGMP) in noninvasive screening for acute cardiac allograft rejection warranting augmentation of immunosuppression. Plasma cGMP levels were measured in 26 patients 1 to 13 months after heart transplantation on the same day the endomyocardial biopsies were performed. Acute moderate rejection (ISHLT 3A or 3B) was found in 10 out of 17 subjects (59%) with plasma cGMP >5 nmol/L, whereas there was mild or no rejection (ISHLT 0 to 1) in 8 from among 9 subjects (89%) with cGMP <5 nmol/L. Because cGMP levels <5 nmol/L appear to argue against the presence of acute rejection requiring therapy modification, our preliminary results suggest that a single plasma cGMP assay might be helpful in establishing indications for endomyocardial biopsy in heart transplant recipients.

Topics: Acute Disease; Adult; Cyclic GMP; Endocardium; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardium; Treatment Outcome

Increases in plasma cyclic GMP levels have been shown to correlate with increased plasma levels of atrial natriuretic peptide (ANP) in patients with fluid overload due to increased secretion of ANP. There is evidence that plasma cyclic GMP levels are also elevated in some patients with acute leukemia, but increased ANP secretion has not been demonstrated. To elucidate the possibility that a newly expressed guanylyl cyclase may be responsible for the increase of plasma cyclic GMP levels patients with acute and chronic leukemia as well as patients with lymphoma and healthy volunteers were studied. Plasma levels of cyclic GMP were measured and isolated peripheral blood mononuclear or bone marrow cells were incubated with increasing concentrations of ANP. The stimulation of cells was measured as cGMP accumulation in the supernatant. Furthermore guanylyl cyclase activity was measured in membrane preparations of peripheral blood mononuclear cells. While leukocytes of healthy subjects were devoid of detectable ANP-stimulated particulate guanylyl cyclase activity, ANP-sensitivity was observed in seven patients with acute lymphoblastic and in three patients with acute myelogenous leukemia. Cyclic GMP in the supernatant of cells was elevated between 2- and 132-fold of basal when cells were incubated with 1 microM ANP for 60 minutes. Like in healthy volunteers, no effect of ANP on freshly isolated mononuclear cells was observed in cases with chronic leukemia or in patients with lymphoma. Expression of ANP-sensitive particulate gunaylyl cyclase may be connected with malignant transformation of lymphocytes in patients with acute leukemia and might be useful for their diagnosis and classification.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Bone Marrow; Child, Preschool; Cyclic GMP; Female; Guanylate Cyclase; Humans; In Vitro Techniques; Leukemia; Leukocytes, Mononuclear; Male; Middle Aged; Receptors, Atrial Natriuretic Factor

Controversy persists regarding the acute responsiveness of atrial (ANP) and brain (BNP) natriuretic peptides in pathophysiological conditions such as acute heart failure (AHF). This study was designed to test the hypothesis that AHF is characterized by selective activation of ANP, but not BNP. We also hypothesized that BNP replacement in AHF would reduce cardiac filling pressures, increase sodium excretion, and inhibit circulating renin. Two groups of anesthetized dogs underwent rapid left ventricular pacing to induce AHF. Group 1 (n = 7) served as control and group 2 (n = 7) received canine BNP (10 ng x kg(-1) x min(-1)). Cardiorenal parameters, circulating natriuretic peptides, 3',5'-cyclic guanosine monophosphate (cGMP), and plasma renin activity (PRA) were determined at baseline and during AHF in both groups. AHF was characterized by reductions in cardiac output (2.3 +/- 0.2 vs. 3.7 +/- 0.3 l/min, P < 0.05), pulmonary capillary wedge pressure (PCWP; 11.7 +/- 0.8 vs. 5.1 +/- 0.3 mmHg, P < 0.05), and selective activation of ANP (250 +/- 51 vs. 39 +/- 13 pg/ml, P < 0.05), with no increase in circulating BNP (49 +/- 15 vs. 60 +/- 16 pg/ml, P = not significant). Compared with control, exogenous supplemental BNP in AHF resulted in marked increases in circulating cGMP (65 +/- 6 vs. 18 +/- 5 pg/ml, P < 0.05), with reductions in PCWP (9.1 +/- 0.9 vs. 12.9 +/- 1.1 mmHg, P < 0.05) and increased urinary sodium excretion (120 +/- 36.8 vs. 24 +/- 6.3 microeq/min, P < 0.05) via reductions in distal tubular sodium reabsorption (94.3 +/- 1.8 vs. 98.0 +/- 0.4%, P < 0.05). Exogenous BNP prevented the increase in PRA that occurred in the control group. We conclude that AHF is characterized by a failure to increase circulating BNP underscoring differential physiological and pathophysiological roles for ANP and BNP in states of immediate cardiac overload. These studies also support a potential role for BNP in the therapeutics of AHF.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cyclic GMP; Dogs; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Kidney; Male; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Pulmonary Wedge Pressure; Radioimmunoassay; Reference Values; Renal Circulation; Renin; Vascular Resistance

Atrial and brain natriuretic peptides exert renal and cardiovascular actions through binding to the natriuretic peptide-A receptor, while C-type natriuretic peptide mediates actions that occur through binding to the natriuretic peptide-B receptor, with subsequent generation of cyclic guanosine monophosphate. This study determined responses of circulating atrial natriuretic peptides in experimental acute heart failure and addressed the hypothesis that elevated circulating atrial natriuretic peptides serve a homeostatic role in regulating sodium excretion and that this action is localized to the glomerulus and distal nephron, sites rich in natriuretic peptide-A receptors.. Studies were performed in the absence and presence of HS-142-1, an inhibitor of the natriuretic peptide receptors. Two groups of anesthetized dogs underwent induction of acute heart failure by rapid ventricular pacing, as characterized by decreases in cardiac output and increases in filling pressures with associated elevation of endogenous atrial natriuretic peptides secondary to increases in atrial stretch. In group 1 (n = 5, vehicle intrarenal bolus), despite acute heart failure-mediated decreases in cardiac output, sodium excretion was preserved with maintenance of the glomerular filtration rate and distal fractional sodium reabsorption. In group 2 (n = 5), in response to the natriuretic peptide receptor antagonist, HS-142-1 (0.5 mg/kg intrarenal bolus), sodium excretion (17.0 +/- 4.4 to 5.9 +/- 3.2 microEq/min; P < .05) and glomerular filtration rate decreased (33.0 +/- 3.6 to 21.0 +/- 3.9 mL/min; P < .05) and distal fractional sodium reabsorption increased (98.0 +/- 0.63 to 99.3 +/- 0.25%; P < .05), in association with a decrease in plasma cyclic guanosine monophosphate (13.0 +/- 3.5 to 6.6 +/- 2.9 pmol/mL; P < .05) and renal cyclic guanosine monophosphate generation (1,216 +/- 421 to 466 +/- 208 pmol/min; P < .05).. This study supports a functionally significant role for the endogenous natriuretic peptide system in preserving sodium homeostasis and glomerular filtration rate in acute heart failure.

Topics: Acute Disease; Analysis of Variance; Animals; Atrial Natriuretic Factor; Cyclic GMP; Dogs; Glomerular Filtration Rate; Guanylate Cyclase; Heart Failure; Hemodynamics; Kidney; Male; Polysaccharides; Receptors, Atrial Natriuretic Factor; Sodium

We examined the hemodynamic and neurohumoral effects of carperitide in dogs with low-output heart failure (LHF) produced by volume expansion, ligation of the left anterior descending coronary artery and methoxamine infusion. Carperitide (0.1 approximately 1 micrograms/kg/min, i.v. infusion for 30 min) decreased pulmonary arterial pressure, right atrial pressure and systemic vascular resistance and increased cardiac output. These pharmacological activities were equivalent to those of nitroglycerin (NG, 3 micrograms/kg/min). Although most of the animals did not excrete urine after induction of LHF, carperitide, unlike NG, increased urine volume. The plasma level of cyclic GMP was elevated about three times by induction of LHF and further increased after treatment with carperitide (1 microgram/kg/min). Carperitide had no effects on plasma renin activity, plasma aldosterone concentration and plasma noradrenaline. These results taken together indicate that carperitide reduces both preload and afterload in association with an increase in cyclic GMP production and improves the untoward hemodynamic alterations in LHF dogs.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Cyclic GMP; Diuresis; Dogs; Female; Hemodynamics; Male; Methoxamine; Nitroglycerin; Peptide Fragments; Renin-Angiotensin System

The major hemodynamic feature of acute lung injury (ALI) is pulmonary hypertension. Both endothelial-dependent and -independent pulmonary vasorelaxation is impaired in ALI due to endotoxemia. We hypothesized that endotoxemia selectively impairs relaxation of the pulmonary artery but does not impair contractility of pulmonary vascular smooth muscle (VSM). Our purpose was to determine the effect of endotoxemia (ETX) on the contractile response of pulmonary VSM to (1) tubular depolarization (KCl), (2) alpha 1-adrenoreceptor stimulation (phenylephrine, PE), (3) 5HT2 receptor stimulation (serotonin, 5HT), and (4) prostaglandin F2 alpha receptor stimulation. Pulmonary artery rings were isolated from rats 6 hr after injection of ETX, 20 mg/kg ip (n > or = 6), or saline (n > or = 6) and suspended on tensiometers in individual organ baths. Endothelial-dependent cGMP-mediated relaxation was determined using the receptor agonist acetylcholine (ACh) in rings preconstricted with PE. Dose-response curves were generated to each contractile agonist. Statistical comparison was performed using one-way ANOVA with post hoc Bonferonni-Dunn, P < 0.05 accepted as significant. Relaxation to ACh was 96.4 +/- 1.3% in controls vs 21.4 +/- 3.1% (P < 0.05) in endotoxin-treated rats. Endotoxin did not affect the maximal tension in response to the contractile agonists nor did it change the concentration required to produce 50% contraction (EC50). From these data we conclude that endotoxemia causes a decrease in vasorelaxation to the endothelial-dependent receptor agonist acetylcholine but does not impair agonist-induced contractility of pulmonary VSM. This suggests that pulmonary hypertension in ALI is mediated by impairment of pulmonary vasodilation with preservation of VSM contractility.

Topics: Acute Disease; Animals; Calcium; Cyclic GMP; Endotoxins; Hypertension, Pulmonary; In Vitro Techniques; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Vasoconstriction; Vasodilation

Adult respiratory distress syndrome is characterized by hypoxia and acute pulmonary hypertension. Therefore we examined the effect of acute hypoxia on the mechanisms of pulmonary vasodilation.. Isolated rat pulmonary artery rings were suspended on tensiometers in a balanced salt solution. A normoxic gas mixture was bubbled through the solution (21% O2, 5% CO2, 74% N2). Rings were preconstricted with phenylephrine, and the following mechanisms of pulmonary vascular smooth muscle relaxation were studied in a random order: (1) endothelial-dependent cyclic guanosine monophosphate-mediated (acetylcholine, 10(-9) to 10(-6) mol/L), (2) endothelial-independent cyclic guanosine monophosphate-mediated (nitroprusside, 10(-9) to 10(-6) mol/L), and (3) beta-adrenergic receptor cyclic adenine monophosphate-mediated (isoproterenol, 10(-9) to 10(-6) mol/L). Separate rings were preconstricted with phenylephrine, and the gas was switched to a hypoxic mixture (0% O2, 5% CO2, 95% N2). After vasoconstriction to hypoxia reached a plateau, the response to the maximal effective dose of the above vasodilators (10(-6) mol/L) was determined in a random order. Statistical analysis was done with one-way analysis of variance with post hoc Bonferroni-Dunn correction. A p value of less than 0.05 was accepted as significant.. Endothelial-dependent and -independent cyclic guanosine monophosphate-mediated relaxation was the same in normoxia and hypoxia. On the other hand, hypoxia inhibited beta-adrenergic receptor cyclic adenine monophosphate-mediated pulmonary vasorelaxation (97.5% +/- 2.5% versus 71.5% +/- 2.3% in hypoxia; p < 0.01).. These data suggest that hypoxia selectively inhibits beta-adrenergic cyclic adenine monophosphate-mediated pulmonary vasorelaxation. This dysfunction of the normal mechanism of pulmonary vasodilation may contribute to the pulmonary hypertension seen in adult respiratory distress syndrome.

Topics: Acetylcholine; Acute Disease; Animals; Cyclic AMP; Cyclic GMP; Endothelium, Vascular; Hypoxia; In Vitro Techniques; Isoproterenol; Lung; Muscle, Smooth, Vascular; Nitroprusside; Rats; Rats, Sprague-Dawley; Vasodilation

To elucidate the pathophysiologic role of alpha-human atrial natriuretic peptide (alpha-hANP) in acute lung injury, plasma alpha-hANP concentrations were measured in 15 patients with severe lung injury, and the relationships of plasma alpha-hANP levels to the severity of lung injury, diuresis/natriuresis, and fluid balance were examined. The mean concentrations of plasma alpha-hANP (188.0 +/- 94.6 pg/ml) in patients with severe lung injury at the entry into the study were significantly (p less than 0.001) higher than those in normal subjects (31.7 +/- 12.0 pg/ml). Plasma alpha-hANP levels decreased in parallel with the improvement of lung injury in nine of 15 patients, whereas they changed little, if any, in the patients who did not recover. Plasma alpha-hANP concentrations correlated positively with urine volume, urinary sodium excretion, and excreted fraction of filtered sodium, but they correlated negatively with fluid balance at the onset of the disease as well as during the clinical course. It is suggested that elevation of circulatory alpha-hANP may reflect an adaptative mechanism to remove excessive fluid retention and reduce pulmonary hypertension for acute lung injury.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Cyclic GMP; Female; Humans; Lung Diseases; Male; Middle Aged; Peptide Fragments

It has been previously shown that induction of experimental esophagitis in the cat by esophageal perfusion for 30 minutes with 0.1N HCl for 4 consecutive days results in a significant reduction of in vivo lower esophageal sphincter (LES) resting pressure and in vitro spontaneous tone without affecting esophageal response to KCl. It has also been shown that basal LES tone and LES contraction in response to acetylcholine depend on the release of calcium from intercellular stores, whereas esophageal contraction is mediated by extracellular calcium. The present report shows that esophageal acid perfusion impairs the transduction pathway mediating lower esophageal sphincter contraction in response to acetylcholine through release of intracellular calcium because LES strips and single cells no longer contract in response to acetylcholine if calcium is removed from the physiologic salt solution. This suggests that either the intracellular calcium stores or the release mechanisms that mediate maintenance of tone and contraction in response to acetylcholine may be damaged. However, the acid perfusion has no effect on the acetylcholine response in the esophagus, which is mediated by the influx of extracellular calcium. In the LES circular muscle, the injury results in reduced levels of inositol phosphates without affecting resting levels of 5'-cyclic adenosine monophosphate or 5'-cyclic guanosine monophosphate. The reduced levels of 1,4,5-inositol trisphosphate are consistent with impairment in the mechanisms responsible for release of intracellular calcium, although concurrent damage to calcium stores may also occur.

Topics: Acute Disease; Animals; Calcium; Cats; Cyclic AMP; Cyclic GMP; Egtazic Acid; Esophagitis; Esophagogastric Junction; Female; In Vitro Techniques; Inositol Phosphates; Male; Signal Transduction

The purpose of this study was to evaluate the pathophysiologic role of atrial natriuretic peptide (ANP) as a pulmonary artery vasodilator in patients with acute respiratory failure receiving artificial ventilation. Twenty-one consecutive patients were studied, 12 without and 9 with preexisting cardiopulmonary disease. Pulmonary artery plasma ANP levels were significantly higher than the levels obtained in the superior vena cava and radial artery. Plasma ANP levels correlated significantly with the plasma levels of its second messenger, guanosine 3',5'-cyclic monophosphate (cGMP). In the 12 patients without prior cardiopulmonary disease, plasma ANP levels correlated significantly with mean pulmonary arterial pressure (MPAP). This correlation was not found in the nine patients with preexisting cardiopulmonary disease. The cGMP/ANP ratio, indicating the biologic effect of ANP, was also higher in the patients without preexisting cardiopulmonary disease. These results are compatible with clearance and vasodilator activity of ANP in the pulmonary vascular bed, but only in patients without preexisting cardiopulmonary disease.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Atrial Function, Right; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Female; Heart Failure; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Pulmonary Artery; Pulmonary Fibrosis; Radial Artery; Respiration, Artificial; Respiratory Insufficiency; Vena Cava, Superior

Nineteen patients with acute pancreatitis were examined for the activity of LDH, NADH-tetrazolium oxidoreductase, acid phosphatase, the content of calcium salts, cAMP and cGMP in biopsy tissue of the pancreas; pancreatic enzymes and bicarbonates in the duodenal contents and pancreatic juice. The activity of enzymes participating in oxidative metabolism in epithelial cells of the intact pancreas appeared elevated. During the development of destructive changes in the pancreatic parenchyma, the processes of intracellular oxidation get inhibited, the enzymes go out into the intercellular space, calcium transport gets impaired, and acid phosphatase is activated. It has been found that in acute destructive pancreatitis, primarily impaired are epithelial cells of the islets, followed by the impairment of the epithelium of the acini and at the last moment of that of the excretory ducts. The data obtained enable one to regard cyclonucleotides, calcium, pancreatic enzymes and lysosomal hydrolases as pathogenetic elements of acute pancreatitis.

Topics: Acute Disease; Adult; Cyclic AMP; Cyclic GMP; Glycolysis; Humans; Middle Aged; Oxidation-Reduction; Pancreas; Pancreatitis

To test the hypothesis that exogenous atrial natriuretic peptide (ANP) prevents the acute pulmonary pressor response to hypoxia, ANP (20-micrograms/kg bolus followed by 1-microgram.kg-1.min-1 infusion) or vehicle was administered intravenously to conscious rats beginning 3 min before exposure to hypoxia or room air for 90 min. Exogenous ANP abolished the acute pulmonary pressor response to hypoxia in association with marked and parallel increases in plasma ANP and guanosine 5'-cyclic monophosphate (cGMP) and with a significant increase in lung cGMP content. To examine whether endogenous ANP modulates the acute pulmonary pressor response to hypoxia, rats were pretreated with a monoclonal antibody (Ab) to ANP and exposed to hypoxia. Mean pulmonary arterial pressure (MPAP) in the Ab-treated rats was not different from control over the first 6 h of hypoxic exposure. Thereafter, the Ab-treated group had significantly higher MPAP than control. Our data suggest that 1) exogenous ANP blocks the pulmonary pressor response to acute hypoxia via stimulation of cGMP accumulation in the pulmonary vasculature, and 2) endogenous ANP may modulate the subacute, but not acute, phase of hypoxic pulmonary hypertension.

Topics: Acute Disease; Animals; Antibodies, Monoclonal; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Heart Rate; Hypertension, Pulmonary; Hypoxia; Lung; Male; Pulmonary Artery; Radioimmunoassay; Rats; Rats, Inbred Strains

Atrial natriuretic factor (ANF) is a peptide hormone of cardiac origin elevated in acute congestive heart failure (CHF), which is degraded by the enzyme neutral endopeptidase 24.11 (NEP). This study was designed to investigate the pulmonary and urinary clearance of ANF before and after the initiation of acute experimental CHF in dogs, and to assess the contribution of enzymatic degradation to these clearances in CHF. This study demonstrated a significant clearance of plasma ANF across the pulmonary circulation at baseline, and a tendency for pulmonary clearance to decrease in CHF (1115 +/- 268 to 498 +/- 173 ml/min, NS). The pulmonary extraction of ANF present at baseline was not altered with acute CHF (36.0 +/- 7.8 to 34.9 +/- 12.1%, NS). NEP inhibition (NEPI) abolished both the clearance and extraction of plasma ANF across the lung in CHF. Similarly, significant urinary clearance of ANF was present at baseline, and in acute CHF the urinary clearance of ANF decreased (0.14 +/- 0.02 to 0.02 +/- 0.01 ml/min, P less than 0.05). NEPI prevented the decrease in the urinary clearance of ANF, and enhanced the renal response to endogenous ANF, independent of further increases in plasma ANF during CHF. This study supports an important role for NEP in the pulmonary and urinary metabolism of endogenous ANF during acute CHF.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Dogs; Heart Failure; Kidney; Lung; Metabolic Clearance Rate; Protease Inhibitors

Previous studies have shown that when atrial natriuretic peptide (ANF) is given to anaesthetized dogs with hypovolemic acute pancreatitis, it will produce a diuresis and natriuresis but will not elevate the glomerular filtration rate (GFR). When the same dose of peptide is given to dogs equally hypovolemic (hemorrhage) but without pancreatitis, a brisk increment in GFR occurs. GFR will, however, rise in dogs with pancreatitis in response to other peptides, such as glucagon. In these studies we assessed cGMP excretion as a marker for ANF effect in both normal anaesthetized dogs and dogs with acute experimental pancreatitis. In each group, urinary output and sodium excretion increased significantly, but GFR rose only in the control group. Urinary excretion of cGMP rose equally and dramatically in both control and experimental animals. We conclude that GFR is prevented from rising in dogs with experimental pancreatitis following ANF, but this effect does not depend on depressed cGMP generation.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Cyclic GMP; Dogs; Female; Glomerular Filtration Rate; Infusions, Intravenous; Male; Pancreatitis; Shock

The content of cyclic nucleotides (cAMP and cGMP), hormones (T3, T4, insulin, protein-bound iodine and thyroid-stimulating hormone) and phosphodiesterase activity were examined in the acute period and over time in blood plasma of patients with ischemic stroke. The parameters under study were found to be interrelated. Also, it has been established that the T4/T3 and cAMP/cGMP ratios and the content of insulin may serve as important biochemical criteria for the gravity of ischemic stroke.

Topics: Acute Disease; Brain Ischemia; Cerebral Infarction; Cyclic AMP; Cyclic GMP; Humans; Insulin; Nucleotides, Cyclic; Phosphoric Diester Hydrolases; Thyroxine; Triiodothyronine

The patients with acute pneumonias demonstrated interdependent changes in lipid peroxidation (LPO), antioxidant system (AOS), immune system (IS), and in the pituitary-adrenocortical system (PAS), related to the character of the disease course. The most pronounced changes were seen in the patients with acute pneumonias eventuating in pneumofibrosis. The high level of LPO was combined with AOS depletion, immunodeficiency formation, and with dysfunction of the PAS. Antibacterial treatment did not exert any appreciable effect on the characteristics under study. Thus, the level of LPO and AOS status are important components in the pathogenesis of acute pneumonias, determining the character of the disease course and outcome. It is advisable that research work aimed at the design of the principles of antioxidant therapy may be intensified.

Topics: Acute Disease; Adrenocorticotropic Hormone; Antioxidants; Cyclic AMP; Cyclic GMP; Humans; Hydrocortisone; Lipid Peroxidation; Pneumonia

Vasoactive humoral factors were measured in 27 patients before and during the first week of conventional treatment of acute heart failure. On admission, all patients were given frusemide intravenously, followed by oral digoxin and diuretic therapy. Before drug treatment, plasma renin activity and plasma angiotensin II concentrations were within normal ranges in the group of patients without previous diuretic treatment, but were significantly higher in those 16 patients already on diuretic drugs when admitted to hospital. After diuretic treatment, however, even the former group revealed activation of the renin-angiotensin system. Plasma concentrations of catecholamines were increased initially but normalized within 1 day. A majority of the patients initially had very high plasma concentrations of atrial natriuretic peptide (mean 276.9 +/- 39.0 pg ml-1) which decreased but did not normalize during the study period. High plasma levels of arginine vasopressin (mean 56.8 +/- 14.6 pg ml-1) were found, but tended to be reduced during treatment. Thus, patients with acute heart failure displayed increased plasma concentrations of atrial natriuretic peptide, arginine vasopressin and catecholamines, but these vasoactive hormones decreased in parallel to clinical improvement during diuretic therapy. In contrast, the renin-angiotensin system became clearly activated.

Topics: Acute Disease; Aged; Aldosterone; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Catecholamines; Cyclic GMP; Diuretics; Female; Furosemide; Heart Failure; Humans; Male; Middle Aged; Neurotransmitter Agents

Plasma cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) taken at distinct times of the day were measured in 45 inpatients with generalized atopic eczema (AE). The results were compared with 34 healthy controls. Female patients not taking oral contraceptives (OC) and male patients revealed significantly higher median levels of cAMP in comparison with the controls (p less than 0.002 for males; p less than 0.001 for females). No significant cAMP differences were found between patients of either sex and female controls taking OC. The median cGMP plasma levels did not differ between patients and controls. Both cyclic nucleotides are discussed under the aspect of cAMP as a second messenger of various hormones, reflecting and integrating different responses of the body to AE as a distressing systemic skin disorder.

Topics: Acute Disease; Adolescent; Adult; Circadian Rhythm; Cyclic AMP; Cyclic GMP; Dermatitis, Atopic; Female; Humans; Male; Middle Aged

To verify the clinical usefulness of extracellular cyclic nucleotide determination as a tumor marker, plasma cyclic AMP (cAMP) and cyclic GMP (cGMP) levels were measured in 70 normal subjects and 173 acute leukemia patients studied in different stages of their disease. Mean plasma cAMP levels were similar in leukemic and normal subjects, although in 48 patients in the active stage of the disease, first diagnosis, or relapse, the cAMP values were below the normal range, and most of these patients failed to respond to chemotherapy. Plasma cGMP levels were markedly elevated in untreated patients, normalized in all patients who attained complete remission, and increased promptly to pretreatment values in patients who relapsed, suggesting that their determination may be useful to monitor the patients' response to treatment.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Cyclic AMP; Cyclic GMP; Female; Humans; Leukemia; Male; Middle Aged; Nucleotides, Cyclic

Topics: Acute Disease; Adolescent; Child; Child, Preschool; Cyclic AMP; Cyclic GMP; Humans; Infant; Intestinal Diseases

A parallel study of the activity of serum cholinesterase and excretion of cyclic guanosine monophosphate made it possible to distinguish 3 types of disorders of cholinergic regulation in exacerbation of bronchial asthma: cholinergic compensation, subcompensation and decompensation. The nature of correlations of the degree of disturbance of cholinergic regulation, intensity of allergic reaction and its type was established. The role and place of the choline blocking agents in multiple modality therapy of bronchial asthma were defined.

Topics: Acid Phosphatase; Acute Disease; Adult; Aged; Asthma; Cholinesterases; Cyclic GMP; Female; Histamine; Humans; Immunoglobulin E; Male; Middle Aged; Status Asthmaticus

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

To verify the clinical usefulness of plasma cyclic nucleotide determination as a tumor marker, levels were measured in 52 normal subjects and in 106 acute leukemia patients. In untreated patients plasma cyclic GMP (cGMP) levels were markedly elevated, whereas cyclic AMP levels did not significantly differ from those of normal subjects. Plasma cGMP levels normalized in all patients who attained complete remission and remained in the normal range during all the remission period. In the patients who relapsed, an early increase in cGMP levels to the pretreatment values was observed, thus suggesting that their determination may be of clinical relevance in monitoring the patients' response to treatment.

Topics: Acute Disease; Adolescent; Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Humans; Leukemia; Male; Middle Aged; Monitoring, Physiologic

Topics: Acute Disease; Adult; Blood Cell Count; Bone Marrow; Cyclic AMP; Cyclic GMP; Female; Humans; Leukemia; Male; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Middle Aged

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

The relationships between the changes in arterial pressure and the content of cyclic nucleotides in the heart and blood plasma were studied on rabbits exposed to acute emotional stress. During 3 hours of the stress program, there were changes in arterial pressure, namely an elevation within the first hour followed by a progressive fall during subsequent 2 hours and death of the animals. The content of cAMP in the heart rose to a greater degree than that of cGMP. The content of cAMP in the blood plasma considerably increased, while the level of cGMP remained unchanged. The data obtained attest to the predominance of activation of adrenergic structures over activation of cholinergic structures.

Topics: Acute Disease; Animals; Cyclic AMP; Cyclic GMP; Humans; Male; Myocardium; Rabbits; Stress, Psychological

Topics: Acute Disease; Adaptation, Physiological; Animals; Brain Ischemia; Cerebral Cortex; Cholinergic Fibers; Cyclic AMP; Cyclic GMP; Female; Ganglia, Sympathetic; Male; Rats; Sympathectomy; Time Factors

Topics: Acute Disease; Adenylyl Cyclases; Adolescent; Adult; Cyclic AMP; Cyclic GMP; Dysentery, Bacillary; Furazolidone; Guanylate Cyclase; Humans; Middle Aged; Tetracycline

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: Acute Disease; Adult; Cyclic AMP; Cyclic GMP; Humans; Male; Middle Aged; Pneumonia

Topics: Acute Disease; Adolescent; Adult; Biopsy, Needle; Convalescence; Cyclic AMP; Cyclic GMP; Duodenum; Humans; Intestinal Mucosa; Intestine, Small; Salmonella Infections

Topics: Acute Disease; Adolescent; Adult; Anti-Bacterial Agents; Cyclic AMP; Cyclic GMP; Dysentery, Bacillary; Female; Furazolidone; Humans; Male; Middle Aged; Shigella flexneri; Shigella sonnei

Topics: Acute Disease; Adrenergic beta-Antagonists; Antigen-Antibody Reactions; Asthma; Bronchi; Cyclic AMP; Cyclic GMP; Histamine Release; Humans; Hypersensitivity; Muscle Contraction; Muscle, Smooth; Prostaglandins; Receptors, Drug; SRS-A

Topics: Acidosis; Acute Disease; Alkalosis; Animals; Bicarbonates; Cyclic AMP; Cyclic GMP; Kidney; Lung; Male; Radioimmunoassay; Rats; Rats, Inbred Strains; Sodium Chloride; Theophylline