Metabolomic Detection Between Pancreatic Cancer and Liver Metastasis Nude Mouse Models Constructed by Using the PANC1-KAI1/CD82 Cell Line.

Background: Pancreatic cancer (PC) has a poor prognosis and is prone to liver metastasis. The KAI1/CD82 gene inhibits PC metastasis. This study aimed to explore differential metabolites and enrich the pathways in serum samples between PC and liver metastasis nude mouse models stably expressing KAI1/CD82. Methods: KAI1/CD82-PLV-EF1α-MCS-IRES-Puro vector and PANC1 cell line stably expressing KAI1/CD82 were constructed for the first time. This cell line was used to construct 3 PC nude mouse models and 3 liver metastasis nude mouse models. The different metabolites and Kyoto encyclopedia of genes and genomes (KEGG) and human metabolome database (HMDB) enrichment pathways were analyzed using the serum samples of the 2 groups of nude mouse models on the basis of untargeted ultra-performance liquid chromatography-tandem mass spectrometry platform. Results: KAI1/CD82-PLV-EF1α-MCS-IRES-Puro vector and PANC1 cell line stably expressing KAI1/CD82 were constructed successfully, and all nude mouse models survived and developed cancers. Among the 1233 metabolites detected, 18 metabolites (9 upregulated and 9 downregulated) showed differences. In agreement with the literature data, the most significant differences between both groups were found in the levels of bile acids (taurocholic acid, chenodeoxycholic acid), glycine, prostaglandin E2, vitamin D, guanosine monophosphate, and inosine. Bile recreation, primary bile acid biosynthesis, and purine metabolism KEGG pathways and a series of HMDB pathways (P < .05) contained differential metabolites that may be associated with liver metastasis from PC. However, the importance of these metabolites on PC liver metastases remains to be elucidated. Conclusions: Our findings suggested that the metabolomic approach may be a useful method to detect potential biomarkers in PC.

B-type natriuretic peptide and cardiac remodelling after myocardial infarction: a randomised trial.

OBJECTIVE: B-type natriuretic peptide (BNP) has favourable effects on left ventricular remodelling, including antifibrotic and antiapoptotic properties. We tested the hypothesis that infusion of BNP after an acute myocardial infarction would reduce left ventricular systolic and diastolic volumes and improve left ventricular ejection fraction compared with placebo. METHODS: A total of 58 patients who underwent successful revascularisation for an acute ST elevation anterior myocardial infarction were randomised to receive 72-hour infusion of BNP at 0.006 µg/kg/min or placebo. Left ventricular end diastolic and systolic volumes and left ventricular ejection fraction were measured at baseline and at 30 days by multigated acquisition scan. Left ventricular infarction size was measured by cardiac MRI. RESULTS: BNP infusion led to significantly higher BNP levels and plasma cyclic guanosine monophosphate at 72 hours. No significant difference in change of left ventricular volumes or ejection fraction from baseline to 30 days was observed between groups. Although left ventricular infarction size measured by cardiac MRI was not significantly different between BNP infusion versus placebo (p=0.39), there was a trend towards reduced infarction size in patients with a baseline ejection fraction of <40% (p=0.14). CONCLUSIONS: Infusion of BNP in patients with an anterior myocardial infarction did not affect parameters of left ventricular remodelling. Patients treated with BNP who had a baseline left ventricular ejection fraction of <40% had a trend towards reduced left ventricular infarction size compared with placebo. These results do not support the use of intravenous BNP in patients after recent myocardial infarction. TRIAL REGISTRATION NUMBER: NCT00573144.

Hemodynamic, Hormonal, and Renal Actions of Phosphodiesterase-9 Inhibition in Experimental Heart Failure.

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

Role of 5'-nucleotidase in thiopurine metabolism: enzyme kinetic profile and association with thio-GMP levels in patients with acute lymphoblastic leukemia during 6-mercaptopurine treatment.

Thiopurines are used for treatment of several diseases. Cytotoxicity is caused by the derived compounds 6-thioguanine nucleotides (TGNs) and methyl-6-thioinosine monophosphate (methylthio-IMP). The 6-thiopurine mononucleotides 6-thio-IMP (thio-IMP), 6-thio-GMP (thio-GMP) and methylthio-IMP can be catabolized by purine 5'-nucleotidase. It has been shown that the various 5'-nucleotidases are key enzymes for (6-thio)-purine metabolism. We aimed to investigate whether the overall 5'-nucleotidase (5'NT) activity is correlated with the efficacy and toxicity of 6-thiopurine nucleotides. Substrate affinity of 5'NT for IMP, GMP, AMP, thio-IMP, thio-GMP and methylthio-IMP was studied in human lymphocytes. For each of the substrates, the pH for optimal overall enzyme activity has been determined at a pH range between 6 and 10. At the optimal pH, assays were performed to establish Km and Vmax values. Optimal pH values for the various substrates were between 7 and 8.5. Km values ranged from 33 to 109 microM, Vmax ranged from 3.99 to 19.5 nmol/10(6) peripheral mononuclear cells (pMNC) h, and Vmax/Km ratios ranged from 105 to 250. The results did not show a distinct preference of 5'NT activity for any of the tested thiopurine nucleotides. The enzyme kinetic studies furthermore revealed substrate inhibition by thio-IMP and thio-GMP as a substrate. Inhibition by thio-GMP also seems to occur in patients treated with 6-mercaptopurine (6 MP); subsequently, this may lead to toxicity in these patients.

Attenuation of biologic compensatory action of cardiac natriuretic peptide system with aging.

Although plasma B-type natriuretic peptide (BNP) levels increase with age, the mechanisms responsible for this increase are unknown. We investigated the predictors of elevated BNP in older subjects without cardiac systolic dysfunction and overt renal dysfunction. Furthermore, we analyzed the relations between BNP and its second messenger, cyclic guanosine monophosphate (cGMP), to aging. In 252 subjects (mean age 69 +/- 12 years) with left ventricular ejection fraction >/=50% and creatinine levels <==1.5 mg/dl, plasma levels of BNP, cGMP, blood urea nitrogen, creatinine, and beta2-microglobulin (an endogenous marker of renal function), estimated glomerular filtration rate, and echocardiographic data were prospectively evaluated. Plasma BNP levels increased with age (r = 0.4, p <0.0001). With use of multivariate analysis, predictors of elevated BNP levels were age, use of beta blockers, and serum beta2-microglobulin levels. The molar ratio of cGMP to BNP significantly decreased with aging (r = 0.55, p <0.0001). Elevated BNP in older subjects with normal cardiac systolic function may be due in part to renal impairment. With aging, biologic compensation of the cardiac natriuretic peptide system may be attenuated.

Nitric oxide and Coxsackievirus B3 myocarditis: differential expression of inducible nitric oxide synthase in mouse heart after infection with virulent or attenuated virus.

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

[The effect of triflusal on human platelet aggregation and secretion: the role of nitric oxide]. / Efecto del triflusal sobre la agregación y secreción de las plaquetas humanas: papel del óxido nítrico.

INTRODUCTION AND AIMS: The thrombotic process is a multicellular phenomenon in which not only platelets are involved but also neutrophils are involved. Recent in vitro studies performed in our laboratory have demonstrated that triflusal reduced platelet aggregation by stimulating nitric oxide (NO) production by neutrophils. The aim of the present study was to evaluate whether the in vivo treatment with triflusal could also modify the ability of neutrophils to produce NO. Furthermore, the role of NO released by neutrophils on platelet aggregation and secretion was also tested. METHODS: The study was performed in 12 healthy volunteers of 32 +/- 6 years of age. The volunteers were treated with triflusal (600 mg/day) for 5 days and platelets and neutrophils were isolated before and after treatment. The ability of neutrophils to produce NO and the capacity of inhibiting platelet aggregation and secretion of transforming growth factor-beta (TGF-beta) were assessed. RESULTS: After the treatment with triflusal we obtained the following results: a) an increase in NO production by neutrophils; b) potentiation of the inhibition of platelet aggregation by neutrophils, an effect that was reverted by incubating neutrophils with an L-arginine antagonist, L-NAME, and c) the presence of neutrophils reduced the release of TGF-beta by platelets measured as index of platelet secretion by a NO-independent mechanism. CONCLUSIONS: Triflusal (600 mg/day/5 days) stimulated NO production by neutrophils. After the treatment with triflusal, neutrophils inhibited both platelet aggregation and secretion. The antiaggregating effect of neutrophils was an NO-dependent mechanism while the inhibition of platelet secretion mediated by neutrophils after the treatment with triflusal was an NO-independent mechanism.

The vasodilator-stimulated phosphoprotein (VASP): target of YC-1 and nitric oxide effects in human and rat platelets.

The effects of the different types of soluble guanylate cyclase (sGC) stimulators on the phosphorylation status of vasodilator-stimulated phosphoprotein (VASP) in both human and rat platelets were studied under in vitro and in vivo conditions. sGC-dependent VASP phosphorylation (at Ser(239) and Ser(157)) both by the new direct sGC stimulator YC-1 and by NO donors was examined by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS/PAGE) with different antibodies. One antibody, which recognizes VASP independent of its phosphorylation state, was used to detect the mobility shift of VASP caused by Ser(157) phosphorylation. The other antibody was specifically directed against VASP phosphorylated at Ser(239), the cGMP-dependent protein kinase (PKG) preferred phosphorylation site of VASP. In vitro YC-1 increased both VASP phosphorylation and cyclic guanosine monophosphate (cGMP) levels as did the NO donors 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA/NO) and sodium nitroprusside (SNP). The combination of both types induced a synergistic effect in both VASP phosphorylation and cGMP increase. In rat platelets, similar effects could be shown in vitro. In vivo we observed a significant increase in cGMP and a distinct effect on VASP phosphorylation in rat platelets 1 h after oral administration of YC-1. These biochemical alterations are supported by a significant prolongation in rat-tail bleeding time. Direct stimulators of sGC like YC-1 are on the one hand direct potent stimulators of the cGMP/PKG/VASP pathway in platelets and on the other hand synergize with NO, the physiologic stimulator of sGC. Therefore YC-1-like substances are interesting tools for the development of new cardiovascular drugs with vasodilatory and antithrombotic properties.

The effects of heparin coating of oxygenator fibers on platelet adhesion and protein adsorption.

UNLABELLED: Platelet adhesion on the cardiopulmonary bypass oxygenator membrane is associated with impaired hemostasis. We investigated the effects of heparin coating of the oxygenator membrane on protein adsorption and platelet adhesion on the surface. Noncoated and heparin-coated polypropylene membranes were incubated in whole blood with small- (1 U/mL) or large-dose (5 U/mL) heparin as an anticoagulant for 3 h at 37 degrees C. The amount of platelets adhering on each fiber was assessed by using enzyme immunoassays using monoclonal antibodies directed against CD42b (GP Ib) and CD61 (GP IIb/IIIa). Platelet activation was assessed by measuring plasma guanosine monophosphate 140 levels. The amount and composition of the adsorbed proteins on the surface were analyzed by using a bicinchoninic acid protein assay and by using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting technique. The heparin coating of the fibers significantly reduced platelet adhesion on the surface. However, platelet activation was reduced by heparin coating only with small-dose heparinization. The adsorption of platelet adhesive proteins such as fibrinogen and von Willebrand factor was not altered, whereas that of fibronectin was increased by heparin coating. We conclude that heparin coating of the oxygenator fibers can decrease platelet adhesion without affecting adsorption of major adhesive proteins. Surface heparin coating is associated with an increased fibronectin adsorption on the fibers. IMPLICATIONS: Heparin coating can reduce platelet adhesion and activation in the presence of small-dose heparinization, potentially reducing the inflammatory response and activation of thrombosis and fibrinolysis.

Digitalis increases brain natriuretic peptide in patients with severe congestive heart failure.

Ouabain can cause increased secretion of atrial natriuretic peptide (ANP) from atrial cardiocyte culture, but the effects of digitalis in a therapeutic range on the secretion of cardiac natriuretic peptide including ANP and brain natriuretic peptide (BNP), mainly from the ventricle, in patients with congestive heart failure remain to be investigated. Therefore we studied the acute effects of intravenous infusion of a relatively low dose of digitalis or placebo on hemodynamics and neurohumoral factors including the plasma levels of ANP and BNP and cyclic guanosine monophosphate, a second messenger of cardiac natriuretic peptide, in 13 patients with severe congestive heart failure. No significant change in the hemodynamic parameters or neurohumoral factors was observed with placebo. After 1 hour of intravenous administration of deslanoside (0.01 mg/kg), there was a significant decrease of plasma renin activity and angiotensin II, aldosterone, and norepinephrine levels but no significant change of plasma levels of vasopressin and a significant decrease of the pulmonary capillary wedge pressure but no significant change in cardiac index. In addition, plasma levels of ANP (217 +/- 47 vs 281 +/- 70 pg/ml, p < 0.05), BNP (628 +/- 116 vs 689 +/- 132 pg/ml, p < 0.05), and cyclic guanosine monophosphate (9.7 +/- 1.1 vs 10.9 +/- 1.5 pmol/ml, p < 0.05) increased despite the decrease of pulmonary capillary wedge pressure (19.7 +/- 2.3 vs 16.8 +/- 2.3 mm Hg, p < 0.05). These results indicate the acute intravenous low dose of digitalis resulted in a significant increase in plasma levels of ANP, BNP, and cyclic guanosine monophosphate concomitant with the significant decrease of pulmonary capillary wedge pressure, suggesting the acute direct action of digitalis on the cardiac natriuretic peptides released from the heart in patients with severe congestive heart failure.

Impairment of antidiuretic hormone and atrial natriuretic peptide regulation in the obese woman with a swelling syndrome and an increase in capillary permeability to albumin.

OBJECTIVE: To study the regulation of antidiuretic hormone (ADH) and atrial natriuretic peptide (ANP) in obese and lean women with a swelling syndrome. PATIENTS: Thirty-four obese women and 12 lean women with a swelling syndrome and an abnormal isotopic test of capillary permeability to albumin were investigated. MEASUREMENTS: After 10 nocturnal hours of fluid restriction, subjects were asked at 8am to ingest a tap water load of 20 ml/kg within 10 min and to remain strictly recumbent until twelve noon on the first day, and to remain standing and to walk around until twelve noon on the second day. Free water clearance and the cGMP/creatinine and albumin/creatinine ratios were determined hourly in the morning. RESULTS: The total 4 h-urinary volume/ingested water volume ratio was significantly lower on the second day both in the lean and the obese patients, the differences being slightly larger in the obese patients. The increase in free water clearance was significantly less on the second day in the obese patients. The increase in cGMP/creatinine ratio was also significantly lower on the second day in the obese patients. The maximum level of the urinary albumin/creatinine ratio was significantly higher on the second day in the obese patients. CONCLUSION: In obese women with a swelling syndrome: (1) The higher increase in the urinary albumin excretion rate after water loading followed by a sustained upright position suggests a widespread alteration in capillary function, which is also indicated by the isotopic test of capillary permeability to albumin. (2) The water load-induced inhibition of ADH secretion and stimulation of ANP secretion or ANP activity, more defective in the upright position than in the recumbent one, is probably another major contributing factor to orthostatic oedema.

Left atrial function and atrial natriuretic factor/cyclic guanosine monophosphate changes in DDD and VVI pacing modes.

Left atrial systolic function and the plasma of atrial natriuretic factor (ANF) and cyclic guanosine monophosphate (cGMP) were investigated as possible markers for the development of pacemaker syndrome during VVI pacing. Patients who developed pacemaker syndrome during VVI pacing had a significant decrease in left atrial emptying fraction and a substantial increase in ANF and cGMP plasma levels.

Increased production of nitric oxide by neutrophils and monocytes from cirrhotic patients with ascites and hyperdynamic circulation.

An increased release of nitric oxide (NO), a powerful vasodilating agent, has been proposed to play a role in the pathogenesis of vasodilation and hyperdynamic circulation associated with advanced cirrhosis. We evaluated NO synthase (NOS) activity in peripheral leukocytes of 12 cirrhotic patients and 9 healthy subjects together with plasma endotoxin levels and systemic hemodynamic (by a noninvasive echocardiographic method). NOS activity was evaluated by (1) measuring the capacity of isolated polymorphonuclear cells (PMNs) and monocytes to convert [3H]arginine to [3H]citrulline; (2) measuring the ability of neutrophils and monocytes to inhibit thrombin-induced platelet aggregation and to increase guanosine 3'-5'-cyclic monophosphate content in coincubated platelets, an expression of NO release from these cells. Both neutrophils and monocytes from cirrhotic patients produced significantly higher amounts of [3H]citrulline than cells obtained from healthy subjects (P < .001 and P < .02 for neutrophils and monocytes, respectively) and were more effective than control cells in inhibiting platelet aggregation (P < .05 and P < .001, respectively for 2 x 10(6) cells) and in increasing guanosine 3'-5'-cyclic monophosphate content in coincubated platelets (P < .05 and P < .001, respectively). The anti-aggregating activity expressed by leukocytes has a pharmacological profile similar to that described for NO, because it increased after addition of superoxide dismutase, a superoxide anion scavenger, and markedly decreased after inhibition of nitric oxide synthesis with NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine-methyl ester (L-NAME). Cirrhotic patients had significantly higher plasma endotoxin levels (P < .001) and cardiac index (P < .01) when compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of hyperventilation-induced attacks with infusion of B-type (brain) natriuretic peptide in patients with variant angina.

B-type (brain) natriuretic peptide (BNP) forms a peptide family with A-type (atrial) natriuretic peptide (ANP), which is involved in the regulation of blood pressure and fluid volume. We have demonstrated that BNP is a novel cardiac hormone secreted predominantly from the ventricle and that plasma levels of BNP markedly increase in proportion to the severity of congestive heart failure. Spasm of a major coronary artery (coronary spasm) is the cause of variant angina and can be induced by hyperventilation. We examined whether BNP infusion suppresses coronary spasm in patients with variant angina. The effect of BNP infusion on anginal attacks induced by hyperventilation was studied in 11 patients with variant angina in whom the attacks were reproducibly induced by hyperventilation. This study was performed in the early morning on 3 consecutive days. Fourteen minutes after infusion of BNP was begun (day 2, 0.05 micrograms/kg/min) or saline (days 1 and 3), hyperventilation was started and continued for 6 minutes. Anginal attacks were induced in all 11 patients by hyperventilation on days 1 and 3, respectively. Anginal attacks were not induced in any patient on day 2 (BNP infusion). Fourteen minutes after BNP infusion was begun, plasma BNP levels increased from 23.7 +/- 6.7 pg/ml to peak levels of 2591 +/- 255 pg/ml (p < 0.01) and plasma ANP levels increased from 28.9 +/- 7.5 pg/ml to peak levels of 69.2 +/- 13.2 pg/ml. Five minutes after BNP infusion was finished, plasma levels of cyclic guanosine monophosphate (cGMP) increased from 20.3 +/- 7.4 pg/ml to peak levels of 63.5 +/- 13.7 pg/ml (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Possible improvement in uteroplacental blood flow during atrial natriuretic peptide infusion in preeclampsia.

OBJECTIVE: To study the effects of low doses of the hormone atrial natriuretic peptide (ANP) on uteroplacental blood flow in patients with preeclampsia. METHODS: Eleven women with preeclampsia were infused intravenously with ANP (10 ng/kg/minute). Uteroplacental blood flow index was measured using dynamic placental scintigraphy with indium-113m. Regional blood flows were assessed by pulsed Doppler ultrasound and expressed as pulsatility index (PI). Hemodynamic measurements and blood sampling for peripheral venous plasma analysis of cyclic guanosine monophosphate (cGMP), an ANP second messenger, were performed before and after 30 minutes of infusion. Nonparametric statistics were used. RESULTS: The uteroplacental blood flow index increased by 28% (-2 to 58%; mean and 95% confidence interval). The Doppler findings were unaffected. Mean arterial blood pressure decreased from 112 (108-117) to 108 (103-114) mmHg (P < .01). Cyclic GMP increased significantly from 9.2 (6.2-12.3) to 17.4 (12.3-22.6) nmol/L (P < .01). Subjects exhibiting a substantial increase in uteroplacental blood flow index (25% or more) demonstrated a significantly greater cGMP response (P < .01) than those who did not (6% or less increase). CONCLUSION: A tendency to an increased uteroplacental blood flow index combined with minor blood pressure reduction after ANP infusion suggest the possibility of uteroplacental vasodilatation.

Endopeptidase 24.11 inhibition by SCH 42495 in essential hypertension.

The detailed integrated renal, hormonal, and hemodynamic effects of acute (first dose) and established (4 days) inhibition of endopeptidase 24.11 by SCH 42495 (200 mg, every 12 hours) were documented in eight patients with essential hypertension in a double-blind, balanced random-order, crossover study. SCH 42495 suppressed plasma endopeptidase activity (> 90%, P < .001) for the duration of the dosing period. Initially, plasma atrial natriuretic factor levels increased markedly (+123%, P < .01) and remained elevated, although to a lesser extent (+34%, P < .01), with established enzyme inhibition. Cyclic guanosine monophosphate in both plasma and urine remained elevated throughout the treatment period. Significant augmentation of sodium excretion in excess of placebo values (96 +/- 27 mmol sodium, P < .001) was established in the initial 24 hours of dosing but later became attenuated, with a mild antinatriuresis (P < .01) in the latter 3 days of treatment. Blood pressure, heart rate, the renin-angiotensin-aldosterone system, and plasma norepinephrine levels were all initially (first dose) unchanged. With established enzyme inhibition (day 4), however, blood pressure was significantly lower (mean 24-hour values, 9.3 +/- 3/-3.8 +/- 1 mm Hg, P < .05 for both systolic and diastolic pressures) than matched placebo values, whereas heart rate was higher (2.7 +/- 1 beats per minute, P < .01). Mean 24-hour values of plasma renin activity (+33%, P < .05), aldosterone (+36%, P < .05), and norepinephrine (+40%, P < .001) were all clearly increased above placebo values with established enzyme inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclic GMP levels in the rat brain and plasma during clinical death and after resuscitation.

Changes of cGMP content in the rat brain and plasma have been evaluated by means of the radioimmunologic method after 5-min clinical death and up to 2 hours after resuscitation. Ischemia produced a decrease of cGMP in the brain, however, at the 15th min after resuscitation a reversible significant rise of nucleotide concentration was noted. In plasma at the end of ischemia and in the postischemic period a significant decrease of cGMP level was observed. The mechanisms of cGMP regulation in the central nervous system and the significance of the obtained results are discussed.

Studies with guanosine-5'-monophosphate (GMP): new method for measurement and effects on blood pressure.

A practical new method for measuring serum guanosine-5'-monophosphate (GMP) was developed and three experiments were performed using this method. In the first, we observed the reduction of blood pressure (BP) and the elevation of serum GMP level persisting for 3 hours in male Japanese White Rabbits administered GMP, 50 mg/kg given as a single oral dose. In the second, 6-week-old male spontaneously hypertensive rats (SHR) received GMP, 200 mg/kg/day, orally for 8 weeks. The systolic BP in the GMP-treated rats, which averaged 170.2 mmHg, was lower than that of the control group, which averaged 188.0 mmHg. Arteriosclerotic findings were milder in the GMP-treated SHR as compared to the control. In the third experiment, the serum GMP level was measured in humans. We observed a significant negative correlation between the serum GMP concentration and systolic or diastolic BP. In conclusion, GMP reduced the BP in experimental animals, suggesting that it may be useful as an antihypertensive agent.

Diurnal change in plasma natriuretic factor and arginine vasopressin in young jersey calves.

Diurnal changes in plasma ANF and AVP levels were investigated in four calves under standardized conditions. Both levels in plasma were measured at hourly intervals for 24 h along with arterial blood pressure, blood haematocrit, plasma cGMP, sodium, potassium, osmolality, proteins and albumin. Plasma ANF exhibited a first peak at mid-day while plasma AVP was low and a second peak at evening while plasma AVP was high. Changes in plasma cGMP correlated with variations in plasma ANF. feeding and/or plasma volume elevation probably accounted for both peaks in plasma ANF and the low mid-day level of plasma AVP, but the rise in plasma AVP at evening may represent a diurnal rhythm.