Plasma cGMP Levels Research Articles

Plasma Cyclic Nucleotide Levels in Acute Leukemia Patients

Abstract 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.

Plasma atrial natriuretic peptide levels in children with cardiac diseases: correlation with cGMP levels and haemodynamic parameters.

In children with various forms of cardiac diseases (aged 2 months to 16 years) significantly higher plasma atrial natriuretic peptide (ANP; range 36-680, median 247 pg/ml) and cyclic 3'5'-guanosine monophosphate (cGMP; range 0.2-46, median 8.2 pmol/ml) levels were found than in control children (p less than 0.0001). In control children (aged 4 months to 17 years) plasma ANP and cGMP levels were measured in the range of 2.4-98 pg/ml and of 0.2-2.8 pmol/ml, respectively. There was a linear correlation between the two parameters in children with cardiac diseases (r = 0.62, p less than 0.01). Children with elevated mean right atrial pressure (i.e., greater than 6 mm Hg) showed significantly higher plasma ANP levels than children with normal atrial pressure (p less than 0.01). However, there was only a weak linear correlation between mean right atrial pressure and plasma ANP levels (r = 0.48, p less than 0.01). Plasma ANP levels from right atrium, pulmonary artery, left atrium and left ventricle were significantly higher than those from vena cava (p less than 0.05). Analysis of ANP-like immunoreactive material by high performance liquid chromatography suggested that alpha-ANP is the major form of circulating ANP in blood of children with cardiac diseases.

Plasma levels of cyclic nucleotides are elevated in atopic eczema.

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.

PLASMA ATRIAL-NATRIURETIC PEPTIDE (ANP) AND cGMP LEVELS IN CHILDREN, cGMP AS MARKER FOR THE EFFECT OF ANP ON TARGET TISSUES

The apparent inability of elevated atrial-natriuretic peptide (ANP) levels to cause natriuresis and diuresis in children with heart failure may be related to a reduced response of target organs to ANP. The cellular effects of ANP seem to be mediated by cGMP as the second messenger of ANP. Simultaneous measurement of ANP and cGMP has been shown to be a useful tool to study the cellular response to ANP. Therefore, plasma ANP and cGMP levels were measured by radioimmonoassay in 168 healthy children and in 47 children with congenital cardiac diseases.In healthy children ANP and cGMP plasma levels were measured in the range of 5-109 pg/ml (mean 45.5) and 0.2-2.8 pmol/ml (mean 1.3) respectively. In children with cardiac diseases significantly higher ANP (range 30-980, mean 280 pg/ml) and cGMP levels (range 0.2-6.0, mean 2.8 pmol/ml) were determined. There was a highly significant correlation between the two in children with cardiac diseases (p<0.001). Furthermore, a significant correlation was found between right atrial pressure and ANP levels (p<0.01) suggesting that atrial stretch is a stimulus for ANP release.The positive correlation between ANP and cGMP levels disagrees with the hypothesis that the cellular response to ANP is diminished in children with cardiac diseases.

Influence of metabolic control of insulin-dependent diabetes on plasma nucleotide levels (cAMP, cGMP) during bicycle exercise.

Plasma concentrations of cyclic nucleotides (cAMP, cGMP) were measured before and during bicycle exercise in 8 well-controlled (mean pre-exercise blood glucose 5.3 mmol/l; HbA1 8.6%) and 8 moderately controlled (mean pre-exercise blood glucose 12.2 mmol/l; HbA1 10.8%) patients aged 18-32 years with insulin-dependent diabetes mellitus (IDDM) and in a group of non-diabetic control subjects matched for age and sex. Pre-exercise plasma cAMP concentrations and the rise with exercise were similar in all study groups. Significantly lower resting cGMP levels were found in well-controlled IDDM patients (3.5 +/- 0.3 pmol/ml, mean +/- SEM) compared to controls (5.6 +/- 1.1 pmol/ml; p less than 0.05) and moderately controlled IDDM patients (5.6 +/- 1.0 pmol/ml; p less than 0.05). By contrast, plasma cGMP levels increased during exercise in the diabetics but not in the controls. These findings indicate a significant difference in responses of plasma cGMP to exercise between IDDM patients and controls.

Increased cyclic GMP in atrial fibrillation

To investigate the role of cyclic nucleotides in the genesis and/or the persistence of atrial fibrillation (AF), plasma levels of cyclic GMP (c-GMP) and cyclic AMP (c-AMP) were measured in dogs with electrically induced AF, and in dogs subjected to high frequency (230 or 410/min) atrial pacing. The atrial fibrillation threshold (AFT) after intravenous administration of a dibutyryl derivative of c-GMP (Dbc-GMP), and the effect of atropine (0.1 mg/kg) on AFT were determined. Plasma levels of c-GMP and c-AMP were also measured in patients during paroxysmal AF and sinus rhythm. The c-GMP level increased significantly 15 min after the onset of artificial AF, and gradually increased during the course of the experiment. The c-GMP level began to increase significantly 15 min after the initiation of pacing at the higher rate (410/min) but not at the lower rate, compared to the prepacing value. The c-GMP level continued to rise until the end of pacing in the animals paced at 410/min. Although Dbc-GMP induced a dose-dependent decrease in AFT, atropine did not prevent the decrease in AFT by Dbc-GMP. In contrast, c-AMP levels were not significantly affected in any of these experiments. Clinical assessment revealed that patients had almost four times higher c-GMP level during AF than during sinus rhythm, though c-AMP levels in these patients did not change significantly during the attack of AF. These results suggest that the increase in c-GMP plays an important role in the maintenance and/or the genesis of AF.

Concomitant increase in plasma atrial natriuretic peptide and cyclic GMP during volume loading.

To investigate the effects of fluid expansion on endogenous atrial natriuretic peptide (ANP) and cyclic 3',5'-guanosine monophosphate (cGMP), four male volunteers were studied before, during and after intravasal volume loading. Volume expansion was performed by intravenous infusion of 2,000 ml isotonic saline solution within 30 min. Mean plasma ANP levels increased 2.5-fold from 31.2 pg/ml to 81.7 pg/ml 40 min after the start of infusion. Plasma cGMP levels paralleled the rise in ANP, showing a mean cGMP increment from 2.7 pmol/ml to a maximum of 8.2 pmol/ml. Both ANP and cGMP levels were back to basal levels 120 min after termination of the infusion. Stimulation of endogenous ANP release by volume loading suggests that ANP is involved in the regulation of fluid homeostasis in man. The parallel rise in plasma cGMP levels supports the idea that cGMP is a mediator for the effects of ANP.

The effects of amrinone does not act through a cyclic nucleotide mechanism amrinone does not act through a cyclic nucleotide mechanism in platelet rich plasma

The purpose of the present study was to investigate in human platelet rich plasma the effects of amrinone, a cardiotonic agent, on platelet aggregation induced by ADP, arachidonic acid (AA), collagen, prostaglandin H 2 (PGH 2), and U46619, a substance reported to mimic the actions of thromboxane A 2. Amrinone inhibited aggregatory responses to all substances studied in a dose-related fashion and this is the first report demonstrating the inhibitory actions of amrinone on platelet aggregation induced by PGH 2. Although amrinone inhibited aggregatory responses to ADP, collagen, PGH 2, and U46619 at similar doses, markedly lower doses of amrinone were necessary to inhibit aggregatory responses to AA. Furthermore, amrinone did not alter CAMP and cGMP levels in human platelet rich plasma. The present data demonstrate that amrinone inhibits human platelet aggregation induced by a variety of substances and independent of changes in cAMP and cGMP levels. Furthermore, the present data suggest that amrinone selectively inhibits aggregatory responses to arachidonic acid prior to the formation of thromboxane A 2.

The increase of cGMP by atrial natriuretic factor correlates with the distribution of particulate guanylate cyclase

We have demonstrated previously that atrial natriuretic factor (ANF) augments urinary, plasma and kidney cGMP levels but has no significant effect upon cAMP. Using cGMP as a marker, we searched for specific target sites involved in the action of ANF in the dog kidney, and observed no changeof cGMP in the proximal tubules, a 2-fold increase over basal levels in the thick loop of Henle and a 3-fold elevation in the collecting duct. The most striking action on cGMP occurred in the glomeruli with a rise of up to 50-fold being evident at 1–2 min. after the addition of ANF. The results obtained in the absence or presence of a phosphodiesterase inhibitor support the notion that the effects of ANF were exerted at the level of guanylate cyclase stimulation rather than cGMP phosphodiesterase inhibition. The action of sodium nitroprusside (SNP), a direct stimulator of soluble guanylate cyclase, differed from that of ANF. The ability of the factor to enhance cGMP levels was correlated with the distribution of particulate guanylate cyclase. This study identifies the glomeruli and the distal part of the nephron as specific targets of ANF and implicates particulate guanylate cyclase as the enzyme targetted for the expression of its action.

Plasma and urine cyclic nucleotide levels in patients with neoplastic diseases.

Plasma and/or urine cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) levels were measured in 67 normal subjects, 55 patients with nonneoplastic diseases, and 324 patients with ten different types of cancer. There were no significant differences in plasma and urine cyclic nucleotide levels between normal subjects and patients with non-neoplastic diseases. In untreated cancer patients, plasma and urine cAMP levels were similar to those of normal subjects, whereas plasma and urine cGMP levels were markedly higher. This pattern was common to all the cancer groups studied. Chemotherapy per se did not seem to influence cyclic nucleotide levels in cancer patients. However, plasma and urine cGMP levels normalized in all patients who attained complete remission. Moreover, in acute leukemia patients who relapsed, plasma cGMP levels increased significantly with respect to the complete remission values, thus suggesting that this parameter may be useful in monitoring the response of cancer patients to treatment.

Effect of native and synthetic atrial natriuretic factor on cyclic GMP

Mammalian atrial cardiocyte granules contain a potent natriuretic and diuretic peptide. Since cGMP appears to be involved in the modulation of cholinergic and toxin-induced sodium transport, we examined the effect of atrial natriuretic factor (ANF) on this nucleotide. Atrial but not ventricular extracts elicited approximately a 28-fold increase of urinary cGMP excretion parallel to the natriuresis and diuresis. The atrial extracts also elevated cGMP levels in kidney slices and primary cultures of renal tubular cells. The effect of ANF on cGMP appeared to be specific since antibodies which were capable of inhibiting the ANF-induced diuresis also suppressed cGMP excretion. Furthermore, during the course of ANF purification, the ANF-induced increase of cGMP production by kidney cells paralleled the heightened specific natriuretic activity of the atrial factor. A synthetic peptide (8–33)-ANF similarly increased urinary plasma and kidney tubular cGMP levels. The exact mechanism of action of ANF on cGMP remains to be elucidated, but indirect inhibition of cGMP phosphodiesterase appears to participate in its effect.

Plasma and urine cyclic nucleotide levels in patients with acute and chronic leukemia

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.

Plasma and Urine Cyclic Nucleotide Levels in Patients With Acute and Chronic Leukemia

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.

Hyperkalemia, hyperglycemia, and plasma levels of cyclic AMP and cyclic GMP induced by portal vein injection of cyclic nucleotides and their butyryl derivatives into dogs.

The levels of serum potassium, blood glucose, and plasma adenosine cyclic 3':5'-monophosphate (cAMP) and guanosine cyclic 3':5'-monophosphate (cGMP) were studied after the portal vein injection of cyclic nucleotides and their derivatives, (cAMP, cGMP, N6, O2'-dibutyryl adenosine 3':5'-monophosphate (DBcAMP), N6-monobutyryl adenosine cyclic 3':5'-monophosphate (NMBcAMP), and O2'-monobutyryl adenosine cyclic 3':5'-monophosphate (OMBcAMP), into dogs. Dose-related hyperglycemic responses were observed after the injection of DBcAMP (1-8 mg/kg). Transient and prominent hyperkalemia and hyperglycemia were caused by the injection of DBcAMP, NMBcAMP, and OMBcAMP (4 mg/kg). The hyperkalemic response was highest with NMBcAMP (1.22 mequiv./L), followed by OMBcAMP (0.64), DBcAMP (0.54), cGMP (0.47), and cAMP (0.41), whereas the hyperglycemic response was highest with NMBcAMP (146 mg/100 mL), followed by DBcAMP (93.6), OMBcAMP (77.1), and cAMP (56.0), and there was only a slight change with cGMP (28.4) compared with the control. The plasma level of cAMP was maximal with DBcAMP (1.92 nmol/mL), followed by NMBcAMP (1.28) and OMBcAMP (0.76), whereas the plasma levels of cGMP showed no evident change, except that caused by DBcAMP (0.27). Of the cyclic nucleotides tested, NMBcAMP was found to be most potent in causing both hyperkalemia and hyperglycemia. Based on these results, possible correlations between hyperkalemia, hyperglycemia, and plasma levels of cAMP and cGMP are discussed.

Plasma guanosine 3',5'-monophosphate responses to methacholine and epinephrine in humans.

The im injection of methacholine into healthy volunteers caused a dose-dependent increase in plasma cGMP levels; this increase was antagonized by atropine, while it was not affected by phentolamine or propranolol. The im injection of epinephrine caused a small but significant rise in plasma cGMP concentrations; this rise was completely blocked by the simultaneous injection of phentolamine, while it was not affected by atropine or propranolol. These data show that changes in the plasma concentration of cGMP may reflect not only cholinergic but also alpha-adrenergic functions in humans.

Changes in the cyclic nucleotides (cCMP, cAMP, and cGMP) of rat thyroid induced by prolonged administration of LATS and TSH.

Abstract. It has recently been suggested that cyclic CMP (cCMP) has a physiological role in cell function. In this study, we examined the content of cCMP, cAMP &amp; cGMP and each hydrolyzing enzyme (phosphodiesterase, (PDE)) in rat thyroid during administration of LATS and TSH for 7 days (Exp. 1), and also in the thyroid of rats given methylthiouracil (MTU) for 4 months (Exp. 2). Each cyclic nucleotide was determined by RIA, and PDE activity was determined according to Kuo's method. Exp. 1: the wet weight of thyroid in the LATS and TSH group increased 3 and 2 times respectively, from the control. Both the LATS and TSH groups showed increased plasma T4 and T3 levels. In both groups the cAMP content per wet weight of thyroid was increased slightly, but cGMP content did not change. In contrast, the cCMP content decreased markedly. Both the LATS and TSH groups showed an increase of cAMP-PDE activity in the thyroid, and no change of cGMP-PDE, while cCMP-PDE decreased markedly. In all groups levels of these 3 cyclic nucleotides and PDE activities in plasma were unaffected. Exp. 2: in the MTU group the thyroid weight increased 4.5 times over the control, and plasma T4 and T3 levels were extremely low. The cAMP content in whole thyroid gland and also per mg wet weight was increased markedly, but cGMP content did not change. cCMP content decreased significantly. The plasma cAMP level increased slightly, but the plasma cGMP and cCMP levels did not change. The increase of cAMP content and cAMP-PDE activity, and conversely the decrease of cCMP content and cCMP-PDE in the thyroid by LATS and TSH stimulation, suggest that cCMP may play a physiologically important role within the cells, similar to cAMP in the mechanism of hormone action.

Plasma cyclic nucleotide responses to insulin-induced hypoglycaemia and methacholine in patients with hyperthyroidism.

The effect of insulin-induced hypoglycaemia and methacholine on plasma cAMP and cGMP levels was studied in normal volunteers, hyperthyroid and hypothyroid patients. A significant positive correlation existed between the maximal increase in plasma cAMP and the maximal decrease in plasma glucose in normals during insulin-induced hypoglycaemia. Therefore, the plasma cAMP response is considered to be dependent on the degree of hypoglycaemia, rather than the dose of insulin. The cAMP response to hypoglycaemia was significantly higher in hyperthyroid patient, and was lower in patients with hypothyroidism than in normals. The cAMP response of the hyperthyroid patients was normalized when their hyperthyroidism was controlled after 3 months of treatment. The plasma level of cGMP was slightly elevated during hypoglycaemia, but there was no significant difference between controls and hyperthyroid patients. The cGMP response to methacholine, which is probably mediated by cholinergic receptors, was significantly potentiated in hyperthyroid patients. The cAMP response, which is presumably dependent on endogenous catecholamines secreted during methacholine-induced hypotension, was also enhanced in hyperthyroid patients. It is likely that beta-adrenergic receptor responses and cholinergic receptor responses are both enhanced in hyperthyroidism.

Plasma levels of cyclic nucleotides in patients with essential hypertension.

We studied plasma levels of cyclic nucleotides and their responses to submaximal exercise as an endogenous adrenergic stimulation in normal subjects, untreated and treated patients with essential hypertension to assess the roles of various hormones and the autonomic nervous system in essential hypertension. Plasma c-AMP level was significantly higher in untreated, diuretic-treated patients and those treated with propranolol than in normal subjects, but plasma c-GMP level was comparable in normal subjects and untreated patients. Plasma c-AMP decreased significantly, whereas plasma c-GMP increase significantly, after chronic propranolol therapy. Plasma c-AMP increased significantly after submaximal exercise in normal subjects, untreated patients and those treated with propranolol, but plasma c-GMP increased significantly only in normal subjects. The increase in plasma c-AMP was significantly higher in untreated patients than in normal subjects and patients treated with propranolol. Moreover, the percent increase in plasma c-AMP was significantly higher in untreated patients than in those treated with propranolol. Therefore, it is suggested that the sympathetic nervous system may be hyperactive, and that a hyperreactivity of the beta-adrenergic receptors may play an important role in essential hypertension.

Cyclic Nucleotides in Progressive Muscular Dystrophy

The authors radioimmunoassayed cyclic nucleotide concentrations in plasma and biopsied muscles of muscular dystrophy and muscles of chicken embryo. c-AMP concentrations in plasma were significantly lowered in Duchenne-type muscular dystrophy and this lowered degree was correlated with the stage of progression. Plasma c-GMP levels were also depressed in Duchenne-type dystrophy. In biopsied muscles, c-AMP concentrations per milligram of non-collagen protein were within normal limits. Therefore, the decrease of plasma c-AMP concentrations might be an expression of total metabolic changes rather than a pathologic process of the muscle itself. As for the dystrophic chicken embryo, both c-AMP and GMP concentrations were decreasing in the pectoral muscles in parallel with the advancement of hatching stages.

Direct Measurement of cGMP in Blood Plasma and Urine by Radioimmunoassay

Antisera, raised against 2'-O-succinyl-cGMP conjugated to ovalbumin or kehole limpet haemocyanin, have been used to develop radioimmunoassays for the direct determination of urine and plasma cGMP levels. Details of these assays are presented, together with evidence for their validity.