The nitric oxide donor SIN-1 is a potent inhibitor of plasminogen activator inhibitor release from stimulated platelets.
Explore the source record for details and available documents.
Blood Platelets↗
Biomedical subjects
R Gerzer
Publications and source records attributed to R Gerzer.
Functional modulation of ANF-sensitive particulate guanylate cyclase by redox mechanisms.
We examined the effects of sulfhydryl-reactive redox agents and of the apparent oxidation-reduction (redox) potential of the assay medium on enzyme activity and atrial natriuretic factor (ANF) binding properties of particular guanylate cyclase from bovine adrenal cortex. Redox potential was varied by addition of redox-reactive agents and quantified by electrochemical measurement. The modification of free SH groups by thiol-reactive agents had only a minor effect on ANF binding or on the extent of ANF-dependent enzyme stimulation whereas free thiol groups were essential for basal enzyme activity of ANF-sensitive particulate guanylate cyclase. Basal and ANF-stimulated particulate guanylate cyclase activity was modulated by exposure to different redox potential states. This modulation was different for the substrates Mg.GTP and Mn.GTP. The apparent redox potential had no influence on the extent of guanylate cyclase activation by ANF. Our results suggest that critical free thiol groups, which are sensitive to thiol-reactive redox agents, are involved in the catalytic, but not in the receptor function of ANF-sensitive particulate guanylate cyclase. These thiol groups could be the structural basis for the effects of redox events which modulate basal enzyme activity, but not activation by ANF.
Adrenal Cortex↗
Autoradiographic localization of [125I]-C-ANP compared to [125I]-ANP in rat tissue.
Whole-body autoradiography demonstrated the different distribution of [125I]-C-ANP and [125I]-ANP to rat tissues. Highest enrichment of radioactivity of both labelled peptides was found in the kidney. In some organs we found remarkable differences between [125I]-ANP and [125I]-C-ANP. In the kidney cortex, especially in the glomeruli, as well as in the endocardium, the zona glomerulosa and the medulla of the adrenal gland, where high levels of radioactivity after [125I]-ANP administration were detected, no or just few radioactivity was found after administration of [125I]-C-ANP. On the other hand in the kidney papilla and the outer subcortical medulla, characteristic blackening was found after [125I]-C-ANP administration. Those differences might be important for the understanding of pharmacological actions of ANP analogues.
Adrenal Glands↗
Preparative polyacrylamide gel electrophoresis apparatus for purification of guanylyl cyclase.
Explore the source record for details and available documents.
Animals↗
Purification of heme-containing soluble guanylyl cyclase.
Explore the source record for details and available documents.
Animals↗
Effects of saline loading during head down tilt on ANP and cyclic GMP levels and on urinary fluid excretion.
In the present study the renal and humoral effects of acute saline infusions were investigated in six healthy male volunteers before, during and after a ten day period of -6 degrees head-down-tilt (HDT). During the whole 23-day study period the subjects received a standardized diet including 40 ml water and 125 mg NaCl per kg body weight per day. After the infusion of 0.9% saline (22 ml/kg within 20 minutes) plasma atrial natriuretic peptide (ANP) levels were only slightly increased (not significant) at the end of the infusion, while plasma cyclic GMP levels were significantly increased by about 40% (p<0.05) one hour later. No difference was observed in the plasma ANP and cyclic GMP changes between the pre-HDT, the HDT and the post-HDT infusion experiment. Urine flow, sodium excretion and urinary cyclic GMP excretion were significantly increased (p<0.05 and below) by 100 to 300% during the second and third hour after each saline infusion. However, during these short-term periods only 20% of the infused water and less than 20% of the infused sodium were excreted. Furthermore, a significantly increased volume, sodium and cyclic GMP excretion was observed for over 48 hours after each fluid load experiment. These data suggest that HDT does not induce major alterations in the regulation of an acute saline infusion and plasma ANP does not play a major role in the diuretic/natriuretic effects of volume loading.
Adult↗
Comparison of anti-platelet properties of molsidomine, isosorbide-5-mononitrate and placebo in healthy volunteers.
The purpose of the present work was to investigate the ex vivo platelet-inhibiting properties of the nitric oxide-containing vasodilator, molsidomine, and the organic nitrate, isosorbide-5-mononitrate, in comparison with placebo. Ex vivo platelet aggregation in 11 healthy volunteers was measured before, as well as 30 and 60 min after, the intake of either 4 mg molsidomine, 20 mg isosorbide-5-mononitrate (ISMN) or placebo in a randomized double-blind fashion. The release of thromboxane was also determined. Threshold doses of platelet-activating factor (PAF) to induce irreversible aggregation were significantly increased by 100 and 120% 30 and 60 min after molsidomine. Slopes of aggregation curves (aggregation induced with 50 and 200 nM PAF) were significantly reduced after molsidomine (P less than 0.01). Small platelet-inhibiting effects were also observed after ISMN and after placebo intake. The release of thromboxane was not influenced when platelets were maximally stimulated either during clotting of whole blood or during aggregation of platelet-rich plasma with a high dose of PAF. Thromboxane release with a low dose of PAF was reduced 30 and 60 min after drug intake, independent of whether molsidomine, ISMN or placebo was applied. The data indicate that the usual clinical doses of molsidomine, but not of ISMN inhibit platelet aggregation in healthy man.
Adult↗
Urodilatin, a kidney-derived natriuretic factor, is excreted with a circadian rhythm and is stimulated by saline infusion in man.
Urodilatin is a recently described, presumably kidney-derived member of the atrial natriuretic peptide family. The first data on a physiological role for urodilatin in the regulation of sodium homeostasis in humans is presented in this work. Urinary urodilatin excretion during a 9-day study in healthy volunteers paralleled the circadian rhythm in urinary sodium excretion. Furthermore, urodilatin and sodium excretion were slightly increased during the first 3 h after an acute isotonic saline infusion and about three-fold elevated during 14 h postinfusion; both parameters remained closely correlated up to 28 h postinfusion. These data suggest that urodilatin is involved in the circadian regulation of sodium excretion and is a physiological regulator of long-term sodium excretion after an acute saline infusion.
Adult↗
Acute effects of beta-adrenergic stimulation with dobutamine on the plasma levels of atrial natriuretic peptide and cyclic guanosine monophosphate in patients with chronic heart failure.
In eight patients (63 +/- 7.9 years) with angiographically documented dilated cardiomyopathy, we studied the acute effects of a beta-adrenergic stimulation with dobutamine on the plasma levels of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP). For this purpose, a four-point dose-response curve was prepared for dobutamine starting with an initial dose of 2.5 micrograms kg-1 min-1, which was increased by 2.5 micrograms kg-1 min-1 at a time up to altogether 10 micrograms kg-1 min-1. Each stage lasted 15 min. ANP and cGMP were determined from the mixed venous blood before the start (t0), at 5 micrograms kg-1 min-1 after 30 min (t1), at 10 micrograms kg-1 min-1 after 60 min (t2) and after subsidence of the drug effect after 90 min (t3). ANP dropped from 380 +/- 151 pg ml-1 (normal range up to 55 pg ml-1) by 38% to 235 +/- 90 pg ml-1 after 30 min and by another 17% to 171 +/- 45 pg ml-1 after 60 min. After the effect of dobutamine had subsided, an increase by 41% to 325 +/- 139 was reached. There was a parallel drop of the mean cGMP level from 5.4 +/- 1.4 pmol.ml-1 by 28% to 3.89 +/- 1.4 pmol.ml-1 (30 min) and by another 14% to 3.2 +/- 0.7 pmol.ml-1 (60 min). After 90 min it was 18% below the initial value, being 4.4 +/- 1.3 pmol.ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Plasma hormones in patients with chronic heart failure before and early after orthotopic heart transplantation.
The aim of this prospective study was to investigate both vasoconstricting and vasodilating plasma hormones and plasma factors regulating the circulatory homeostasis in patients with endstage congestive heart failure before and early after orthotopic heart transplantation and to evaluate factors which may influence their regulation. 19 patients with endstage congestive heart failure were analyzed serially before and 3-4 weeks after orthotopic heart transplantation. A significant decrease in plasma concentrations of noradrenaline (457 +/- 202 vs. 204 +/- 88 pg/ml; p less than 0.001), adrenaline (43 +/- 32 vs. 26 +/- 11 pg/ml), atrial natriuretic peptide (341 +/- 218 vs. 139 +/- 64 pg/ml; p less than 0.005), cyclic guanosine monophosphate (13.8 +/- 7.8 vs. 6.6 +/- 2.2 pmol/ml, p less than 0.05) and in plasma renin activity (16.6 +/- 13.0 vs. 2.0 +/- 2.4 ng AI/ml/h; p less than 0.01) was found after transplantation. The data indicate that the marked increase in plasma catecholamine concentrations and renin activity in endstage congestive heart failure is reversible as early as 3-4 weeks after heart transplantation. This is most likely the consequence of normalization of cardiac function. While elevation of atrial natriuretic peptide and cyclic guanosine monophosphate as well as increased vasoconstrictor activity in heart failure appear to be related to impaired ventricular function, the persistent moderate elevation of both vasodilating agents after transplantation may be compensatory to counteract cyclosporin-induced arterial hypertension after heart transplantation.
Adult↗
[Thrombocyte aggregation and fibrinolysis in healthy probands treated with molsidomine, isosorbide-5-mononitrate and placebo].
Twelve healthy volunteers received either a single oral dose of molsidomine (4 mg), isosorbide-5-mononitrate (ISMN, 20 mg), or placebo in a randomized, double-blind fashion. Blood was drawn prior to, as well as 30 and 60 min after intake of the respective drug. Platelet aggregation and the plasma levels/activity of plasminogen activator (tPA) and its inhibitor (PAI-1) were determined. In contrast to ISMN and placebo, molsidomine provoked a significant reduction in platelet aggregability. No alteration in plasma tPA concentrations was observed independent of whether molsidomine, ISMN, or placebo was applied. However, plasma PAI-1 activity was considerably reduced following molsidomine, but not altered following ISMN or placebo. We conclude that a single oral dose of molsidomine, but not of ISMN inhibits platelet aggregation and increases the fibrinolytic potential in healthy volunteers.
Adult↗
[Effect of molsidomine on thrombocyte aggregation in unstable angina pectoris after parenteral administration of nitroglycerin].
In the present study, we took whole blood from 12 patients treated with heparin, acetylsalicylic acid, and nitroglycerin i.v., to measure the aggregability of platelets after acute and prolonged i.v. application of nitroglycerin and after oral application of molsidomine. Aggregation was induced by platelet-activating-factor (PAF). As a measure for platelet aggregability, we determined the PAF-concentration needed to induce irreversible aggregation (threshold dose) and the maximum slope of the aggregation curve with 50 nM PAF. At the beginning, 1 h after the onset of nitroglycerin infusion (3 mg/h), 24 h and 1 h after increasing the nitroglycerin dose (5 mg/h), neither the maximum slope nor the threshold dose for PAF-induced aggregation differed significantly. However, after additional oral application of molsidomine the maximum slope of the aggregation curve decreased significantly. These data indicate that molsidomine decreases the aggregability of platelets in patients, even after pretreatment with heparin, acetylsalicylic acid, and nitroglycerin.
Angina, Unstable↗
[Platelet aggregation with SIN 1: comparison with isosorbide-5-mononitrate and acetylsalicylic acid].
SIN 1, the bioactive metabolite of molsidomine, not only appears to lack the problem of inducing nitrate tolerance, but also exerts antiaggregatory and fibrinolytic properties. These effects, which either are not or only in part shared by the drug isosorbide-5-mononitrate, might be beneficial in the prevention of thromboembolic complications in cardiovascular disease. In contrast to the effects of acetylsalicylic acid, SIN 1 already inhibits aggregation during the first phase of aggregation, and it inhibits aggregations induced by agonists that are not or only marginally influenced by acetylsalicylic acid (such as the aggregation induced by platelet activating factor). Thus, the antiaggregatory effects of molsidomine cannot replace the effects of acetylsalicylic acid, while a combination of both drugs might be of benefit in the treatment of patients with cardiovascular disease.
Aspirin↗
Cyclic nucleotides differentially regulate the synthesis of tumour necrosis factor-alpha and interleukin-1 beta by human mononuclear cells.
Recent reports have shown that phosphodiesterase (PDE) inhibitors suppress production of tumour necrosis factor-alpha (TNF-alpha) in mouse macrophages. In the present study we show that theophylline, pentoxifylline and 3-isobutyl-1-methylxanthine markedly suppress the lipopolysaccharide (LPS)-induced synthesis of TNF-alpha (also) in human mononuclear cells. This effect is selective for TNF-alpha since up to several-fold higher concentrations of these PDE inhibitors do not affect production of interleukin-1 beta (IL-1 beta) in the same system. The observed effect of PDE inhibitors appears to be mediated by accumulation of cAMP since (i) addition of PDE inhibitors increases cAMP while cGMP levels are only marginally elevated; (ii) raising cAMP by another mechanism (enhanced formation induced by prostaglandin E2; PGE2) leads to a similar suppression of TNF-alpha production; and (iii) raising cGMP by activating the soluble guanylate cyclase by 3-morpholinosydnonimine (SIN 1) does not inhibit TNF-alpha synthesis. However, SIN 1 suppressed the synthesis of IL-1 beta. Selective suppression of TNF-alpha synthesis by PDE inhibitors may contribute to their beneficial effects in animal models of septic shock or lung injury and may thus have clinical implications.
Cell Line↗
Kinetic characterization of atrial natriuretic factor-sensitive particulate guanylate cyclase.
The present investigation describes kinetic characteristics of membrane-bound and Triton X-100-solubilized atrial natriuretic factor (ANF)-sensitive guanylate cyclase from bovine adrenal cortex. The kinetic analysis of both enzyme forms suggests that in the presence of manganese, ANF induces or stabilizes at least two apparent GTP*Mn2(+)- and in addition two Mn2(+)-binding sites. Addition of the natriuretic drug amiloride favors this state. ATP increases the vmax in the presence of ANF for GTP*Mg2+, but not for GTP*Mn2+ as a substrate. With GTP*Mg2+, amiloride has no effect on basal or ANF-stimulated activity, but slightly reduces the effect of ATP. Under all conditions tested, the enzyme follows regular Michaelis-Menten kinetics in the presence of Mg2+ and exhibits positive cooperativity with Mn2+. Positive cooperativity is also retained after Triton extraction. The results indicate that Triton extraction has no major influence on the kinetic properties of particulate guanylate cyclase when the extraction procedure is done carefully. The data also support the suggestion that multiple interactions of subunits might occur upon activation of the enzyme by ANF in the presence of Mn2+.
Adrenal Cortex↗
Effects of a small bolus dose of ANF in healthy volunteers and in patients with volume retaining disorders.
Thirty-seven patients with volume-retaining disorders (liver cirrhosis with ascites, n = 8; heart failure NYHA III-IV, n = 12; endstage renal failure, n = 17) and twelve healthy age-matched controls were given a small dose (33 micrograms) of hANF (human atrial natriuretic factor). We tested the resulting hemodynamic and renal effects as well as the effect on plasma cyclic GMP levels and compared them with the properties of platelet ANF receptors. The ANF injection evoked an increase in cyclic GMP plasma levels of 19.3 +/- 2.2 nM in healthy controls. This increase tended to be smaller in the cirrhosis group (15.5 +/- 3.3 nM) and in the heart failure group (16.8 +/- 2.3 nM) than in the dialysis group (20.5 +/- 2.5 nM). The invasion rates of cyclic GMP were comparable in all groups, but the evasion rates increased more in the heart failure and endstage renal failure groups (27.9 +/- 7.7 min and 26.1 +/- 3.4 min, respectively) than in the cirrhosis and control groups (14.9 +/- 1.9 min and 14.2 +/- 1.9 min, respectively). Patients with endstage renal failure and congestive heart failure showed a smaller decrease in diastolic blood pressure than controls and patients with liver cirrhosis. Renal actions of ANF were diminished in cirrhosis and heart failure patients. Binding capacities of platelet ANF receptors were higher in the control group (12.2 +/- 1.5 receptors/cell) than in the patient groups (cirrhosis, 7.8 +/- 1.2; endstage renal failure, 8.0 +/- 0.9; heart insufficiency, 8.0 +/- 1.0 receptors/cell), with no differences among the patient groups. Binding affinities were not significantly different. Correlation analysis showed that the relationship between the actions of ANF and the increases in plasma cyclic GMP levels is loose and cannot predict the hemodynamic or renal effects of exogenous ANF in a given patient. Although the behavior of plasma cyclic GMP levels fails to predict the responsiveness of the body to ANF in a given patient, it does reflect the differences between the patient groups and the control group. In contrast, we found no correlation between the properties of platelet ANF receptors and ANF action.
Adult↗
Effect of molsidomine on ex vivo platelet aggregation and plasma guanosine 3':5'-cyclic monophosphate levels in healthy volunteers.
To find out whether 3-morpholino-sydnonimine (SIN 1), the active metabolite of molsidomine, exerts its antiaggregatory effects not only in vitro but also in vivo, we tested ex vivo aggregation before and after intravenous application of molsidomine in healthy volunteers. We also measured plasma levels of guanosine 3':5'-cyclic monophosphate (cyclic GMP) as SIN 1, the bioactive metabolite of molsidomine, becomes effective via activation of soluble guanylate cyclase. In eight out of ten subjects molsidomine had an inhibitory effect on platelet aggregation and a higher threshold concentration of platelet-activating factor was required after molsidomine application to induce irreversible aggregation. Despite the effect on platelets, plasma cyclic GMP levels did not increase. These results suggest that the nitric oxide-containing SIN 1 inhibits platelet aggregation not only in vitro but also in vivo and that this property can be a beneficial effect in antianginal therapy.
Adult↗
Effect of prolonged physical exercise on fluid regulating hormones.
Sixteen well-trained young men performed a test marathon to study the behaviour of atrial natriuretic peptide (ANP) and its second messenger cyclic guanosine monophosphate (cGMP) in relation to changes in plasma volume (PV) and plasma proteins, arginine vasopressin (AVP), renin, aldosterone, potassium and sodium. Blood samples were drawn under standardized conditions before and immediately after the run, as well as 3 h and 31 h after the run. Directly after the run, a two-and-a-half fold increase of plasma ANP and a twofold increase of plasma cGMP level were found, whereas PV decreased significantly by 7.4%. At this time renin-, aldosterone- and AVP-secretion were much stimulated. Thirty-one hours after the run, PV was markedly greater (10%) than before the race, whereas plasma proteins had returned to pre-exercise values. The ANP and cGMP were not significantly altered compared to the pre-race values. We have concluded that ANP and the other volume-regulating hormones may play an important role during and immediately after prolonged physical exercise but not in the longer recovery period. It seems that an influx of plasma proteins into the vascular space is responsible for the increased PV at this time.
Adult↗