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J M Heim

Publications and source records attributed to J M Heim.

36 records · Page 2Linked to original sources
PubMed1990

[Inhibition of platelet aggregation by endothelium-derived relaxing factor-like agents].

In the last years, an inhibition of aggregation by organic nitrates or by similar drugs has been demonstrated by some authors, but has also been ruled out by other authors. The present work was thus performed to study a possible inhibition of platelet aggregation by the respective drugs in comparison with the molecular mechanism of action of these drugs, that is activation of soluble guanylate cyclase. We found that in vitro, organic nitrates activate soluble guanylate cyclase and inhibit platelet aggregation only in millimolar concentrations, while sodium nitroprusside and SIN-1, the active metabolite of molsidomine, influence these parameters in micromolar concentrations. This difference between the actions of the O-NO2-containing nitrates and the NO-containing compounds nitroprusside and SIN-1 is, however, not apparent ex vivo. Ex vivo, not only molsidomine, that is converted in the liver to SIN-1, but also isosorbide-5-mononitrate inhibited platelet aggregation. Thus, it appears that organic nitrates can in vivo release nitric oxide in a tissue other than platelets in amounts that are high enough to inhibit platelet aggregation. These studies suggest, that an antiaggregatory effect may participate in the clinical actions not only of drugs that directly resemble EDRF, such as SIN-1, but also by the organic nitrates. However, since nitrates cannot be activated directly by the platelets, it appears that also the antiaggregatory effects of nitrates, but not of molsidomine, underlie the mechanisms of tolerance development.

Animals↗
PubMed1989

Urodilatin and beta-ANF: binding properties and activation of particulate guanylate cyclase.

Urodilatin (ANF-(95-126] and beta-ANF, the antiparallel dimer of ANF-(99-126), are naturally occurring members of the ANF family. We studied their receptor binding properties in human platelets and Triton-solubilized membranes from bovine adrenal cortex and their ability to activate particulate guanylate cyclase in bovine adrenal cortex. In human platelets containing R2-receptors not coupled to particulate guanylate cyclase urodilatin binds with similar affinity as ANF-(99-126) (KD: 55 pM), whereas beta-ANF has an affinity lower than the truncated ANF-(103-123) (KD: 295 pM and 154 pM). Scatchard analysis indicates one binding site for urodilatin as well as for beta-ANF. In adrenal cortex containing predominantly R1-receptors coupled to particulate guanylate cyclase, urodilatin binds with a higher affinity (KD: 30 pM) than ANF-(99-126) (KD: 52 pM) and stimulates to a similar extent to ANF-(99-126) (about two fold at 1 muM), whereas beta-ANF has a smaller affinity (KD: 120 pM) and stimulates particulate guanylate cyclase to a lower extent than ANF-(99-126). The data from platelets and adrenal cortex show that beta-ANF has low binding affinities but stimulates particulate guanylate cyclase, whereas urodilatin appears to be a physiological R1-agonist.

Adrenal Glands↗
PubMed1989

Effects of a bolus dose of atrial natriuretic factor in young and elderly volunteers.

We assessed the haemodynamic and renal effects as well as the effects on plasma cGMP levels of a small i.v. dose (33 micrograms) of human atrial natriuretic factor (99-126; hANF) in two age groups of healthy volunteers. Binding properties of platelet ANF receptors were also measured. The elderly (four males, eight females, mean age 52.3 years) showed increased haemodynamic (decrease in blood pressure) and renal responses (diuresis, natriuresis, calciuresis) as well as greater increases in plasma cGMP levels and urinary cGMP excretion than the young subjects (four males, 12 females, mean age 26 years). Binding capacities and affinities of platelet ANF receptors were identical in both groups. These data indicate that the sensitivity to ANF increases with age and that this increased sensitivity is reflected in the reactivity of plasma cGMP levels but not in the properties of platelet ANF receptors. The data may be important for the therapeutic use of ANF, for the understanding of the physiological regulation of ANF action and may underline the necessity of using age-matched control subjects for clinical studies on the possible therapeutic effectiveness of ANF.

Adult↗
PubMed1989

Effects of clonidine and dihydralazine on atrial natriuretic factor and cGMP in humans.

The effects of a 1-wk treatment with clonidine (75 micrograms/day twice a day) and dihydralazine (25 mg/day twice a day) on base-line levels of plasma atrial natriuretic factor (ANF) and plasma and urinary guanosine 3',5'-cyclic monophosphate (cGMP) and their changes by acute saline infusion (2 liters) in eight normal subjects were evaluated. Basal ANF was decreased to 65% in the clonidine group compared with both the control and dihydralazine groups. Volume loading increased plasma ANF levels by 30-40% of base-line values in the control and the dihydralazine groups and by 15% in the clonidine group. Basal plasma and urinary cGMP levels were raised by 30 and 90% in the dihydralazine group compared with both other groups. Volume loading increased plasma cGMP levels by 40% in the control and clonidine-treated groups and by 25% in the dihydralazine-treated group. It is concluded that ANF may contribute to hemodynamic effects of clonidine but not to those of dihydralazine. Dihydralazine increases plasma and urinary cGMP, supposedly by direct activation of the soluble guanylate cyclase.

Adult↗
PubMed1989

Inhibition of platelet activating factor-induced platelet aggregation by molsidomine, SIN-1, and nitrates in vitro and ex vivo.

We compared in vitro the effects of molsidomine, its active metabolite SIN-1, sodium nitroprusside, and the organic nitrates nitroglycerin, isosorbide-5-mononitrate, and isosorbide-2,5-dinitrate on platelet aggregation induced by platelet activating factor and on the activity of soluble guanylate cyclase. In addition, the effects of molsidomine and of isosorbide-5-mononitrate on ex vivo platelet function were studied. In vitro, SIN-1 and sodium nitroprusside were about 100-fold more potent activators of platelet guanylate cyclase and inhibitors of platelet activating factor-induced aggregation than the other agents. In contrast, in ex vivo experiments, not only molsidomine but also isosorbide-5-mononitrate inhibited platelet activating factor-induced aggregation. These data indicate that molsidomine, SIN-1, and organic nitrates can in vivo, like endothelium-derived relaxing factor, inhibit platelet aggregation and exert antithrombotic properties, although nitrates apparently cannot be converted in platelets to active metabolites. Since the antiaggregatory properties are observed when platelet activating factor is used as an aggregant, and since platelet activating factor-induced aggregation is only weakly influenced by inhibitors of cyclo-oxygenase, this effect might be useful clinically.

Cyclic GMP↗
PubMed1989

[Hemodynamic and medicamentous modification of stimulated atrial natriuretic factor secretion].

The secretion of atrial natriuretic factor (ANF) and its adaptation to pharmacologic and hemodynamic interventions were investigated in 36 patients with sinus rhythm. To provoke standardized secretion of ANF all patients underwent two periods of rapid right ventricular pacing for 4 min with a 15 min interval. Immediately after the first pacing eight patients received 5 mg verapamil, 10 patients 5 mg atenolol and 10 patients 4 mg molsidomine intravenously. Eight patients remained untreated and served as controls. The amounts of atrial pressure increments due to pacing were identical (70% over basal pressure) in all patients. After molsidomine, but not after the other drugs, basal right atrial pressure was lowered. In controls the secretion of ANF due to the second stimulation was significantly (2.5-fold) larger than the secretion induced by the first stimulation. In patients receiving verapamil the secretion response after the second pacing was blunted. Atenolol did not affect the release of ANF. After molsidomine the upward regulation of the ANF secretion rate - seen in controls - was abolished. Thus, the myoendocrine cells are capable for a fast upward regulation of their ANF secretion rate after repeated stimuli. Verapamil directly blocks stimulated ANF secretion, whereas beta-blockade shows no effect. Molsidomine seems to impair enhanced ANF release by lowering basal atrial pressure.

Adult↗
PubMed1988

Direct comparison of the effects of nitroprusside, SIN 1, and various nitrates on platelet aggregation and soluble guanylate cyclase activity.

We have directly compared the effects of the nitrates isosorbide-5-mononitrate, nitroglycerin and isosorbide dinitrate and of the nitric oxide-containing sodium nitroprusside and 3-morpholino-sydnonimine (SIN 1) as well as of the bioinactive precursor of SIN 1, molsidomine, on platelet activating factor-induced platelet aggregation and activation of soluble guanylate cyclase. The effects of these agents on the aggregation and on soluble guanylate cyclase activity of human platelets were closely correlated. Whereas nitroprusside and SIN 1 were very potent inhibitors of aggregation and activators of soluble guanylate cyclase in micromolar concentrations, the other drugs were effective only at millimolar concentrations. Preincubation of platelets with cysteine did not or only slightly increase the ability of isosorbide-5'-mononitrate and isosorbide dinitrate to inhibit aggregation, but a clear increase was observed after preincubation with nitroglycerin. These data support the concept that cyclic GMP is the mediator of nitric oxide-induced inhibition of platelet aggregation and indicate that nitrates cannot directly inhibit aggregation or be converted to nitric oxide-containing agents by a specific mechanism in platelets. The data also suggest that SIN 1 and nitroprusside, but not or only to a certain degree the nitrates, can be considered as exogenous endothelium-derived relaxing factors.

Adult↗
PubMed1988

Amiloride increases the sensitivity of particulate guanylate cyclase to atrial natriuretic factor.

The natriuretic agent amiloride induces a shift of the dose-response curve of particulate guanylate cyclase to atrial natriuretic factor (ANF) to the left. The ANF concentration for half-maximal activation of guanylate cyclase is shifted from 20 to 3 nM in the presence of 100 microM amiloride. This effect is observed with GTP*Mn2+, but not with GTP*Mg2+ as substrate. Amiloride derivatives, which inhibit a specific Na+-channel, also shift the dose-response curve to the left. These data suggest that some of the effects of amiloride may be mediated by an increased sensitivity of particulate guanylate cyclase to ANF.

Amiloride↗
PubMed1988

Binding sites for atrial natriuretic peptide on platelets in patients with congestive cardiomyopathy.

The aim of the present investigation was to evaluate a possible down-regulation of atrial natriuretic peptide (ANP) binding sites on platelets in patients with chronically elevated ANP plasma levels. The assay procedure was proved to be able to measure the total number of binding sites even in the presence of high ANP plasma levels. We studied 15 adult patients with congestive cardiomyopathy in comparison to 18 healthy volunteers. In the patients the median ANP plasma level (median = 375, range: 155-900 pg ml-1) was about six-fold higher than in the healthy volunteers (median: 55.5, range: 20-90 pg ml-1). The median cyclic guanosine monophosphate (cGMP) plasma level (median: 6.2, range: 2.5-21.4 pmol ml-1) was about three-fold higher than in the healthy volunteers (median: 1.8 range: 1-2.8 pmol ml-1). Despite these markedly elevated ANP and cGMP plasma levels we did not find significantly less receptors per platelet in the patients (median: 19, range: 7.2-60.2) than in the healthy volunteers (median: 24.5, range: 14.8-41.1). Furthermore, there was no difference in the dissociation constants between the patients (median: 10.5, range: 7.9-27.4 pmol l-1) and the control subjects (median: 8.9, range: 5.4-17 pmol l-1).

Aged↗
PubMed1988

Influence of diurnal rhythm, posture and right atrial size on plasma atrial natriuretic peptide levels.

A diurnal rhythm of plasma atrial natriuretic peptide (ANP) and cyclic 3'5'guanosine monophosphate (cGMP) was found in nine healthy adult volunteers. Significantly higher levels of both parameters were found in the morning (8 a.m.) than later during the day and night (p less than 0.05). Different postures had only a little influence on plasma ANP and cGMP levels in seven healthy adult volunteers using a tilt table. Tilted from supine into upright, head-down (-20 degrees) and then again into supine posture, significant differences of both parameters were only found between levels shortly after the end of the upright posture and those at the end of the head-down posture (p less than 0.05). Furthermore, in infants with various congenital heart diseases (n = 19) and control infants (n = 35) the right atrial area was determined by two-dimensional echocardiography and related to plasma ANP levels. Out of 19 infants with cardiac disease, 11 showed an enlarged right atrial area (i.e. above the 95th percentile in the range of control infants). All these 11 infants also had higher plasma ANP levels (range 115-670 pg/ml) than the healthy infants (range 5-98 pg/ml). These data support the assumption that atrial wall distension seems to be a stimulus for ANP release.

Adult↗
PubMed1988

Is cyclic GMP a clinically useful marker for ANF action?

The action of ANF is, at least in part, mediated by the activation of particulate guanylate cyclase. Increases in plasma ANF levels induce a marked increase in the plasma levels and urinary excretion of cyclic GMP. In contrast to agents that stimulate particulate guanylate cyclase, activators of soluble guanylate cyclase, such as the bioactive molsidomine metabolite, SIN 1, induce only a modest, not significant, increase in plasma cyclic GMP levels. Thus, increases in plasma cyclic GMP levels appear to be specific for the activation of particulate guanylate cyclase. Cyclic GMP is stable in whole blood in the presence of EDTA and can easily be measured in plasma and urine. It may therefore be a valuable alternative for ANF measurement in the clinical routine. In contrast to urinary ANF excretion, the urinary excretion of cyclic GMP sensitively reflects increases in plasma ANF levels. Measurement of cyclic GMP excretion may therefore be an alternative for plasma ANF and plasma cyclic GMP measurement especially in situations where blood drawing is difficult, e.g. in newborns. Measurement of basal cyclic GMP followed by determination of increases in cyclic GMP levels after injection of a small ANF bolus dose tests the cellular sensitivity to ANF. This may give further insight in the mechanism of the regulation of ANF effects. Therefore, cyclic GMP in many cases appears to be a sensitive marker for the action of ANF in man.

Atrial Natriuretic Factor↗
PubMed1987

Effects of clonidine and dihydralazine on plasma ANF and cyclic GMP levels in humans during volume loading.

Acute volume loading increases plasma atrial natriuretic factor (ANF) levels in man and animals. In the present work we have compared the effects of a 1-week oral application of clonidine (2 x 0.075 mg/day) to dihydralazine (2 x 25 mg/day) in eight healthy volunteers on changes in plasma ANF and plasma and urine cyclic GMP levels after acute volume loading with 2 I physiological saline i.v. Basal plasma ANF levels before infusion were decreased by clonidine to 65% of the untreated controls and remained unaltered with dihydralazine. Volume loading increased plasma ANF levels by about 40% in the control and 30% in the dihydralazine treated group, whereas plasma ANF remained unchanged by volume loading in the clonidine-treated group. Dihydralazine increased basal cyclic GMP levels and urinary cyclic GMP excretion by 30 and 90%, respectively. Basal cyclic GMP levels were identical without treatment and after clonidine treatment. Saline infusion increased cyclic GMP levels by 40% in the control and clonidine-treated groups, and by 25% in the dihydralazine-treated group. Urinary cyclic GMP excretion increased by 2.1-, 1.6-, and 1.2-fold, respectively, in the controls, after clonidine, or after dihydralazine. The results of this study suggest that ANF is involved in the hormonal and hemodynamic effects that are induced by clonidine, but not in those induced by dihydralazine.

Adult↗
PubMed1987

Cellular mechanisms of action of atrial natriuretic factor.

Atrial natriuretic factor (ANF) interacts with its target cells through specific receptors. This interaction induces, in most cell types, the activation of particulate guanylate cyclase and decreased Calcium mobilisation. In addition, ANF also decreases adenylate cyclase activity in some tissues. Activation of particulate guanylate cyclase, and additionally inhibition of adenylate cyclase, appear to initiate the cellular responses to circulating ANF. The activation of particulate guanylate cyclase is tissue-specific, immediate and can be demonstrated also on the solubilized enzyme. The ANF receptor appears to be tightly coupled to particulate guanylate cyclase. The increased formation of cyclic GMP induces cGMP-dependent protein phosphorylation in target cells. In addition, cyclic GMP inhibits Calcium mobilisation in several tissues. This may explain observations of inhibition of Calcium mobilisation after ANF. Cyclic GMP is not only degraded by phosphodiesterase, but is also extruded from target cells. As a consequence of cGMP extrusion, ANF increases the levels of cyclic GMP in plasma and urine in animals and man. Cyclic GMP is also increased in various disease states, in which ANF is increased. In contrast, cyclic AMP plasma levels are unaltered after ANF elevations. At present, the exact mechanisms, by which cellular functions are altered by ANF are still incompletely understood. It is anticipated, that the close correlation between the cyclic GMP system and effects of ANF in various target tissues is a key finding that will help elucidate the exact mechanisms of ANF action.

Adenylyl Cyclase Inhibitors↗
PubMed1977

Interaction of zinc and hemoglobin: binding of zinc and the oxygen affinity.

Stripped human hemoglobin was shown to have a high apparent zinc association constant of 1.3 X 10(7) M-1 with a stoichiometry of one zinc for every two hemes. The saturation of this site produces a dramatic 3.7-fold increase in the oxygen affinity. The effect of zinc on the oxygen affinity is interrelated with the interaction of 2,3-diphosphoglyceric acid (2,3-DPG) and hemoglobin. Thus, a smaller zinc effect is observed in the presence of added 2,3-DPG. Information about the location of the zinc-binding site responsible for the increased oxygen affinity has been obtained by comparing the binding of zinc to various hemoglobins. Blocking the beta93 sulfhydryl group decreases the apparent zinc association constant by an order of magnitude. The substitution of histidine-beta143 in hemoglobin Abruzzo [beta143 (H21) His leads to Arg] and hemoglobin Little Rock [beta143 (H21) His leads to Gln] decreases the apparent zinc association constant by two orders of magnitude. The substitution of histidine-beta143 by other amino acids and the reaction of the beta93 sulfhydryl group are known to produce dramatic increases in the oxygen affinity. The binding of zinc to one or both of these amino acids can, therefore, explain the zinc-induced increase in the oxygen affinity.

Diphosphoglyceric Acids↗