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Patients with paroxysmal supraventricular tachycardia (SVT) may have a polyuria after termination of tachycardia. There is increasing evidence that the renal peptide urodilatin (ANP (95-126))--and not plasma ANP (ANP (99-126))--is the member of the natriuretic peptide family mediating natriuresis and diuresis in man. In patients with SVT we, therefore, analyzed the relationship between diuresis, natriuresis, plasma ANP, urinary urodilatin excretion and renal excretion of cyclic GMP, the second messenger in the ANP system. During and after clinical presentation with spontaneously occurring SVT, two patients with AV-nodal and one patient with atrioventricular reentry tachycardia (heart rate 160 to 200 bpm) were studied. Urinary urodilatin excretion was correlated to diuresis (r = 0.73) and natriuresis (r = 0.93); similarly urinary cyclic GMP excretion was related to diuresis (r = 0.80) and natriuresis (r = 0.87; p < 0.001, respectively). In contrast, there was no significant correlation between plasma ANP concentrations and diuresis (r = 0.28, n.s.) or natriuresis (r = 0.11, n.s.). As an explorative analysis, stepwise multiple linear regression identified urinary urodilatin as the most important contributor to diuresis and natriuresis after SVT. These data on polyuria after spontaneous SVT further support the view that in man urodilatin is the member of the natriuretic peptide family participating in kidney physiology.

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.

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.

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.

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.

In eight patients (63 +/- 8 years) with dilated cardiomyopathy, the acute effects of positive inotropic stimulation with dopexamine hydrochloride, a beta-2-agonistic and DA1-dopaminergic catecholamine, on the plasma levels of ANP and cGMP were tested. A four-point dose-response curve was prepared for dopexamine from 1 microgram/kg/min to 4 micrograms/kg/min. Each infusion stage lasted 15 min; ANP and cGMP were taken from the mixed venous blood. Hemodynamic parameters were determined by a Swan-Ganz catheter; cardiac output was determined by thermodilution. ANP dropped by 40% from 348 +/- 124 pg/ml to 208 +/- 70 pg/ml (p less than or equal to 0.01), while cGMP dropped by 25% from 4.8 +/- 1.6 pmol to 3.6 +/- 1.3 pmol/ml at the time of maximum hemodynamic effect after 1 h. Linear regression analyses revealed a significant relationship (p less than or equal to 0.01) between ANP as the independent variable and cGMP as the dependent variable. The hemodynamic determinants of the ANP concentration proved to be--independently of each other--the pulmonary capillary wedge pressure (p less than or equal to 0.01) and the mean right atrial pressure (p less than or equal to 0.01). The results show that chronically elevated ANP and cGMP levels can be strikingly reduced within a short time, whereby ANP and cGMP show similar kinetics. The results suggest a use of ANP and cGMP as humoral parameters in the therapy control of chronic heart failure.

Ibopamine is a novel oral dopamine analogue with positive inotropy and diuretic effects. In a double-blind, randomized study, the drug was investigated in 10 patients (mean age 49 +/- 10 years, six male, four female) with mild heart failure (NYHA classes II: six patients, III: four patients). Effects of single oral doses of 200 mg ibopamine, of 40 mg furosemide, and of 200 mg ibopamine plus 40 mg furosemide were compared in each patient at 3-day-intervals. One h after application, systolic and diastolic blood pressure increased from 119 +/- 11 to 124 +/- 8, and from 75 +/- 4 to 80 +/- 6 mm Hg (p less than 0.01) in the ibopamine group, while changes in both other groups and changes of the heart rate were insignificant. During 2 h after drug ingestion urinary flow was raised from 124 +/- 81 to 227 +/- 166 ml/2 h in the ibopamine group (p less than 0.05), while the application of furosemide (with or without ibopamine) resulted in several fold increases of urinary flow. After ibopamine, the 2-h-creatinine-clearance rose from 123 +/- 73 to 130 +/- 85 ml/min (not significant). Sodium excretion remained unchanged by ibopamine, potassium excretion was increased from 2.9 +/- 1.7 to 4.0 +/- 3.3 mmol/h (p less than 0.05), while effects of furosemide were several fold of those of ibopamine. Atrial natriuretic factor concentrations in plasma increased significantly after ibopamine and after ibopamine plus furosemide (p less than 0.01), but remained constant after furosemide alone.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.