Biomedical subjects

C Hirth

Publications and source records attributed to C Hirth.

At least 55 records · Page 3Linked to original sources

PubMed1988

The reduction of renin and aldosterone as a response to acute hypervolemia is blocked by a monoclonal antibody directed against atrial natriuretic peptides.

We have previously reported that the strong diuresis, natriuresis and urinary cyclic GMP excretion after acute volume loading in rats are caused by ANP and can be blocked by additionally given monoclonal antibodies directed against ANP. The present report describes that in contrast to the changes in ANP and cyclic GMP, the plasma renin activity and aldosterone concentration are decreased after volume loading. This decrease is completely blocked by simultaneous administration of the monoclonal antibodies. Plasma cyclic AMP levels are not affected. From this study it seems to be clear that the inhibition of the renin-aldosterone system is not a direct effect of volume expansion but is specially mediated by the released ANP.

Aldosterone↗

PubMed1988

Diuretic effect of nitrendipine contributes to its antihypertensive efficacy: a review.

The mechanism of the antihypertensive effect of nitrendipine is believed to be vasodilation, resulting in a reduction of the total peripheral resistance. However, in contrast to other arteriolar vasodilators, nitrendipine exerts natriuretic and diuretic effects that are more pronounced in hypertensive than in normotensive rats. In rat kidneys, nitrendipine caused a complete reversal of the decrease of glomerular filtration rate (GFR) induced by norepinephrine or angiotensin II, probably due to a selective antagonism of preglomerular vasoconstriction. A selective dilation of afferent arterioles was shown in microcirculatory studies on hydronephrotic kidneys. In normotensive rats with intact kidneys, nitrendipine increases natriuresis by inhibition of sodium reabsorption, presumably in the proximal tubuli. In normotensive humans, natriuresis was enhanced also by a primary tubular effect of nitrendipine. In hypertensive patients, an initial increase in GFR was observed; a persistent diuretic effect under chronic treatment was due to a tubular action. In spontaneously hypertensive rats (SHR), chronic treatment with nitrendipine resulted in a regression of cardiac hypertrophy in parallel with a reduction of plasma levels of atrial natriuretic peptides (ANPs), probably due to the persistent natriuretic effect. Treatment with minoxidil resulted in fluid retention, increase in ANP levels, and aggravation of cardiac hypertrophy.

Animals↗

PubMed1988

[Physiologic importance of atrial natriuretic peptide in volume expansion and hypertension: experimental studies].

The release of atrial natriuretic peptides (ANP) is stimulated by acute volume expansion. In order to elucidate the importance of the ANP release for the physiological response to volume expansion, a monoclonal antibody was used in rats. This antibody against ANP specifically blocks the ANP effects in vivo. The acute natriuresis induced by isotonic volume expansion is blocked by the antibody. However, the excretion of an additional sodium load (saline with an additional amount of 50 mmol/l sodium) is not entirely ANP-dependent. Acute volume expansion induces a dramatic decrease of plasma renin activity and a slight decrease of plasma aldosterone concentration measured 5 min after volume expansion. These effects are blocked by simultaneous administration of the monoclonal antibody. The endogenous level of ANP that can be reached in volume expansion is thus sufficient for suppression of the renin-aldosterone system. The physiological importance of ANP underlined in these volume expansion experiments raises the question of its role in pathophysiological states such as hypertension. In old, spontaneously hypertensive rats (SHR) ANP plasma levels and relative heart weights are higher than in age-matched normotensive Wistar Kyoto rats (WKY).(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗

PubMed1988

[Significance of atrial natriuretic peptide in heart failure: experimental findings].

We investigated the role of atrial natriuretic peptide (ANP) in a rat model of chronic heart failure (CHF) (coronary ligation) by four different studies: (1) stimulation of secretion of ANP by volume loading, (2) infusion of 1 micrograms/min of rat ANP (99-126), (3) correlations of pressure measurements of right atrium (RAP) and LVEDP versus plasma ANP levels and ANP mRNS versus infarct size, (4) blocking endogenous plasma levels of ANP with monoclonal ANP antibody. In severe CHF, volume loading did not exert a significant increase in plasma ANP, in contrast to moderate CHF or to normal animals. Infusion of ANP reduced RAP and LVEDP without significant increase in renal blood flow (radioactive microspheres) in rats with severe cardiac failure, in contrast to normal animals. A close relationship was found between LVEDP and atrial plasma levels. After injection of ANP antibody, filling pressures and systemic vascular resistance increased, indicating that removal of ANP may enhance arterial vasoconstriction or elevated endogenous ANP to exert a vasodilatory action in severe heart failure. Nevertheless, the cardiocirculatory effects, primarily on renal blood flow, appear to be limited.

Animals↗

PubMed1987

Aryl diazo compounds and diazonium salts as potential irreversible probes of the gamma-aminobutyric acid receptor.

The synthesis of different diazonium salts derived from homo- and heterocyclic aromatic amines bearing anionic residues is described. The chemical stabilities of these compounds were established at different pH's, and the compounds were tested accordingly in binding experiments for the rat brain gamma-aminobutyric acid (GABA) receptor, for which they could ultimately be used as irreversible affinity or photoaffinity probes. The aromatic heterocyclic series studied were 2-aminoimidazole, 2-aminothiazole, and 4-aminopyridine N-oxide. The derived diazonium salts are unstable compounds at neutral pH unless they are able to be deprotonated to the corresponding diazo form. As such, the 2-diazoimidazole-4(5)-acetic acid (3b) is stable in neutral medium and recognizes the GABA receptor (IC50 = 70 microM). The homocyclic aromatic diazonium salts showed sufficient stability to be tested in binding experiments. The diazonium salts derived from m-sulfanilic acid and 8-sulfonaphthylamine were the most interesting (10b, IC50 = 10 microM; 15b, IC50 less than 100 microM). In this series, the compounds that deprotonate at neutral pH (hydroxybenzenediazonium derivatives 12b-14b) showed increased chemical stability but decreased affinity for the GABA receptor. This difference between the diazoimidazole and the diazohydroxybenzene series is attributed to a different charge distribution between the two series. The ligands 3b, 10b, and 15b can be used as potential irreversible probes for the GABA receptor.

Affinity Labels↗

PubMed1987

Tissue protection by nifedipine and its calcium antagonistic derivatives in vascular damage.

Calcium ions are ubiquitous messengers of numerous cellular functions. Under normal conditions, they translate the membrane signal into specific cellular activity by electromechanical or electrosecretory coupling. An enhancement of the transmembrane calcium influx results in exaggerated cellular function, such as increased vascular contractility. Therefore, a reduction of transmembrane calcium influx by calcium antagonists effectively reduces high blood pressure (BP). It has been shown that the long-term treatment of genetically hypertensive rats with dihydropyridine calcium antagonists ameliorates the tissue damage that occurs in association with high BP in various organs. This tissue protection is not secondary to the reduction of hypertension as it can be demonstrated in the absence of BP reduction. This favourable effect may be attributed to the prevention of intracellular calcium overload which results in an exhaustion of energy-rich phosphates, excessive activation of proteolytic and phospholytic enzymes, membrane destruction and cellular death. In acute ischaemia experiments, inhibition of excessive transmembrane calcium influx by the dihydropyridine calcium antagonists prevents vascular and parenchymal damage. Moreover, long-term treatment with dihydropyridine calcium antagonists prevents vascular and parenchymatous damage in advanced or accelerated hypertension. In accordance with this concept, calcium antagonists have been shown to exert protective effects against acute ischaemic damage in both the heart and the kidney.

Humans↗

PubMed1987

Calcium antagonism and protection of tissues from calcium damage.

Calcium antagonism of nifedipine, nitrendipine or nisoldipine prevented salt-induced hypertension, renovascular damage and mortality in Dahl salt-sensitive (S) rats. The calcium agonist BAY K 8644 accelerated the development of salt-induced hypertension in S rats. In some S rats on a low-salt diet BAY K 8644 induced renovascular damage without sustained hypertension. In stroke-prone spontaneously hypertensive rats (SHRSP) on a normal diet the natural appearance of stroke was correlated with an increased calcium content in brain and kidney tissue. Nimodipine prevented stroke and the increase in brain calcium content without affecting the high blood pressure. A similar protective effect without substantial influence on high blood pressure was achieved by bilateral parathyroidectomy. Hypertension-associated vascular damage does not necessarily depend on the systemic intravascular pressure. In malignant hypertension the deleterious calcium overload in tissues may be activated or inhibited independently of the regulation of arterial blood pressure.

Animals↗

PubMed1987

Role of nisoldipine on blood pressure, cardiac hypertrophy, and atrial natriuretic peptides in spontaneously hypertensive rats.

The effect of long-term treatment with the calcium antagonist nisoldipine on development of hypertension, cardiac hypertrophy, and plasma levels of atrial natriuretic peptides (ANP) was determined in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) of the same age. Measurement of immunoreactive ANP in plasma provided a sensitive marker for the severity of hypertension and the associated cardiac overload. Long-term treatment with nisoldipine prevented the development of hypertension, the associated heart failure, and the increase of plasma levels of ANP in SHR but had no effect on systolic blood pressure, heart weight, and plasma levels of ANP in WKY. In addition, nisoldipine had a therapeutic effect in old SHR with manifest cardiac failure in end-stage hypertension, as evidenced not only by the reduction of blood pressure but also by the reduction of cardiac hypertrophy, of elevated immunoreactive ANP in plasma, and of increased plasma renin activity.

Animals↗

PubMed1987

Renal effects of 1,4-dihydropyridines in animal models of hypertension and renal failure.

Renal effects of 1,4-dihydropyridine (DHP)-type calcium antagonists (nitrendipine and nisoldipine) were analyzed in diverse conditions, such as long-term antihypertensive treatment, acute saline-loading, and acute renal failure in rats. In spontaneously hypertensive rats (SHR), 60-week treatment with nitrendipine resulted in normotensive blood pressure values without increasing body weight, an indicator of salt-water retention, or increasing plasma renin activity and plasma aldosterone concentration compared with the untreated rats. After acute saline-loading of normotensive or hypertensive rats, administration of calcium antagonists nitrendipine and nisoldipine increased urinary volume and sodium excretion. This was in contrast to the effects observed with the vasodilator minoxidil, with which salt-water retention was shown. In acute renal failure induced by 60-min renal ischemia in uninephrectomized rats, administration of nisoldipine decreased mortality rate and improved kidney function. The increase in renal tissue calcium content and the decrease in ATP content associated with the renal failure was abolished by nisoldipine treatment. In conclusion, renal protective effects are present with DHP-type calcium antagonists; however, mechanisms in situations such as hypertension or acute renal failure might be different and deserve further analysis.

Acute Kidney Injury↗

PubMed1987

Blockade of the response to volume expansion by monoclonal antibodies against atrial natriuretic peptides.

It is known that plasma levels of atrial natriuretic peptides (ANP) increase in response to volume expansion. However, the extent to which these increased levels of ANP participate in the renal response to volume expansion remained unknown. This question can be answered with the aid of a monoclonal antibody that binds specifically to the biologically active forms of ANP: Ascitic fluid containing this monoclonal antibody dose-dependently and specifically blocks the natriuretic, diuretic and hypotensive effects of synthetic atriopeptin II given intravenously in rats. Volume expansion induced by injection of 20 ml/kg homologous blood in anaesthetized rats evokes massive diuresis and natriuresis. Pretreatment with ascitic fluid containing monoclonal antibody completely blocks this diuretic and natriuretic response during the first 20 min after volume expansion. Thus the initial renal response to volume expansion is due to the increase in endogenous ANP. Similar results were obtained for volume expansion with isotonic saline in conscious rats. It is supposed that the effects of ANP are mediated through particulate guanylate cyclase activation and intracellular cyclic guanosine-monophosphate (cGMP) accumulation in target tissues including renal and vascular smooth muscles cells. Besides increasing plasma ANP levels (measured by radioimmunoassay) volume expansion also induces an increase of cGMP levels both in plasma, urine and in renal tissue. This increase is ANP-dependent as it can be blocked by the monoclonal antibody.

Animals↗

PubMed1986

The elevation of cyclic GMP as a response to acute hypervolemia is blocked by a monoclonal antibody directed against atrial natriuretic peptides.

Substantial volume expansion in conscious rats induces a strong diuresis and natriuresis that is caused by the increase in plasma levels of atrial natriuretic peptides (ANP) as measured by a radioimmunoassay. This renal response could be blocked by monoclonal antibodies directed against ANP. Parallel to the change in ANP, the cyclic GMP levels in plasma, urine and kidney tissue were increased after volume loading and reduced after additionally given antibodies. From this study it seems to be clear that the cyclic GMP rise is not a direct effect of volume expansion but is specifically mediated by the released ANP.

Animals↗

PubMed1986

The use of a monoclonal antibody to measure plasma atriopeptins in rat.

A monoclonal antibody with specificity for atrial natriuretic peptides (ANP) was produced, that can be used for the radioimmunological determination of ANP-immunoreactivity (ANP-IR) in rat plasma. The antibody recognizes atriopeptin I, II, III, as well as alpha-hANP and alpha-hANP fragment (7-28) and does not crossreact with ANP-fragments (13-28) and (18-28). Plasma levels of ANP-IR in conscious Wistar rats were determined before and after volume-loading. Basal plasma levels of ANP-IR were 108 +/- 12 pg/ml, and after volume-loading increased to 800 +/- 59 pg/ml.

Animals↗

PubMed1986

Electrophysiological actions of histamine and H1-, H2-receptor antagonists in cardiac tissue.

Electrophysiological investigations of histamine in different cardiac tissues have led to the following results: Histamine and the H2-agonists dimaprit and impromidine show similar actions on electrophysiological parameters of ventricular myocardium (especially a decrease in action potential duration), which are completely blocked by cimetidine and enhanced by the phosphodiesterase inhibitor 1-methyl,3-isobutylxanthine (IBMX). These effects may be explained by an increase in cellular cAMP leading to an increase in slow inward current and outward currents as shown by voltage clamp experiments. Histamine in contrast to IBMX increases action potential duration at 90% repolarization (APD90) in atria. Histamine effects in atrial myocardium are completely reversed by the H1-antagonist dimetindene. Stimulation of atrial H1-receptors is suggested to directly cause an increase in Ca-channel conductance independent of intracellular cAMP content. Histamine reduces AH-interval, increases V max of NH-cells and may induce AV-node arrhythmias (at concentrations greater than or equal to 3 mumol/l). These effects remain unchanged by dimetindene, but are reversed by cimetidine. The results indicate that histamine increases AV-nodal conduction via H2-receptors. Unspecific membrane actions of cimetidine are not observed up to 100 mumol/l. Dimetindene increases action potential duration (APD) in left atria and decreases Vmax at concentrations greater than or equal to 10 mumol/l. However, H1-antagonistic actions of dimetindene are already observed at concentrations 1,000 to 10,000 times lower (pA2-values 8.39-9.12) so that unspecific membrane actions are suggested not to occur on a therapeutic dose level.

1-Methyl-3-isobutylxanthine↗

PubMed1985

Aryldiazonium salts as photoaffinity labels of the nicotinic acetylcholine receptor PCP binding site.

Several aryldiazonium salts are described as irreversible blockers of the phencyclidine binding site of the nicotinic cholinergic receptor. A partial hydrophobic character increases the affinity of these salts for the phencyclidine binding site. Photoaffinity labelling with a tritiated diazonium salt in the presence of either carbamylcholine or alpha-bungarotoxin leads to incorporation of radioactivity into the 4 subunits of the receptor. Among these diazonium salts, an imidazole derivative is unique in that the photoinduced irreversible blocking in only effective when the receptor is in a desensitised state.

Affinity Labels↗

PubMed1985

In vitro studies on the pharmacological properties of diacetolol, the major metabolite of acebutolol in man.

The cardioselectivity and specificity of diacetolol, the major metabolite of the beta-adrenoceptor blocking drug acebutolol, was studied in the isolated right atrium of the guinea-pig and rat and the papillary muscle and trachea of the guinea-pig. The beta-adrenoceptor blocking potency of diacetolol is about ten times lower than that of acebutolol. Like acebutolol, diacetolol was a more effective isoprenaline antagonist in the heart than in the trachea, thus showing relative cardioselectivity. The high water solubility of diacetolol and acebutolol led to a much faster disappearance of the beta-blockade after washout than the blockade by the lipid soluble agents propranolol and penbutolol. Like acebutolol, diacetolol had a weak intrinsic sympathomimetic activity. Cardiac depressant effects, e.g. decrease of maximum upstroke velocity and duration of the action potential and reduction in force of contraction, occurred with concentrations 100-1000 times higher than those needed for beta-blockade, thus indicating relative specificity.

Acebutolol↗

PubMed1985

Antiarrhythmic and electrophysiological actions of flecainide, bepridil and amiodarone on isolated heart preparations during controlled hypoxia.

A model of arrhythmias based on the application of sinusoidal alternating current (ac) to isolated heart preparations has been employed to determine the effects of hypoxia (30 vol % O2 in the perfusion medium) on the threshold of arrhythmia and asystole. With this method three representatives of different classes of antiarrhythmic drugs, flecainide, bepridil and amiodarone, have been investigated in isolated papillary muscles and left atria from guinea-pigs. Hypoxia reduces both the threshold for ac-arrhythmia and the threshold for ac-asystole. Flecainide (3 and 10 mumol/l) elevates both thresholds under normoxia and has a protective effect against the hypoxia-induced reduction of threshold. Bepridil (10 mumol/l) is without effect on the threshold of ac-arrhythmia in papillary muscle, prevents the hypoxia-induced decline of the threshold of ac-arrhythmia in left atria and depresses the threshold of ac-asystole both in normoxia and hypoxia. amiodarone (10 mumol/l) elevates the threshold of ac-arrhythmia both during normoxia and hypoxia in papillary muscle but only during the second hour of hypoxia in left atria. The results may be interpreted with respect to the inhibitory action on Na+-channels (flecainide), Ca2+-channels (bepridil) or protective effects against hypoxia-induced changes in action potential duration (amiodarone, but also flecainide and bepridil) as shown by additional electrophysiological experiments.

Action Potentials↗

PubMed1984

Clinical and immunologic evaluation of tyrosine-adsorbed Dermatophagoides pteronyssinus extract: a double-blind placebo-controlled trial.

We evaluated the clinical efficacy and immunologic changes associated with the administration of tyrosine-adsorbed Dermatophagoides pteronyssinus (Dpt) extract. The study was carried out in a double-blind, placebo-controlled fashion in 18 patients with Dpt-induced asthma during a trial period of at least 12 mo. Patients initially received six increasing doses once a week; the top dose of 400 Noon units was repeated at monthly intervals. Clinical response was on the basis of diary cards on which symptoms and medication scores were recorded; daily lung function measurements were made by use of a mini Wright's peak flow meter. The entire spectrum of physiologic measurements, medications, and symptoms were taken into account by computing daily scores over a 2-week period. Total IgE, Dpt-specific IgE antibodies, and leukocyte histamine release were measured before treatment and during hyposensitization. Changes in Dpt-specific IgG were evaluated with a double antibody antigen-binding assay by use of the purified fraction of mite extract F4P1. All patients had measurable levels of IgG antibodies to F4P1 before treatment. Treatment with tyrosine-adsorbed Dpt extract resulted in a significant increase of specific-IgG antibodies in the treated group at 2 and 6 mo only (nonparametric rank sum test). Variations relative to the pretreatment values of total and specific IgE were not significantly different in the treated and in the control patients after 2.6 and 12 mo. No significant decrease in leukocyte sensitivity was observed after treatment. It was only possible to demonstrate a significant diminution in the mean medication score (nonparametric sign test) in the first 6 mo for the treated group; independently of the beginning of the treatment, the treated group demonstrated a reduction of the mean medication score and an improvement in peak expiratory flow rate lung function before the midsummer months when seasonal increase in mite density can occur. Particular attention was paid to the methodological problems raised during this study and inherent in a trial in house dust-mite asthma.

Adsorption↗

PubMed1984

Long-term course of pulmonary arterial pressure in chronic obstructive pulmonary disease.

Ninety-three patients with severe chronic obstructive pulmonary disease (COPD) of the bronchitic (n = 74) or emphysematous type (n = 19), who all had arterial hypoxemia, underwent 2 right cardiac catheterizations in a clinical steady state, with a delay of 5 yr or more between the first and the last catheterization. No patients received long-term O2 therapy or pulmonary vasodilator drugs. Patients were divided into 2 groups according to the initial level of mean pulmonary artery pressure (Pap). Group 1 included 61 patients without initial pulmonary arterial hypertension (PAH), Pap being less than 20 mmHg; the average delay between the 2 catheterizations was 93.4 +/- 26.8 months. Group 2 included 32 patients with initial PAH (Pap greater than or equal to 20 mmHg), and the average delay was 85.0 +/- 26.0 months. The changes in Pap were small. They ranged from 15.5 +/- 2.4 to 19.6 +/- 7.0 mmHg in Group 1 (p less than 0.001) and from 25.8 +/- 5.6 to 27.8 +/- 9.5 mmHg in Group 2 (NS). The average increase in Pap was 0.65 mmHg/yr in Group 1 and 0.39 mmHg/yr in Group 2 (no statistical difference between the 2 groups). The other hemodynamic parameters (pulmonary capillary wedge pressure, right ventricle filling pressure, cardiac output) did not change. Hemodynamic "worsening," which was defined by an increase in Pap by greater than or equal to 5 mm Hg, was observed in 29% of the patients (n = 27). In these patients, there was a marked worsening of hypoxemia, which was not observed in the remaining 66 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗