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Biomedical subjects

A J Porsius

Publications and source records attributed to A J Porsius.

At least 55 records · Page 3Linked to original sources

In vivo anaphylaxis in the rat: effects of phosphodiesterase inhibitors.

On the basis of their inhibitory capacities on the phosphodiesterase enzyme system, we studied the anti-anaphylactic effect of milrinone and sulmazole in comparison with theophylline. For this purpose anaphylactic shock was induced in actively sensitised, spontaneously breathing rats. Milrinone, sulmazole and theophylline reduced anaphylactic bronchoconstriction without affecting the antigen induced fall in blood pressure. Surprisingly, sulmazole reduced mortality significantly.

Anaphylaxis↗

In vitro method for measurement of cardiac performance and responses to inotropic drugs after experimentally induced myocardial infarction in the rat.

In this paper, a method is described for the measurement of the performance of rat hearts with an experimentally induced myocardial infarction of the left ventricle. After ether anesthesia of the animals and left thoracotomy, the left coronary artery was ligated, and the thorax was rapidly closed. The whole procedure took no more than 2 min. Forty-eight hours after the operation, the hearts were prepared for retrograde constant pressure perfusion, according to the Langendorff technique. The effects of the betasympathomimetic drug dobutamine and of the novel phosphodiesterase inhibitor milrinone on the contractile force of the right ventricle and the infarcted left ventricle, as well as on the total coronary flow, were quantified. Sham operated animals were used as control. The maximal obtainable stimulation of the contractility of infarcted hearts by dobutamine was significantly reduced from control. Milrinone increased the contractility in control animals, although to a much lesser extent. This increase was significantly smaller in infarcted hearts. The stimulation of the coronary flow by dobutamine and milrinone was significantly reduced in hearts with an infarction. Milrinone potentiated the effect of isoprenaline significantly. The results of the present study indicate the usefulness and reproducibility of this model for the evaluation of the efficacy of positive inotropic agents on the heart in the presence of a myocardial infarction.

Animals↗

Anti-allergic effects of milrinone and sulmazole in isolated rat lungs in comparison with theophylline.

Milrinone and sulmazole, two recently developed drugs, inhibit specific fractions of the phosphodiesterase (PDE) isozyme system. Since theophylline aspecifically inhibits the PDE complex, we compared the effects of milrinone and sulmazole with those of theophylline on antigen-induced bronchoconstriction, vasoconstriction, mediator release and leukotriene production. In the isolated perfused and ventilated lung of actively sensitized rats, we elicited antigen-induced bronchoconstriction, vasoconstriction and release of mediators like histamine, 5-hydroxytryptamine (5-HT) and slow-reacting substance of anaphylaxis (SRS-A). Milrinone, sulmazole and theophylline inhibited antigen-induced bronchoconstriction and vasoconstriction in a dose-dependent manner with minor differences in potency. Antigen-induced release of preformed mediators like histamine and 5-HT was inhibited only at high concentrations of milrinone, whereas sulmazole failed to inhibit mediator release. Theophylline also failed to inhibit 5-HT release. However, SRS-A synthesis was markedly reduced by these drugs in relatively low concentrations. It is concluded that milrinone and sulmazole have anti-allergic effects similar to those of theophylline and that all three PDE inhibitors reduce SRS-A synthesis.

Airway Resistance↗

Comparison of the anti-anaphylactic effects of milrinone, sulmazole and theophylline in the rat.

Milrinone and sulmazole, two recently developed cardiotonic drugs, inhibit specific fractions of the phosphodiesterase (PDE) isozyme system, while theophylline inhibits the PDE complex aspecifically. Since these drugs were shown to have anti-allergic effects in isolated lungs, we wanted to study milrinone and sulmazole in comparison with theophylline in an in vivo model of anaphylaxis. For this purpose, actively sensitized rats were intravenously challenged with antigen, while tracheal pressure, oesophageal pressure, blood pressure and airflow were continuously monitored. Antigen challenge induced a transient bronchoconstriction and a persistent fall in blood pressure until death occurred. Anaphylactic shock was consistently followed by metabolic acidosis. Milrinone, 3 mg/kg, and theophylline, 40 mg/kg (but not 10 mg/kg), reduced anaphylactic bronchoconstriction. Sulmazole, 40 mg/kg, almost abolished bronchoconstriction. Although milrinone, sulmazole and theophylline, 40 mg/kg, caused a fall in blood pressure prior to antigen challenge, total fall in blood pressure (drug-induced and antigen-induced) was not affected by these drugs. Surprisingly, sulmazole reduced mortality significantly. This phenomenon is probably related to the less severe metabolic acidosis in the presence of sulmazole.

Acid-Base Equilibrium↗

Density of beta adrenoceptors in rat heart and lymphocytes 48 hours and 7 days after acute myocardial infarction.

Down regulation of the beta adrenoceptor is thought to play an important role in the diminished response to catecholamines in heart failure. beta Adrenoceptor densities were measured on membrane homogenates of rat right ventricle and lymphocytes 48 h or 7 d after experimental myocardial infarction, and in rats exposed to a continuous infusion of isoprenaline (400 micrograms.kg-1.h1). The performance of the rat hearts was also evaluated 48 h post infarction in an isolated retrograde perfused heart preparation. In contrast to a 60% down regulation in right ventricle and a 20% down regulation in lymphocyte membranes after isoprenaline infusion, there was no change in right ventricle and lymphocyte beta adrenoceptor densities after myocardial infarction. Left ventricular contractile performance was significantly depressed 48 h after myocardial infarction. Mean basal left ventricular pressure decreased from 108(SEM 3) to 63(4) mm Hg while the maximal response to dobutamine was decreased from 204(4) to 105(12) mm Hg (n = 8). No correlation was found between the receptor densities of right ventricular and lymphocyte membranes. We conclude that diminished response to beta sympathomimetics after myocardial infarction cannot be attributed to a loss of surface beta adrenoceptors, and that the lymphocyte beta adrenoceptor does not provide an adequate system to monitor small receptor changes on the myocardium.

Animals↗

Pharmacokinetics of lisinopril in hypertensive patients with normal and impaired renal function.

The pharmacokinetics of lisinopril was studied after administration of single and multiple doses of 5 mg to hypertensive patients with normal and impaired renal function. In patients with severe renal failure the peak concentrations were higher, the decline in serum concentration was slower and the time to peak concentration was extended. Accumulation of lisinopril was highly correlated with the creatinine clearance. The effective half-life was doubled and tripled in patients with mild and severe renal impairment, respectively, as compared to patients with a normal renal function. Lisinopril lowered blood pressure in all three groups over 24 h. It is suggested that smaller doses of lisinopril should be administered to patients with severe renal failure.

Acute Kidney Injury↗

Endocrine therapy of breast cancer.

The aim of this literature study is to evaluate the various endocrine drugs used in the treatment of breast cancer in order to compare their therapeutic efficacy. Hormone-dependent metastasized breast cancer of post-menopausal women can be treated with four equivalent drugs: tamoxifen, megestrol, medroxyprogesterone, and--combined with steroid suppletion therapy--aminoglutethimide. Each of these drugs induces (partial) remissions in 50-60% of estrogen receptor-positive tumors. Because of its relatively few and less serious side-effects tamoxifen is the agent of first choice for soft tissue and lung metastases. Due to its potentially enhanced objective and more pronounced subjective side-effects, aminoglutethimide may be preferred in bone metastases. In view of the only minor activity of hormonal agents in liver metastases, combination chemotherapy with concomitant, sequential or alternating use of hormonal agents should be considered in this condition. Until now, only tamoxifen seems suitable for the treatment of premenopausal metastasized hormone-dependent breast cancer. In the adjuvant setting, preoperatively initiated and as soon as possible postoperatively continued endocrine therapy seems to be of the utmost importance to counteract (occult) metastases while reducing the need for extensive surgery.

Aromatase Inhibitors↗

The inhibitory effect of fentanyl, nicomorphine and 6-nicotinoyl morphine on phrenic nerve activity in relation to their cardiovascular effects in the anaesthetized cat.

The inhibitory effects of the morphine-like drugs fentanyl, nicomorphine (3,6-dinicotinoyl morphine, Vilan) and its active metabolite 6-nicotinoyl morphine (6-NM) on phrenic nerve activity (PNA) were quantified. Therefore, the drugs were simultaneously infused into the left and right vertebral artery of anaesthetized cats. Previously we demonstrated that drugs, administered via these arteries, accumulate within the pontomedullary region, whereas only insignificant amounts reach higher brain areas and peripheral structures. The results were compared with the effects of i.v. administration. It is shown that fentanyl already inhibits PNA after 60 ng via the vertebral arteries. Nicomorphine and its metabolite have much less influence on respiration (factor 564 and 47, respectively). The difference in potency between nicomorphine and 6-NM was less after i.v. injection, indicating that nicomorphine needs metabolization in order to unfold full biological activity. Haemodynamic parameters are not affected after central administration even when PNA is almost completely depressed. After i.v. injection of relatively high doses, blood pressure falls, but probably not by an interaction with opiate receptors in the lower brain stem, since it could not be reversed by intravertebral naloxone.

Animals↗

Depressor effects, drug concentration and cholinesterase activities in the brain after administration of paraoxon in the cat.

After simultaneous administration of paraoxon into both the left and right vertebral artery (4-8 micrograms) or into a femoral vein (150-550 micrograms.kg-1) of the anaesthetized cat, dose-dependent drug concentrations are measured in various brain regions. These amounts induce inhibition of brain acetylcholinesterase activity and dose-dependent depressor effects. Although paraoxon is rapidly eliminated from the CNS, enzyme activity remains at a low level. After central application of paraoxon into both vertebral arteries no detectable amounts are found in the hypothalamus and acetylcholinesterase activity in that brain region is not or only slightly affected. Curves representing the relationship between the decrease in blood pressure and the concentration of paraoxon or enzyme inhibition in the medulla oblongata are steep. Also, a steep dose-response curve for the depressor response to paraoxon is found. A reduction of brain enzyme activity to about 35% has no influence on blood pressure. However, inhibition by 65-100% induces dose-dependent depressor effects. The results support earlier findings that the depressor response to paraoxon is mediated by a central mechanism. This site of action is probably located within the medulla oblongata region.

Acetylcholinesterase↗

Inhibition of efferent sympathetic nerve activity by centrally administered paraoxon in the cat.

We recently found that central administration of the cholinesterase inhibitor paraoxon lowered blood pressure substantially. It was postulated that the decrease in pressure was mediated by a reduction of sympathetic outflow. In the present study, efferent splanchnic nerve activity in anaesthetized and paralysed cats was recorded, and quantified by measuring the variance of signal amplitude. After administration of 8 micrograms paraoxon into the vertebral arteries, blood pressure and splanchnic nerve activity decreased simultaneously. A mean fall of 46 +/- 6% and 45 +/- 13% (mean +/- S.E.M.) respectively was reached within 12 min and was maintained during the period studied (30 min). When the effect of paraoxon was antagonized by dexetimide, both blood pressure and splanchnic nerve activity returned to control values. Since previous work has shown that the depressor action could not be prevented by efferent vagal blockade it seems likely that the fall in blood pressure after paraoxon was mainly caused by a decreased sympathetic outflow. In addition, we varied the amplifier band width in recording splanchnic nerve activity. The measurement of frequencies between 10 and 225 Hz appeared to be sufficient for studying the change in activity after paraoxon.

Animals↗

Depressor effects of isoguvacine propyl ester and isoarecaidine propyl ester due to stimulation of central GABA receptors in the cat.

Upon their simultaneous administration into the left and right vertebral artery of the cat, 2 x 30 micrograms isoarecaidine propyl ester (IAPE) and 2 x 30 micrograms isoguvacine propyl ester (IGPE) induce hypotension and bradycardia. These effects were antagonized by (+)-bicuculline or picrotoxin. IAPE is rapidly hydrolyzed by cat brain tissue in vivo. It is suggested that both IAPE and IGPE are prodrugs and that the corresponding carboxylic acids are GABA agonists and responsible for the cardiovascular effects evoked.

Animals↗

The central effects of paraoxon on blood pressure of rabbits after intravenous administration or infusion via a vertebral artery.

In the present study paraoxon (28-825 micrograms/kg, i.v.) was administered into rabbits treated with N-methylatropine (1 mg/kg). In urethane-anaesthetized rabbits pressor and depressor effects were observed. In pentobarbitone-anaesthetized rabbits, however, only depresssor effects were noticed. Dexetimide (0.25-0.5 mg/kg) prevented the pressor and depressor action of paraoxon. Furthermore, paraoxon (83-825 micrograms) was infused into a vertebral artery of pentobarbitone-anaesthetized animals. After administration via this route the depressor effect was similar to i.v. administration. 30 min after administration of paraoxon acetylcholinesterase activity was determined in the medulla oblongata, the pons and the hypothalamus. The enzyme has to be inhibited almost completely to induce an effect on blood pressure. It is concluded that the vascular effects of paraoxon seem to be mediated by a mechanism involving stimulation of central muscarinic receptors, probably by accumulated acetylcholine, which in turn induces a decrease in blood pressure.

Acetylcholinesterase↗

The inotropic and chronotropic effects of physostigmine and neostigmine on guinea-pig isolated atria.

1 Physostigmine (0.1-1 mM) induced dose-dependent negative and neostigmine (0.1-1 mM) positive inotropic effects on driven guinea-pig isolated atria. Physostigmine decreased and neostigmine increased cardiac frequency of spontaneously beating atria. 2 The depression of amplitude of contraction by physostigmine cannot be attributed to its inhibitory effect on tissue cholinesterase. The negative inotropic action of physostigmine is not influenced by preincubation with atropine. 3 The positive inotropic effect of neostigmine is not caused by a nicotine-like action of the drug. Neostigmine (1 mM) counteracts the negative inotropic effect of acetylcholine. The possible mechanisms of action are discussed.

Animals↗

The effects of paraoxon on blood pressure in the anaesthetized and in the conscious rat.

1 Intravenous administration of paraoxon (150-825 mug/kg) to anaesthetized rats induced long-lasting, dose-dependent pressor effects. Only after injection of 825 mug/kg paraoxon was the pressor response followed by a depressor effect and a bradycardia that could be blocked by N-methylatropine. Intracerebroventricular injection of paraoxon into anaesthetized rats also induced pressor effects.2 In order to elucidate the mechanism of the pressor action rats were given dexetimide, N-methylatropine, mecamylamine, phentolamine, prazosin, yohimbine, atenolol and metoprolol. If treatment with these drugs resulted in a low initial blood pressure, vasopressin was infused to elevate blood pressure to normal levels. The influence of adrenalectomy, pretreatment with reserpine and midcollicular transection was also examined.3 The pressor effect of paraoxon was not influenced by N-methylatropine or mecamylamine. However, a combination of these drugs as well as dexetimide, phentolamine or prazosin combined with yohimbine, reduced or prevented the pressor effect.4 In conscious rats the effects of paraoxon and the action of antimuscarinic drugs upon the pressor response were similar to those observed in anaesthetized animals.5 Acetylcholinesterase activities were measured in various brain regions and in whole blood. Paraoxon concentrations within the CNS were also measured.6 It is concluded that the pressor effect of paraoxon in anaesthetized and conscious rats is mediated by a central mechanism, although a contribution of peripheral acetylcholinesterase inhibition in sympathetic ganglia to this pressor effect cannot be ruled out.

Acetylcholinesterase↗

The pressor effects of paraoxon in the pithed rat.

1 In pithed rats paraoxon 825 microgram/kg induced a short-lasting pressor effect. Lower doses of the drug were ineffective. 2 The pressor effect was prevented by N-methylatropine, dexetimide and alpha-receptor blocking agents but not by mecamylamine. 3 When blood pressure of pithed rats was elevated either by the continuous infusion of vasopressin or by electrical stimulation of the pithing rod, both 275 and 825 microgram/kg paraoxon induced further pressor effects. The effectiveness of various receptor blocking agents was similar to that observed in pithed rats without vasopressin. 4 It is concluded that the pressor effect of paraoxon is mediated by ganglionic muscarinic receptors. Stimulation of these receptors by accumulated acetylcholine results in an increase in postganglionic sympathetic activity and causes pressor effects. 5 The peripheral action of paraoxon is compared with its action in intact anaesthetized animals.

Animals↗

Centrally induced cardiovascular effects and kinetic behaviour of isoarecaidine propyl ester in the cat.

The present investigation deals with effects of isoarecaidine propyl ester (IAPE) on blood pressure and heart rate of the anaesthetized cat. The kinetic behaviour of the drug in plasma and various brain tissues was also studied. The results indicate that the ester (4 mg.kg-1) induces a depressor effect and bradycardia after i.v. administration. Injection of IAPE (up to 60 micrograms.kg-1) into the left vertebral artery lowers blood pressure in a dose-dependent manner. When administered simultaneously into the left and right vertebral artery, low doses (6 micrograms. kg-1) produce a substantial fall in blood pressure. Although the fall in blood pressure after i.v. injection lasts for more than 60 min, plasma half life is extremely short (t1/2 = 6.3 sec). The possible metabolism of the ester was studied in the pons, medulla oblongata and cerebellum. Thirty min after the injection into the left vertebral artery, IAPE is almost entirely hydrolyzed in the pontomedullary region. This degradation is prevented by pretreatment with paraoxon, that abolishes the depressor action of IAPE. It is suggested that accumulated isoarecaidine in the pontomedullary region is responsible for the depressor response to IAPE. Since IAPE does not seem to influence blood pressure and heart rate via a peripheral mechanism and lowers blood pressure and cardiac frequency by a central action, this drug is considered to be of pharmacological interest. The mechanism of action is discussed.

Animals↗

Quantitative determination of the cholinesterase inhibitor physostigmine in brain tissue samples using reversed-phase high-performance liquid chromatography.

A high-performance liquid chromatographic method, based on a dynamic cation-exchange system was used for the determination of physostigmine in brain tissue extracts. The precision and detection limit of the method as well as the extraction efficiency were established. The distribution of physostigmine over several parts of the brain after intravertebral application is reported.

Animals↗