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Biomedical subjects

A J Porsius

Publications and source records attributed to A J Porsius.

At least 37 records · Page 2Linked to original sources
PubMed1994

Comparison of the antiatherogenic effects of isradipine and ramipril in cholesterol-fed rabbits: II. Effect on regression of atherosclerosis and restoration of endothelial function.

We report the effects of isradipine and ramipril on regression of diet-induced atherosclerosis in rabbits. Regression of diet-induced atherosclerosis was not significantly affected by ramipril, but isradipine significantly retarded regression. Thirty rabbits in three groups were fed a 0.3% cholesterol diet for 4 weeks. After this induction period, group IIr received the 0.3% cholesterol diet, group IIIr received the 0.3% cholesterol diet with isradipine (0.33 mg/kg/day), and group IVr received the 0.3% cholesterol diet with ramipril (0.33 mg/kg/day) for 12 more weeks. The rabbits then received a standard diet and remained on their respective drug regimen for 12 more weeks. Group Ir (10 rabbits) received a standard diet for 28 weeks. Acetylcholine (ACh)-induced maximal endothelium-dependent relaxations (EDR) of aortic rings were significantly less in group IIr (22.8 +/- 3.2%) than in group Ir (66.4 +/- 4.0%; p < 0.05). Ramipril and isradipine did not improve EDR as compared with group IIr. Regression of atherosclerosis was accompanied by an improved endothelium-dependent releasing factor (EDRF) release from the endothelium, but ramipril and isradipine did not promote this process. In addition, regression was associated with increasing sensitivity of vascular smooth muscle to EDRF that was significantly retarded by isradipine but not ramipril. Basal cyclic GMP levels were significantly reduced in aortic rings from group IIr as compared with group Ir. Ramipril, but not isradipine, restored basal cyclic GMP levels to control values. Both isradipine and ramipril protect against endothelial degeneration in hypercholesterolemic rabbits. However, isradipine but not ramipril inhibits regression of diet-induced atherosclerosis in rabbits.

Acetylcholine↗
PubMed1993

Modulation by pertussis toxin of salbutamol- and arecoline-induced effects in the isolated heart and aorta of the rat.

The modulatory effects of pertussis toxin pretreatment on responses mediated via beta-adrenoceptors and muscarinic acetylcholine receptors were investigated in isolated rat hearts and aortic rings 4 days after in vivo administration of pertussis toxin. In isolated hearts, pertussis toxin increased heart weight and baseline coronary flow values but did not effect baseline left ventricular pressure values. In unpaced hearts, pertussis toxin inhibited the arecoline-induced cardiac standstill, while in paced hearts, the beta 2-adrenoceptor agonist salbutamol produced a dose-dependent vasodilation with similar characteristics in pertussis toxin and control preparations. Pertussis toxin had no effect on myocardial or aortic cyclic nucleotide levels and the myocardial beta-adrenoceptor density (Bmax) and dissociation constant (Kd). In precontracted aortic rings, pertussis toxin had no effect on the salbutamol or arecoline induced vasorelaxation. In summary, we demonstrated a reduced cholinergic responsiveness in isolated hearts but an intact beta 2-adrenoceptor pathway in isolated hearts as well as in isolated aortic rings after pertussis toxin pretreatment. In aortic rings no change in muscarinic acetylcholine receptor responsiveness occurred.

Albuterol↗
PubMed1993

Vitamin E in extrapyramidal disorders.

In this article the effect of vitamin E on two extrapyramidal disorders, tardive dyskinesia and Parkinson's disease, is reviewed. After a brief description of the symptoms, the current hypotheses for the pathogenesis of these diseases are described. A summary of the clinical research that has been done to establish the effectiveness of vitamin E is given. In tardive dyskinesia four clinical trials (double-blind, placebo-controlled) showed improvement in the symptoms with vitamin E in doses of up to 1,600 IU/day. Preliminary studies concerning Parkinson's disease suggested that vitamin E (2,000 IU/day) probably cannot prevent the development of the disease. It was suggested that vitamin E is able to slow the progression of the illness. The results from a large double-blind, placebo-controlled clinical trial, however, did not show any beneficial effect of vitamin E in Parkinson's disease.

Basal Ganglia Diseases↗
PubMed1993

The use of hypoglycaemic and cardiovascular drugs in 582 patients with diabetes mellitus. Description and quality assessment.

The medication of 582 patients taking insulin or oral hypoglycaemic agents has been analysed. A characterization is given of the patients and their antidiabetic medication. Subsequently, a description of the use of cardiovascular drugs, in comparison with an age-matched control group, is presented. The diabetic population investigated has an average age of 67 years. Most cardiovascular agents, with the exception of thiazide diuretics, are used to a larger extent in the diabetic group in comparison with the control group. Non-selective beta-blockers, possibly hazardous in patients with diabetes mellitus, appear to be prescribed without restriction in the diabetic patients investigated. The results of this study suggest that the choice of drugs for the treatment of cardiovascular co-morbidity in patients with diabetes mellitus can be improved.

Adult↗
PubMed1992

A drug use review study in patients with obstructive lung disease. Assessment of the quality of drug therapy.

This study presents the results of an analysis of the pharmacy records of 778 patients with asthma or chronic obstructive lung diseases. The high percentage of patients taking oral corticosteroids was striking. Inhaled beta-agonists for use as needed have been prescribed to only a minority of patients using these agents. Only half of the patients on beta-agonists used inhaled corticosteroids prophylactically. Drug interactions capable of causing changes in plasma theophylline concentrations appeared in only a small number of patients. The results from studies like the one presented here can provide valuable data to be used for further discussion between physicians and pharmacists about rational drug therapy.

Adrenal Cortex Hormones↗
PubMed1992

Modulation of antigen- and ischemia-induced effects by the platelet-activating factor antagonist WEB-2086 in isolated sensitized rat hearts.

The modulatory role of the platelet-activating factor (PAF) antagonist WEB-2086 (30 microM) on the response to antigen-induced (trinitrophenyl-haptenized ovalbumin) and global ischemia (30 and 60 min)-induced changes in the response to antigen was studied in isolated hearts from actively sensitized rats. In sensitized normoxic hearts, both antigen (0.8 mg) and PAF (100 pmol) induced a short-term increase followed by a long-term decrease in coronary flow (CF). The antigen- but not the PAF-evoked increase in CF was accompanied by a substantial release of histamine. WEB-2086 enhanced the vasodilator effect and abolished the vasoconstrictor effect of 100 pmol of PAF but neither modified the coronary vascular effects of antigen nor the antigen-induced histamine release. Ischemia for 60 min followed by 30 min of reperfusion increased the diastolic left ventricular pressure but a 30-min period of ischemia and reperfusion had no effect on baseline cardiac function. WEB-2086 had no effect on ischemia-induced changes in cardiac function. A 30-min period of global ischemia enhanced the antigen-induced decrease in CF and systolic left ventricular pressure (SLVP). A 60 min period, however, suppressed the antigen-induced effects on CF and SLVP as well as antigen-induced histamine release. WEB-2086 partly protected the heart against the enhanced antigen-induced decrease in CF and SLVP after a 30-min period of global ischemia but no modulatory role of WEB-2086 was observed after 60 min of global ischemia. Our conclusions are that (a) PAF is not involved in rat cardiac anaphylaxis since WEB-2086 was proven to be inactive; (b) cardiac ischemia and cardiac anaphylaxis have interrelated mechanism of action since ischemia changed the anaphylactic response, which indicates that coincidence of these two pathological events could influence the clinical outcome; and (c) PAF is possibly involved in rat cardiac ischemia since WEB-2086 partly protected the heart against the enhanced antigen-induced decrease in CF and SLVP after 30 min of ischemia and reperfusion.

Anaphylaxis↗
PubMed1991

Functional characterization of the muscarinic receptor in rat lungs.

The effects of various muscarinic antagonists on antigen- and acetylcholine-induced bronchoconstriction were studied. In isolated and ventilated lungs of naive rats, the pA2 values with respect to acetylcholine-induced bronchoconstriction were 9.01 (atropine), 8.39 (ipratropium bromide), 7.39 (pirenzepine), 5.94 (AF-DX 116, a M2-selective muscarinic antagonist), 6.91 (UH-AH 37, a novel muscarinic antagonist) and 9.37 (4-DAMP: 4-diphenylacetoxy-N-methylpiperidine methobromide). Except for ipratropium bromide, the slopes of the Schild plots were not significantly different from unity. None of the drugs were potent or effective in inhibiting bronchoconstriction or histamine release evoked by antigen challenge in actively sensitized rats. However, in vivo, in anesthetized spontaneously breathing rats, vagotomy and atropine (1 mg/kg) did reduce antigen-induced bronchoconstriction. It is concluded that functional muscarinic receptors in isolated rat lungs are probably of the M3 receptor subtype. With respect to antigen-induced bronchoconstriction and mediator release in a denervated model such as the isolated lung, they are of little, if any, importance. In vivo, vagotomy and atropine reduced antigen-induced bronchoconstriction, probably by blockade of a vagal reflex which is thought to play a role in antigen-evoked bronchoconstriction.

Acetylcholine↗
PubMed1991

Effects of milrinone, sulmazole and theophylline on adenosine enhancement of antigen-induced bronchoconstriction and mediator release in rat isolated lungs.

The effects of adenosine and some of its analogues on bronchoconstriction and mediator release were studied in isolated lungs of actively sensitized rats. The influence of two novel cardiotonic drugs, milrinone and sulmazole on these adenosine-induced effects was compared with that of theophylline, a well known adenosine antagonist. Adenosine (ADO) and its analogues N-ethyl-carboxamide-adenosine (NECA) and R-phenyl-isopropyladenosine (R-PIA), dose-dependently enhanced antigen-induced bronchoconstriction. The enhancement of anaphylactic bronchoconstriction by adenosine and its analogues was accompanied by a rise in histamine release. The rank order of potency for adenosine and analogues with respect to enhancement of anaphylactic bronchoconstriction, was NECA greater than or equal to R-PIA greater than ADO. An unequivocal classification of the adenosine receptor involved, was therefore not possible. Dipyridamole and S-(p-nitrobenzyl-6-thioinosine) (NBTI), both inhibitors of adenosine uptake, had no inhibitory influence on the adenosine-induced enhancement of anaphylactic bronchoconstriction, indicating that this enhancement is mediated by an extra-cellular receptor. Theophylline, milrinone and sulmazole inhibited the enhancement of anaphylactic bronchoconstriction, without affecting preformed mediator release. Theophylline and sulmazole were both more effective as inhibitors of adenosine-enhanced bronchoconstriction than as inhibitors of antigen-induced bronchoconstriction, suggesting adenosine antagonism. Milrinone was equi-effective as inhibitor of both types of bronchoconstriction. Since adenosine antagonism has been associated with the side effects of theophylline it will be interesting to further investigate the therapeutic merits of novel cyclic nucleotide phosphodiesterase inhibitors in the treatment of asthma.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1991

Cardiovascular responses to the stereoisomers of dobutamine in isolated rat hearts 48 hours after acute myocardial infarction.

Effects of acute myocardial infarction (48 h) on cardiovascular responses to (+/-)-, (-)-, and (+)-dobutamine were studied in isolated perfused rat hearts. The effects of the racemate and the isomers on ventricular pressure were measured simultaneously in infarcted left ventricle and noninfarcted right ventricle. Administration of (+/-)-, (-)-, and (+)-dobutamine resulted in dose-dependent increases in inotropic parameters and coronary flow (CF) in both control and in infarcted hearts. As compared with the (+)-isomer, the racemate and the (-)-isomer in both control and infarcted hearts were approximately 1.5 and 15 times weaker with respect to inotropic parameters. For (+/-)-, (-)-, and (+)-dobutamine, there was no significant difference in pD2 values in any of the inotropic measurements between the infarcted group and the corresponding control group. The maximal obtainable responses were significantly lower in the infarcted groups as compared with their corresponding control group. In control hearts, effects of isoproterenol and methoxamine as compared with (+/-)-dobutamine were approximately 2 log units more and 2 log units less in potency, respectively. The inotropic effects of (-)-dobutamine but not those of methoxamine were completely antagonized by propranolol (0.3 microM). Although the results provide evidence for the existence of myocardial alpha 1-adrenoceptors, all forms of dobutamine exerted positive inotropic effects through activation of beta-adrenoceptors both in control and in infarcted in rat hearts.

Adrenergic alpha-Agonists↗
PubMed1991

Characterization and modulation of antigen-induced effects in isolated rat heart.

The response to antigen (trinitro-phenyl-haptenized ovalbumin) and the modulatory role of several antiallergic drugs was studied in isolated hearts from actively sensitized rats. Antigen induced a triphasic effect on coronary flow (CF) and left ventricular pressure (LVP) characterized by short-term increase (0-1.5 min = phase 1) and a severe decrease (1.5-7.5 min = phase 2) followed by a less pronounced long-lasting decrease (7.5- greater than 20 min = phase 3). The first phase was accompanied with a substantial release of 5-hydroxytryptamine (5-HT), histamine, and leukotrienes measured in cardiac effluents. The histamine2 (H2)-receptor antagonist cimetidine (60 microM) reversed the antigen-induced increase in CF to a decrease. In contrast, H1-receptor blockade by mepyramine (6 microM) had no effect. Methysergide (10 microM) and ketotifen (0.1 microM) evoked a mild suppression during all three phases. Indomethacin (10 microM) was almost inactive while tolfenamic acid (1 microM) was slightly active in this respect during phase 2. Addition of the 5-lipoxygenase inhibitor AA 861 (1 microM) resulted in complete suppression of the antigen-induced decrease in CF. The leukotriene antagonist FPL 55712 (5 and 50 nM) evoked a dose-dependent suppression with respect to the anaphylactic phases 2 and 3. A similar reduction was obtained with sodium cromoglycate (1 mM). AA 861, FPL 55712, and sodium cromoglycate also suppressed the antigen-induced decrease in LVP. The antigen-induced histamine release was not affected by the aforementioned drugs. Our results provide evidence that H2-receptor blockade during cardiac anaphylaxis enhances coronary constriction and may be detrimental in this condition. On the other hand, leukotriene antagonists and 5-lipoxygenase inhibitors may exert beneficial effects during cardiac anaphylaxis. Further experiments in this area are needed to clarify the precise role of mast cell-generated mediators in cardiac anaphylaxis possibly leading to new therapeutic approaches in this life-threatening disorder.

Anaphylaxis↗
PubMed1990

Cardiovascular responses to milrinone in pertussis toxin-pretreated pithed rats.

The modulating effects of pertussis toxin on angiotensin II and B-HT 920-evoked hemodynamic changes were compared with those of milrinone to evaluate the possible role of guanine nucleotide regulatory proteins (G proteins) in the mechanism of action of milrinone. Both milrinone and pertussis toxin shifted the blood pressure dose-response curves of B-HT 920 to the right, but the responses to angiotensin II were decreased after milrinone pretreatment only. The increase in cardiac frequency evoked by milrinone and isobutylmethylxanthine (IBMX) was not sensitive to pertussis toxin. In contrast, the decrease in systolic blood pressure elicited by milrinone could be prevented by pertussis toxin pretreatment, suggesting the involvement of a regulatory protein. Milrinone and IBMX did not influence the effects of arecoline on blood pressure or heart rate in either normal or pertussis toxin-pretreated rats. It is concluded that milrinone may affect a G protein, but not the adenylate cyclase-associated inhibitory protein, Gi.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Plasma elimination of milrinone in rats in relation to its hemodynamic effects.

Milrinone (1,6-dihydro-2-methyl-6-oxo[3,4'-bipyridine]-5-carbonitrile) is a cardiotonic drug, currently under clinical investigation for the treatment of congestive heart failure. Its positive inotropic properties and its strong vasodilative action contribute to a favorable therapeutic effect. Plasma elimination of milrinone is generally by renal excretion of the unchanged drug. Since hemodynamic effects might influence the pharmacokinetics of renally eliminated drugs, we have investigated the plasma elimination of milrinone after different iv bolus doses of the compound in healthy rats. Half-times were 20.6 +/- 5.5 min (0.3 mg/kg milrinone), 17.0 +/- 1.8 min (1.0 mg/kg), 31.4 +/- 4.5 min (3.0 mg/kg), and 95.5 +/- 18.4 min (10.0 mg/kg). Clearances of milrinone showed a positive correlation with doses. Hemodynamic effects were dose dependent and (plasma) concentration dependent, and the maximum decrease in diastolic blood pressure was 54.5 +/- 0.5 mmHg. The half-effective plasma concentration of milrinone was 1.0 +/- 0.2 microM. The maximum increase in heart rate was 15%. We conclude that milrinone plasma elimination in rats is dose dependent, probably resulting from its strong vasodilator properties.

Animals↗
PubMed1990

Adenosine enhances antigen-induced bronchoconstriction and histamine release in rat isolated lungs.

The effects of adenosine and some of its analogues on bronchoconstriction and mediator release were studied in isolated lungs of actively sensitized rats. Adenosine (ADO) and its analogues R-phenyl-iso-propyl-adenosine (R-PIA) and N-ethyl-carboxamide-adenosine (NECA), enhanced antigen-induced bronchoconstriction in a dose-dependent manner. The enhancement of anaphylactic bronchoconstriction by adenosine and its analogues was accompanied by a rise in histamine release. The observed rank order of potency for adenosine and analogues (NECA greater than or equal to R-PIA greater than ADO) did not permit an unequivocal classification of the adenosine receptor involved. Dipyridamole and S-(p-nitrobenzyl-6-thioinosine) (NBTI), both inhibitors of adenosine uptake, had no inhibitory influence on the adenosine-induced enhancement of anaphylactic bronchoconstriction. Therefore, this enhancement was likely to be mediated through an extra-cellular receptor. Theophylline inhibited the enhancement of anaphylactic bronchoconstriction by adenosine in a concentration-dependent manner, without affecting preformed mediator release.

Adenosine↗
PubMed1990

Modulation of histamine release by rat peritoneal mast cells in a superfusion set-up.

A new method is presented for studying mediator release in isolated peritoneal cells of the rat. Using a superfusion technique, cells can be maintained in a continuously cleared medium. Cells were stimulated with antigen, compound 48/80 or A23187 to characterize this preparation. In addition, inhibitory effects of theophylline, isoprenaline and cromoglycate on compound 48/80-induced histamine release were studied. We conclude that superfusion is a valid alternative to study mediator release from isolated peritoneal cells.

Animals↗
PubMed1990

Modulation of adrenoceptor-mediated cardiovascular effects by short-term in vivo infusion of isoproterenol in rats.

After a 16-h in vivo infusion period of isoproterenol (400 micrograms/kg/h) from a minipump implanted subcutaneously (s.c.) in rats, we observed an increase in heart weight due to tissue edema. In isolated perfused heart preparations, the EC50s of isoproterenol to induce positive inotropy and increase in coronary flow were increased approximately 7 and 4 times, respectively. Isoproterenol dose-response curves performed in trachea preparations, were shifted to the right by about fivefold as compared with the control group. In the presence of phentolamine, the isoproterenol induced maximal relaxation in the isolated aorta from isoproterenol-pretreated animals was reduced from 46.5 to 9.2% as compared with saline-pretreated rats. In the absence of phentolamine, the epinephrine (EPI) and norepinephrine (NE) cumulative dose-response curves in this preparation were not affected by isoproterenol pretreatment with respect to EC50 and maximal effect. However, in the presence of phentolamine, the contractile response to a supramaximal dose of NE (10 microM) amounted to 30 and 70% in the saline- and isoproterenol-pretreated rats, respectively. In the presence of both phentolamine and propranolol, a similar response of 70% was observed by this supramaximal dose of agonist in the saline-pretreated rats as well. In anesthetized rats, 120 min after removal of the minipumps, sodium nitroprusside induced increase in heart rate (HR) was reduced after isoproterenol pretreatment, whereas for salbutamol the decrease in diastolic blood pressure (DBP) was also reduced. As compared with salbutamol, a marked increase was observed in the ratio of mean arterial blood pressure (MAP) to HR for SNP after isoproterenol pretreatment. The phenylephrine-induced increase in MAP was increased after isoproterenol pretreatment. We conclude that in the pathogenesis of heart failure the beta-adrenoceptor-mediated effects of catecholamines are attenuated and alpha-adrenoceptor-mediated effects become progressively important.

Animals↗