Journal of pharmacological methods最新文献

{"title":"Simple method to produce acute heart failure by coronary vessel embolization in closed chest rats with muspheres","authors":"E.A. Gorodetskaya,&nbsp;S.F. Dugin,&nbsp;O.S. Medvedev,&nbsp;A.E. Allabergenova","doi":"10.1016/0160-5402(90)90048-P","DOIUrl":"10.1016/0160-5402(90)90048-P","url":null,"abstract":"<div><p>Changes in left ventricle (LV) function, systemic, and regional hemodynamics as a result of coronary artery embolization by 15 μm muspheres were studied in rats. Selective coronary embolization was produced by injection of muspheres during ascending aorta occlusion animals by using an “L”-shaped wire in closed chest animals. Maximal developed LV systolic pressure (LVSP_max) was determined during ascending aorta occlusion. Coronary embolization evoked reductions in LVSP_max and + dP/dt_max and then decreased in basal LVSP, dP/dt_max, dP/dt_max/P, with a parallel increase in LV end-diastolic pressure (LVEDP). The number of muspheres accumulating in the heart following coronary embolization was about 40% of the total amount of the injected muspheres (300,000–400,000). In conscious rats 48 hr after coronary vessel embolization (in LV myocardium 100,003 ± 4,334 muspheres per gram) the cardiac index, mean arterial pressure, −dP/ dt_max and stroke volume were reduced by 35.6%, 20%, 17.2%, and 26.7%, respectively, when compared with sham-operated rats. LVEDP was increased by 40%, when compared with sham-operated rats. These results show that in this rat model of coronary vessel embolization heart failure develops. The model created may be used for the studies of pathophysiology of acute heart failure as well as for screening new compounds potentially effective in heart failure.</p></div>","PeriodicalId":16819,"journal":{"name":"Journal of pharmacological methods","volume":"24 1","pages":"Pages 43-51"},"PeriodicalIF":0.0,"publicationDate":"1990-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0160-5402(90)90048-P","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13368869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New chronic gastric cannula for feeding ethanol liquid diet to young and old rats","authors":"Donald H. Johnson ,&nbsp;Robert E. Kimura ,&nbsp;Raymond E. Galinsky","doi":"10.1016/0160-5402(90)90047-O","DOIUrl":"10.1016/0160-5402(90)90047-O","url":null,"abstract":"<div><p>Fifty-eight male Fischer-344 rats ages 5 and 23 mo were fed a liquid diet containing ethanol for 6 wk by means of a newly designed chronic gastric cannula that permitted maximum allowable freedom with minimum stress. Rats were weaned onto the Lieber-DeCarIi diet and fed 10 mL three times daily by bolus injection. With or without ethanol, the minimum daily intake of calories necessary to maintain body weight was determined to be approximately 150–160 kcal/kg/day for the young adult rats and 120–125 kcal/kg/day for the aged animals.</p></div>","PeriodicalId":16819,"journal":{"name":"Journal of pharmacological methods","volume":"24 1","pages":"Pages 37-42"},"PeriodicalIF":0.0,"publicationDate":"1990-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0160-5402(90)90047-O","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13368868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebral ischemia model with conscious mice","authors":"Norio Himori ,&nbsp;Hiroshi Watanabe,&nbsp;Nobuhide Akaike,&nbsp;Mitsue Kurasawa,&nbsp;Jiro Itoh,&nbsp;Yushiro Tanaka","doi":"10.1016/0160-5402(90)90059-T","DOIUrl":"10.1016/0160-5402(90)90059-T","url":null,"abstract":"<div><p>During anesthesia in mice, both common carotid arteries were tied loosely with an overhand knot suture (an occluder), while two snares (releasers) were placed in the knot so that it could be repeatedly tightened to occlude the arteries and loosened again to allow for reperfusion while the mice were conscious and unrestrained. The incidence of mortality as well as impairment of brain metabolism depended upon the length of cerebral ischemia. Cortical electroencephalogram (EEG) clearly reflected the regional ischemia as evidenced by electrical quiescence. Less mortality was observed with ischemic mice treated with dextrorphan (30 <span><math><mtext>mg</mtext><mtext>kg</mtext></math></span> p.o.). On day 1 (24 hr after ischemia), there were impairments in complex motor coordination, multichoice swim performance, and step-through or thermal pain-motivated avoidance responses. Thereafter, the battery of tests progressively improved. This improvement depended on the period of resumption of cerebral blood flow; the 7-day, postischemic lapse significantly reduced the deficit observed. Reduction in the degree of habituation of exploratory activity was also clearly observed following ischemic insult. Dextrorphan (1–30<span><math><mtext>mg</mtext><mtext>kg</mtext></math></span>i.p.) given to ischemic mice was effective in the habituation and step-through-type passive avoidance test paradigms. In conclusion, 1) the decline in cognition as observed with ischemic mice is due to the temporal and reversible derangement of their neuronal networks; 2) excessively released glutamate is probably of major pathogenic importance in the consequences of cerebral ischemia based on the positive results of the N-methyl-D-aspartate receptor antagonist, dextrorphan; 3) the simple technique could be useful in elucidating the pathophysiologic mechanisms of ischemically elicited derangement of the cerebral organization; and 4) the model could be used to assess the efficiency of drugs with high clinical predictivity.</p></div>","PeriodicalId":16819,"journal":{"name":"Journal of pharmacological methods","volume":"23 4","pages":"Pages 311-327"},"PeriodicalIF":0.0,"publicationDate":"1990-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0160-5402(90)90059-T","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13318676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rat model for evaluating inhibitors of human renin","authors":"Donald T. Pals,&nbsp;Judy A. Lawson,&nbsp;Sally J. Couch","doi":"10.1016/0160-5402(90)90052-M","DOIUrl":"10.1016/0160-5402(90)90052-M","url":null,"abstract":"<div><p>A rat model that provides a rapid method for the in vivo evaluation of potential inhibitors of human renin has been developed and validated. Recombinant human renin was infused intravenously into anesthetized, nephrectomized, ganglion-blocked rats. The resulting blood pressure had an approximate 60 mm Hg human renin-dependent component. The angiotensin I to angiotensin II converting enzyme inhibitor, captopril, and the renin inhibitor, ditekiren (U-71038), were capable of abolishing this component after oral administration. Oral administration of ditekiren to rats receiving human renin infusions evoked dose-dependent hypotensive responses that were greater in magnitude and longer in duration than those elicited in rats receiving hog renin infusions. Observations made in the renin-infused rats reflected the results of in vitro kinetic studies that had indicated a greater binding affinity of ditekiren for human renin than for hog renin.</p></div>","PeriodicalId":16819,"journal":{"name":"Journal of pharmacological methods","volume":"23 4","pages":"Pages 239-245"},"PeriodicalIF":0.0,"publicationDate":"1990-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0160-5402(90)90052-M","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13349081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of muscarinic cholinergic drugs as determined by ex vivo (3H)-oxotremorine-M binding","authors":"V.H. Sethy,&nbsp;J.W. Francis","doi":"10.1016/0160-5402(90)90057-R","DOIUrl":"10.1016/0160-5402(90)90057-R","url":null,"abstract":"<div><p>The pharmacokinetic parameters of muscarinic cholinergic drugs after intravenous (IV) and oral administration to mice was determined with ex vivo (3H)-oxotremorine-M (3H-Oxt) binding to the brain. Oxotremorine had a long duration of action, and arecoline had a short one. There was a significant correlation between the ex vivo ED50 and the in vitro inhibition constants (Ki). Tremorine, a prodrug, inhibited ex vivo binding, but was relatively inactive in in vitro binding. The quaternary amines, methylscopolamine and oxotremorine-M, and the hydrophilic compound, pirenzepine, were relatively weak in inhibiting ex vivo binding because of their poor penetration of the blood-brain barrier. Oxotremorine and BM-5 were similarly bioavailable to the brain by the IV and the oral route. These results indicate that the pharmacokinetic profile of muscarinic cholinergic drugs can be determined with ex vivo (3H)-Oxt binding.</p></div>","PeriodicalId":16819,"journal":{"name":"Journal of pharmacological methods","volume":"23 4","pages":"Pages 285-296"},"PeriodicalIF":0.0,"publicationDate":"1990-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0160-5402(90)90057-R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13519560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Statistical modeling of the effects of drug combinations","authors":"John L. Plummer ,&nbsp;Tim G. Short","doi":"10.1016/0160-5402(90)90058-S","DOIUrl":"10.1016/0160-5402(90)90058-S","url":null,"abstract":"<div><p>A method is described for identifying and quantitating departures from additivity (i.e., synergism and antagonism) when drugs having like effects are given in combination. It is applicable for both graded and quantal (e.g., after probit or logit transformation) responses. Log(dose)-response curves of both drugs should be linear but need not be parallel. The following model is fitted to dose-response data for both the individual drugs and combinations of drugs: <em>Y</em> = <em>β</em>_<em>o</em> + β₁log(iA + p.b + β₄(A.P.B)^{<span><math><mtext>1</mtext><mtext>2</mtext></math></span>} where <em>Y</em> is the response, <em>A</em> is the amount of drug <em>A</em>, <em>B</em> is the amount of drug <em>B</em>, and <em>P</em> is a relative potency of the drugs given by <em>log</em>(<em>P</em>) = <em>β</em>₂ + <em>β</em>₃<em>log</em>(<em>B</em>'), in which <em>B</em>' is the solution to <em>B</em>' — <em>B</em> — <span><math><mtext>A</mtext><mtext>P</mtext></math></span> = 0. If log(dose)-response curves of the two drugs are parallel, β₃ = 0, and <em>P</em> becomes a constant parameter to be estimated. A positive value of β₄ corresponds to synergism and a negative value to antagonism. Hypothesis tests may be carried out to determine whether β₄ is significantly different from zero.</p></div>","PeriodicalId":16819,"journal":{"name":"Journal of pharmacological methods","volume":"23 4","pages":"Pages 297-309"},"PeriodicalIF":0.0,"publicationDate":"1990-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0160-5402(90)90058-S","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13349082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved methods for baroreceptor investigations in chronically instrumented rats","authors":"Roland Veelken,&nbsp;Thomas Unger,&nbsp;Oleg S. Medvedev","doi":"10.1016/0160-5402(90)90053-N","DOIUrl":"10.1016/0160-5402(90)90053-N","url":null,"abstract":"<div><p>We developed a novel approach using inflatable cuffs in order to test the baroreceptor reflex in conscious rats. The cuffs we employed differ from previous approaches in which cuffs are implanted in the thorax. Instead, we placed cuffs around the abdominal aorta and vena cava immediately below the diaphragm. We assessed the utility of this approach in several ways. First, we found that implantation could be accomplished without the stress associated with opening the thoracic cavity. Functioning preparations were far easier to obtain compared to the thoracic approach. The thoracic approach using two-vessel constriction resulted in inordinant mortality and failed preparations. We found that blood pressure changes could be easily exerted over a considerable range in conscious animals with the abdominal cuffs. For instance, blood pressure could be easily manipulated over a range of 100 mmHg (increased or decreased by 50 mmHg from baseline). This simpler and more reliable approach will facilitate baroreceptor investigations in conscious rats.</p></div>","PeriodicalId":16819,"journal":{"name":"Journal of pharmacological methods","volume":"23 4","pages":"Pages 247-254"},"PeriodicalIF":0.0,"publicationDate":"1990-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0160-5402(90)90053-N","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13518171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Tris, HEPES, and TES buffers on binding at μ-, δ-, and κ-opioid sites in guinea pig brain","authors":"S.J. Paterson,&nbsp;L.E. Robson,&nbsp;H.W. Kosterlitz,&nbsp;W-Q. Jin","doi":"10.1016/0160-5402(90)90056-Q","DOIUrl":"10.1016/0160-5402(90)90056-Q","url":null,"abstract":"<div><p>In homogenates of guinea-pig brain minus cerebellum, the δ-binding of 1.5 nM [³H]-[D-Pen²,D-Pen⁵]enkephalin is little affected by the type and concentration of the three buffers, Tris-HCl, HEPES-KOH, or TES-KOH (10–75 mM). However, the μ-binding of 1 nM [³H][D]A[a²,MePhe⁴,GIy-ol⁵]enkephalin or the κ-binding of 1.5 nM [³H]-U-69,593 is influenced by the choice of buffer. A suitable concentration of buffer for further analyses of opioid binding has been found to be 10 mM. At each site, the effects of MgCl₂ on binding are the same whether 10 mM Tris-HCl, HEPES-KOH, or TES-KOH are used but variations of the effects of NaCl confirm the view that μ- and κ-sites, but not δ-sites, are affected by choice of buffer. Furthermore, under some assay conditions the effects of NaCl and MgCl₂ at the κ-sites of guinea-pig cerebellum differ from their effects in brain minus cerebellum, indicating that these are differences of binding characteristics at the κ-sites of these tissues.</p></div>","PeriodicalId":16819,"journal":{"name":"Journal of pharmacological methods","volume":"23 4","pages":"Pages 275-283"},"PeriodicalIF":0.0,"publicationDate":"1990-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0160-5402(90)90056-Q","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13318675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in the ionic environment may alter the kind of antagonism of some histamine H2-receptor blockers in the guinea pig papillary muscle","authors":"E. Poli,&nbsp;G. Coruzzi,&nbsp;G. Bertaccini","doi":"10.1016/0160-5402(90)90055-P","DOIUrl":"10.1016/0160-5402(90)90055-P","url":null,"abstract":"<div><p>The effect of changes in the composition of the bathing medium on the effect of histamine and histamine H₂-receptor antagonists was investigated in the isolated guinea pig papillary muscle. Ringer or Krebs-Henseleit solutions were used as nutrient fluids. They mainly differed with respect to pH and to Mg²⁺ and H₂ PO₄⁻ content. Whereas the effect of histamine was not altered by ionic changes, the antagonism by some H₂ blockers was different in the two nutrient solutions. The insurmountable antagonism elicited by high concentrations (≥10⁻⁶M) of famotidine, oxmetidine and mifentidine in Ringer solution was converted to surmountable when these drugs were tested in Krebs-Henseleit solution. Conversely, the antagonism induced by ranitidine was surmountable in both solutions, and that induced by high amounts of loxtidine was insurmountable in both nutrient fluids. Results obtained in Ringer solution were not modified by pH adjustments or by the addition of ions present in Krebs-Henseleit medium. These results suggest that the interaction of histamine with H₂ receptors in the guinea pig papillary muscle was not influenced by alterations in the ionic composition of the nutrient fluid, whereas the antagonism may be critically dependent on the ionic environment.</p></div>","PeriodicalId":16819,"journal":{"name":"Journal of pharmacological methods","volume":"23 4","pages":"Pages 265-274"},"PeriodicalIF":0.0,"publicationDate":"1990-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0160-5402(90)90055-P","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13130284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug effects on function in the ferret ischemic hindlimb","authors":"Edward O. Weselcouch,&nbsp;Christine D. Demusz","doi":"10.1016/0160-5402(90)90054-O","DOIUrl":"10.1016/0160-5402(90)90054-O","url":null,"abstract":"<div><p>In this article a new model of peripheral occlusive arterial disease is described. The lower hindlimb of an anesthetized ferret was fixed to a holder, the distal end of the Achilles tendon attached to an isometric force transducer, and a passive preload of 100 g was applied to the muscle preparation. The hindlimb was stimulated to contract isometrically via supramaximal electrical stimulation of the sciatic nerve. During the initial period, when femoral blood pressure equaled aortic blood pressure, net contractile force peaked within 1 or 2 min (372 ± 24<em>g</em>, <em>n</em> = 20) and gradually declined to about 85% of peak over 20 min. Following 60 min of ischemia (induced by partial occlusion of the abdominal aorta), when blood pressure in the contralateral femoral artery was about 45 mm Hg, the 15-min area under the force-time curve (AUC) was 33.2 ± 2.5% (<em>n</em> = 4) of the initial value. To validate the utility of this model in the search for treatment of peripheral vascular diseases, two drugs were tested. Pentoxifylline, which is clinically effective, attenuated the loss of function observed during ischemia in a dose-related manner, but nifedipine, which is without clinical benefit, had no effect at a dose that was extremely hypotensive. Because femoral perfusion pressure was controlled, systemic hemodynamic effects of test compounds are minimized as potential mechanisms of action, simplifying the evaluation of novel pharmacotherapy for treatment of ischemic diseases.</p></div>","PeriodicalId":16819,"journal":{"name":"Journal of pharmacological methods","volume":"23 4","pages":"Pages 255-264"},"PeriodicalIF":0.0,"publicationDate":"1990-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0160-5402(90)90054-O","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13518172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}