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Biomedical subjects

E O Mikkelsen

Publications and source records attributed to E O Mikkelsen.

At least 19 recordsLinked to original sources
PubMed1992

Difference between aortic and renal vascular reactivity in cyclosporin A treated rats and the effect of cicletanine.

4 Groups of 2 month-old male Wistar rats were treated with a) cyclosporin A (CyA) 30 mg/kg/day alone, b) CyA plus cicletanine (Cic) 60 mg/kg/day, c) vehicle (vegetable oil) 1 ml/100 g rat/day and d) no treatment for 8 weeks. The reactivity of isolated papillary muscle to isoprenaline and Ca2+ was not altered in any of the treated groups. Endothelium-dependent relaxation induced by acetylcholine was inhibited in aorta ring segments from CyA-treated rats as compared to that of control and CyA + Cic-treated rats. The relaxation induced by acetylcholine in rat aortas was similar in all groups in the presence of 10 microM indomethacin. Noradrenaline sensitivity of aortic segments was not affected by any treatments applied. The Ca(2+)-concentration response curves of aorta segments from CyA-treated and CyA + Cic-treated rats were shifted to the right as compared to control rats. In interlobar renal arteries the endothelium-dependent relaxation induced by acetylcholine was not affected by any form of treatment. In renal arteries 10 microM indomethacin increased the maximal relaxation induced by acetylcholine about 50%. In these vessels noradrenaline sensitivity in CyA and CyA + Cic treated rats was higher than in controls. Cocaine, 3 microM, shifted the noradrenaline concentration response curve to the left about 0.4 log units in all renal vessel groups, thus renal vascular smooth muscle sensitivity to noradrenaline was significantly greater in vessels from rats receiving CyA than in vessels from control rats. Administration of CyA induced only slight renal morphological changes. Cic was without effect on CyA induced morphological abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Stereoselective pharmacodynamic action of (+)-S-12967 and (-)-S-12968, isomers of a new slow acting 1,4-dihydropyridine derivative with calcium channel agonistic and antagonistic effects on rat aorta.

The effects of (+)-S-12967 and (-)-S12968, isomers of a new dihydropyridine (1,4-DHP) derivative [2(7-amino 2,5-dioxaheptyl) 3-ethoxycarbonyl 4-(2,3-dichlorophenyl) 5-methoxycarbonyl 6-methyl 1,4-dihydropyridine] were studied on contractile responses of isolated thoracic aortas from rats and compared to that of nifedipine. The maximal relaxant effect of both isomers was reached in about 2 hr whereas the maximal relaxant effect to nifedipine was obtained within 30 min. The two 1,4-DPH isomers and nifedipine had a far more potent inhibitory effect on potassium (K+) than on noradrenaline (NA) induced contractions. They shifted the K+, Ca2+ and NA-concentration response-curves to the right and depressed the maximal vessel response to these agonists. Nifedipine was about 10 times more potent than the (-)-isomer which again was about 100 times more potent that the (+)-isomer. In contrast to nifedipine (-)-S-12968 and (+)-S-12967 had a dual action on K+ and Ca(2+)-induced contractions as both isomers in low concentrations, 3 x 10(-9)M and 3 x 10(-7)M, respectively, shifted the K(+)-concentration response curves to the left and increased the maximal response. In K(+)-depolarized preparations they increased the response to low Ca(2+)-concentrations without affecting the maximal vessel response at the highest Ca(2+)-concentrations. The result indicates that (+)-S-12967 and (-)-S-12968 possess Ca(2+)-agonistic as well as Ca-antagonistic properties. Compared to nifedipine both isomers are slow acting vasodilators. Their action as regards their potency is stereoselective and the (-)-isomer is more potent than the (+)-isomer.

Animals↗
PubMed1992

Comparison of the effects of thapsigargin and BAY K 8644 on spontaneous mechanical activity in rat portal vein and contractile responses of rat cardiac muscle.

The effect of thapsigargin, 10(-9)-10(-6) M, and Bay K 8644, 10(-9)-10(-7) M, was studied on isolated portal veins and cardiac muscles from rats. In rat portal veins thapsigargin induced a concentration dependent increase in the amplitude of the spontaneous mechanical activity without increasing the frequency of spontaneous activity. Thapsigargin was less effective than Bay K 8644 in increasing the amplitude of the mechanical activity. In contrast to thapsigargin Bay K 8644, 10(-6) M increases the frequency of the mechanical activity. Atropine, 10(-6) M, and phentolamine, 10(-6) M, had no effect on the thapsigargin and Bay K 8644 induced increase in mechanical activity. Nitrendipine, 10(-6) M, totally abolished the mechanical response in preparations stimulated by thapsigargin and Bay K 8644. In rat atrial and papillary muscles Bay K 8644 increases the frequency in right atrium and tension in both atrial and papillary muscles. Thapsigargin was without effect on the frequency and tension in the cardial preparations. In conclusion, thapsigargin increases the amplitude of spontaneous activity in rat portal veins. In contrast to Bay K 8644 thapsigargin was less effective in increasing the amplitude and had no effect on the frequency of spontaneous activity; furthermore, thapsigargin was without effect on cardiac muscles. The results support the view that an endoplasmatic Ca2(+)-pump sensitive to thapsigargin is of importance for spontaneous activity in portal veins while such pump is of minor importance for contractile activity in cardiac muscles.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Effects of pyrroloisoquinoline enantiomers ((+)- and (-)-McN-5652-Z) on behavioral and pharmacological serotonergic mechanisms in rats.

A behavioral syndrome consisting of 5-hydroxytryptamine (5-HT)-dependent behaviors (e.g. forepaw treading, retropulsion and splayed hindlimbs) as well as hyperthermia occurred after bilateral injection of the (6S, 10bR)-(+)-enantiomer of McN-5652-Z into the cerebral ventricles in pargyline-treated rats. Both the behavioral syndrome and hyperthermia produced by (+)-McN-5652-Z were counteracted by parachlorophenylalanine or ketanserin. The (6R, 10bS)-(-)-enantiomer of McN-5652-Z influenced neither behavior nor body temperature. The enantiomers of McN-5652-Z differed also in their ability to inhibit ex vivo binding of paroxetine in rat frontal cortex and hypothalamus, in vitro uptake of 5-HT in rat blood platelets, and 5-HT-induced contraction of rat vascular smooth muscle, with (+)-McN-5652-Z being most active. No difference was observed between the effects of (+)- and (-)-McN-5652-Z on 5-HT metabolism by rat brain monoamine oxidase. Molecular models of N-protonated enantiomers having a cis B,C-ring juncture and a B-ring chair conformation were differentiated using a hypothetical model of the 5-HT uptake area. The findings indicate that the enantiomers of McN-5652-Z are useful tools for studying the stereoselectivity of behavioral and pharmacological effects exerted by serotonergic neurotransmission.

Animals↗
PubMed1990

5-Hydroxytryptamine does not release endothelium-derived relaxing factor in rat isolated coronary arteries.

Removal of the endothelium from isolated rat proximal and distal coronary artery segments shifted the 5-HT concentration-response curve to the left without affecting, the maximal contractile response. 5-HT had no relaxing effect in 10(-5) M prostaglandin F2 alpha-precontracted vessels with an intact endothelium in the presence of 10(-5) M ketanserin. The spontaneous myogenic tone increased in both proximal and distal coronary artery segments after the endothelium had been removed. Indomethacin (10(-5) M) reduced the response of the proximal coronary artery segments to 5-HT by 35% but indomethacin had no effect on the 5-HT concentration-response curve of the distal coronary artery segments. Indomethacin relaxed precontracted (40 mM potassium) proximal coronary artery segments independently of the presence of the endothelium, suggesting a non-specific relaxing effect of indomethacin in these arteries. It is concluded that rat coronary artery endothelium is unresponsive to 5-HT because it lacks 5-HT1 receptors. The increased 5-HT sensitivity and spontaneous myogenic tone of endothelium-denuded rat coronary arteries is probably due to the elimination of the relaxing stimulus mediated by spontaneously released endothelium-derived relaxing factor.

Acetylcholine↗
PubMed1990

[Stereochemistry--an overlooked problem in medical treatment and research].

On the background of marketing of an increasing number of drug racemates with the subsequent problems for medical treatment and research, a short review is given focusing on the optic isomery and the significance of optic isomeric drugs for medical treatment and research. Different problems, which may arise in relation to the use of drug racemates are mentioned. The racemic problem is elucidated by examination of and reference to existing studies on drug racemates including studies on pharmacodynamic and pharmacokinetic properties of pure (+) and (-)enantiomers. As the receptor systems of the organism and the process of drug metabolization are stereoscelective, the ideal demand to drug racemates should be that they are regarded as two different drugs until investigations have clarified the degree of pharmacodynamic/pharmacokinetic differences between the (+) and (-)enantiomer. Whether the single enantiomer should be preferred to the racemate may be difficult to decide and may require considerable research, but solution of this can, on the other hand, give valuable advances in drug treatment, for instance in form of drugs with more selective and fewer side effects.

Chemistry, Pharmaceutical↗
PubMed1990

Studies on the stereoselective effects of a novel 5-HT2 receptor antagonist on contractile responses of rat aorta.

The effect of the enantiomers of a novel 5-HT2 receptor antagonist, (+/-)-(1R,3S)-1-[2-[4-[3-(p-fluorophenyl)-1-indanyl]-piperazinyl] ethyl]-2-imidazolidinone, was studied on serotonin (5-HT), noradrenaline (NA), potassium (K+), and calcium (Ca2+)-induced contractions in isolated rat thoracic aorta. The enantiomers shifted the 5-HT, NA, K+, and Ca2+ concentration-response curves to the right in a concentration-dependent manner and depressed the maximal contractile responses. The (+)-enantiomer was a far more potent inhibitor of 5-HT-induced contractions than the (-)-enantiomer. The (+)-enantiomer and phentolamine, both at 10(-6) M, had equal inhibitory effects on NA-evoked contractions. The (+)-enantiomer was again more potent inhibiting NA-induced contractions than the (-)-enantiomer. Both enantiomers had an equieffective inhibitory effect on K+ and Ca2(+)-induced contractions. The results show that the 5-HT and alpha-adrenoceptor antagonism of the two enantiomers is stereoselective, the (+)-enantiomer being more potent than the (-)-enantiomer. In contrast the enantiomers had equal, nonstereoselective inhibitory effects on K+ and Ca2(+)-evoked contractions.

Animals↗
PubMed1990

Effects of the optical isomers of a novel 5-HT2 antagonist and (-)-Bay K 8644 on spontaneous mechanical activity in rat portal veins.

The effect of the (+)-enantiomer (Ir) and the (-)-enantiomer (Lu) of a novel 5-HT2 antagonist was studied on spontaneous mechanical activity in rat portal veins and compared to that of the Ca-agonist (-)-Bay K 8644. Ir and Lu (10(-8) to 10(-5) M) were found to equally increase the spontaneous mechanical activity in rat portal veins. At high concentrations (10(-4) M) Ir and Lu totally abolished spontaneous activity. The frequency of the spontaneous activity was equally decreased by the two enantiomers. The increase in spontaneous activity induced by Ir and Lu was abolished in Ca-free medium and restored by readdition of Ca. The augmenting effect of the enantiomers on mechanical activity was not influenced by atropine but was totally eliminated by the Ca-antagonist nifedipine. The Ca-agonist (-)-Bay K 8644 was more potent in increasing the amplitude of the mechanical activity than the enantiomers and had a concentration-dependent increasing effect on the frequency of the spontaneous activity. The results indicate that in rat portal veins Ir and Lu have a dual non-stereoselective effect which may include a Ca-agonistic stimulating mechanism of action as well as a pacemaker blocking effect.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

[Bioaccessibility of diazepam administered as Valium and Valaxon tablets].

A double-blind, cross-over investigation undertaken of the bioaccessibility of diazepam in 12 healthy volunteers revealed that there is no significant difference as regards the bio-accessibility of diazepam administered as Valaxon or as Valium tablets. It is concluded that pharmokinetic studies such as this can provide important clinical information and are easy to carry out in a hospital department.

Adult↗
PubMed1988

Comparison of the effect of irindalone, a novel serotonin 5-HT2 antagonist and ketanserin on mechanical responses of rat thoracic aorta.

The relaxant effect of irindalone [+)-(1R, 3.S)-1-[2-[4-[3-(p-fluorophenyl)-1-indanyl]-1-piperazinyl] ethyl]2-imidazolidinone) and ketanserin was studies on active tension in isolated rat thoracic aorta. Irindalone and ketanserin caused a concentration-related inhibition of serotonin-induced contractions and shifted the serotonin curve to the right. Irindalone was more potent in inhibiting the serotonin-induced contractions and ketanserin was. The slopes of the Schild plots for the two substances were slightly, but not significantly, different from each other. This indicates that irindalone had a more pronounced serotonin antagonistic effect than ketanserin.

Animals↗
PubMed1988

Serotonin response increases with age in rat coronary resistance arteries.

The effect of aging on morphological and mechanical characteristics and the serotonin reactivity of ring preparations of coronary resistance arteries isolated from a specific part of the left coronary artery were studied in male Wistar rats at 6 weeks, 3 months, and 2 years of age. The media to lumen ratio of the coronary vessels was unaffected by aging, although the effective lumen diameter increased from 176 micron at 6 weeks to 212 micron at 2 years of age. The maximal active tension development, active pressure, and active media stress generation of the vessels were also unaffected by aging. At all ages the spontaneous calcium dependent intrinsic tone was similar, equal to 13% of maximal agonist induced tension development. Serotonin induced a concentration dependent contraction at all ages. Maximal vessel response to serotonin increased with age from 0.38 N.m-1 to 1.45 N.m-1 at 6 weeks and 2 years of age respectively. Serotonin sensitivity was higher in the older rats than in the younger rats. Tachyphylaxis to serotonin developed only in vessels from 6 week old rats. The results confirm that the morphology and mechanics of resistance arteries remain stable over a large age range but that the vascular reactivity to specific agents, such as serotonin, may change over that period. The results also indicate that the coronary blood flow may be seriously affected by serotonin induced vasoconstriction with increasing age in rats.

Aging↗
PubMed1988

Effects of thapsigargin in isolated rat thoracic aorta.

The effect of thapsigargin (Tg) was studied in rat thoracic aorta. Tg (10(-8)-10(-5) M) had a dual effect on rat aorta. Thus, Tg induced a concentration dependent increase in basal tone in normal physiological salt solution (PSS), while Tg in potassium (K+) precontracted aortic rings caused a concentration related relaxation and shifted the K+-concentration response curve to the right and depressed the maximal response to K+. Removal of vascular endothelium abolished the relaxant response to Tg and increased the sensitivity of the preparations to the contractile effect of Tg. The contractile response to Tg was resistent to wash-out in drug-free PSS and was not affected by phentolamine, indomethacin or mepyramine but partly reduced by the calcium-antagonist nitrendipine and eliminated by wash-out in calcium-free PSS. Atropine eliminated the endothelium dependent relaxant effect of carbachol, but had no effect on the Tg or on the calcium ionophore A 23187 evoked relaxation. Ultraviolet radiation decreased the relaxant effect of Tg and A 23187 without affecting the carbachol induced relaxations. The results showed that vascular endothelium depressed the contractile effect of Tg and that Tg like A 23187 had an endothelium dependent relaxant effect on rat aorta different from that of carbachol. The results indicate that Tg in vascular smooth muscle acts by stimulating the transmembranal influx of extracellular calcium.

Animals↗
PubMed1988

Influence of endothelium on the response to calcium agonists, calcium, potassium and noradrenaline in rat aorta.

We have studied the influence of endothelium on BAY K 8644, CGP 28392, potassium, noradrenaline and calcium induced responses in isolated thoracic aorta from rats. In aortic preparations with intact endothelium BAY K 8466 and CGP 28392 (10(-9)-10(-5) M) had a concentration dependent contractile effect, but BAY K 8644 was more effective in contracting the vessels than CGP 28932. Removal of endothelium increased the contractile response to both substances without affecting the difference in contractile effect between the two calcium agonists. In high concentrations (10(-4) M) BAY K 8644 and CGP 28392 had an equal relaxing effect on potassium precontracted preparations, which was unaffected by removal of endothelium. Removal of endothelium caused a shift to the left of the potassium and noradrenaline concentration response curves without any change in maximal contractile response. The contractile response to calcium in BAY K 8644 and potassium activated vessels was unaffected by removal of endothelium. We conclude that endothelium derived factor(s) depress the contractile response to calcium agonists, potassium, and noradrenaline but has no influence on the relaxant effect of BAY K 8644 and CGP 28392 in rat aorta. The influence of endothelium on the contractile effect on BAY K 8644 and potassium seems not to be due to a direct effect on calcium influx but rather to an influence on the membrane potential of the smooth muscle cells.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1987

Active, passive and myogenic characteristics of isolated rat intramural coronary resistance arteries.

We have investigated the active, passive and myogenic tension-internal circumference relations of rat intramural coronary and, as controls, mesenteric small arteries (internal diameter ca. 200 micron) using an isometric myograph. The active tensions of the vessels (when fully activated with 30 microM serotonin in K-saline) reached a maximum (2.54 N/m, coronary; 3.39 N/m, mesenteric) at an internal circumference, L0, where the passive tensions (measured in Ca-free solution) were 0.80 N/m (coronary) and 0.74 N/m (mesenteric). Below 0.8 L0 and above 1.2 L0 the active tensions fell linearly, the zero tension intercepts being 0.37 L0 and 1.74 L0 (coronary) and 0.40 L0 and 1.72 L0 (mesenteric). The passive wall tensions of the vessels rose exponentially as a function of internal circumference, the wall tension at 1.5 L0 being 10.0 N/m (coronary) and 8.5 N/m (mesenteric). In normal physiological salt solution, the coronary vessels had a Ca2+ dependent myogenic tone which was also dependent on the internal circumference. Maximum myogenic tone (0.54 N/m) was obtained at 1.18 L0. The mesenteric vessels had no such myogenic tone. Histological examination showed that the media/lumen ratios of both vessel types were the same, and that the smooth muscle content of the media was greater in the coronary (81%) than in the mesenteric (72%) vessels. The smaller active tension of the coronary vessels could not therefore be ascribed to a reduced smooth muscle content, but possibly in part to an observed heterogeneous arrangement of the smooth muscle cells in the coronary vessels.

Animals↗
PubMed1987

Comparison of the inhibitory effects of nifedipine and nimodipine on mechanical responses of isolated rat coronary small arteries.

The effect of nifedipine and nimodipine was studied on the spontaneous myogenic tone and on the serotonin-, potassium-, and calcium-induced contractile responses in coronary resistance arteries from 2-year-old male Wistar rats. Both drugs depressed completely and concentration-dependently the spontaneous myogenic tone. At the highest concentration, nifedipine and nimodipine reduced the serotonin and potassium responses to an average of 19% and 6% of control response. The drugs had an equipotent inhibitory effect on the serotonin response. Nimodipine, however, was more potent than nifedipine, inhibiting the potassium response. In vessels maximally activated by serotonin and potassium, both drugs concentration-dependently inhibited the calcium concentration-response curves. Nifedipine and nimodipine had an equieffective and equipotent inhibitory effect on the calcium responses in serotonin-activated vessels. Nimodipine was more potent than nifedipine, inhibiting the calcium response of potassium-activated vessels. In the highest concentration, nimodipine was also more effective than nifedipine (p less than 0.01) in inhibiting the calcium response. In conclusion, both nifedipine and nimodipine are potent and effective vasodilators, having similar actions on the spontaneous myogenic tone and serotonin-induced responses in the rat coronary resistance arteries, but nimodipine is more potent and more effective than nifedipine in inhibiting potassium-induced responses.

Animals↗