Biomedical subjects

M V Budihna

Publications and source records attributed to M V Budihna.

5 recordsLinked to original sources

PubMed1999

Stereoselective and endothelium-independent action of nicardipine on the isolated porcine coronary artery.

The qualitative and quantitative effects of the (+)-S and (-)-R enantiomers and of the racemic mixture of the Ca2+ channel antagonist, nicardipine, were compared on the isolated porcine coronary artery with intact and removed endothelium. All three forms of nicardipine inhibited the contractions induced by KCl (5-90 mM) in both vessel preparations. The potency (IC50) of the (+)-S and (-)-R enantiomers and of the racemic mixture was 6.6, 31.8 and 10.9 nM in the vessel with endothelium and 6.4, 41.9 and 9.8 nM in the vessel without endothelium. The parameters of the concentration-response curves for each form of nicardipine at a submaximal KCl (60 mM) concentration and the potency ratios between the two enantiomers ((+)-S/(-)-R) were not statistically significantly different (P>0.05) in the two vessel preparations. In conclusion, qualitatively, all three forms of nicardipine showed only Ca2+ channel antagonistic effects in both vessel preparations. Quantitatively, the inhibition of contraction was stereoselective, the (+)-S enantiomer being the most potent, and was endothelium-independent.

Animals↗

PubMed1996

Computer support for experiments on isolated hearts.

The left ventricular pressure (LVP) and ECG signals that appear during and after ischaemia tend to be very irregular (fibrillation, arrhythmia). Computer based data acquisition system, that we developed to support experiments on isolated Langendorff's rat heart, enabled the usage of methods derived from non-linear dynamics. To classify the irregularity of heart action, ECG and LVP time series have been used to calculate correlation dimension (D2) and largest Lyapunov exponent. We compared the results of signals derived from isolated heart at standard conditions and hearts rendered ischaemic for 60 minutes. Our results show that the level of irregularity can be classified efficiently using the quoted approach.

Animals↗

PubMed1994

Pharmacological studies with two new ergoline derivatives, the potential antipsychotics LEK-8829 and LEK-8841.

The pharmacological properties of 9,10-didehydro-N-methyl-N-(2-propynyl)-6-methyl-8 beta-aminomethylergoline (LEK-8829) and 9,10-didehydro-N-methyl-N-(2-propynyl)-2-bromo-6-methylergoline -8-beta-carboxamide (LEK-8841), new ergoline derivatives, were compared with those of haloperidol and clozapine by in vitro radioligand displacement assays, various behavioral tests and blood pressure measurements. Both ergolines displayed low affinity for rat striatal 3H-SCH23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pin e)- labeled dopamine (D)1 binding sites and high affinity for striatal 3H-spiperone-labeled D2 and cortical 3H-ketanserin-labeled serotonin-2 (5-HT2) sites. The ratio of pKi values 5-HT2/D2 was 1.11 for LEK-8829 (close to that of clozapine, 1.13) and 0.98 for LEK-8841 (close to that of haloperidol, 0.95). All compounds inhibited apomorphine-induced locomotor activity in rats, apomorphine-induced climbing behavior in mice and 5-hydroxytryptophan-induced head twitches in mice and induced catalepsy in rats and in mice. LEK-8829 and clozapine, but not LEK-8841 and haloperidol, showed a certain degree of mesolimbic selectivity, i.e., they caused more potent inhibition of apomorphine-induced locomotion compared with the induction of catalepsy in rats. In the case of LEK-8829, nonspecific effects that presumably predict a side effect profile, such as potentiation of pentobarbital-induced anesthesia in mice (sedation), antagonism of oxotremorine-induced tremors in mice (anticholinergic activity), spontaneous locomotor activity in mice and norepinephrine-induced lethality in rats (sedation and hypotension), were relatively weak compared with the activities described earlier. In contrast, LEK-8841 showed nonspecific effects at the similar dose levels as dopamine and 5-HT antagonistic effects. The results of direct measurements of the influences of both compounds on blood pressure agreed with the previously mentioned findings, i.e., LEK-8829 was relatively less hypotensive than LEK-8841 was. It is suggested that LEK-8829 might be an efficient antipsychotic with a reduced propensity to cause sedative, anticholinergic and hypotensive side effects. A certain degree of mesolimbic selectivity also points toward the possibility of a reduced propensity to cause extrapyramidal symptoms. In contrast, in regard to side effects (including extrapyramidal symptoms), the profile of LEK-8841 is less promising.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1993

Ca2+ channel antagonists inhibit the intestinal absorption of digoxin in the guinea-pig.

Simultaneous administration of digoxin and Ca2+ channel antagonists results in an increased plasma level of digoxin. A possible mechanism underlying this interaction might be the influence of Ca2+ channel antagonists on the enteral absorption of digoxin. To study this interaction, two groups of experiments were performed with guinea-pigs. In the first group, the influence of Ca2+ channel antagonists on the rate of enteral absorption of digoxin in vivo was studied. In the second group, the influence of Ca2+ channel antagonists on the transfer of digoxin through the wall of the isolated everted small intestine in vitro was investigated. The intravenously determined minimal lethal dose of digoxin 30 min after its intraduodenal administration was increased in animals pretreated with either verapamil, diltiazem, nifedipine or nicardipine. Addition of either verapamil or diltiazem to the solution on the mucosal side of isolated everted small intestine sacs decreased the transfer of digoxin through the intestinal wall. Similar results obtained in both groups indicate that, under our experimental conditions, Ca2+ channel antagonists inhibit the enteral absorption of digoxin in the guinea-pig.

Animals↗

PubMed1992

Structure-activity study of some newly synthesized ergoline derivatives on 5-HT2 receptors and alpha-adrenoceptors in rabbit isolated aorta.

In a structure-activity study, carried out in rabbit isolated aorta, the effect of different structural modifications in the ergoline nucleus upon the activity at 5-HT2 receptors and alpha-adrenoceptors was determined. 9,10-didehydro-N-methyl-N-(2-propynyl)-6-methylergoline-8 beta-carboxamide (LEK 8842) was chosen as the basic backbone of this study. The parent compound LEK 8842 showed strong alpha-adrenoceptor agonistic activity and partial 5-HT2 receptor agonistic activity, and its potency (pD2 = 6.41) was comparable with that of 5-hydroxytryptamine (5-HT, pD2 = 6.84) and noradrenaline (pD2 = 6.82). Hydrogenation of the double bond in the position 9,10 (LEK 8822) attenuated the potency (pD2 = 5.35) as well as the intrinsic activity on alpha-adrenoceptors and eliminated 5-HT2 receptor agonistic activity. LEK 8822 acted on the alpha-adrenoceptors not only as a partial agonist but also as a competitive antagonist of responses elicited by noradrenaline. When tested against 5-HT, LEK 8822 acted as an antagonist. Bromination in position 2 yielded the derivative LEK 8841 with no agonistic activity at concentrations up to 3 mumol/l, yet the affinity for 5-HT2 receptors and alpha-adrenoceptors was preserved. LEK 8841 was the only one that acted as pure simple competitive antagonist of responses elicited by 5-HT (pA2 = 7.93) and noradrenaline (pA2 = 6.45). Its activity was qualitatively similar to that observed with the 5-HT2/alpha-adrenoceptor antagonist ketanserin which was tested for comparison. Concerning selectivity for 5-HT2 receptors versus alpha-adrenoceptors, LEK 8841 proved to be more selective for 5-HT2 receptors than ketanserin. pA2 values for ketanserin antagonistic activity to 5-HT and to noradrenaline were 8.22 and 7.48, respectively. Finally, quaternization in the N(6) position (LEK 8827) almost completely eliminated affinity for 5-HT2 receptors and for alpha-adrenoceptors. This study has shown that relatively small modifications in the structure of the ergoline system led to pronounced changes in the affinity as well as intrinsic activity at both receptors studied.

Animals↗