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Gorazd Drevensek

Publications and source records attributed to Gorazd Drevensek.

8 recordsLinked to original sources
PubMed2006

Effects of endothelin antagonist tezosentan on orthodontic tooth movement in rats.

INTRODUCTION: Endothelin is a cytokine peptide present in the periodontal ligament in physiological conditions. Its concentration in the periodontal ligament doubles after 3 hours of axial loading of a tooth. The role of endothelin in orthodontic tooth movement has not yet been explained. We tried to determine the effect of tezosentan, a specific dual endothelin receptor antagonist, on orthodontic tooth movement in rats. METHODS: Twenty-one rats were divided into 3 groups (n = 7). In the tezosentan group, closed-coil springs were placed, and the animals were treated daily with tezosentan; in the coil-spring group, closed-coil springs were placed, and the animals were treated with an inert physiological solution. The appliance was placed between the maxillary left first molar and the incisor. The third group was the control group. On days 0, 7, 14, and 25, the distances between the maxillary molars and incisors were measured at the experimental and contralateral sides. RESULTS: Changes in measured distances at the experimental sides were significantly different between the tezosentan and the coil-spring groups on day 25 (P < .001), with the tezosentan group showing greater changes in the measured distances. There were no differences between the tezosentan and the coil-spring groups at the contralateral side. In the control group, the measured distance increased at both sides (P < .001). CONCLUSIONS: Tezosentan, an endothelin dual antagonist, enhanced tooth movements in rats.

Analysis of Variance↗
PubMed2006

Direct thrombin inhibitors built on the azaphenylalanine scaffold provoke degranulation of mast cells.

The main structural feature of direct thrombin inhibitor LK-732 responsible for the appropriate interaction at the thrombin active site is a strong basic group. A possibility that a strong basic group of LK-732 might contribute to the mast cell degranulation effect and consequent reduction of tracheal air flow (TAF) and fall of mean arterial blood pressure (MAP) in rats was investigated in the present study. At doses up to 5 mg/kg (i.v.), LK-732 did not cause significant changes of TAF and MAP. At 7 mg/kg (i.v.), a sudden reduction of TAF and a fall of MAP was observed within 5 min after LK-732 administration (75% mortality, p = 0.007). A less basic direct thrombin inhibitor LK-658 (21 mg/kg, i.v.) did not significantly disturb TAF and MAP. A reduction of TAF and a fall of MAP caused by LK-732 (7 mg/kg, i.v.) was almost completely abolished in rats with degranulated mast cells (0% mortality, p = 0.008). LK-732 concentration-dependently degranulated rat peritoneal mast cells in vitro (pEC(50) = 1.92 +/- 0.05 muM). A structure-activity relationship (SAR) study revealed that the terminal basic groups attached to the aromatic ring are responsible for the mast cell degranulation effect. A good correlation was observed between mast cell degranulation and pK(b) of analogues of LK-732 (R(2) = 0.49), but not between mast cell degranulation and thrombin K(i) (R(2) = 0.23). LK-732-induced reduction of TAF, the fall of MAP and high mortality originate from LK-732-induced mast cell degranulation. As judged by the SAR study, this effect could be overcome by reducing the basicity of LK-732.

Animals↗
PubMed2005

Modulation of a dog's internal organ function by selective stimulation of the splanchnic nerve.

The superficial regions of the dog splanchnic nerve were selectively stimulated with 33-electrode spiral cuffs in 11 circumferential groups of three electrodes to modulate the function of the innervated internal organs and glands. In two adult Beagle dogs under general anaesthesia, the cuffs were chronically implanted on the nerve trunks before the celiac ganglion. Superficial regions of the nerves were selectively stimulated for 15 s with biphasic, rectangular, current pulses (2 mA intensity, 200 micros duration, and 20 Hz frequency) which were delivered sequentially to the corresponding group of three electrodes. The results showed that Group no. 8 of three electrodes elicited the highest influence on pressure within the bladder. Namely, a decrease in pressure starting from 34.97 mmHg at the beginning of stimulation to 34.92 mmHg at the end of stimulation was observed. It was also shown that only Group no. 4 of three electrodes significantly modified the endocrine function of the pancreas. A considerable increase in glucagon secretion with a peak value of 47 pg/ml and an insignificant change in insulin secretion were also observed. The results of histological observations demonstrated that the use of the cuff was associated with a buildup of connective tissue encapsulation around the cuff as well as within it. However, functional deficits were not observed in the animal, and most of the fibers appeared to be histologically normal after stimulation. The results of this study clearly demonstrate that internal organs and glands can be selectively stimulated through the selective stimulation of innervating superficial regions of the autonomous peripheral nerve.

Animals↗
PubMed2005

Antithrombotic potential of new direct thrombin inhibitors built on the azaphenylalanine scaffold in two rat venous thrombosis models.

The antithrombotic potential of new direct thrombin inhibitors built on the azaphenylalanine scaffold (LK-732, LK-639 and LK-731) and their amidoxime prodrugs (LK-658, LK-633 and LK-730) was studied in comparison to argatroban and nadroparin in two rat models of venous thrombosis, induced either by complete stasis combined with hypercoagulability (model 1) or by partial stasis combined with vessel injury (model 2). In initial experiments LK-732 was established as the most promising antithrombotic of the LK inhibitors and as such was further tested. In model 1, intravenous bolus administration of LK-732 produced a dose-dependent inhibition of thrombus formation with an ID50 value of 1.3 mg/kg. This ID50 value was approximately four times higher than the ID50 value of argatroban (0.3 mg/kg; p=0.011). However, in model 2, LK-732 and argatroban decreased thrombus weight by 50% at similar ID50 values (3.8 mg/kg vs 3.0 mg/kg, respectively; p=0.726). The ex vivo anticoagulant effect of LK-732 was substantially weaker compared to argatroban at doses that produced comparable antithrombotic effects. After subcutaneous administration, in vivo thrombus weight reduction of LK inhibitors (10 mg/kg) ranged between 22 to 48%. However, their oral antithrombotic effect at a dose of 30 mg/kg was rather low. LK amidoxime prodrugs failed to produce a substantial antithrombotic effect after subcutaneous (10 mg/kg) as well as after oral administration (30 mg/kg). In conclusion, thrombin inhibitors built on the azaphenylalanine scaffold represent a new group of intravenously effective antithrombotics. However, optimisation of the oral antithrombotic effect of amidoxime prodrug LK-658 of the lead inhibitor LK-732 is required for justifying further development of these inhibitors.

Administration, Oral↗
PubMed2002

Nicardipine diminished equinatoxin II-induced decrease of coronary flow in isolated rat and pig hearts.

Equinatoxin II (EqT II) is a basic, cardiotoxic polypeptide. The vasoconstrictory effect of the toxin on isolated porcine coronary arteries was diminished by nicardipine, an L-type calcium channel antagonist. A comparison was made of the effects of EqT II alone and EqT II in the presence of nicardipine on the coronary flow in porcine and rat hearts isolated according to Langendorff's method. In both models EqT II decreased coronary flow in a dose-dependent manner and there were no statistically significant differences between the two models (p>0.05). However, 1 M nicardipine diminished the effects of EqT II on coronary flow in isolated porcine hearts more than in isolated rat hearts (p<0.05). The results suggest that the activation of L-type calcium channels is one of the mechanisms involved in the lowering of coronary flow induced by EqT II.

Animals↗
PubMed2002

Tezosentan inhibits both equinatoxin II and endotelin-1 induced contractions of isolated porcine coronary artery in a similar way.

In the present study we examined the endothelium-dependent mechanism in the constriction of the isolated porcine coronary artery induced by Equinatoxin II (EqT II). EqT II is a polypeptide isolated from the sea anemone (Actinia equina, L.). Contractions induced by endothelin-1 (ET-1) were compared with the contractions induced by EqT II. The force of contraction induced by 100 nM EqT II reached only 30% of the force of contraction induced by 100 nM ET-1. EC50 for ET-1 was 5.14 nM, and for EqT II 101.1 nM. The effects of tezosentan, an endothelin ETA/B receptor antagonist, on contractions induced by either ET-1 or EqT II were compared. Tezosentan inhibited both ET-1 and, to a lesser extent, EqT II-induced contractions of isolated porcine coronary artery. Our present results confirm the involvement of endothelium in the EqT II-induced contractions of coronary arteries. The mode of action of tezosentan upon EqT II-induced contractions indicate that besides its pore-forming effect in the membranes, endothelium, and specifically endothelin-dependent mechanisms, are very important components of the toxin constrictory effects.

Animals↗
PubMedDate not supplied

Hypoxic and pharmacological preconditioning preserves vasomotor response of porcine coronary artery.

Vasomotor response of the coronary artery depends on both endothelial and smooth muscle cells. Response is altered by hypoxia-reoxygenation-induced damages. Hypoxic preconditioning and pharmacological preconditioning as well can prevent these alterations. We compared the effectiveness of both types of preconditioning against hypoxia-reoxygenation-induced changes in vasomotor response of the isolated artery. Porcine arterial rings (3-4 mm wide) were cut from the left anterior descending porcine coronary artery and placed in Krebs-Henseleit solution. In order to obtain control response of the arteries, we contracted arterial rings with 20 mM KCl before ("standard contraction") and after 60-min hypoxia and 30-min reoxygenation. In other groups, nitric oxide-synthase and cyclooxygenase were inhibited. Then, the rings were pre-contracted with U46619 and relaxed by cumulative addition of the substance P. Contractions and relaxations of non-preconditioned and hypoxically or pharmacologically preconditioned rings were compared. Hypoxic preconditioning was performed by two periods of 5-min hypoxia and 10-min reoxygenation. For pharmacological preconditioning, we used application of adenosine, adrenaline, acetylcholine and angiotensin II. Analysis was performed with one-way ANOVA, followed by Dunnett's Multiple Comparison Test. After hypoxia-reoxygenation, in non-preconditioned rings KCl-induced contractions were significantly increased compared to standard contraction. Relaxations of hypoxically and pharmacologically preconditioned rings (expressed as percentages of U46619-induced pre-contraction) were significantly decreased (p < 0.01) compared to hypoxic but not to normoxic rings. Hypoxic and pharmacological preconditioning may preserve contraction and endothelium-dependent relaxation of porcine coronary artery after long-lasting hypoxia-reoxygenation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗