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Metka V Budihna

Publications and source records attributed to Metka V Budihna.

7 recordsLinked to original sources
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

Long-term effects of elemental mercury on renal function in miners of the Idrija Mercury Mine.

BACKGROUND: The kidneys are one of the main target organs for elemental mercury (Hg(0)). The influence of Hg(0) on kidneys has been extensively studied but the long-term effects on this organ have not yet been determined with certainty. The basic aim of this research was to study the effects of a long-term exposure to Hg(0) vapours on the renal function in miners in the post-exposure period. METHODS: The population studied comprised 53 miners (33 active and 20 retired) from the Idrija Mercury Mine as the exposed miners group and 53 unexposed workers as the control group. On the basis of mine exposure records (air and biological monitoring), the environmental and biological indicators of the past exposure to Hg(0) were calculated for each miner. Kidney function was determined in both groups, i.e. in the exposed miners as well as in the controls. Glomerular kidney function was evaluated by a quantitative analysis of albumin and IgG in urine. Tubular kidney function, however, was determined by a quantitative analysis of alpha(1)-microglobulin in urine and by the enzymatic activity of N-acetyl-beta-d-glucosaminidase (NAG). RESULTS: The mean exposure time in miners was 15 years. The total number of cycles of exposure ranged from 13 to 119. The mean annual time-weighted exposure was 0.29 mg m(-3) and the mean integrated exposure intensity (IEI) was 1413 mg m(-3)-h. Throughout the period of exposure the average urine mercury concentration in miners was 68.24 microg l(-1) and the average sum of peak urine mercury concentrations was 3901 microg l(-1). Albumin, IgG and alpha(1)-microglobulin in urine were significantly elevated in the exposed miners compared with the unexposed controls (t = 2.17, P = 0.03; t = 2.81, P < 0.01; and t = 2.07, P = 0.04). No significant differences were found in the urine NAG activity when the exposed miners and the unexposed workers were compared. Among the indicators of renal function only alpha(1)-microglobulin in the urine correlated significantly with the IEI (r = 0.73; P <or= 0.01) and with the sum of peak mercury urine concentrations (r = 0.67; P <or= 0.01) in the group of miners who still worked, while no significant correlations were found between these parameters in the group of the retired miners. CONCLUSION: The results of the differences in albumin, IgG and alpha(1)-microglobulin concentrations in urine between the exposed miners and unexposed controls suggest that a long-term occupational exposure to Hg(0) could cause renal dysfunction. A high correlation between alpha(1)-microglobulin in urine and the IEI as well as between alpha(1)-microglobulin in urine and the sum of peak urine mercury concentrations in the group of active but no longer exposed miners indicates that a long-term occupational exposure to Hg(0) may cause a non-permanent tubular dysfunction.

Adult↗
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↗
PubMed2004

Mibefradil is more effective than verapamil for restoring post-ischemic function of isolated hearts of guinea pigs with acute renal failure.

The deleterious intracellular Ca(2+) overload in the ischemic-reperfusion injury of the heart can be even more expressed in subjects with acute renal failure in whom maintenance of intracellular Ca(2+) has already been disturbed in normoxia. To study the influence of acute renal failure in ischemic-reperfusion injury on the heart, we used isolated Langendorff's hearts of guinea pigs with gentamicin-induced acute renal failure. We examined arrhythmias, heart contractility and myocardial cell damage during reperfusion. Two specific Ca(2+) channel antagonists, mibefradil (0.1 and 1 microM) and verapamil (0.1 microM), were used to test the possible involvement of T-type and L-type Ca(2+) channels in these processes. We exposed hearts to 50 min of zero-flow global ischemia and 60 min of reperfusion. During reperfusion, unrecoverable ventricular fibrillation appeared more often in hearts of animals with acute renal failure than in control hearts (80% vs. 0%, respectively). Mibefradil, but not verapamil, applied either pre- or post-ischemically, terminated ventricular fibrillation in all hearts of animals with acute renal failure. Mibefradil (0.1 microM only) improved contractility in hearts of animals with acute renal failure during reperfusion by 30%. During reperfusion, lactate dehydrogenase (LDH) release rate increased less in hearts of guinea pigs with acute renal failure than in control hearts and only verapamil decreased it additionally. Thus, our results suggest a more important role of T- than of L-type Ca(2+) channels in ischemic-reperfusion injury in isolated guinea pig hearts with acute renal failure.

Acute Kidney Injury↗
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↗