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Bertera F.,Juan P. Garrahan Pediatric Hospital | Bertera F.,Institute of Physiopathology and Clinical Biochemistry | Di Verniero C.A.,Juan P. Garrahan Pediatric Hospital | Di Verniero C.A.,Institute of Physiopathology and Clinical Biochemistry | And 9 more authors.
Xenobiotica | Year: 2012

Cardiovascular effects and pharmacokinetics of carvedilol were assessed in fructose-fed rats using pharmacokineticpharmacodynamic (PKPD) modeling. Male SpragueDowley rats were randomly assigned to receive tap water (C rats) or fructose solution (10% w/v) (F rats) during 6 weeks. Effects of carvedilol (13mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Carvedilol plasma pharmacokinetics was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by PKPD modeling. Vascular sympatholytic activity of carvedilol was assessed by estimation of drug effects on low frequency blood pressure variability using spectral analysis. A greater volume of distribution and clearance of S-carvedilol compared to R-enantiomer was found in both experimental groups. Although PKPD properties of S-carvedilol chronotropic effect were not altered in F rats, hypertensive rats showed greater efficacy to the carvedilol hypotensive response after administration of the higher dose. A similar potency of carvedilol to inhibit sympathetic vascular activity was found in F rats. Carvedilol showed enantioselective pharmacokinetic properties with increased distribution in F rats compared with normotensive animals. An enhanced hypotensive activity of carvedilol was found in F rats compared with C rats, which is not related to enhance sympatholytic activity. © 2012 Informa UK, Ltd. Source

Donato M.,University of Buenos Aires | D'Annunzio V.,University of Buenos Aires | Buchholz B.,University of Buenos Aires | Miksztowicz V.,Institute of Physiopathology and Clinical Biochemistry | And 8 more authors.
Experimental Physiology | Year: 2010

The activation of matrix metalloproteinases (MMPs) contributes to myocardial injury at the onset of reperfusion; however, their role in ischaemic postconditioning is unknown. The aim of the present study was to examine the effects of ischaemic postconditioning on MMP activity in isolated rabbit hearts. The isolated rabbit hearts were subjected to 30 min of global ischaemia followed by 180 min of reperfusion (I/R group; n = 8). In the ischaemic postconditioning group (n = 8), a postconditioning protocol was performed (2 cycles of 30 s reperfusion-ischaemia). In other experiments, we added doxycycline, an MMP inhibitor, at 25 (n = 7) or 50 μmol l-1 (n = 8) during the first 2 min of reperfusion. Coronary effluent and left ventricular tissue were collected during pre-ischaemic conditions and at different times during the reperfusion period to measure MMP-2 activity and cardiac protein nitration. We evaluated ventricular function and infarct size. In the I/R group, infarct size was 32.1 ± 5.2%; Postcon reduced infarct size to 9.5 ± 3.8% (P < 0.05) and inhibited MMP-2 activity during reperfusion. The administration of doxycycline at 50 μmol l-1 inhibited MMP-2 activity and cardiac protein nitration and reduced the infarct size to 9.7 ± 2.8% (P < 0.05). A lower dose of doxycycline (25 μmol l -1) failed to inhibit MMP-2 activity and did not modify the infarct size. Our results strongly suggest that ischaemic postconditioning may exert part of its cardioprotective effects through the inhibition of MMP-2 activity. © 2010 The Physiological Society. Source

Santander Y.,University of Buenos Aires | Bertera F.M.,University of Buenos Aires | Bertera F.M.,Institute of Physiopathology and Clinical Biochemistry | Del Mauro J.S.,University of Buenos Aires | And 6 more authors.
Revista Argentina de Cardiologia | Year: 2015

The cardiovascular and pharmacokinetic effects of nebivolol were evaluated in hypertensive fructose-fed and control rats, analyzing the effect of intravenously administered nebivolol 3 or 10 mg/kg on blood pressure, heart rate, and short-term and beat-to-beat blood pressure variability. The enantioselective pharmacokinetic profile of d- and l-nebivolol enantiomers was evaluated. Short-term and beat-to-beat blood pressure variability was assessed using standard deviation and blood pressure spectral analysis, respectively. The hypertensive state altered the pharmacokinetics of nebivolol, evidenced by reduction of nebivolol clearance in the fructose group compared to the control group after administration of the highest dose. The antihypertensive effect of nebivolol was similar in both groups, while the bradycardic effect was greater in control rats. Although no significant differences were found in beat-to-beat blood pressure variability, short-term blood pressure variability showed greater reduction after nebivolol administration in fructose-fed rats compared to control normotensive animals (-57.9%±11.8% vs.-19.6%±9.2%; p<0.05). In conclusion, although nebivolol reduces blood pressure and blood pressure variability in both groups, no significant differences were found in the pharmacokinetics and cardiovascular effects of fructose-fed rats, except for lower bradycardic efficacy and greater reduction in short-term blood pressure variability. © 2015, Sociedad Argentina de Cardiologia. All rights reserved. Source

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