Pharmacokinetic and pharmacodynamic alterations of methyldopa in rats with aortic coarctation. A study using microdialysis.
A pharmacokinetic-pharmacodynamic study of methyldopa (MD) was made in anesthetized sham operated (SO) and aortic coarctated (ACo) rats by using a vascular shunt probe for arterial microdialysis and simultaneous blood pressure recording. Anesthetized Wistar rats were used 7 days after aortic coarctation or sham operation. A vascular shunt probe was inserted into the carotid artery and a concentric probe was placed into the striatum or posterior hypothalamus. MD and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in the dialysates by HPLC-EC. MD (50 mg kg(-1)i.p.) induced an increase of heart rate in SO (Delta HR: 108 +/- 22 bpm, n= 6) and in ACo rats (Delta HR: 55 +/- 10 bpm, n= 6, P< 0.05, one way ANOVA). Moreover, MD also reduced the mean arterial pressure (MAP) of SO rats (Delta MAP: -10 +/- 4 mmHg, n= 6) and ACo animals (Delta MAP: -51 +/- 9 mmHg, n= 6, P< 0.05, one way ANOVA). Analysis of the arterial blood dialysates showed a lower half-life of MD in ACo rats (t(1/2): 1.5 +/- 0.3 h, n= 6, P< 0.05, 't' test) than in SO rats (t(1/2): 3.7 +/- 1.0 h, n= 6). A low accumulation and a fast decay of striatal MD levels were seen in ACo rats. However, peak levels of drug were greater in the hypothalamic dialysates of ACo rats than in SO animals samples. On the other hand, MD also induced an increase of DOPAC levels in the hypothalamic dialysates of ACo rats. In conclusion, the aortic coarctation modifies the pharmacokinetic and cardiovascular effect of MD in the rat. The action of this drug on dopaminergic neurotransmission is also altered in the ACo animals.
Höcht
C
C
Department of Pharmacology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, (C1113AAD) Buenos Aires, Junín 956, Argentina. chocht@ffyb.uba.ar
Opezzo
J A
JA
Gorzalczany
S B
SB
Priano
R M
RM
Bramuglia
G F
GF
Taira
C A
CA
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001017:Aortic Coarctation / Q000378:metabolism* / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D015314:Dialysis Solutions / Q000493:pharmacokinetics; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008750:Methyldopa / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D017551:Microdialysis / Q000379:methods; D051381:Rats; D017208:Rats, Wistar
D000959:Antihypertensive Agents; D015314:Dialysis Solutions; D015102:3,4-Dihydroxyphenylacetic Acid; D008750:Methyldopa