Effect of dehydration and hyperosmolal hydration on lignocaine and metabolites disposition in conscious rabbits.
1. The present study aimed to investigate the effect of dehydration and hyperosmolal hydration on the disposition of lignocaine and two of its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). 2. Lignocaine was infused to three groups of conscious rabbits: controls, rabbits previously deprived of water for 48 h and rabbits receiving an infusion of 2.5% NaCl. 3. In dehydrated and hyperosmolal-hydrated rabbits, plasma osmolality was 321 +/- 1 and 313 +/- 1 mOsm kg-1, respectively (P < 0.01 compared to controls, 285 +/- 1 mOsm kg-1). In dehydrated animals, baseline values of plasma arginine vasopressin (AVP) concentrations and plasma renin activity (PRA) were higher than in controls, i.e. 12.4 +/- 1.4 pg ml-1 and 15.4 +/- 1.7 ng AI ml-1 h-1 vs. 3.4 +/- 0.2 pg ml-1 (P < 0.01), and 5.1 +/- 0.6 ng AI ml-1 h-1 (P < 0.01), respectively; atrial natriuretic peptide (ANP) decreased from 55 +/- 11 to 32 +/- 4 pg ml-1 (P < 0.05). Compared to controls, hyperosmolal hydration only increased AVP to 15.5 +/- 0.7 pg ml-1 (P < 0.01). 4. Under both experimental conditions, lignocaine plasma concentrations were almost double (P < 0.01) those in controls, due to a lower systemic clearance, e.g. 54 +/- 3 and 59 +/- 1 vs. 96 +/- 5 ml min-1 kg-1, respectively. Plasma levels of MEGX increased (P < 0.01) only in dehydrated animals, although GX plasma concentrations were augmented (P < 0.01) about three fold in both groups of animals. The changes in lignocaine plasma concentrations were correlated with AVP levels (R2 = 0.5168, P<0.001).5. To document the effect of AVP on hepatic plasma flow, another group of rabbits received on separate occasions two doses of AVP (17 and 84 ng kg-1) while receiving an infusion of in docyanine green. AVP reduced hepatic plasma flow from 38.9 +/-2.7 ml min-1 to 19.6 +/-2.5 ml min-1 (P<0.01).The predicted maximal AVP-induced decrease in hepatic plasma flow was 19.6 ml min-1 kg- 1(Emax), and AVP concentration eliciting 50% of Em.. (ED50) was 28.7 pg ml-1.6 It is concluded that both dehydration and hyperosmolal hydration alter the disposition of lignocaine and two of its metabolites.
Chamelian
M
M
Department of Pharmacology, School of Medicine, University of Montréal, Québec, Canada.
Lécrivain
A
A
Robichaud
A
A
du Souich
P
P
D000818:Animals; D001127:Arginine Vasopressin / Q000097:blood / Q000502:physiology; D009320:Atrial Natriuretic Factor / Q000097:blood; D003681:Dehydration / Q000378:metabolism*; D015232:Dinoprostone / Q000652:urine; D008012:Lidocaine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D009994:Osmolar Concentration; D010953:Plasma Volume / Q000502:physiology; D011817:Rabbits; D012083:Renin / Q000097:blood
D001127:Arginine Vasopressin; D009320:Atrial Natriuretic Factor; D008012:Lidocaine; C001306:glycinexylidide; C001173:monoethylglycinexylidide; D012083:Renin; D015232:Dinoprostone