Facilitation of central imidazoline I(1)-site/extracellular signal-regulated kinase/p38 mitogen-activated protein kinase signalling mediates the hypotensive effect of ethanol in rats with acute renal failure.
OBJECTIVE
This study investigated the role of central sympathetic activity and related mitogen-activated protein kinase (MAPK) signalling in the cardiovascular effects of ethanol in a model of acute renal failure (ARF).


METHODS
The effects of pharmacological interventions that inhibit peripheral or central sympathetic activity or MAPK on the cardiovascular actions of ethanol in rats with ARF induced by glycerol were evaluated.


RESULTS
Glycerol (50%, 10 mL.kg(-1), i.m.) caused progressive increases and decreases in blood pressure (BP) and heart rate (HR) respectively. Subsequent i.v. ethanol (0.25 or 1 g.kg(-1)) elicited dose-related changes in BP (decreases) and HR (increases). These effects were replicated after intracisternal (i.c.) administration of ethanol. Blockade of nicotinic cholinoceptors (nAChR, hexamethonium, 20 mg.kg(-1)) or alpha(1)-adrenoceptors (prazosin, 1 mg.kg(-1)) attenuated cardiovascular effects of ethanol. Ethanol hypotension was also attenuated after the centrally acting sympatholytic drug moxonidine (selective I(1)-site agonist, 100 microg.kg(-1) i.v.), but not guanabenz (selective alpha(2)-receptor agonist, 30 microg.kg(-1), i.v.), suggesting involvement of central circuits of I(1) sites in ethanol-evoked hypotension. Selective blockade I(1) sites (efaroxan) but not alpha(2) (yohimbine) adrenoceptors abolished the hypotensive response to ethanol. Intracisternal administration of PD98059 or SB203580, inhibitors of extracellular signal-regulated kinase (ERK 1/2) and p38 MAPK, respectively, reduced the hypotensive action of moxonidine or ethanol. When used simultaneously, the two MAPK inhibitors produced additive attenuation of ethanol hypotension.


CONCLUSIONS
Sympathoinhibitory pathways of central I(1)-sites and downstream ERK/p38 MAPK signalling were involved in the hypotensive action of ethanol in ARF.
Department of Pharmacology, University of Alexandria, Egypt. mahelm@hotmail.com
Mahmoud M
MM
El-Mas
Hanan M
HM
El-Gowelli
Abdel-Rheem M
AR
Ghazal
Osama F
OF
Harraz
Mahmoud M
MM
Mohy El-Din
D058186:Acute Kidney Injury / Q000503:physiopathology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D005990:Glycerol / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced*; D054755:Imidazoline Receptors / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002492:Central Nervous System Depressants; D054755:Imidazoline Receptors; C410887:imidazoline I1 receptors; D000431:Ethanol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D005990:Glycerol