Involvement of proopiomenalocortin-derived peptides in endogenous central histamine-induced reversal of critical haemorrhagic hypotension in rats.
An increase in endogenous central histamine concentrations, after loading with histamine precursor L-histidine or inhibition of histamine N-methyltransferase (HNMT) activity, produces the reversal of critical hypotension with improvement in survival of haemorrhage-shocked rats. In the present study, the involvement of proopiomelanocortin (POMC)-derived peptides in central histamine-induced resuscitating action was examined in male anaesthetised Wistar rats subjected to a haemorrhagic hypotension of 20-25 mmHg resulting in the death of all control animals within 30 min. HNMT inhibitor metoprine (20 microg) administered intracerebroventricularly (i.c.v.) at 5 min of critical hypotension produced a long-lasting pressor effect with a 100% survival rate at 2 h. The action was accompanied by 34.5% and 28.9% higher plasma concentrations of ACTH and alpha-MSH, respectively, in comparison to concentrations in the saline-injected group as measured 20 min after treatment. Melanocortin type 4 (MC(4)) receptor antagonist HS014 (5 microg; i.c.v.) inhibited metoprine-induced increase in mean arterial pressure, which resulted from decreased regional vascular resistance, however, it did not affect the heart rate and the survival at 2 h. On the other hand, glucocorticoid type II receptor blocker mifepristone (30 mg/kg; sc) had no effect. In conclusion, POMC-derived peptides, acting centrally via MC(4) receptors, participate in endogenous central histamine-induced resuscitating effect in rats.
Jochem
J
J
Department of Physiology, Medical University of Silesia, Zabrze, Poland. jjochem@poczta.onet.pl
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001923:Brain Chemistry / Q000502:physiology; D004195:Disease Models, Animal; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006470:Hemorrhage; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects; D006632:Histamine / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D007022:Hypotension / Q000503:physiopathology*; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008297:Male; D015735:Mifepristone / Q000008:administration & dosage / Q000493:pharmacokinetics; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000493:pharmacokinetics; D011333:Pro-Opiomelanocortin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D011739:Pyrimethamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4 / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D012771:Shock, Hemorrhagic / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D013152:Splanchnic Circulation / Q000187:drug effects; D013997:Time Factors; D000521:alpha-MSH / Q000097:blood
C116941:HS014 cyclic peptide; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; C006308:metoprine; D015735:Mifepristone; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; D006632:Histamine; D000324:Adrenocorticotropic Hormone; D011739:Pyrimethamine