Mechanism of the acute pressor effect and bradycardia elicited by diaspirin crosslinked hemoglobin in anesthetized rats

Abstract

Diaspirin crosslinked hemoglobin (DCLHb) is a chemically stabilized hemoglobin (Hb) that induces an increase in blood pressure and a decrease of heart rate when injected intravenously in some animals. The mechanism by which DCLHb elicits these hemodynamic effects was studied in pentobarbital-anesthetized, vagotomized rats using a variety of drugs known for their inhibitory action towards endogenous hemodynamically active systems. The hypertensive episode elicited by DCLHb (100 or 400 mg.kg-1) was attenuated in animals pretreated with NG-nitro-L-arginine (inhibitor of nitric oxide synthases) throughout the 30-min period of observation, but it was not reduced in those pretreated with a variety of sympatholytic drugs (e.g., prazosin), atropine, BIBP-3226 (neuropeptide Y antagonist), indomethacin, [1-(beta-mercapto-beta,beta-cyclopentanemethylene propionic acid), 2-(0-methyl) tyrosine]-Arg8 vasopressin (vasopressin antagonist), losartan (angiotensin antagonist), bosentan (endothelin antagonist), or L-arginine-(nitric oxide precursor), compared with control animals. With the exception of propranolol and BIBP-3226, none of the aforenamed inhibitors reduced the amplitude of the bradycardia associated with the pressor effect of DCLHb. These results suggest that: (i) the acute (< 30 min) pressor activity of DCLHb in our animal model requires the presence of an endogenous nitric oxide generating system to be expressed; (ii) the bradycardia elicited by DCLHb might involve the participation of neuropeptide Y and (or) its NPY-1 receptors, but it is unlikely to involve a baroreceptor-mediated vagal reflex, at least in our animal model.

Measurement of blood volume after haemodilution with haemoglobin‐based oxygen carriers by a radiolabelled‐albumin method

“…The possible mechanisms proposed to account for the pressor action of HBOCs are: vasoconstriction due to NO scavenging by cell‐free haemoglobin, increased endothelin‐1 synthesis, sensitization of α‐adrenergic receptors and blood flow autoregulation at the microcirculatory level (Nolte et al ., 1997; Gulati et al ., 1999; Winslow, 1999; Habler & Messmer, 2000). As expected, changes in heart rate after haemodilution were in opposite directions in Hb‐Dex‐BTC and αα‐Hb animals compared with HES animals (Moisan et al ., 1998). Bradycardia is indeed an expected regulatory process mediated by baroreceptors in response to increased blood pressure (Persson, 1996).…”

Oxygen Carriers (“Blood Substitutes”)Raison d'Etre, Chemistry, and Some PhysiologyBlut ist ein ganz besondrer Saft

“…The most widely accepted hypothesis is that NO is being neutralized by one or more reactions with Hb (section III.A), especially when the Hb product can leak out of the vascular space, thus gaining access to the basal site of the endothelium where NO is produced. 305,316,493,1028,1088,1111,[1119][1120][1121]1124,1128,1130,1136,1137,1146,1159,[1175][1176][1177][1178][1179] Binding of NO to Hb occurred at different rates for differently modified Hbs and was usually faster than for unmodified Hb. 271,314,315 Depletion of NO could also occur through reaction with O 2 •resulting from Hb autoxidation.…”

SwePep, a Database Designed for Endogenous Peptides and Mass Spectrometry

“…For example, hemorphins are small peptides generated by enzymatic hydrolysis of hemoglobin or blood (19 -21). Their physiological functions are discussed because they are found in a variety of mammalian tissues and fluids (22)(23)(24)(25)(26)(27). Hemorphin peptides were previously found in brain tissue not proteolytically deactivated (28) but were not detected in tissue that had been proteolytically deactivated (4).…”