Effects Of Cross-activation Between Central Istaminergic And Cholinergic Systems On Carotid Inus Baroreceptor Reflex

Objective:To investigate the role of cross-activation between central histaminergic andcholinergic systems in regulating carotid sinus baroreceptor reflex (CSR) and thepossible regulatory mechanisms.Method:The bilateral carotid sinus areas were isolated under anesthesia with pentobarbitalsodium in the Sprague Dawley rats (sinus nerve were reserved) to be independent ofsystemic circulation. The intracarotid sinus pressure (ISP) and mean arterial pressure(MAP) were simultaneously recorded, via pressure transducers connected with thecatheters which were inserted into the left or right isolated carotid sinus and into thefemoral artery respectively. ISP was set at the level of0mmHg to eliminate the effect ofinitial internal pressure of the carotid sinus on the CSR function. To trigger CSR, theISP was quickly elevated from0mmHg to280mmHg in a stepwise manner (40mmHg)which were added at every step for over4sec, and then ISP returned to0mmHg insimilar steps. The original data of ISP and corresponding MAP were fitted to a modifiedlogistic equation with five parameters to obtain the ISP-MAP, ISP-Gain relationshipcurves and the CSR characteristic parameters, which were statistically compared andanalyzed separately. Under the precondition of no influence on the basic levels of theartery blood pressure, effects and the potential regulatory mechanism of precedingmicroinjection with artificial cerebrospinal fluid (ACSF) or different cholinergicreceptor antagonists (the selective cholinergic M1receptor antagonist, i.e., pirenzepine,PRZ or the selective cholinergic M2receptor antagonist, i.e., methoctramine, MTR orthe selective cholinergic N1receptor antagonist, i.e., hexamethonium, HEX) into thenucleus tractus solitarius (NTS) or locus ceruleus (LC) on the changes in function of CSR induced by the intracerebroventricular (i.c.v.) histamine (HA) in rats were studied.Meanwhile, actions and the possible modulatory mechanism of precedingmicroinjection with the ACSF or different histaminergic receptor antagonists (theselective histaminergic H1receptor antagonist, i.e., chlorpheniramine, CHL or theselective histaminergic H2receptor antagonist, i.e., cimetidine, CIM) into the NTS orthe LC on the changes in function of CSR resulted from the i.c.v. cholinesteraseinhibitor, physostigmine (PHY) were also examined in order to analyze and to revealeffects of cross-activation between central histaminergic and cholinergic systems onregulating CSR.Results:1. Effects of microinjection of histamine (HA) or physostigmine (PHY) into thelateral ventricles on CSR with different dosesRespective intracerebroventricular microinjection (i.c.v.) of HA or PHY with threedifferent doses (low, medium and high doses) significantly shifted the ISP-MAPrelationship curve upwards (P <0.05), and moved the middle part of ISP-Gainrelationship curve downwards (P <0.05), and reduced parameters such as the MAPchanging range and reflex maximum gain (Gmax)(P <0.05), but increased parameter setpoint (P <0.05), which suggest that the central HA or acetylcholine (ACh) can result ina inhibitory rapid resetting of CSR function.2. Effects of preceding microinjection with different cholinergic receptorantagonists into the NTS on the changes in function of CSR induced by i.c.v. HA2.1Standalone microinjection with different cholinergic receptor antagonists, PRZ(for M1receptor) or MTR (for M2receptor) or HEX (for N1receptor) into the NTS witheach given dose, had no effect on the CSR function respectively (P0.05).2.2The pretreatment of PRZ or MTR into the NTS with each same dose, however,could attenuate CSR resetting resulted from i.c.v. HA in some degrees, whichremarkably moved the ISP-MAP relationship curve downwards (P <0.05), and shiftedthe middle part of ISP-Gain relationship curve upwards (P <0.05), and increasedparameters the MAP changing range and Gmax(P <0.05), but decreased parameters suchas saturation pressure (SP) and intracarotid sinus pressure at maximum gain (ISPGmax)(P <0.05). The catabatic effects of pretreatment with MTR on CSR resetting induced byi.c.v. HA were more than those with PRZ (P <0.05), but pretreatment of HEX with given dose into the NTS had no effects on CSR resetting induced by i.c.v. HA (P0.05).3. Effects of preceding microinjection with different cholinergic receptorantagonists into the LC on the changes in function of CSR induced by i.c.v. HA3.1Standalone microinjection with different cholinergic receptor antagonists, PRZor MTR or HEX into the LC with each given dose, also had no effect on the CSRfunction respectively (P0.05).3.2The effects of pretreatment of PRZ or MTR into the LC with each same doseon CSR changes induced by i.c.v. HA were similar to those of pretreatment into theNTS, and attenuating actions of pretreatment with PRZ into the LC on CSR resettinginduced by i.c.v. HA were less than those with MTR (P <0.05), however, pretreatmentof HEX with given dose into the LC also had no effects on CSR resetting induced byi.c.v. HA (P0.05).4. Effects of preceding microinjection with different histaminergic receptorantagonists into the NTS on the changes in function of CSR induced by i.c.v. PHY4.1Standalone microinjection with different histaminergic receptor antagonists,CHL (for H1receptor) or CIM (for H2receptor) into the NTS with each given dose, hadno effect on the CSR function respectively (P0.05).4.2The pretreatment of CHL or CIM into the NTS with each same dose, however,could alleviate CSR resetting resulted from i.c.v. PHY in some degrees, whichremarkably shifted the ISP-MAP relationship curve downwards (P <0.05), and movedthe middle part of ISP-Gain relationship curve upwards (P <0.05), and increasedparameters the MAP changing range and Gmax(P <0.05), but decreased parameters suchas saturation pressure (SP) and intracarotid sinus pressure at maximum gain (ISPGmax)(P <0.05). The catabatic effects of pretreatment with CHL on CSR resetting induced byi.c.v. PHY were more than those with CIM (P <0.05).5. Effects of preceding microinjection with different histaminergic receptorantagonists into the LC on the changes in function of CSR induced by i.c.v. PHY5.1Standalone microinjection with different histaminergic receptor antagonists,CHL or CIM into the LC with each given dose, also had no effect on the CSR functionrespectively (P0.05).5.2The effects of pretreatment of CHL or CIM into the LC with each same dose onCSR changes induced by i.c.v. PHY were similar to those of pretreatment into the NTS, and attenuating actions of pretreatment with CIM into the LC on CSR resetting inducedby i.c.v. PHY were less than those with CHL (P <0.05).Conclusion:1. Microinjection of the histamine or cholinesterase inhibitors, physostigmine intothe lateral ventricle obviously results in a inhibitory rapid resetting of CSR functionwith a dose-dependent manner.2. CSR resetting resulted from intracerebroventricular histamine may be partlyrelated to descending histaminergic pathways from hypothalamus to nucleus tractussolitarius (NTS) and from hypothalamus to locus ceruleus (LC) which perhapstransactivate cholinergic system in the NTS and LC respectively, and then displayactions via the M1, M2receptors mediation, especially M2receptor but not N1receptor.3. CSR resetting induced by intracerebroventricular physostigmine is probably inpart involved in descending cholinergic pathways from hypothalamus to nucleus tractussolitarius (NTS) and from hypothalamus to locus ceruleus (LC) which possiblytransactivate histaminergic system in the NTS and LC separately, and then show effectsby the H1, H2receptors mediation, especially H1receptor.