Effects Of Central Cholinergic System On Carotid Sinus Baroreceptor Reflex And Its Mechanism

Objective: To investigate the effects of central cholinergic system on carotid sinus baroreceptor reflex (CSR) and its mechanism.Method: The bilateral carotid sinus areas were isolated under anesthesia with pentobarbital sodium in the Sprague-Dawley rats. The intracarotid sinus pressure (ISP) and mean arterial pressure (MAP) were simultaneously recorded, via pressure transducers connected with the catheters which were inserted into the left or right isolated carotid sinus and femoral artery respectively. ISP was set at the level of 0 mmHg to eliminate the effect of initial internal pressure of the carotid sinus on the CSR function. To trigger CSR, the ISP was quickly elevated from 0 mmHg to 280 mmHg in a stepwise manner—40 mmHg which were added at every step for over 4 sec, and then ISP returned to 0 mmHg in similar steps. The original data of ISP and corresponding MAP were fitted to a modified logistic equation with five parameters to obtain the ISP-MAP,ISP-Gain relationship curves and the CSR characteristic parameters, which were statistically compared and analyzed separately. Under the condition of no influence on the basic levels of the artery blood pressure, the effects and the potential regulatory mechanism of the central cholinergic system on the CSR were studied by microinjection of the cholinesterase inhibitors, physostigmine (PHY) and various selective cholinergic receptors antagonists into the lateral ventricles and / or nuclei (locus ceruleus, nucleus tractus solitarius). Results:1. The effects of physostigmine (PHY) into the lateral ventricles on CSR Respective intracerebroventricular microinjection, (i. c. v.) of PHY with three different doses(low,medium and high doses ) significantly shifted the ISP-MAP relationship curve upwards, and moved the middle part of ISP-Gain relationship curve downwards, and reduced parameters the MAP changing range and reflex maximum gain (Gmax), but increased parameters such as set point, saturation pressure (SP) and ISP at Gmax (ISPGmax) (P <0.05), which suggest that the central acetylcholine (ACh) can result in a inhibitory rapid resetting of CSR function.2. Effects of preceding microinjection of different cholinergic receptor antagonists into the lateral ventricle on CSR changes induced by i. c. v. PHYStandalone i. c. v. selective cholinergic receptors antagonists, prienzepine (PRZ, for M₁ receptor) or methoctramine (MTR, for M₂ receptor) or hexamethonium (HEX, for N₁ receptor) with given dose, had no effect on the CSR function respectively (P >0.05).The pretreatment of PRZ or MTR into the lateral ventricle with each same dose, however, could attenuate CSR resetting resulted from i.c.v. PHY in some degrees, which remarkably moved the ISP-MAP relationship curve downwards, and shifted the middle part of ISP-Gain relationship curve upwards, and increased parameters the MAP changing range and Gmax, but decreased parameters such as saturation pressure (SP) and ISPGmax (P <0.05). The catabatic effects of pretreatment with MTR on CSR resetting induced by i.c.v. PHY were more than those of PRZ (P <0.05), but pretreatment of HEX with same dose into the lateral ventricle had no effects on CSR resetting induced by i.c.v. PHY (P >0.05).3. Effects of preceding microinjection of different cholinergic receptor antagonists into the locus ceruleus on CSR changes resulted from i. c. v. PHYStandalone microinjection of selective cholinergic receptors antagonists, PRZ or MTR, or HEX into the locus ceruleus (LC) with given dose, also had no effect on the CSR function respectively (P >0.05). The effects of pretreatment with different cholinergic receptor antagonists, PRZ or MTR using corresponding dose into the LC on CSR changes induced by i. c. v. PHY were similar to those of pretreatment into the lateral ventricle, and attenuating action of pretreatment with PRZ into the LC on CSR resetting induced by i.c.v. PHY were less than that of MTR (P <0.05), however, pretreatment of HEX with same dose into the LC also had no effects on CSR resetting induced by i.c.v. PHY (P >0.05).4. Effects of preceding microinjection of different cholinergic receptor antagonists into the nucleus tractus solitarius on CSR changes induced by i. c. v. PHYStandalone microinjection of selective cholinergic receptors antagonists, PRZ or MTR, or HEX into the nucleus tractus solitarius (NTS) with given dose, also had no effect on the CSR function respectively (P >0.05).The pretreatment with different cholinergic receptor antagonists, PRZ or MTR using corresponding dose into the NTS, could strengthen CSR resetting induced by i.c.v. PHY (P <0.05), and the intensive effects of pretreatment with MTR on CSR resetting induced by i.c.v. PHY were more than those of PRZ (P <0.05), but pretreatment of HEX with same dose into the NTS also had no effects on CSR resetting induced by i.c.v. PHY (P >0.05).Conclusion:1. Microinjection of the cholinesterase inhibitors, physostigmine into the lateral ventricle obviously results in a inhibitory rapid resetting of CSR function with a dose-dependent manner.2. Pretreatments of cholinergic receptor antagonists, PRZ or MTR into the lateral ventricle may attenuate CSR resetting resulted from i.c.v. PHY, the catabatic effects of the selective M₂ receptor antagonist are more obvious than those of the selective M₁ receptor antagonist, and the selective N₁ receptor antagonist has no effect, which indicate that the M₁ and M₂ receptors in the nuclei around the lateral ventricle mediate effects of central cholinergic system on carotid sinus baroreceptor reflex resetting, and the M₂ receptor may play more important roles than M₁ receptor. 3. The effects of the pretreatment with M₁ or M₂ receptors antagonist into the LC on CSR resetting resulted from i.c.v. PHY, are similar to the above-mentioned conclusion 2, and suggest that M₁ and M₂ receptors, especially M₂ receptor in the LC may be involved in the effects of central cholinergic system on carotid sinus baroreceptor reflex resetting, and the descending cholinergic pathway from the hypothalamus to LC might be related to effects of central cholinergic system on CSR.4. The effects of the pretreatment with M₁ or M₂ receptors antagonist into the NTS on CSR resetting induced by i.c.v. PHY, are converse to the above-mentioned conclusion 2 and 3, and denote that M₁ and M₂ receptors, especially M₂ receptor in the NTS may negatively regulate effects of central cholinergic system on carotid sinus baroreceptor reflex resetting and might facilitate the CSR function, and the descending cholinergic pathway from the hypothalamus to NTS may be participate in modulating effects of central cholinergic system on CSR.5. N₁ receptors in the hypothalamus, LC and NTS may not be related to effects of central cholinergic system on carotid sinus baroreceptor reflex resetting.