Baroreceptor control of pressure-flow relationships during hypoxemia

In the absence of peripheral chemoreceptors, the effects of graded hypoxemia on the carotid sinus control of central and regional hemodynamics were studied in anesthetized mongrel dogs. Baroreceptor stimulation was effected by carotid sinus isolation and perfusion under controlled pressure. Blood flows were measured in the aorta and the celiac, mesenteric, left renal, and right iliac arteries. Carotid sinus reflex set-point pressures were well maintained until hypoxemia was severe. Carotid sinus reflex set-point gain was maximal during mild hypoxemia. Reflex operating point regional flows were unaffected by hypoxemia. A factorial analysis of overall reflex increases in mean aortic pressure, flow, and power during reduced baroreceptor stimulation showed potentiation by increasing hypoxemia. Corresponding effects of baroreceptor stimulation and hypoxemia on aortic resistance and heart rate were additive. Celiac, renal, and iliac blood flows increased during both hypoxemia and reduced baroreceptor stimulation. Only in the celiac bed were blood flow changes independent of concomitant changes in cardiac output. Thus, at maximum sympathetic stimulation (low carotid sinus pressure) during hypoxemia, the cardiovascular system maintained both central and regional blood flows at high systemic blood pressures independent of the peripheral chemoreceptors.     

大鼠侧脑室内注射组胺对颈动脉窦压力感受性反射的影响及其中枢机制

在50只麻醉的大鼠孤离双侧颈动脉窦区,将不同窦内压（ISP）与其对应的平均动脉压（MAP）值进行Logistic五参数曲线拟合,根据所得ISP-MAP关系曲线及其特征参数,观察侧脑室注射（i.c.v)组胺（HA）对颈动脉窦压力感受性反射（CSR）的影响,并对其作用机制进行了初步探讨。结果如下：（1）i.c.v.HA(100ng)导致ISP-MAP关系曲线显著上移,ISP和增益（Gain)关系曲线中部明显下移,反射参数中阈压（TP）,饱和压（SP）和最大增益时的窦内压（ISPGmax)值增大,MAP反射变动范围（MAPrange)及反射最大增益（Gmax)减小。（2）预先i.c.v.H1受体拮抗剂氯苯吡胺（CHL,5μg）或H2受体拮抗剂西咪替丁（CIM,15μg）,可明显减弱HA的上述效应,CIM的这种减弱作用不如CHL的显著。（3）预先同时i.c.v.CHL和CIM（分别为5和15μg）,能完全取消HA的效应。（4）预先向孤束核（NTS）内注射CHL（0.5μg）或CIM（1.5μg）,对HA效应的影响与i.c.v.CHL或CIM后的相类似,但NTS内注射CHL或CIM后i.c.v.HA所致的TP变化表现明显下降。以上结果提示,侧脑室给HA使CSR产生快速重调定,反射敏感性下降,功能受抑;其机制是通过中枢HA受体介导,H1受体的作用比H2受体更为明显;下丘脑-NTS的HA能通路可能是HA调节CSR的下行通路之一。NTS处的HA受体在i.c.v.HA抑制CSR的机制中可能发挥重要的作用。     

Baroreceptor influence on a spinal cardiovascular reflex

A stretch of the walls of the thoracic aorta, performed in vagotomized cats without obstructing aortic flow, induces increases in heart rate, myocardial contractility, and arterial pressure. These reflex responses are still present after high spinal section. Cats under chloralose-urethane anesthesia were vagotomized and one carotid sinus was isolated and perfused with arterial blood at constant flow. The contralateral carotid sinus nerve and both aortic nerves were sectioned. A stretch of the walls of the thoracic aorta between the 7th and 10th intercostal arteries induced a reflex increase in mean arterial pressure 29 +/- 2 mmHg (mean +/- SE). Stepwise increases of carotid sinus pressure (CSP) or electrical stimulation of the carotid sinus nerve induced stepwise decreases of this reflex response. At maximal baroreceptor stimulation (CSP 212 +/- 9 mmHg) the reflex response to aortic stretch was reduced by 42%. These experiments show that this spinal cardiovascular reflex is at least partially under the inhibitory control of the baroreceptor input.     

Influence of substance P on carotid sinus nerve baro- and chemoreceptor activity in rabbits.

Substance P (SP) is abundant in the carotid sinus nerve (CSN) and has been implicated in baro- and chemoreceptor reflexes. We examined the effect of SP on blood pressure, heart rate, phrenic nerve activity, hindlimb perfusion pressure, and cardiac contractile strength in urethane-anesthetized rabbits with bilaterally cut cervical sympathetic, vagus, and aortic depressor nerves. Retrograde simultaneous injection of SP (0.5-2.7 micrograms/kg in 0.2-0.3 ml saline) into both carotid sinus areas via the internal carotid arteries decreased blood pressure (by 56%), heart rate (by 13%), cardiac contractility (by 25%) and phrenic nerve activity (by 77%). The effect on hindlimb perfusion pressure was variable. There was both a reflex effect and direct hindlimb vasodilation. In another group of rabbits, the carotid sinus areas were vascularly isolated and perfused with SP (0.19 micrograms/min dissolved in Locke's solution) or Locke's solution alone for 5 min. While carotid sinus perfusion pressure was maintained in the range of 80-120 mmHg, mean arterial blood pressure, heart rate, and unit activity from the CSN were recorded. SP increased the activity of 11 of 18 baroreceptor fibers and inhibited all of 20 chemoreceptor fibers. SP decreased mean arterial blood pressure and heart rate, but the changes were less than those obtained with injection of SP into nonisolated carotid sinus arteries because systemic effects of SP, which in some cases counteracted the reflex effects, were eliminated.     

激动中枢组胺能受体对应激大鼠颈动脉窦压力感受性反射重调定的影响

应激1周的大鼠,麻醉后弧离双侧颈动脉窦区,将不同窦内压（ISP）与其对应的平均动脉压（MAP）值进行Logistic5个参数曲线拟合。根据所得ISP－MAP关系曲线及其特征参数,分别观察侧脑室(i.c.v.）注射和弧束核（NTS）内注射组胺受体拮抗剂对颈动脉窦压力感受性反射（CSR）的影响,并与相应的非应激CSR水平进行比较。结果如下：（1）应激导致ISP－MAP关系曲线显著全面上移,窦内压和增益（ISP-Gain）关系曲线中部明显下移,反射参数中阈压（TP）、饱和压（SP）、调定点（set point）和最大增益时的窦内压（ISPGmax）值增大,MAP反射变动范围（MAPrange）及反射最大增益（Gmax）减小;（2）I.c.v.H1或H2受体拮抗剂氯苯吡胺（CHL）15μg或西咪替丁（CIM）15μg,在20min内均可明显减弱应激对CSR的上述改变,CIM的这种减弱作用不如CHL的显著;（3）NTS内注射CHL（0.5μg）或CIM（1.5μg）,对应激所致CSR变化的影响与i.c.v.CHL或CIM后的相类似;（4）分别i.c.v.和NTS内注射CHL或CIM后,均不能使应激的CSR水平完全恢复到相应的非应激对照水平。以上结果提示,应激引起CSR重调定,反射敏感性下降;其部分机制可能是激活中枢组胺能系统,通过中枢组胺能受体（H1和H2受体）尤其是H1受体介导而发挥作用;下丘脑－NTS的组胺能通路可能是应激导致CSR重调定的下行通路之一。     

Role of acetylcholine, histamine and gastrin in the acid response to intracisternal injection of TRH analog, RX 77368, in the rat

The role of gastrin, acetylcholine and histamine in the acid response to central vagal activation induced by intracisternal injection of the stable analog, RX 77368, was further investigated in urethane-anesthetized rats with gastric fistula. The gastrin monoclonal antibody 28-2 injected intravenously, at a dose previously shown to prevent gastrin-induced stimulation of acid secretion, did not alter the peak acid response to intracisternal injection of RX 77368 (15 ng). The TRH analog (30 ng) injected into the cisterna magna increased levels of histamine measured in the hepatic portal blood. Cimetidine administered at a dose which completely blocked the stimulation of gastric acid secretion produced by intravenous infusion of histamine, inhibited by 62% the stimulatory effect of intracisternal RX 77368 (30 ng). The M1 muscarinic antagonist, pirenzepine, completely prevented the acid secretion induced by intracisternal RX 77368 (30 ng). These results indicate that the acid response to central vagal activation by the TRH analog in rats involved M1 muscarinic receptors along with histamine release acting on H2 histaminergic receptors whereas gastrin does not appear to play an important role.     

Characterization of the inotropic response induced by stimulation of beta-adrenergic and H1 histaminergic receptors in guinea pig left atria.

The inotropic response induced by beta-adrenergic and H1 histaminergic receptor stimulation was characterized in guinea pig left atria by obtaining dose-response relationships for isoproterenol and histamine under various experimental conditions. Conditions (hypothermia, high frequencies of stimulation, and large extracellular calcium concentrations) which enhanced the ability of cardiac muscle to develop force also increased the sensitivity of the left atrium to isoproterenol while decreasing its efficacy. On the other hand, conditions which enhanced the ability of cardiac muscle to develop force depressed the efficacy of histamine to such an extent that the sensitivity to histamine was also decreased. In addition, conditions which markedly depressed the ability of cardiac muscle to develop force also decreased the efficacy and sensitivity to histamine. The data indicate that while beta-adrenoceptor stimulation results in an inotropic response under all conditions studied, stimulation of H1 histaminergic receptors results in an inotropic response only within a narrow range of experimental conditions.     

Role of central histaminergic mechanism in behavioural depression (swimming despair) in mice

The role of the central histaminergic system in depression was studied by using swimming despair test in mice - a behavioural model of depression. In this test, immobility of mice reflects a state of depression. Intracerebral (ic) injection of histamine (50-200 micrograms) increased significantly the immobility. The H1-receptor blocker mepyramine (2.5-20 mg/kg ip) had no effect while H2-receptor blocker cimetidine (100-200 micrograms ic) caused a significant decrease in immobility. The histamine induced facilitation was blocked completely by cimetidine and antidepressant drugs-imipramine and desipramine, but remained unaffected in mice pretreated with mepyramine or atropine. The H2 agonist impromidine (20-40 micrograms ic) also enhanced significantly, the immobility which was blocked by cimetidine and antidepressant drugs. It has been concluded that central H2-receptors facilitate depression and antidepressant drugs block central H2-receptors.     

MLR-induced inhibition of barosensory cells in the NTS

A central motor command arising from the mesencephalic locomotor region (MLR) is widely believed to be one of the neural mechanisms that reset the baroreceptor reflex upward during exercise. The nucleus tractus solitarius (NTS), a dorsal medullary site that receives input from baroreceptors, may be the site where central command inhibits baroreceptor input during exercise. We, therefore, examined the effect of electrical stimulation of the MLR on the impulse activity of cells in the NTS in decerebrate paralyzed cats. Of 129 NTS cells tested for baroreceptor input by injection of phenylephrine (7-25 microg/kg iv) or inflation of a balloon in the carotid sinus, 58 were stimulated and 19 were inhibited. MLR stimulation (80-150 microA) inhibited the discharge of 48 of the 58 cells stimulated by baroreceptor input. MLR stimulation had no effect on the discharge of the remaining 10 cells, each of which displayed no spontaneous activity. In contrast to the 77 NTS cells responsive to baroreceptor input, there was no change in activity of 52 cells when arterial pressure was increased by phenylephrine injection or balloon inflation. MLR stimulation activated each of the 52 NTS cells. For 23 of the cells, the onset latency to MLR stimulation was clearly discernable, averaging 6.4 +/- 0.4 ms. Our findings provide electrophysiological evidence for the hypothesis that the MLR inhibits the baroreceptor reflex by activating NTS interneurons unresponsive to baroreceptor input. In turn, these interneurons may release an inhibitory neurotransmitter onto NTS cells receiving baroreceptor input.     

Release of calcitonin gene-related peptide in the pig nasal mucosa by antidromic nerve stimulation and capsaicin

The overflow of calcitonin gene-related peptide like-immunoreactivity (CGRP-LI) in the nasal venous effluent upon antidromic stimulation of the maxillary division of the trigeminal nerve with 6.9 Hz for 3 min or upon capsaicin (0.3 mumol bolus injection) were analysed in the nasal mucosa of sympathectomized pentobarbital anaesthetized pigs. The overflow of CGRP-LI upon antidromic stimulation displayed a slower appearance in the venous effluent than the overflow upon bolus injection of capsaicin. The vascular effects as revealed by the arterial blood flow, the venous blood flow, the blood volume of the nasal mucosa, i.e., the filling of the capacitance vessels and the superficial mucosal blood flow as revealed by the laser-Doppler signal were also studied. Antidromic stimulation of the trigeminal nerve as well as capsaicin bolus injection induced a marked vasodilation which was parallel to the overflow of CGRP. However, capsaicin bolus injection also resulted in a marked increase in the mean arterial blood pressure which may be due to reflex activation of sympathetic fibers. In conclusion, we have demonstrated that chemical stimulation with capsaicin as well as antidromic stimulation of nasal sensory nerves in sympathectomized animals induces both vasodilation and overflow of CGRP-LI in vivo. This indicates that CGRP may contribute to the sensory regulation of the microcirculation in the nasal mucosa.     

Glutamatergic mechanisms in the nucleus tractus solitarius in blood pressure control

The nucleus tractus solitarius (NTS), the site of termination of visceral afferents of the ninth and tenth cranial nerves, mediates and integrates the reflex cardiovascular and noncardiovascular responses to stimulation of cardiopulmonary and other visceral afferents. On injection into the NTS, the amino acid L-glutamate (L-Glu) and its excitatory analogs produce dose-dependent hypotension and bradycardia, a baroreceptor reflex-like response. The L-Glu antagonist glutamate diethyl ester blocks the response both to L-Glu and to baroreceptor reflex activation. Electrical stimulation of vagal c-fibers selectively releases 3H into a push-pull cannula after preloading of the NTS with L-[3H]Glu or D-[3H]aspartate. The NTS contains a high-affinity uptake system for inactivation of L-Glu. Like L-Glu, acetylcholine and serotonin, which are also found in the NTS, both elicit a baroreceptor reflex-like response when microinjected into the NTS. However, cholinergic and serotonergic antagonists do not block the baroreceptor reflex. A glutamatergic neuron (or neurons) projecting into NTS appears to be an integral part of the baroreceptor reflex arc.     

Nitric oxide infused in the solitary tract nucleus blocks brain glucose retention induced by carotid chemoreceptor stimulation

Previous work has shown that the carotid body glomus cells can function as glucose sensors. The activation of these chemoreceptors, and of its afferent nucleus in the brainstem (solitary tract nucleus - STn), induces rapid changes in blood glucose levels and brain glucose retention. Nitric oxide (NO) in STn has been suggested to play a key role in the processing of baroreceptor signaling initiated in the carotid sinus. However, the relationship between changes in NO in STn and carotid body induced glycemic changes has not been studied. Here we investigated in anesthetized rats how changes in brain glucose retention, induced by the local stimulation of carotid body chemoreceptors with sodium cyanide (NaCN), were affected by modulation of NO levels in STn. We found that NO donor sodium nitroprusside (SNP) micro-injected into STn completely blocked the brain glucose retention reflex induced by NaCN chemoreceptor stimulation. In contrast, NOS inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) increased brain glucose retention reflex compared to controls or to SNP rats. Interestingly, carotid body stimulation doubled the expression of nNOS in STn, but had no effect in iNOS. NO in STn could function to terminate brain glucose retention induced by carotid body stimulation. The work indicates that NO and STn play key roles in the regulation of brain glucose retention.     

Effect of restraint stress on nociceptive responses in rats: role of the histaminergic system

Stress induced analgesia (SIA) is well known, but the reverse phenomenon, hyperalgesia is poorly documented. This study investigated the role of the histaminergic system in restraint stress hyperalgesia in rats, using thermal stimulation method (hot plate and tail flick tests). Paw licking and tail withdrawal latencies were taken before and after restraint for about one hour. Significant decreases were obtained in these latencies after the restraint in both tests. Administration of H1 and H2 receptor blockers, chlorpheniramine and cimetidine respectively 30 mins before the restraint still resulted in significant reductions in these latencies, connoting the persistence of hyperalgesia, showing that histamine H1 and H2 receptors did not participate in the mechanism of restraint stress hyperalgesia. We therefore suggest a histaminergic independent mechanism for restraint stress induced hyperalgesia.     

The influence of alpha-fluoromethylhistidine and histamine receptor antagonists on the beta-endorphin-induced corticosterone response

Involvement of a central histaminergic mechanism in the stimulating effect of beta-endorphin (beta-End) on the pituitary-adrenocortical activity, measured indirectly through corticosterone secretion, was investigated in conscious rats. The rise in serum corticosterone levels, induced by beta-End injected intraventricularly (icv) was considerably impaired by pretreatment with naltrexone, an opioid receptor antagonist. The stimulating effect of beta-End was almost totally suppressed by a prior icv administration of mepyramine, a histamine H1-receptor antagonist, and also considerably reduced by pretreatment with cimetidine, an H2-receptor antagonist. The strongest suppression, by 83%; of the beta-End-induced corticosterone response was evoked by a prior administration of alpha-fluoromethylhistidine, an inhibitor of neuronal histamine synthesis in the brain. These results indicate that both the brain neuronal histamine and central histamine H1- and H2-receptors are considerably involved in the beta-endorphin-induced stimulation of the pituitary-adrenocortical activity.     

On the haemodynamic effects of biogenic amines in isolated fish gills

The effects of histidine and histamine on branchial vascular haemodynamics were studied using the isolated, perfused gill of the tropical cichlid, Oreochromis (Sarotherodon) niloticus. Histidine had no vasoactive effect while histamine induced vasodilatation. Histamine-induced vasodilatation was irreversibly inhibited by the H1 and H2 receptor antagonists, piriton and cimetidine, respectively. This suggests a possible involvement of the non-neurogenic histaminergic system, acting directly via H1 and H2 histamine receptors, in the regulation of branchial vascular haemodynamics in teleosts.     

5-HT-mediated inhibition of cardiovagal baroreceptor reflex response during defense reaction in the rat

Previous studies showed that the cardiac response of the baroreceptor reflex (bradycardia) is inhibited during the defense reaction evoked by direct electrical or chemical stimulation of the periaqueductal gray (dPAG) in the rat. Whether central serotonin and nucleus tractus solitarius (NTS) serotonin(3) (5-HT(3)) receptors might participate in this inhibition was investigated in urethane-anesthetized and atenolol-pretreated rats. Our results showed that both electrical and chemical stimulation of the dPAG produced a drastic reduction of the cardiovagal component of the baroreceptor reflex triggered by either intravenous administration of phenylephrine or aortic nerve stimulation. This inhibitory effect of dPAG stimulation on the baroreflex bradycardia was not observed in rats that had been pretreated with p-chlorophenylalanine (300 mg/kg ip daily for 3 days) to inhibit serotonin synthesis. Subsequent 5-hydroxytryptophan administration (60 mg/kg ip), which was used to restore serotonin synthesis, allowed the inhibitory effect of dPAG stimulation on both aortic and phenylephrine-induced cardiac reflex responses to be recovered in p-chlorophenylalanine-pretreated rats. On the other hand, in nonpretreated rats, the inhibitory effect of dPAG stimulation on the cardiac baroreflex response could be markedly reduced by prior intra-NTS microinjection of granisetron, a 5-HT(3) receptor antagonist, or bicuculline, a GABA(A) receptor antagonist. These results show that serotonin plays a key role in the dPAG stimulation-induced inhibition of the cardiovagal baroreceptor reflex response. Moreover, they support the idea that 5-HT(3) and GABA(A) receptors in the NTS contribute downstream to the inhibition of the baroreflex response caused by dPAG stimulation.     

Maintaining hypertension in negative emotional exposures as one of the functions of the baroreceptor reflex

Changes in the heart rate and blood pressure induced by different emotiogenic influences were studied in rats with intact and denervated baroreceptor afferents of the carotid sinuses and aortic arch. Aversive emotiogenic stimuli failed to induce hypertension in rats with denervated baroreceptor areas, while self-stimulation in these rats caused a profound rise in arterial pressure. It is concluded that maintenance of hypertension induced by aversive emotiogenic influences is a manifestation of baroreceptor reflex.     

Influence of cyclooxygenase inhibitors on the central histaminergic stimulations of hypothalamic - pituitary - adrenal axis.

Brain histamine participates in central regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Endogenous prostaglandins modulate signal transduction of different neurotransmitters involved in activation of HPA axis. In the present experiment we investigated whether endogenous prostaglandins are involved in the stimulation of ACTH and corticosterone secretion by histaminergic systems in the rat brain. Histamine (50 microg), histamine-trifluoromethyl-toluidine derivative (HTMT, 75microg) a selective and potent H(1)-receptor agonist, and amthamine (50 microg) a H(2)-receptor agonist given intracerebroventricularly (i.c.v.) to non-anesthetized rats considerably increased ACTH and corticosterone secretion 1h after administration. A non-selective cyclooxygenase inhibitor indomethacin (2 mg/kg i.p. or 10 microg i.c.v.), piroxicam (0.02 and 0.2 microg i.c.v.) a more potent antagonist of constitutive cyclooxygenase (COX-1) and compound NS-398 (0.1 and 1.0 microg i.c.v.), a selective inhibitor of inducible cyclooxygenase (COX-2) were given 15 min before histamine and histamine receptor agonists. One hour after the last injection trunk blood from decapitated rats was collected for hormones determination. The histamine-induced ACTH and corticosterone secretion was significantly diminished by piroxicam and was not markedly altered by indomethacin and compound NS-398. The HTMT-elicited increase in ACTH and corticosterone secretion was significantly prevented by indomethacin and was not affected by piroxicam or compound NS-398. The amthamine-evoked increase in ACTH and corticosterone secretion was not markedly influenced by any cyclooxygenase blocker applied in the present experiment. These results indicate that the histamine H(1)-receptor transmitted central stimulation of the HPA axis is considerably mediated by prostaglandins generated by consititutive cyclooxygenase, whereas stimulation transmitted via H(2)-receptor does not significantly depend on endogenous prostaglandins mediation.     

Thioperamide, a selective histamine H3 receptor antagonist, protects against PTZ-induced seizures in mice

The effect of selective histamine H3-receptor antagonist thioperamide was studied on PTZ-induced seizures in mice. Thioperamide significantly protected clonic seizures induced by PTZ in a dose-dependent manner. The effect of thioperamide was completely countered by pretreatment with R (alpha)-methylhistamine (RAMH), a selective H3-receptor agonist suggesting that the observed effect of thioperamide was elicited by histamine H3-receptors. RAMH alone did not significantly modify PTZ seizures. The findings are consistent with a role for the histaminergic neuronal system in seizures and suggest that H3-receptors may play an important role in modulating clonic seizures induced by PTZ in mice.     

Ontogeny of Histaminergic Neurotransmission in the Rat Brain: Concomitant Development of Neuronal Histamine, H-1 Receptors, and H-1 Receptor-Mediated Stimulation of Phospholipid Turnover

The ontogeny of histaminergic neurotransmission in the rat brain was studied by assessing development of histamine levels in brain regions, along with H-1 receptor binding of [3H]mepyramine and H-1 receptor-mediated cellular events. In the hypothalamus, which is rich in histaminergic innervation, levels of the amine were low at birth, increased sharply at 8 days of age, and reached adult concentrations shortly thereafter; this pattern is typical of most neurotransmitters. In contrast, regions poor in neuronal histamine showed an initially high histamine level and a subsequent decline with development, as is known to occur during general growth of tissues. The developmental profile of H-1 receptor binding sites resembled that of the neuronal histamine pool, and the increases with age resulted from changes in the number of binding sites without alterations in Kd. Cellular responses to H-1 receptor activation were assessed by determining the stimulation of phospholipid turnover evoked by intracisternally administered histamine, a process that has been shown to involve only the neuronal compartment. Again, the developmental profile was superimposable upon that of H-1 receptor binding and that of hypothalamic histamine levels. These studies indicate that ontogeny of histaminergic neurotransmission is a coordinated process, with simultaneous development of neuronal histamine, its key biosynthetic enzyme, and H-1 receptors coupled directly to cellular events.