Acetylcholine in the posterior hypothalamic nucleus is involved in the elevated blood pressure in the spontaneously hypertensive rat

Intravenous injection of physostigmine, 40 and 80 ug/kg, in unanesthetized normotensive rats increased systolic blood pressure (SBP) by 21 +/- 3 and 42 +/- 7 mmHg. This pressor response was 80% inhibited by intracerebroventricular (icv) injection of hemicholinium-3 (HC-3), 20 ug. Simultaneous icv injection of HC-3 and choline (365 ug) prevented the inhibition of the pressor response by HC-3. In spontaneously hypertensive rats, injection of HC-3 either icv (20 ug) or bilaterally into the posterior hypothalamic nuclei (1 ug) decreased SBP by about 40 mmHg. The effect of intrahypothalamic HC-3 was completely blocked by simultaneous injection of choline (24.3 ug) into the same site. The hypotensive effect of icv HC-3 was completely blocked by icv choline (243 ug) and was inhibited up to 60% by injections of choline (24.3 ug) into the posterior hypothalamic nuclei.     

The ganglionic blocking properties of the cholinesterase reactivator, HS-6.

Following intravenous administration of the cholinesterase reactivator HS-6 (30 mg/kg), blood pressure fell (up to 50 mmHg) and maximal blood levels of HS-6 reached 242 microgram/ml. HS-6 attenuated the pressor response resulting from carotid occlusion and the depressor effect of vagal stimulation. Doses of HS-6 below those used to protect against soman in different animal species (10--30 mumol/kg) progressively blocked the ganglion-stimulating effects of nicotine and dimethylphenylpiperazinium but not the pressor effect following adrenaline, a pattern similar to that produced by hexamethonium but only 1/84 as potent. HS-6, like hexamethonium and mecamylamine, progressively blocked the contraction of the nictitating membrane of the cat resulting from preganglionic stimulation. The results indicate that HS-6 possesses ganglion-blocking properties at doses likely to be used in the protection against soman poisoning. The ganglion-blocking properties of the drug may be a factor in the beneficial effects of HS-6.     

Pressor effect of NG-nitro-L-arginine in pentobarbital-anesthetized rats

The pressor effect of NG-nitro-L-arginine (L-NNA), a potent inhibitor of nitric oxide (NO) synthesis, was studied in pentobarbital anesthetized rats. Iv injections of L-NNA from 0.25 to 8 mg/kg caused bradycardia and a dose-dependent increase in mean arterial pressure (MAP) with a maximal response of 43 +/- 5 mmHg and ED50 value of 1.3 +/- 0.2 mg/kg. The time course of the response to the injection of a single dose of L-NNA was also determined. Peak response was reached 60 min after the injection of a single dose (4 mg/kg, iv) and the effect lasted greater than 5 h. The rising phase of the pressor response was accompanied by slight bradycardia while the recovery phase was associated with significant tachycardia. Iv injections of L-arginine (12.5-200 mg/kg) caused transient dose-dependent reductions in MAP. The pressor effect of L-NNA (4 mg/kg, iv bolus) was dose-dependently attenuated by L-arginine. The results show that L-NNA is an efficacious and long-acting pressor agent and are consistent with the hypothesis that endogenous NO plays an important role in the regulation of blood pressure.     

Attenuation of pressor responses to intracerebroventricular angiotensin I by angiotensin converting enzyme inhibitors and their effects on systemic blood pressure in conscious rats

The components of the renin-angiotensin system exist in the brain but their physiological role is uncertain. The effects of two angiotensin converting enzyme (ACE) inhibitors, MK 421 (or its diacid) and captopril, on brain ACE activity, as measured by inhibition of the pressor response to intracerebroventricularly (i.c.v.) administered angiotensin I (AI), and the potential contribution of the central nervous system to their antihypertensive activity were evaluated in the present series of experiments. The diacid of MK 421 (1 and 10 ug) and captopril (3 and 10 ug) given i.c.v. to conscious normotensive rats reduced the pressor response to i.c.v. AI indicating that they can inhibit brain ACE. Responses to AII were unaffected. Oral administration of maximal antihypertensive doses of MK 421 (10 mg/kg) and of captopril (30 mg/kg) to normotensive rats did not attenuate pressor responses to i.c.v. AI indicating that brain ACE was not inhibited under these circumstances. Intracerebroventricular administration of MK 421 diacid, (10 and 30 ug) and captopril (30 and 100 ug) did not lower baseline blood pressure of spontaneously hypertensive rats. These experiments indicate that MK 421 and captopril can inhibit brain ACE but that the central renin-angiotensin system probably does not contribute to their antihypertensive activity.     

+]-Huperzine A protects against soman toxicity in guinea pigs

The chemical warfare nerve agent (CWNA) soman irreversibly inhibits acetylcholinesterase (AChE) causing seizure, neuropathology and neurobehavioral deficits. Pyridostigmine bromide (PB), the currently approved pretreatment for soman, is a reversible AChE inhibitor that does not cross the blood–brain barrier (BBB) to protect against central nervous system damage. [−]-Huperzine A, a natural reversible AChE inhibitor, rapidly passes through the BBB and has numerous neuroprotective properties that are beneficial for protection against soman. However, [−]-Huperzine A is toxic at higher doses due to potent AChE inhibition which limits the utilization of its neuroprotective properties. [+]-Huperzine A, a synthetic stereoisomer of [−]-Huperzine A and a weak inhibitor of AChE, is non-toxic. In this study, we evaluated the efficacy of [+]-Huperzine A for protection against soman toxicity in guinea pigs. Pretreatments with [+]-Huperzine A, i.m., significantly increased the survival rate in a dose-dependent manner against 1.2× LD₅₀ soman exposures. Behavioral signs of soman toxicity were significantly reduced in 20 and 40 mg/kg [+]-Huperzine A treated animals at 4 and 24 h compared to vehicle and PB controls. Electroencephalogram (EEG) power spectral analysis showed that [+]-Huperzine A significantly reduces soman-induced seizure compared to PB. [+]-Huperzine A (40 mg/kg) preserved higher blood and brain AChE activity compared to PB in soman exposed animals. These data suggest that [+]-Huperzine A protects against soman toxicity stronger than PB and warrant further development as a potent medical countermeasure against CWNA poisoning.     

Imidazoline receptors of the paraventricular nucleus on the pressor response induced by stimulation of the subfornical organ

In the present experiments we investigated a possible involvement of imidazoline receptors of the paraventricular nucleus (PVN) of the hypothalamus on the pressor effects of the angiotensin II (ANG II) injected into the subfornical organ (SFO), in male Holtzman rats (250–300 g) with a cannula implanted into the third ventricle (3rdV), PVN and SFO. At first we tested the participation of α₂ and imidazoline agonist and antagonist compounds on the pressor effect of ANG II injected into the 3rdV. Based on the results we may conclude that clonidine associated with rilmenidine was able to block the hypertensive response to ANG II. The ANG II (20 pmol) injected into SFO induced a robust increase in blood pressure (37 ± 2 mmHg). Isotonic saline (0.15 M) NaCl did not produce any change in blood pressure (5 ± 2 mmHg). The injection of rilmenidine (30 μg/kg/1 μL), an imidazoline agonist agent injected into PVN before ANG II injection into SFO, blocked the pressor effect of ANG II (5 ± 2 mmHg). Also, the injection of idazoxan (60 μg/kg/μL) before rilmenidine blocked the inhibitory effect of rilmenidine on blood pressure (39 ± 4 mmHg). The injection of clonidine (20 nmol/μL) prior to ANG II into the 3rdV produced a decreased in arterial blood pressure (37 ± 2 mmHg) to (15 ± 4 mmHg). The injection of yohimbine (80 nmol/μL) prior to clonidine blocked the effect of clonidine on the effect of ANG II (27 ± 2 mmHg). The injection of rilmenidine prior to ANG II also induced a decrease in arterial blood pressure (10 ± 3 mmHg). The injection of idazoxan prior to rilmenidine also blocked the inhibitory effect of rilmenidine (24 ± 3 mmHg). In summary, the present study demonstrated that rilmenidine decreases the hypertensive effect of ANG II, with more potency than clonidine, even when injected into 3rdV or PVN. This study established that the PVN interacts with SFO by imidazoline receptors in order to control the arterial blood pressure.     

Inhibition of acetylcholinesterase in the gut inhibits schedule-controlled behavior in the rat

Rats were trained to press a lever under a multiple Fixed-Ratio 25 Fixed-Interval 50-second schedule of food reinforcement. Subcutaneous injection of soman, 80 micrograms/kg, suppressed responding under both schedules and inhibited acetylcholinesterase (AChE) in the brain. AChE activity in the gastrointestinal tract was not significantly inhibited. In contrast, i.p. injection of either soman (10-40 micrograms/kg), neostigmine (75 micrograms/kg) or DFP (350 micrograms/kg) caused marked suppression of behavior and AChE activity of the gut, without affecting brain AChE. These doses caused marked increases in peristaltic activity and likely caused gastrointestinal spasm. Injection of DFP, 500 micrograms/kg, s.c., inhibited AChE in both the brain and gut. The results indicate that inhibition of AChE in the gastrointestinal tract by certain anticholinesterase agents may be involved in the behavioral effects attributed to these drugs.     

Sympathetic innervation of the splanchnic region mediates the beneficial hemodynamic effects of 8-OH-DPAT in hemorrhagic shock

Administration of the 5-HT(1A) receptor agonist, 8-OH-DPAT, improves cardiovascular hemodynamics and tissue oxygenation in conscious rats subjected to hypovolemic shock. This effect is mediated by sympathetic-dependent increases in venous tone. To determine the role of splanchnic nerves in this response, effects of 8-OH-DPAT (30 nmol/kg iv) were measured following fixed-arterial blood pressure hemorrhagic shock (i.e., maintenance of 50 mmHg arterial pressure for 25 min) in rats subjected to bilateral splanchnic nerve denervation (SD). Splanchnic denervation decreased baseline venous tone as measured by mean circulatory filling pressure (MCFP) and accelerated the onset of hypotension during blood loss. Splanchnic denervation did not affect the immediate pressor effect of 8-OH-DPAT but did reverse the drug's lasting pressor effect, as well as its ability to increase MCFP and improve metabolic acidosis. Like SD, adrenal demedullation (ADMX) lowered baseline MCFP and accelerated the hypotensive response to blood withdrawal but also reduced the volume of blood withdrawal required to maintain arterial blood pressure at 50 mmHg. 8-OH-DPAT raised MCFP early after administration in ADMX rats, but the response did not persist throughout the posthemorrhage period. In a fixed-volume hemorrhage model, 8-OH-DPAT continued to raise blood pressure in ADMX rats. However, it produced only a transient and variable rise in MCFP compared with sham-operated animals. The data indicate that 8-OH-DPAT increases venoconstriction and improves acid-base balance in hypovolemic rats through activation of splanchnic nerves. This effect is due, in part, to activation of the adrenal medulla.     

Cholinergic neurons and the cardiovascular response produced by central injection of substance P in the normotensive rat

The role of cholinergic neurons in central cardiovascular regulation is not well understood, however, activation of brain cholinergic neurons in several species evokes a hypertensive response. As with central cholinergic stimulation, intracerebroventricular (i.c.v.) injection of substance P (sP) elicits a pressor response in unanesthetized rats. The purpose of this study was to determine whether the cardiovascular effects following i.c.v. injection of this neuropeptide are mediated by central cholinergic neurons. Therefore, the cardiovascular response to sP was examined in control rats, and in animals pretreated centrally with classical pre- and post-synaptic cholinergic antagonists. Drugs were administered directly into the lateral ventricle while rats were freely-moving in their home cages. I.c.v. injection of sP produced a dose - dependent increase in arterial pressure and heart rate. The hypertensive response was significantly reduced by pretreatment with hemicholinium-3. This dose (20 ug) of hemicholinium-3 is capable of producing a maximal depletion of brain acetylcholine levels. The increase in heart rate to substance P was not as sensitive to hemicholinium-3 pretreatment as was blood pressure. Central pretreatment with the nicotinic receptor antagonist, hexamethonium was more effective than the muscarinic antagonist, atropine in blocking the pressor response to sP. Hexamethonium did not significantly alter the tachycardic response to the peptide, but atropine produced a small, but significant reduction in the response. Therefore, the pressor response to central injection of sP may be mediated to a large extent through cholinergic pathways involving nicotinic receptors.     

Relationship between reversible acetylcholinesterase inhibition and efficacy against soman lethality

Carbamate pretreatment (45% inhibition, reversible), combined with therapy, protected rats from soman-induced lethality [The Pharmacologist 23, 224 (1981)]. The present study was done to see if less than 45% inhibition protects and to see if reversible acetylcholinesterase (AChE) inhibition and efficacy against soman lethality are correlated. At 30 min pre-soman, guinea pigs and rats received (im) either pyridostigmine (Py) or physostigmine (Ph) to inhibit whole blood AChE from 10 to 70%; at 1 min post-soman (sc), they received (im) atropine (16 mg/kg)/2-PAMCl (50 mg/kg) and mecamylamine (0.8 mg/kg)/atropine (16 mg/kg), respectively. Protective ratios (PRs) were computed and they ranged from 3.1 to 7.7 for guinea pigs and from 1.8 to 2.4 for rats. In guinea pigs the PRs for Py + therapy were roughly similar to those of Ph + therapy. In both species at 30 min after im injection of Py and Ph, a linear relationship was found between percentage of whole blood AChE inhibition and ln dosage of carbamate. Positive correlation (p less than 0.05) was found between the degree of reversible AChE inhibition by pretreatment, coupled with therapy, and efficacy against soman lethality. The present data indicate that inhibition levels as low as 10% may provide some protection.     

刺激清醒大鼠躯体神经对失血性低血压的升压效应

在清醒雄性大鼠中经静脉抽出血液总量的约50%,造成失血性低血压。对照组大鼠在失血后不予处理。刺激组大鼠在失血后半小时用低频电脉冲刺激坐骨神经30min。刺激组动物的平均动脉压在刺激肘和刺激停止后2小时内均显著高于对照组。在同时记录内脏神经放电的动物中还看到,刺激坐骨神经时交感神经活动显著加强。这可能和血压、心率的恢复有关。在失血动物中刺激坐骨神经引起的升压效应不能被静脉内注射纳洛酮(8mg/kg)翻转;预先注射纳洛酮也不能阻断这种升压效应。在用水合氯醛麻醉的大鼠中,失血后刺激坐骨神经仍能引起升压反应。但如在刺激坐骨神经前静脉注射东莨菪碱(8—20mg/kg),则在多数动物中上述升压反应的幅度显著减小,甚至消失。实验结果表明,在失血性低血压的大鼠中,刺激坐骨神经可促进机体代偿反应,进一步加强交感神经活动,有利于血压的恢复。这一效应可能需要胆硷能递质参与,而内啡肽系统似乎不起重要作用。     

Nitric oxide modulates sympathoexcitatory cardiac-cardiovascular reflexes elicited by bradykinin

A number of studies have demonstrated an important role for nitric oxide (NO) in central and peripheral neural modulation of sympathetic activity. To assess the interaction and integrative effects of NO release and sympathetic reflex actions, we investigated the influence of inhibition of NO on cardiac-cardiovascular reflexes. In anesthetized, sinoaortic-denervated and vagotomized cats, transient reflex increases in arterial blood pressure (BP) were induced by application of bradykinin (BK, 0.1-10 microg/ml) to the epicardial surface of the heart. The nonspecific NO synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA, 10 mg/kg iv) was then administered and stimulation was repeated. L-NMMA increased baseline mean arterial pressure (MAP) from 129 +/- 8 to 152 +/- 9 mmHg and enhanced the change in MAP in response to BK from 32 +/- 3 to 39 +/- 5 mmHg (n = 9, P < 0.05). Pulse pressure was significantly enhanced during the reflex response from 6 +/- 4 to 27 +/- 6 mmHg after L-NMMA injection due to relatively greater potentiation of the rise in systolic BP. Both the increase in baseline BP and the enhanced pressor reflex were reversed by L-arginine (30 mg/kg iv). Because L-NMMA can inhibit both brain and endothelial NOS, the effects of 7-nitroindazole (7-NI, 25 mg/kg ip), a selective brain NOS inhibitor, on the BK-induced cardiac-cardiovascular pressor reflex also were examined. In contrast to L-NMMA, we observed significant reduction of the pressor response to BK from 37 +/- 5 to 18 +/- 3 mmHg 30 min after the administration of 7-NI (n = 9, P < 0.05), an effect that was reversed by L-arginine (300 mg/kg iv, n = 7). In a vehicle control group for 7-NI (10 ml of peanut oil ip), the pressor response to BK remained unchanged (n = 6, P > 0.05). In conclusion, neuronal NOS facilitates, whereas endothelial NOS modulates, the excitatory cardiovascular reflex elicited by chemical stimulation of sympathetic cardiac afferents.     

Nociceptin in rVLM mediates electroacupuncture inhibition of cardiovascular reflex excitatory response in rats.

Electroacupuncture (EA) at Neiguan-Jianshi acupoints through an opioid mechanism inhibits the cardiovascular pressor response induced by mechanical stimulation of the stomach. Because nociceptin also may regulate cardiovascular activity through its action in the brain stem, we hypothesized that this neuromodulator serves a role in the EA-related inhibitory effect. Blood pressure in ventilated male Sprague-Dawley rats (400-600 g) anesthetized by ketamine and alpha-chloralose was measured during balloon inflation of the stomach. Gastric distension with 6-8 ml of air induced consistent pressor reflexes of 26 +/- 1 mmHg that could be repeated every 10 min for 100 min. When nociceptin (10 nM) was microinjected into the rostral ventrolateral medulla (rVLM), the pressor response induced by gastric distension was inhibited by 68 +/- 6%. Thirty minutes of EA also decreased the reflex response by 75 +/- 11%; microinjection of saline into the rVLM did not alter the inhibitory effect of EA. In contrast, microinjection of a nociceptin receptor antagonist into the rVLM promptly reversed the EA response. Pretreatment with the opioid receptor antagonist naloxone did not influence the EA-like inhibitory effect of nociceptin on the distension-induced pressor reflex (22 +/- 1 to 8 +/- 2 mmHg). Furthermore, a mu-opioid receptor agonist microinjected into the rVLM after microinjection of a nociceptin receptor antagonist during EA promptly reversed the nociceptin receptor antagonist-related inhibition of the EA effect. Thus, in addition to the classical opioid system, nociceptin, through opioid receptor-like-1 receptor stimulation in the rVLM, participates in the modulatory influence of EA on reflex-induced increases in blood pressure.     

Correlations Between Acetylcholinesterase Activity in Guinea-Pig Iris and Pupillary Function: A Biochemical and Pupillographic Study

: Acetylcholinesterase (AChE) in guinea pig iris was inhibited by methylisocyclopentylfluorophosphate (soman) administered topically or parenterally, and enzyme activity was correlated to pupillary diameter by infrared pupillography. After a single topical soman instillation into the conjunctival sac there was an almost linear relationship between the reduction in AChE activity and pupillary diameter. Topical administration of soman at 24-h intervals in doses capable of almost complete inhibition of AChE in iris was accompanied by a reduced miotic effect of this drug. This was indicated by a reduced rate of the soman-induced pupillary constriction, a less pronounced reduction in pupillary diameter, and a more rapid return of the pupillary diameter to normal size. The change in pupillary diameter occurred after three daily administrations and remained constant during 31 days of treatment. These observations were seen irrespective of inhibition of blood AChE. The decrease in response to repeated administration could not be explained by a reduced inhibitory effect of soman on AChE, by a more rapid de novo synthesis of AChE, or by a change in the number of the muscarinic receptors as determined by quinuclidinyl benzilate binding. When soman or DFP was administered subcutaneously in high doses a severe AChE inhibition was obtained in iris without any concomitant miosis.     

Central cardiovascular effects of baclofen in spontaneously hypertensive rats

This study was conducted to investigate the effects of centrally administered baclofen on blood pressure and heart rate in conscious spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Administration of baclofen (1.0 microgram/kg) into the lateral cerebral ventricle (icv) produced an increase in mean arterial pressure (MAP) in both SHR and WKY rats. The increase in MAP was significantly lower in SHR (13 +/- 3 mmHg) when compared with WKY (27 +/- 5 mmHg). The changes in heart rate (HR) were variable, from no change to a very small increase and did not differ significantly between SHR and WKY rats. The ability of baclofen to interfere with baroreceptor reflexes was also tested in separate experiments. In SHR, icv injection of baclofen (1.0 microgram/kg) significantly suppressed the pressor response and bradycardia evoked by phenylephrine 3.0 micrograms/kg iv, whereas in WKY, the pressor and HR responses to similar injections of phenylephrine were not affected by icv baclofen. Similarly, baclofen treatment modified hypotensive response and reflex tachycardia induced by nitroprusside (10.0 micrograms/kg) iv in SHR but not in WKY rats. Administration of sympathetic ganglionic blocker hexamethonium (HEX; 25 mg/kg) iv produced an equivalent decrease in MAP between SHR and WKY following icv injection of baclofen (1.0 microgram/kg). These results suggest that the effects of baclofen on the baroreceptor reflexes in SHR may not be mediated by a change in peripheral sympathetic tone.     

Analysis of the afferent limb of the vesicovascular reflex using neurotoxins, resiniferatoxin and capsaicin

The afferent limb of the vesicovascular reflex (VV-R) evoked by distension or contraction of the urinary bladder (UB) was studied in urethane-anesthetized female rats by examining the changes in VV-R after administration of C-fiber afferent neurotoxins [capsaicin and resiniferatoxin (RTX)]. Systemic arterial blood pressure increased parallel (5.1 to 53.7 mmHg) with graded increases in UB pressure (20 to 80 cm H(2)O) or during UB contractions. The arterial pressor response to UB distension was significantly reduced (60-85%) by acute or chronic (4 days earlier) intravesical administration of RTX (100-1,000 nM) or by capsaicin (125 mg/kg sc) pretreatment (4 days earlier). Chronic neurotoxin treatments also increased the volume threshold (>100%) for eliciting micturition in anesthetized rats but did not change voiding pressure. Acute RTX treatment (10-50 nM) did not alter the arterial pressor response during reflex UB contractions, whereas higher concentrations of RTX (100-1,000 nM) blocked reflex bladder contractions. It is concluded that VV-R is triggered primarily by distension- and contraction-sensitive C-fiber afferents located, respectively, near the luminal surface and deeper in the muscle layers of the bladder.     

原发性高血压患者红细胞抗高血压因子对高血压...

The effects of antihypertensive factor (AHF) from erythrocytes of essential hypertensive human subjects on the systolic blood pressure (SBP) and diastolic blood pressure (DBP) in spontaneously hypertensive rats (SHR), renal hypertensive rats (RHR), Wistar-Kyoto rats (WKY) and Wistar rats were examined. Single intraperitoneal injection of AHF (1.6 mg/kg body weight) resulted in a significant decrease in SBP of SHR and RHR. At 10 min postinjection, AHF lowered the SBP in SHR by 34.0 mmHg. SBP recovered to the original level at 3 h. The maximal decrease of SBP in RHR by 92.5 mmHg was at 24h postadministration and the SBP did not recover until the 9th day. When AHF was administered via femoral vein (0.8 mg/kg body weight), the maximal decrease values of the SBP and the DBP were 42.8 and 48.2 mmHg in SHR at 12 min and 38.3 and 42.5 mmHg in RHR at 25 min postinjection respectively. The DBP in Wistar rats decreased considerably (from 96.7 +/- 12.9 to 83.3 +/- 11.7 mmHg) at 5 min postadministration of AHF, but no effect on DBP in WKY rats was observed. The depressor effect of AHF on SBP in RHR was dose-dependent. AHF could also antagonize the pressor effect of norepinephrine in Wistar rats.     

Centrally acting leptin induces a resuscitating effect in haemorrhagic shock in rats

Centrally acting leptin induces the activation of the sympathetic nervous system with a pressor effect in normotensive rats. The purpose of the study was to examine central leptin-evoked action in critical haemorrhagic hypotension. In anaesthetized male Wistar rats subjected for irreversible haemorrhagic shock with mean arterial pressure (MAP) 20-25 mmHg haemodynamic parameters and plasma concentrations of adrenaline and noradrenaline were measured. Leptin given intracerebroventricularly (20 μg) evoked long-lasting rises in MAP and heart rate (HR), with a subsequent increase in renal, mesenteric and hindquarters blood flows and a 100% survival at 2 h. MAP and peripheral blood flow changes were inhibited by a pre-treatment with α(1)- and α(2)-adrenoceptor antagonists prazosin (0.5 mg/kg) and yohimbine (1 mg/kg), while β-adrenoceptor antagonist propranolol (1 mg/kg) blocked leptin-induced HR changes, without influence on MAP, peripheral blood flows and survival. Twenty min after leptin treatment, there were higher plasma concentrations of noradrenaline, but not adrenaline, in comparison with the saline-treated control group. In conclusion, centrally acting leptin induces a long-lasting pressor effect with an improvement in the survival rate in haemorrhage-shocked rats. The effect may be associated with the activation of the sympathetic nervous system.     

Depressor effect of kynurenine and its metabolites in rats

Kynurenine in doses of 0.2 ng to rats weighing 160–240 g elicited a measurable decline in blood pressure. The depressor effect increased with dosage and reached a maximum of about 30 mm Hg at a dose of approximately 100 ug. At higher doses (400 to 2000) ug kynurenine elicited a pressor response of about 15 mm Hg. Other kynurenines tested also lowered blood pressure. It is possible that the increased formation of kynurenine and its metabolites is involved in disturbances of circulation under stress, when the formation of these compounds is increased by activation of liver tryptophan pyrrolase.     

5-HT1A receptor agonist 8-OH-DPAT acts in the hindbrain to reverse the sympatholytic response to severe hemorrhage

Central administration of serotonergic 5-HT1A receptor agonists delays the reflex sympatholytic response to severe hemorrhage in conscious rats. To determine the region where 5-HT1A receptor agonists act to mediate this response, recovery of mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) was compared in hemorrhaged rats after injection of the selective 5-HT1A agonist, (+)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), in various regions of the cerebroventricular system or the systemic circulation. Three minutes after injection of 8-OH-DPAT (48 nmol/kg), MAP and RSNA were higher in hemorrhaged rats given drug in the fourth ventricle (94 +/- 5 mmHg, 82 +/- 18% of baseline) or the systemic circulation (90 +/- 4 mmHg, 113 +/- 15% of baseline) than in rats given drug in the Aqueduct of Sylvius (63 +/- 4 mmHg, 27 +/- 11% of baseline), the lateral ventricle (42 +/- 3 mmHg, -8 +/- 18% of baseline), or in rats given saline in various brain regions (47 +/- 5 mmHg, -42 +/- 10% of baseline). A lower-dose injection of 8-OH-DPAT (10 nmol/kg) also accelerated the recovery of MAP and RSNA in hemorrhaged rats when given in the fourth ventricle (94 +/- 26 mmHg, 72 +/- 33% of baseline 3 min after injection) but not the systemic circulation (46 +/- 4 mmHg, -25 +/- 30% of baseline). These data indicate that 8-OH-DPAT acts on receptors in the hindbrain to reverse the sympatholytic response to hemorrhage in conscious rats.