Adrenomedullary pressor responses to stimulation of the rostral hypothalamus in the rat: influence of adrenaline-induced vasodilation and reflex cardioinhibition

Electrical stimulation (100 Hz, 1 ms, 150 microA, 10 s) of the anterior hypothalamus in chloralose-anesthetized rats evoked a biphasic pressor response consisting of an initial sharp rise in arterial pressure at the onset of stimulation, followed by a second elevation after cessation of the stimulus. This response was accompanied by an increase in plasma noradrenaline and adrenaline levels. Peripheral sympathectomy with guanethidine selectively abolished the primary phase of the biphasic pressor response, while bilateral removal of the adrenal medulla eliminated only the secondary component. After alpha-adrenergic blockade with phentolamine, the primary phase of the stimulation-induced response was reduced while the secondary pressor component was blocked and replaced by a significant hypotension. The intravenous administration of sotalol enhanced the secondary pressor component without affecting the stimulation-induced plasma noradrenaline and adrenaline responses. After treatment with atropine, the secondary pressor effect was also potentiated, as the reflex bradycardia normally associated with the response was eliminated. A subsequent administration of sotalol in these rats further potentiated the secondary pressor component to stimulation. In rats treated with atropine and sotalol, the sympathetic vasomotor and the adrenomedullary pressor responses could be dissociated according to thresholds and stimulus frequency or current-response characteristics. The results suggest that in intact rats, adrenaline-induced vasodilation and reflex cardiac inhibition contribute to either reduce or mask the adrenomedullary component of the biphasic pressor response evoked by stimulation of the anterior hypothalamus. The study also raises the hypothesis of a dual regulation of both components of the sympathetic system in the anterior hypothalamic region.     

Peripheral and central mechanisms of the pressor response elicited by stimulation of the locus coeruleus in the rat

Electrical stimulation of the pontine nucleus locus coeruleus (LC) caused an increase of the arterial blood pressure in anesthetized rats, and elevated plasma noradrenaline (NA) and adrenaline (A) levels. The stimulation-induced pressor response was characteristically biphasic and consisted of a sharp rise in arterial pressure at the onset of the stimulation, followed by a second elevation at the end of the stimulus. Bilateral adrenalectomy or adrenal demedullation completely blocked the secondary phase of the pressor response elicited by stimulation, but did not affect the primary phase. The latter was specifically eliminated by the destruction of the peripheral sympathetic vasomotor axons with intravenous 6-hydroxydopamine (6-OHDA). The active sites eliciting the secondary adrenomedullary pressor component appeared to be restricted to the nucleus LC, whereas the primary sympathetic vasomotor response could be elicited from sites in and around the nucleus. After brain transection at the midbrain level, stimulation of LC failed to evoke the adrenomedullary pressor response, while the sympathetic vasomotor component was not affected. Similarly, destruction of brain NA neurons by intraventricular administration of 6-OHDA did not change the sympathetic vasomotor response, but virtually abolished the adrenal response. The results demonstrate that the pressor response to stimulation of LC in the rat is due to both increased sympathetic vasomotor activity and CA released from the adrenal medulla. The study also provides evidence suggesting that the noradrenergic LC cell group play an important role in the activation of the adrenal medulla, but is not essential for the activation of the sympathetic vasoconstrictor fiber system.     

Adrenomedullary secretory response to midbrain stimulation in rat: effects of depletion of brain catecholamines or serotonin

Electrical stimulation of the periaqueductal gray substance (PAG) of the rostral midbrain of the rat produced biphasic or monophasic pressor responses depending on the duration of the stimulus train. Marked increases in plasma noradrenaline (NA) and adrenaline (A) levels accompanied the pressor responses, indicating the participation of the adrenal medulla. Depletion of central catecholamines (CA) by intraventricular administration of 6-hydroxydopamine (6-OHDA) did not affect the primary vasomotor component but markedly depleted adrenal CA levels and attenuated the adrenomedullary component of the response to brain stimulation. The intraperitoneal administration of p-chlorophenylalanine (pCPA) not only depleted brain serotonin (5-HT) levels but also reduced brain CA levels significantly. The adrenaline (A) levels were reduced in the adrenal glands of these rats and the adrenal secretory response to brain stimulation was attenuated. In contrast, the selective destruction of central 5-HT neurons by intraventricular injection of 5,7-dihydroxytryptamine (5,7-DHT) in rats pretreated with desmethylimipramine (DMI) did not influence either the pressor nor the plasma CA responses to brain stimulation. Furthermore, the adrenal glands of these rats were normal. The results suggest that: (i) the central catecholaminergic neurons play an important role in the regulation of the adrenal glands but are not essential for the activation of the sympathetic vasoconstrictor fiber system: (ii) the pressor and plasma CA responses to PAG stimulation are not dependent on the central serotonergic system.     

Differentiated pressor and sympathetic responses to dual brain stimulation: ventromedial hypothalamus versus locus coeruleus

Sensitivity of the ventromedial hypothalamus (VMH) to electrical stimulation was compared with that of the locus coeruleus (LC) in urethane-anesthetized rats. Based not only on current strengths required to elicit threshold effects, but also on magnitude of pressor responses to suprathreshold stimulation, the LC was consistently more sensitive than the VMH. Despite this greater pressor sensitivity, splanchnic nerve firing increased almost equally upon stimulation of either brain area. Similar comparisons made in other rats following bilateral adrenalectomy or pretreatment with a vasopressin antagonist showed no significant alteration of pressor and sympathetic responsiveness to stimulation of either the LC or the VMH. When frequency of neural firing was recorded from a lumbar sympathetic trunk instead of the splanchnic nerve, increases in sympathetic nerve activity produced by LC stimulation were significantly larger than those produced from the VMH. The results suggest that greater pressor sensitivity of the LC is due, at least in part, to stronger constriction in vascular beds innervated by the lumbar sympathetic chains.     

Stimulation of NTS A1 adenosine receptors evokes counteracting effects on hindlimb vasculature

Our previous studies concluded that stimulation of the nucleus of the solitary tract (NTS) A2a receptors evokes preferential hindlimb vasodilation mainly via inducing increases in preganglionic sympathetic nerve activity (pre-ASNA) directed to the adrenal medulla. This increase in pre-ASNA causes the release of epinephrine and subsequent activation of beta-adrenergic receptors that are preferentially located in the skeletal muscle vasculature. Selective activation of NTS A1 adenosine receptors evokes variable, mostly pressor effects and increases pre-ASNA, as well as lumbar sympathetic activity, which is directed to the hindlimb. These counteracting factors may have opposite effects on the hindlimb vasculature resulting in mixed vascular responses. Therefore, in chloralose-urethane-anesthetized rats, we evaluated the contribution of vasodilator versus vasoconstrictor effects of stimulation of NTS A1 receptors on the hindlimb vasculature. We compared the changes in iliac vascular conductance evoked by microinejctions into the NTS of the selective A1 receptor agonist N6-cyclopentyladenosine (330 pmol in 50 nl volume) in intact animals with the responses evoked after beta-adrenergic blockade, bilateral adrenalectomy, bilateral lumbar sympathectomy, and combined adrenalectomy + lumbar sympathectomy. In intact animals, stimulation of NTS A1 receptors evoked variable effects: increases and decreases in mean arterial pressure and iliac conductance with prevailing pressor and vasoconstrictor effects. Peripheral beta-adrenergic receptor blockade and bilateral adrenalectomy eliminated the depressor component of the responses, markedly potentiated iliac vasoconstriction, and tended to increase the pressor responses. Lumbar sympathectomy tended to decrease the pressor and vasoconstrictor responses. After bilateral adrenalectomy plus lumbar sympathectomy, a marked vasoconstriction in iliac vascular bed still persisted, suggesting that the vasoconstrictor component of the response to stimulation of NTS A1 receptors is mediated mostly via circulating factors (e.g., vasopressin, angiotensin II, or circulating catecholamines released from other sympathetic terminals). These data strongly suggest that stimulation of NTS A1 receptors exerts counteracting effects on the iliac vascular bed: activation of the adrenal medulla and beta-adrenergic vasodilation versus vasoconstriction mediated by neural and humoral factors.     

Involvement of the ventrolateral medulla in the mediation of pressor responses of the rat to afferent vagal stimulation

Electrical stimulation of afferent vagal fibres evoked a pressor response in rats after transection of the spinal cord. The pressor response was accounted for by an increased release of vasopressin because it was abolished by the intravenous injection of a vasopressin antagonist. Bilateral electrolytic lesions at the sites of the caudal ventrolateral medulla markedly reduced the pressor response to afferent vagal stimulation but not that to carotid occlusion. It is concluded that the area of the caudal ventrolateral medulla is involved in mediation of the vasopressin-induced pressor response to afferent vagal stimulation.     

L-NAME raises systolic blood pressure in the pithed rat by a direct adrenal epinephrine releasing action

It is generally thought that inhibition of nitric oxide synthase leads to blood pressure elevation largely through reduction in vascular levels of the vasodilator nitric oxide. However, there are several reports suggesting that NO synthase inhibitors cause adrenal epinephrine (E) release by both central and peripheral mechanisms. We investigated the role of adrenal E in the pressor effects of the nitric oxide synthase inhibitor L-NAME in the pithed rat to help distinguish central from peripherally mediated actions. L-NAME (10 mg/kg) raised both systolic and diastolic BP by about 30 mm Hg (P < .01) in the absence of exogenous electrical stimulation of sympathetic nerves. During stimulation at 10 V and frequencies of 1 or 2 Hz, systolic BP was about 70 mm Hg higher in L-NAME treated rats than in drug free stimulated rats. This enhancement of systolic BP by L-NAME was less pronounced at 5 or 10 Hz stimulation frequencies. Following these types of electrical stimulations of pithed rats, both plasma norepinephrine (NE) and E levels were dramatically elevated above resting plasma levels. L-NAME pretreatment of these electrically stimulated rats increased plasma E levels by an additional 60% and decreased NE by 18%. Acute adrenalectomy dramatically reduced plasma E levels and abolished the ability of L-NAME to enhance the pressor effect of sympathetic stimulation. In contrast, acute adrenalectomy of unstimulated pithed rats did not significantly reduce the pressor response to L-NAME. We conclude that adrenal E release may mediate much of the systolic pressor response of L-NAME in the stimulated pithed rat, but the magnitude of this effect varies with stimulation frequency. Since pithing disrupts central pathways, this induction of adrenal E release by L-NAME is a peripheral effect.     

Effects of repetitive stimulation of the locus coeruleus on spinal inhibitory responses to suprasegmental stimulation in cats

Effects of repetitive stimulation of the locus coeruleus on spinal responses to activation of cortico-, reticulo-, and vestibulospinal tracts were studied in decerebellate cats anesthetized with chloralose. Descending influences of these structures were assessed from changes in amplitude of extensor and flexor monosynaptic discharges or from the magnitude of postsynaptic potentials recorded from the corresponding motoneurons. Stimulation of the motor cortex or modullary reticular formation as a rule evoked two-component inhibitory responses in extensor motoneurons and excitatory-inhibitory responses in flexor motoneurons. Stimulation of locus coeruleus effectively depressed the amplitude of the late component and, to a lesser degree, that of the early component of inhibition arising after stimulation of the cerebral cortex or reticular formation. During stimulation of the locus coeruleus no marked changes were found in inhibitory responses evoked by vestibulospinal influences in flexor motoneurons, and also in excitatory responses arising after stimulation of the above-mentioned descending pathways in both groups of motoneurons.     

Adrenaline in various organs of the rat: its origin, location and diurnal fluctuation

In order to examine the origin and location of adrenaline in peripheral organs of mammals, adrenaline and noradrenaline were measured in several organs of the rat after adrenalectomy, guanethidine treatment and imipramine injection. One week after bilateral adrenalectomy, adrenaline disappeared almost completely from the heart, spleen and submaxillary gland. Chronic administration of guanethidine caused decreases in both noradrenaline and adrenaline in the peripheral organs. Injection of imipramine induced a reduction of adrenaline concentration in the spleen and submaxillary gland. It is considered that adrenaline in the peripheral organs of mammals is mostly derived from the adrenal gland and that circulating adrenaline is taken up by sympathetic nerve endings in the organs. The adrenaline content of the peripheral organs increased after electric foot-shock and changed according to the time of day. The peak of the circadian rhythm appeared about 6 hours after the peak of the urinary adrenaline rhythm. These findings suggest that adrenaline in body organs plays some role in the responses of the sympathetic nervous system to stressful conditions or even to daily activities.     

Effect of naloxone on physostigmine-induced pressor response in adrenalectomized rats

Physostigmine-induced pressor response was studied in adrenalectomized rats. The increase in mean arterial blood pressure elicited by intravenous administration of physostigmine was not altered by adrenalectomy or sham-operation. The pressor response to intracerebroventricular administration of physostigmine was found to be partially inhibited in both acutely adrenalectomized and sham-operated rats, but not in those adrenalectomized 24 h earlier. This inhibition was completely prevented by naloxone pretreatment. The results suggest that endogenous opioid peptide release induced by surgical stress may be responsible for inhibition of the pressor effect of centrally administered physostigmine in rats.     

Pressor effects of systemic administration of methionine and leucine enkephalin in the conscious rat

Experiments were designed using conscious Sprague-Dawley rats to determine the blood pressure (BP) and heart rate (HR) responses to intravenous doses of (1) the adrenal catecholamines noradrenaline (NA) and adrenaline (A), (2) adrenal pentapeptides methionine enkephalin (ME) and leucine enkephalin (LE), (3) combination (i.v.) injections of both ME or LE with NA or A that modulate the hemodynamic responses when the adrenal catecholamines were given alone, and (4) the possible receptor mechanisms mediating the resultant BP and HR response to i.v. pentapeptide administration. NA (0.48 and 2.4 nmol) and A (0.3 and 1.5 nmol) given i.v. evoked potent, dose-related pressor responses associated with reflex bradycardia. ME and LE (1.6 - 48 nmol) elicited transient (10-20 s) increases in mean arterial pressure (MAP), which was associated either with no change in mean heart rate (MHR), such as ME, or with slight bradycardia (i.e., LE). Combining ME or LE (16 nmol) with NA (2.4 nmol) or A (0.3 or 1.5 nmol) did not change MAP and MHR from when these respective doses of NA or A were given alone. However, 16 nmol of ME or LE with a low dose of NA (0.48 nmol) increased the pressor response compared with NA (0.48 nmol) given alone. Other experiments whereby specific receptor blockers (naloxone, diprenorphine, atropine, propranolol, phentolamine or guanethidine) were given i.v. 5 min before subsequent i.v. administration of LE or ME (16 nmol) indicated that only phentolamine or guanethidine could completely suppress the pressor responses of LE and ME. Naloxone and diprenorphine pretreatment attenuated the pressor response of LE but did not affect the BP response to ME.(ABSTRACT TRUNCATED AT 250 WORDS)     

Theta driving both inhibits and potentiates the effects of nicotine on dentate gyrus responses

The medial septal area of conscious rats was stimulated through previously implanted electrodes at a frequency of 7.7 Hz for 20 min each day for 7 days to evoke rhythmic slow activity in CA1 at a similar frequency to spontaneous theta. Two weeks later in the anaesthetized rats the effects of a single subcutaneous injection of nicotine (0.4 mg x kg(-1)) on fEPSPs, evoked in the dentate gyrus by separate stimulation of the MPP and LPP, were studied and compared with those obtained in controls. Nicotine increased the firing of locus coeruleus neurones and the slope of the fEPSPs evoked by LPP stimulation, but not by MPP stimulation. Prior theta driving considerably increased the effect of nicotine on the responses evoked by stimulation of the MPP and abolished the nicotine-induced potentiation of the responses evoked by stimulation of the LPP. The results are attributed to theta driving increasing the amount of noradrenaline released by nicotine and to noradrenaline producing a beta-adrenoceptor long-lasting potentiation at the medial perforant path synapse and a long-lasting depression at the lateral perforant path synapse.     

迷走、蓝斑、下丘脑垂体加压反应及其对休克具有保护作用的初步探讨

我们自发现垂体后叶能因迷走神经反射刺激而分泌加压素后,复证实催产素亦可因同样机制分泌(张等,1937;1938)并在狗、猫、羊、猪(吕运明等1939)、猴等(唐正荣,1981)作迷走-加压反应以比较观察。切除垂体或两侧肾上腺再刺激迷走神经中枢端,血压仍升高(吕运明等1965;1977;1978)二者完全切除后,加压反应基本消失,但有时仍出现加压现象,这种加压物质起源于何处,其化学性质为何,还不清楚。 有人认为垂体后叶加压素对于高血压发病机制有关(Tayer等,1955;Sharpless等,1961;上田英雄等,1963;Croton等,1978),对休克具有保护作用,我们设想迷走、蓝     

Effect of adrenalectomy on acceleration of gluconeogenesis by calcium ions, adenosine 3'':5''-cyclic monophosphate and adrenaline in rat kidney tubules.

1. Gluconeogenesis from pyruvate was measured in renal-cortical-tubules fragments prepared from fed male rats 6-8 days after adrenalectomy or sham adrenalectomy. The response of this process to 3':5'-cyclic AMP and adrenaline was compared in these two states at two Ca2+ concentrations. 2. Adrenalectomy decreased the percentage stimulation of gluconeogenesis by 3':5'-cyclic AMP, but increased percentage stimulation by adrenaline. Cortisol treatment of adrenalectomized rats (50 mg/kg, twice daily for 2 days) did not reverse the change in responsiveness to 3':5'-cyclic AMP and adrenaline. 3. Stimulation of gluconeogenesis by 1 micron-adrenaline was unaffected by 10 micron-propranolol (beta-blocker) in either state. Phentolamine (alpha-blocker; 10 micron) totally blocked stimulation of gluconeogenesis by 1 micron-adrenaline in the sham-operated condition, but was only partially effective in this respect after adrenalectomy.     

Release of histamine and adrenaline in vivo following intravenous administration of neurotensin

Plasma histamine levels of rats anesthetized with pentobarbital sodium were significantly increased by intravenous administration of neurotensin (NT, 1 nmole/kg) with the maximum effect at 3 min, and a return to the initial levels in 20 min. Treatment of animals with compound 48/80 or disodium cromoglycate completely inhibited the elevation of histamine level by NT, however, treatment with reserpine or diphenhydramine and adrenalectomy did not affect the elevation. Plasma adrenaline levels increased transiently 1 min after NT injection, and adrenalectomy and treatment with compound 48/80 or diphenhydramine markedly reduced the elevation of adrenaline levels after NT injection. Plasma levels of noradrenaline were unchanged upon NT injection. These results provide direct evidence of the release of endogenous histamine and adrenaline following NT administration, and suggest the contribution of these amines to the NT-induced triphasic blood pressure responses (the first depressor, second pressor and third depressor responses) reported previously.     

蓝斑对迷走─心血管反射的影响

实验用家兔３６只,采用低频（５－８Ｈｚ）和高频（５０－１００Ｈｚ）电流刺激颈部迷走神经中枢端（ＶＡＳ）,建立迷走－减压和迷走－升压反射,两种频率电刺激均导致肾交感神经传出活动（ＲＳＡ）减少。以迷走－血压反射和迷走－交感反射为指标,连续电流刺激蓝斑（ＬＣ）或ＬＣ微量注射谷氨酸钠均抑制迷走－血压反射和迷走－交感反射。而连续电流刺激ＬＣ或ＬＣ微量注射谷氨酸钠本身均引起平均动脉血压升高和ＲＳＡ增加。本文对新近提出的对ＬＣ整体功能认识的理论,结合本文的结果进行了讨论     

Changes in postsynaptic responses in spinal motoneurons during repetitive stimulation of the locus coeruleus

Experiments on cats anesthetized with chloralose showed that repetitive stimulation of the locus coeruleus is accompanied by a decrease in IPSPs evoked by stimulation of flexor reflex afferents in extensor motoneurons. The effect appeared 600 msec after the beginning of stimulation and reached its maximum after 1500–2000 msec. Repetitive stimulation of the locus coeruleus did not change the membrane potential and did not affect EPSPs or IPSPs evoked by stimulation of low-threshold muscle afferents; EPSPs due to activation of high-threshold cutaneous and muscle afferents likewise remained unchanged. Repetitive stimulation of more central regions of the brain stem was accompanied not only by a decrease in IPSPs evoked by stimulation of flexor reflex afferents in extensor motoneurons, but also by a decrease in amplitude of EPSPs arising in response to stimulation of these same afferents in flexor motoneurons. These effects were not connected with activation of monoaminergic structures, for unlike effects arising during stimulation of the locus coeruleus, they were also found in previously reserpinized animals.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 14, No. 1, pp. 51–59, January–February, 1982.     

蓝斑对迷走—心血管反射的影响

实验用家兔３６只,采用低频和高频电流刺激颈部迷走神经中枢端,建立迷走－减压和迷走－升压反射,两种频率电刺激均导致肾交感神经传出活动减少。以迷走－血压反射和迷走－交感反射为指标,连续电流刺激蓝斑或ＬＣ微量注射谷氨酸钠均抑制迷走－血压反射和迷走－交感反射。     

NTS A(2a) purinoceptor activation elicits hindlimb vasodilation primarily via a beta-adrenergic mechanism

Previously, we have shown that activation of adenosine A(2a) receptors in the subpostremal nucleus tractus solitarii (NTS) via microinjection of the selective A(2a) receptor agonist CGS-21680 elicits potent, dose-dependent decreases in mean arterial pressure and preferential, marked hindlimb vasodilation. Although A(2a) receptor activation does not change lumbar sympathetic nerve activity, it does markedly enhance the preganglionic adrenal sympathetic nerve activity, which will increase epinephrine release and could subsequently elicit hindlimb vasodilation via activation of beta(2)-adrenergic receptors. Therefore we investigated whether this hindlimb vasodilation was due to neural or humoral mechanisms. In chloralose-urethan-anesthetized male Sprague-Dawley rats, we monitored cardiovascular responses to stimulation of NTS adenosine A(2a) receptors (CGS-21680, 20 pmol/50 nl) in the intact control animals; after pretreatment with propranolol (2 mg/kg iv), a beta-adrenergic antagonist; after bilateral lumbar sympathectomy; after bilateral adrenalectomy; and after combined bilateral lumbar sympathectomy and adrenalectomy. After beta-adrenergic blockade, stimulation of NTS adenosine A(2a) receptors produced a pressor response and a hindlimb vasoconstriction. Lumbar sympathectomy reduced the vasodilation seen in the intact animals by approximately 40%, and adrenalectomy reduced it by approximately 80%. The combined sympathectomy and adrenalectomy virtually abolished the hindlimb vasodilation evoked by NTS A(2a) receptor activation. We conclude that the preferential, marked hindlimb vasodilation produced by stimulation of NTS adenosine A(2a) receptors is mediated by both the efferent sympathetic nerves directed to the hindlimb and the adrenal glands via primarily a beta-adrenergic mechanism.     

Epicardial application of bradykinin elicits pressor effects and tachycardia in guinea pigs. Possible mechanisms

Topical application of bradykinin (BK) to the surface of the left ventricle (epicardial application) of anesthetized guinea pigs elicited dose-dependent pressor effects and tachycardia. The pressor effect of epicardial BK was reduced by prior systemic treatment of animals with pentolinium or a combination of phentolamine and propranolol, but it was not affected by acute bilateral vagotomy or systemic administration of atropine, indomethacin, naloxone or a combination of mepyramine and cimetidine. The tachycardia caused by epicardial BK was not affected by any of the aforementioned drugs or by section of the vagi. Both the pressor effect and tachycardia evoked by epicardial BK were abolished by prior epicardial application of lidocaine, a local anesthetic, or by chronic systemic capsaicin treatment. These results suggest that the pressor effect of epicardial BK is partially reflex in nature and likely to result from the stimulation by BK of cardiac sympathetic, capsaicin-sensitive primary afferents, whereas the tachycardia caused by epicardial BK could be mediated by an intracardiac release of (a) cardioaccelerating substance(s) from cardiac, capsaicin-sensitive sensory nerve fibers and/or terminals.