Pharmacological analysis of the role of central alpha-2 adrenergic and imidazoline receptors in mechanism of the hypotensive effect of clonidine in rats

The role of alpha 2-adrenergic and imidazoline receptors in the hemodynamic response to clonidine (manifested by reduced arterial pressure, heart rate, and renal blood flow rate) was studied by injecting their antagonists with different affinity (yohimbine and idazoxan) into narcotized Sprague--Dawley rats. The local introduction (microinjection into rostral ventrolateral medulla) and systemic administration (intraperitoneal injection) of the drugs showed that the hemodynamic effect of clonidine is mediated predominantly by the central alpha 2-adrenergic receptors, rather than by the imidazoline receptors.     

The cardiovascular actions of clonidine and neuropeptide-Y in the ventrolateral medulla of the rat.

1. The cardiovascular responses to neuropeptide-Y (NPY) (25 and 50 pmol) and clonidine (10 and 20 nmol) were examined following microinjection into the rostral ventrolateral medulla (RVLM) and the caudal ventrolateral medulla (CVLM). Mean arterial pressure (MAP) and heart rate (HR) were measured in anaesthetized rats, pre- and post-injection. 2. The alpha 2-adrenoceptor agonist clonidine (10 and 20 nmol) reduced MAP and HR significantly when microinjected into the CVLM and RVLM. 3. NPY (25 and 50 pmol) microinjected into the CVLM decreased MAP and HR. However, in the RVLM neither dose had a significant cardiovascular effect. 4. The possibility of a functional interaction between the adrenergic system and NPY was examined by co-administration of clonidine and NPY in doses that gave submaximal blood pressure responses. In the CVLM this produced hypotension and bradycardia which was similar in magnitude to the sum of their individual responses, indicating that in this area their actions appear to be independent. 5. In the RVLM, where NPY has no significant cardiovascular effects, co-administration with clonidine, did not alter the response to clonidine. 6. It appears that in the areas investigated, there is no functional interaction between NPY and clonidine.     

Site-dependent inhibition of neuronal c-jun in the brainstem elicited by imidazoline I1 receptor activation: role in rilmenidine-evoked hypotension

Clonidine (a mixed alpha2-adrenoceptor and imidazoline I1 receptor agonist)-evoked hypotension was associated with dissimilar reductions in c-jun gene expression in the rostral ventrolateral medulla (RVLM) and the nucleus tractus solitarius (NTS) in normotensive rats. In the present study, we investigated the relative contribution of the alpha2-adrenoceptor vs. the imidazoline I1 receptor to the reduction in c-jun gene expression in these two brainstem areas. In conscious spontaneously hypertensive rats (SHRs), equihypotensive doses of three centrally acting hypotensive drugs with different selectivity for the two receptors were administered intracisternally (4 microl) to limit their actions to the brain. As a control, a similar hypotensive response was elicited by i.v. hydralazine. Clonidine (0.5 microg), or alpha-methylnorepinephrine (alpha-MNE, 4 microg), a highly selective alpha2-adrenoceptor agonist, similarly reduced c-jun mRNA expression in the NTS and rostral ventrolateral medulla. In contrast, a similar hypotensive response (-37+/-3.5 mm Hg) caused by the selective imidazoline I1 receptor agonist rilmenidine (25 microg) was associated with reduction in c-jun mRNA expression in the rostral ventrolateral medulla, but not in the NTS. Further, intra-rostral ventrolateral medulla rilmenidine (40 nmol) reduced c-Jun protein expression in rostral ventrolateral medulla and blood pressure and both responses were antagonized by selective imidazoline I1 receptor (efaroxan, 4 nmol), but not alpha2-adrenoceptor (SK&F 86466, 10 nmol) blockade. These results suggest: (1) the c-jun containing neurons in the brainstem are involved in the centrally mediated hypotension elicited by centrally acting antihypertensive agents, and (2) the alpha2-adrenoceptor modulates c-jun gene expression in the NTS and rostral ventrolateral medulla implicated in centrally mediated hypotension, and (3) the imidazoline I1 receptor mediated inhibition of c-jun gene expression in the rostral ventrolateral medulla, but not in the NTS, contributes to the centrally mediated hypotension by the second generation drugs.     

Posterior hypothalamic receptors involved in the cardiovascular changes elicited by electrical stimulation of the rostral ventrolateral medulla.

The posterior hypothalamic receptors involved in the cardiovascular responses to electrical stimulation of the rostral ventrolateral medulla were investigated in urethane-anaesthetized rats. Electrical stimulation of the rostral ventrolateral medulla produced a significant increase in systolic blood pressure. This response was significantly attenuated by the prior administration of d,l-propranolol (20 micrograms), clonidine (8 micrograms), atropine (8 micrograms) or methysergide (10 micrograms) into the posterior hypothalamus, but not by cimetidine (11 micrograms), chlorpheniramine (12 micrograms), naloxone (10 micrograms) or a vasopressin V1 antagonist (100 ng). The effect of clonidine (8 micrograms) on the pressor response to stimulation of the rostral ventrolateral medulla was antagonized by idazoxan (66 micrograms). These results confirm that the cardiovascular changes elicited by stimulation of the rostral ventrolateral medulla area are, in part, centrally modulated by alpha 2 and beta-adrenoceptors in the posterior hypothalamus which exert respectively, inhibitory and stimulatory effect. Furthermore the results indicate the involvement of posterior hypothalamic cholinergic and serotonergic receptors in the pressor response produced by stimulation of the rostral ventrolateral medulla.     

Rilmenidine lowers arterial pressure via imidazole receptors in brainstem C1 area.

We sought to determine the site of action and receptor type responsible for the antihypertensive actions of rilmenidine, an oxazoline analogue of clonidine. In anesthetized paralyzed rats decerebration did not alter the dose dependent reductions in arterial pressure and heart rate elicited by i.v. drug. Rilmenidine microinjected bilaterally into the C1 area of the rostral ventrolateral medulla (RVL), but not nucleus tractus solitarii (NTS) nor caudal ventrolateral medulla (CVL), elicited dose-dependent falls in arterial pressure and heart rate at doses an order of magnitude less than required systemically. Prior microinjection into the C1 area of the selective alpha 2-adrenoceptor antagonist SKF-86466, even at high doses, failed to modify the hypotension to i.v. rilmenidine. However, microinjection of 3- to 10-fold lower doses of idazoxan, a ligand for imidazole as well as alpha 2-adrenoceptors, blocked the effects. Rilmenidine also competed with the clonidine analogue [3H]p-aminoclonidine ([3H]PAC) at specific binding sites in membranes of bovine ventrolateral medulla and frontal cortex. In RVL rilmenidine competed with binding to imidazole and alpha 2-adrenergic binding sites with a 30-fold selectivity for the imidazole binding sites. In frontal cortex binding was of lower affinity and restricted to alpha 2-adrenergic sites. We conclude that rilmenidine, like clonidine, acts to lower arterial pressure by an action on imidazole receptors in the C1 area of RVL. The higher selectivity of rilmenidine for imidazole to alpha 2-adrenoceptors as compared to clonidine may explain the lower sedative effects of rilmenidine.     

CVLM咪唑啉-I和α_2-肾上腺素受体共同参与可乐定的降压效应

目的　探讨大鼠尾端延髓腹外侧区 (CVLM)咪唑啉 I受体 (I1R)和α2 肾上腺素受体 (α2 AR)在介导可乐定中枢降压机制中的作用。方法　在氨基甲酸乙酯麻醉SD大鼠中 ,观察CVLM内局部给予I1R和α2 AR阻断剂后对基础血压(BP)、心率 (HR)以及外周给予可乐定导致降压效应的变化。结果　双侧CVLM分别微量注射选择性α2 AR阻断剂育亨宾 (单侧剂量 5 0 0 pmol·L-1,10 0nl,n =8)或I1R和α2 AR混合性阻断剂idazoxan(单侧剂量 2nmol·L-1,10 0nl,n =10 )后不仅明显降低BP和HR(P <0 0 1) ,而且能明显减弱静脉给予可乐定 (5 μg·kg-1)导致的降压效应 (P <0 0 1) ,此外 ,idazoxan对可乐定降压效应的减弱作用高于育亨宾 (P <0 0 1)。结论　CVLM内I1R和α2 AR共同参与维持紧张性心血管活动和介导可乐定的降压效应     

Sympathoinhibitory effects of clonidine are transmitted by the caudal ventrolateral medulla in cats

We examined mechanisms of the central sympathoinhibitory actions of systemically administered clonidine in anesthetized cats. To avoid influences of sympathetic chemo- and baroreflexes, the animals were deafferentated by cutting the carotid sinus and vagal nerves bilaterally. Intravenous (i.v.) injections of clonidine (25-250 nmol/kg) caused significant (50-90%) decreases in preganglionic sympathetic nerve activity (SNA) recorded from the white ramus of the third thoracic segment. Microinjections (500 nl) into the rostral ventrolateral medulla (RVLM) of clonidine at doses (50-500 pmol in 500 nl), which probably produced higher local concentrations than produced by systemic administration, caused only slight reductions of SNA and small decreases in arterial blood pressure (BP). Furthermore, sympathoinhibition and hypotension caused by intravenous clonidine was almost unaffected by prior microinjection of alpha2-receptor antagonist rauwolscine (500 pmol) into the RVLM. Microinjections of clonidine into the caudal ventrolateral medulla (CVLM), which provides important inhibitory input to the RVLM, had no significant effects. However, chemical lesions of the CVLM with kainate (5.0 nmol), effectively blocked the sympathoinhibitory effects of subsequently administered intravenous clonidine. The results suggest that the central sympathoinhibitory effects of therapeutically relevant doses of systemically administered clonidine may be primarily mediated by pathways that activate the CVLM rather than by direct actions within the RVLM.     

Mediation of the hypotensive action of systemic clonidine in the rat by alpha 2-adrenoceptors.

1. During the past few years it has been shown that the sympatholytic effect resulting from localized microinjection of clonidine and other imidazolines into the rostral ventrolateral medulla (RVL) results from activation of 'imidazoline' receptors (I1 receptors) rather than from an alpha 2-adrenoceptor-mediated effect. 2. The relative contributions of these two receptor systems to the hypotensive action of systemically administered clonidine have not been studied. Clonidine has affinity for both I1 and alpha 2-adrenoceptors; guanabenz represents a useful pharmacological tool, since it activates only the alpha 2-adrenoceptor. 3. Antagonists acting at both I1 and alpha 2-adrenoceptors (idazoxan) and at only alpha 2-adrenoceptors (SK&F 86466; 6-chloro-3-methyl-2,3,4,5-tetrahydro-3-benzazepine) are available. Idazoxan (1 mg kg-1, i.v.) and SK&F 86466 (3 mg kg-1, i.v.) produced an equivalent degree of blockade of the pressor response to guanabenz or clonidine in the pithed rat, a response mediated by the alpha 2-adrenoceptor. 4. Guanabenz (30 micrograms kg-1, i.v.) and clonidine (10 micrograms kg-1, i.v.) lowered blood pressure in the chloralose-anaesthetized spontaneously hypertensive rat by 48 +/- 4.6 mmHg and 44 +/- 5.4 mmHg, respectively; this response, for either agonist, was blocked by both idazoxan and SK&F 86466. 5. These data show that the hypotensive effect of intravenously administered clonidine results from activation of central alpha 2-adrenoceptors, with no significant contribution from an I1-mediated effect. Thus clonidine can lower blood pressure by different receptor mechanisms, dependent on the route of administration.     

Low dose of moxonidine within the rostral rentrolateral medulla improves the baroreflex ;ensitivity control of sympathetic activity in hypertensive rat

Aim:

To determine the effects of the centrally antihypertensive drug moxonidine injected into the rostral ventrolateral medulla (RVLM) on baroreflex function in spontaneously hypertensive rats (SHR).

Methods:

Baroreflex sensitivity control of renal sympathetic nerve activity (RSNA) and barosensitivity of the RVLM presympathetic neurons were determined following application of different doses of moxonidine within the RVLM.

Results:

Three doses (0.05, 0.5, and 5 nmol in 50 nL) of moxonidine injected bilaterally into the RVLM dose-dependently reduced the baseline blood pressure (BP) and RSNA in SHR. At the highest dose (5 nmol) of moxonidine injection, the maximum gain (1.24%±0.04%/mmHg) of baroreflex control of RSNA was significantly decreased. However, the lower doses (0.05 and 0.5 nmol) of moxonidine injection into the RVLM significantly enhanced the baroreflex gain (2.34%±0.08% and 2.01%±0.07%/mmHg). The moxonidine-induced enhancement in baroreflex function was completely prevented by the imidazoline receptor antagonist efaroxan but not by the α₂-adrenoceptor antagonist yohimbine. A total of 48 presympathetic neurons were recorded extracellularly in the RVLM of SHR. Iontophoresis of applied moxonidine (30–60 nA) dose-dependently decreased the discharge of RVLM presympathetic neurons but also significantly increased the barosensitivity of RVLM presympathetic neurons.

Conclusion:

These data demonstrate that a low dose of moxonidine within the RVLM has a beneficial effect on improving the baroreflex function in SHR via an imidazoline receptor-dependent mechanism.     

Harmane produces hypotension following microinjection into the RVLM: possible role of I(1)-imidazoline receptors

The beta-carboline, harmane (0.1 - 1.0 nmol) produces dose dependent hypotension when microinjected unilaterally into the rostral ventrolateral medulla (RVLM) of the anaesthetized rat. The potency of harmane on blood pressure is similar to that of the imidazoline, clonidine. The hypotensive effects of both clonidine and harmane are reversed by microinjection of the relatively I(1)-receptor selective antagonist efaroxan (20 nmol). These results are consistent with harmane acting at an I(1)-receptor in the RVLM. This is the first report of an endogenous ligand for I(1)-receptors that has central effects on blood pressure.     

Contribution of alpha 2-adrenoceptors to the central cardiovascular effects of clonidine and S 8350 in anaesthetized rats.

1. The alpha 2-adrenoceptor agonist clonidine elicits centrally mediated effects through an interaction with both alpha 2-adrenoceptors and imidazoline binding sites. 2. We selected a new oxazoline derivative, S 8350, which competes with [3H]-yohimbine for binding to cerebral alpha 2-adrenoceptors (IC50, 67 +/= 17 nmol/L) and displays a higher affinity (35-fold) for alpha 2- than for alpha 1-adrenoceptors. 3. As observed for clonidine, intravenous (i.v.) administration of S 8350 resulted in a brief pressor effect followed by a prolonged hypotension. When S 8350 was administered i.v. to spinally pithed rats, only a rise in blood pressure was observed. 4. In order to discriminate the cardiovascular effects related to the central imidazoline receptor or alpha 2-adrenoceptor activation, the effects of intracisternal (i.c.) administration of clonidine and S 8350 were investigated in the rat. 5. In the anaesthetized rat, both clonidine and S 8350 displayed a profound central (i.c. route) hypotensive effect associated with a bradycardia. 6. The cardiovascular effects of S 8350 were abolished by the central administration of the selective alpha 2-adrenoceptor antagonist rauwolscine. Conversely, rauwolscine completely prevented bradycardia but it induced only a partial reversion of the hypotension elicited by clonidine. 7. These results suggest that central alpha 2-adrenoceptors are responsible for hypotension and bradycardia while imidazoline binding sites do not apparently contribute to heart rate control.     

The baroreflex and beyond: control of sympathetic vasomotor tone by GABAergic neurons in the ventrolateral medulla

1. Barosensitive, bulbospinal neurons in the rostral ventrolateral medulla (RVLM), which provide the major tonic excitatory drive to sympathetic vasomotor neurons, are prominently inhibited by GABA. 2. A major source of the GABAergic inhibition to presympathetic RVLM neurons arises from an area immediately caudal to the RVLM, known as the caudal ventrolateral medulla (CVLM). 3. Arterial baroreceptor afferents projecting to the nucleus tractus solitarius (NTS) provide a major tonic excitatory input to GABAergic CVLM neurons. These CVLM cells are a critical component for baroreflex-mediated changes in presympathetic RVLM neuronal activity, sympathetic nerve activity (SNA) and arterial pressure (AP). 4. Some GABAergic CVLM neurons are tonically activated by inputs independent of arterial baroreceptors or the NTS, providing a GABAergic-mediated inhibition of the presympathetic RVLM neurons that is autonomous of baroreceptor inputs. 5. GABAergic CVLM neurons appear to play two distinct, yet important, roles in the regulation of sympathetic vasomotor tone and AP. They dampen immediate changes in AP via the baroreflex and tonically inhibit the activity of the presympathetic RVLM neurons by baroreceptor-independent mechanisms. This baroreceptor-independent, GABAergic inhibition of presympathetic RVLM neurons may play an important role in determining the long-term level of sympathetic vasomotor tone and AP.     

NMDA受体机制在动脉压力反射中的介导作用(英文)

目的:研究N-甲基-D-天门冬氨酸(NMDA)受体机制在动脉压力反射中的作用。方法:头端延髓腹外侧区(RVLM)前交感神经元(presympathetic neuron)与动脉压力反射相关,它们可被电刺激主动脉神经或升高动脉血压所抑制,其自发放电具有心性节律。根据这一特性,本研究用电生理学方法在17只雄性SD大鼠鉴定了27个假想的(putative)RVLM前交感神经元。以这些神经元对电刺激主动脉神经的反应为指标,观察在同侧孤束核(NTS)或尾端延髓腹外侧区(CVLM)微注射选择性NMDA受体拮抗剂CPP(0.1μL,50mmol/L)的作用。结果:在NTS微注射CPP可完全阻断或减弱电刺激主动脉神经引起的神经元抑制,但血压升高引起的神经元抑制不能完全被消除,神经元放电的心性节律仍然存在;在CVLM,CPP不仅完全阻断电刺激主动脉神经引起的神经元抑制,而且阻断血压升高引起的神经元抑制,神经元放电的心性节律消失。结论:NMDA受体机制在动脉压力反射中起着重要的介导作用;单侧孤束核的压力敏感神经元向单侧RVLM投射。     

Effects of medullary alpha2-adrenoceptor blockade in the rat

The effect of alpha2-adrenoceptor blockade in the medulla was studied in pentobarbital anesthetized rats in which arterial blood pressure, heart rate and renal sympathetic nerve activity were analysed. Three series of experiments were performed: (1) i.c. administration of alpha2-adrenoceptor antagonists with different subtype affinities; (2) i.v. administration of methoxy-idazoxan to study its effects on neuronal activity into the rostral ventral medulla; (3) microinjections of methoxy-idazoxan in rostral ventral medulla and nucleus tractus solitarii. Methoxy-idazoxan (0.1-3 microg x kg(-1) i.c., n=5), but not saline, rauwolscine, BRL 44408 (2-[2H-(1,3,dihydroisoindol)methyl]-4,5dihydroimidazol) or ARC 239 (2-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquilindione) (each at 10-100 microg x kg(-1) i.c., n=5-5-6-5, respectively), increased mean arterial blood pressure, heart rate and renal nerve activity (+19+/-6 mm Hg, +72+/-22 beats x min(-1), +43+/-9%) and blocked the sympatho-inhibitory action of clonidine (10 microg x kg(-1) i.v.). In further experiments, methoxy-idazoxan, BRL 44408 and the highest dose of rauwolscine i.c., reversed the clonidine-induced sympatho-inhibition (order of potency: methoxy-idazoxan>BRL4440>rauwolscine, n=6 each), whereas ARC 239 (n=5) or saline (n=7) did not. Methoxy-idazoxan i.v. (n=7, 10-100 microg x kg(-1)) increased the renal sympathetic nerve and rostral ventral medulla neuronal activity and the heart rate (+36+/-7%, +66+/-29% and +18+/-9 beats x min(-1)) without a significant effect on mean arterial blood pressure. Microinjection of methoxy-idazoxan (1 nmol/40 nl) into the rostral ventral medulla reversed the effect of clonidine microinjected into the same site (2 nmol/40 nl, n=5). In another group of rats (n=8), methoxy-idazoxan increased mean arterial blood pressure, heart rate and renal nerve activity (+16+/-2 mm Hg, +42+/-7 beats x min(-1), +24+/-5%) and blocked the effect of clonidine i.v. (10 microg x kg(-1)). Bilateral microinjections into the nucleus tractus solitarii (n=5) did not alter mean arterial blood pressure but decreased heart rate and sympathetic nerve activity (-30+/-16 beats x min(-1), -20+/-14%). Our results offer direct in vivo evidence for the main role of the alpha2A/D-adrenoceptors located in the ventral pressor area. The data show that the sympathy-excitatory effect of alpha2-adrenoceptor antagonists is due to the blockade of a tonic activation of these alpha2A/D-adrenoceptors present in the rostral ventral pressor area.     

MICROINJECTION OF KAINIC ACID INTO THE ROSTRAL VENTROLATERAL MEDULLA CAUSES HYPERTENSION AND RELEASE OF NEUROPEPTIDE Y-LIKE IMMUNOREACTIVITY FROM RABBIT SPINAL CORD

Microinjections of kainic acid were made into the pressor area of the rostral ventrolateral medulla oblongata of anaesthetized rabbits, in the region of the C1 adrenaline-containing neurons. Over the 65 min following the microinjection, there was a significant increase in blood pressure, as well as an increase in the release of neuropeptide Y-like immunoreactivity into the spinal subarachnoid space. These data provide evidence for a functional bulbospinal neuropeptide Y-containing projection which may be responsible for mediating the pressor effects of stimulation of the rostral ventrolateral medulla.     

Vasopressor and depressor areas in the rat medulla: Identification by microinjection of l-glutamate

l-Glutamate (in 0.1 μl of 0.9% NaCl) was injected via multibarrelled glass micropipettes into the ventrolateral medulla of urethane-anesthetized rats. This area, explored stereotaxically, extended from 2.2mm rostral (near trapezoid bodies) to 0.4mm caudal, with respect to the obex, 2.4mm lateral to the mid-line on each side and 2.4mm deep from the ventral surface of the medulla. Two types of responses were elicited by injection of l-glutamate. One type was a dose-related increase in arterial pressure and heart rate; these responses were elicited from the lateral portion of nucleus reticularis gigantocellularis, the medial aspect of nucleus reticularis parvocellularis and the dorsal-lateral reticular nucleus. The second type of response was a dose-related fall in arterial pressure with no change in heart rate; this response was localized caudal to pressure areas in the caudal ventrolateral part of nucleus reticularis gigantocellularis, ventrolateral nucleus reticularis ventralis, nucleus ambiguus and the A₁ region. Glutamic acid diethylester (GDEE), an antagonist of l-glutamate, blocked all the cardiovascular effects of l-glutamate. These results indicate the presence of receptors for glutamate in the pressor and depressor areas. Glutamic acid diethylester caused a fall in blood pressure when injected on its own into pressor sites suggesting the existence of a glutaminergic input to the pressor sites. Inhibition of neuronal activity in pressor sites produced by microinjection of muscimol (a potent neuroinhibitory analogue of GABA) caused a decrease in blood pressure. On the other hand, pressor responses resulted following similar inhibition in the depressor sites. These results indicate that the pressor and depressor sites identified in the ventral medulla of the rat may have an important role to play in central cardiovascular regulation.     

莫索尼定对去缓冲神经大鼠延髓腹外侧头端神经元自发电活动的影响

在去缓冲神经大鼠观察莫索尼定对延髓腹外侧头端区 (RVLM) 神经元自发电活动的影响. 向颈总动脉内注射莫索尼定2, 10, 50 μg·kg^-1后, 同步记录神经元放电图,血压及心率. 结果显示,莫索尼定剂量依赖性地降低RVLM 神经元放电率,血压和心率. 莫索尼定10, 50 μg·kg^-1使放电率分别减少23% 和41%. 动脉注射选择性I₁-咪唑啉受体阻断剂依法克生10 μg·kg^-1, 可完全拮抗莫索尼定10 μg·kg^-1 的作用. 结果提示, 莫索尼定通过激动延髓腹外侧头端区神经元上的I₁-咪唑啉受体,抑制其自发放电活动.     

Differences in the central hypotensive actions of alpha-methyldopa and clonidine in the spontaneously hypertensive rat: contribution of neurons arising from the B3 and the C1 areas of the rostral ventrolateral medulla.

The rostral ventrolateral medulla (RVLM) is the proposed site of origin of bulbospinal excitatory vasomotor neurons, and this brainstem area gives rise to chemically distinct populations of neurons, including serotonin-containing neurons of the B3 group and epinephrine-containing neurons of the C1 group, which independently serve sympathoexcitatory functions. In the present study, we sought to establish (a) whether distinct and chemically specific pathways originating in the C1 or B3 regions are involved in the antihypertensive effects of alpha-methyldopa (methyldopa) and clonidine and (b) if so, whether these effects are related to an activation of alpha-adrenoceptors in these areas. Microinjections of methyldopa (6 nmol) or clonidine (5 nmol) were made in the C1 or B3 area in intact spontaneously hypertensive rats (SHR), pretreated with 5,7-dihydroxytryptamine (5,7-DHT) or with phentolamine. The microinjection of clonidine into both the B3 and the C1 area caused a rapid decrease in arterial pressure, whereas microinjection of methyldopa lowered the arterial pressure only after injection into the B3 area. Pretreatment with intracerebroventricular (i.c.v.) 5,7-DHT attenuated the hypotension produced by microinjection of clonidine into the B3 area, suggesting that this effect is mediated by serotonin-containing neurons. Central pretreatment with phentolamine reduced the hypotensive effects produced by injection of clonidine into either area and of methyldopa into the B3 region, consistent with previous suggestions that these central effects are mediated through alpha-adrenoceptors. These results suggest that both serotonin-containing and epinephrine-containing neurons contribute to the central action of clonidine, whereas the effects of methyldopa injection in RVLM appear to be mediated by serotonin-containing but not by epinephrine-containing neurons.     

Cardiovascular effects of microinjections of quipazine into nuclei of the medulla oblongata in anaesthetized cats: comparison with L-glutamate.

Unilateral microinjections of quipazine (0.9 micrograms in 50 nl) into the subretrofacial nucleus produced hypertension and a slight tachycardia associated with an increase in renal sympathetic nerve activity. Microinjections of quipazine lateral, caudal or rostral to this nucleus failed to alter blood pressure and heart rate. Similarly, microinjections of l-glutamate (3 nmol in 15 nl) into the subretrofacial nucleus elicited hypertension, tachycardia and renal sympatho-excitation. The magnitude of the pressor response to quipazine was smaller than the response elicited by l-glutamate but its duration was longer. Microinjections of quipazine into the lateral tegmental field at l-glutamate hypertensive sites failed to alter arterial blood pressure and heart rate. In contrast, microinjections of quipazine into the caudal ventrolateral medulla or into the nucleus tractus solitarii produced hypotension and sympatho-inhibition. These effects were prevented by microinjections of the 5-HT2 receptor antagonists, LY 53857 or BW 501C. The present results indicate that stimulation of 5-HT2 receptors of the subretrofacial nucleus produces hypertension and sympatho-excitation whereas stimulation of 5-HT2 receptors in the caudal ventrolateral medulla and in the nucleus tractus solitarii produces hypotension and sympatho-inhibition.     

Relative importance of rostral ventrolateral medulla in sympathoinhibitory action of rilmenidine in conscious and anesthetized rabbits

The pressor region of the rostral ventrolateral medulla (RVLM) is a critical site in the sympathoinhibitory action of imidazoline receptor agonists as shown by studies in anesthetized animals. The aim of this study was to compare the importance of the RVLM in mediating the inhibitory action of rilmenidine on renal sympathetic nerve activity (RSNA) and arterial pressure in urethane-anesthetized rabbits (n = 11) and in conscious, chronically instrumented rabbits (n = 6). Bilateral microinjection of rilmenidine (4 nmol in 100 nl) into the RVLM caused a greater decrease in resting arterial pressure in anesthetized animals (-19 mm Hg) than in conscious animals (-8 mm Hg). By contrast, the decrease in resting RSNA evoked by rilmenidine was similar in conscious (-27%) and anesthetized (-36%) rabbits. Furthermore, rilmenidine microinjection into the RVLM was equally effective in inhibiting the RSNA baroreflex in both groups of animals. The upper plateau of the RSNA baroreflex decreased by 37% and 42%, and gain decreased by 41% and 44% after rilmenidine treatments in conscious and anesthetized rabbits, respectively. We conclude that the RVLM plays an equally important role in the inhibitory action of rilmenidine on RSNA in conscious and anesthetized rabbits either at rest or during baroreflex responses. A relatively moderate effect of rilmenidine on arterial pressure in conscious, chronically instrumented rabbits may relate to a lower level of sympathetic drive compared with anesthetized animals.