Sympathetic Nerve Endings Research Articles

Mice deficient in p52/NF-κB as a model for studying prion disease

AbstractA tight functional link between the central nervous and peripheral immune system closely related to the activity of NF-κB transcription factor has been evidenced in numerous brain pathological conditions. One of the most instructive examples is a prion neuroinvasion and the development of transmissible spongioform encephalopathy (TSE) or prion diseases. The failure of peripherally administrated prions to elicit disease in immune-deficient mice indicates that preserved organ microarchitecture is crucial for TSE pathogenesis and it seems to go through topographic relationships between follicular dendritic cells and sympathetic endings in lymphoid organs. New insight into the molecular requirements for follicular dendritic cell (FDC) development in NF-κB p52 deficient mice highlights the role of NF-κB transcription factor in prion disease progression. However, adoptive transfer of wild type bone marrow cells (NF-κB +/+ background) into p52 deficient animals (NF-κB -/- background) does not correct the FDC defect. RT-PCR analysis of the expression level of mRNA for LTa, LTb, TNFRI and BLC of the splenic cells from p52/NF-κB mutant/wt BM chimera did not reveal major changes compared to wt/wt BM chimeras, indicating that their normal expression within splenic tissue does not assure for complete restoration of the FDC network in p52/NF-κB mutant. This implies that the distance between FDCs and splenic nerve terminals around the central arteriole is longer and could interfere with prion spreading in lymphoid organs prior to neuroinvasion. In light of the fact that prion neuroinvasion highly depends on the physical distance between sympathetic nerve endings and FDCs dendritic extensions, it is not hard to imagine that this could be the way to approach the problem of prion diseases development.

Endothelin-1 and Norepinephrine Overflow from Cardiac Sympathetic Nerve Endings in Myocardial Ischemia

In protracted myocardial ischemia, sympathetic activation with carrier-mediated excessive norepinephrine (NE) release from its nerve endings due to reversal of NE transporter in an outward direction is a prominent cause of arrhythmias and cardiac dysfunction. Endothelin-1 (ET-1) and its receptors are intimately involved in the regulation of this carrier-mediated NE overflow in protracted myocardial ischemia. The ET-1 system is often complex, sometimes involving opposing actions depending on which receptor subtype is activated, which cells are affected, and whether stimuli are endogenously generated or exogenously applied. Therefore, a detailed understanding of the ET-1 system is important for applying drugs acting on this system in clinical settings for the treatment of ischemic cardiac disease. This article provides a detailed analysis of how the ET-1 system is involved in the regulation of carrier-mediated NE release from sympathetic nerve endings in protracted myocardial ischemia.

Renin-Angiotensin System and Sympathetic Neurotransmitter Release in the Central Nervous System of Hypertension

Many Studies suggest that changes in sympathetic nerve activity in the central nervous system might have a crucial role in blood pressure control. The present paper discusses evidence in support of the concept that the brain renin-angiotensin system (RAS) might be linked to sympathetic nerve activity in hypertension. The amount of neurotransmitter release from sympathetic nerve endings can be regulated by presynaptic receptors located on nerve terminals. It has been proposed that alterations in sympathetic nervous activity in the central nervous system of hypertension might be partially due to abnormalities in presynaptic modulation of neurotransmitter release. Recent evidence indicates that all components of the RAS have been identified in the brain. It has been proposed that the brain RAS may actively participate in the modulation of neurotransmitter release and influence the central sympathetic outflow to the periphery. This paper summarizes the results of studies to evaluate the possible relationship between the brain RAS and sympathetic neurotransmitter release in the central nervous system of hypertension.

N-type Calcium Channel Inhibition With Cilnidipine Elicits Glomerular Podocyte Protection Independent of Sympathetic Nerve Inhibition

We recently demonstrated that cilnidipine, an L/N-type calcium channel blocker, elicits protective effects against glomerular podocyte injury, in particular, in obese hypertensive rats that express the N-type calcium channel (N-CC). Since the N-CC is known to be expressed in sympathetic nerve endings, we evaluated the reno-protective effects of cilnidipine in innervated and denervated spontaneously hypertensive rats (SHR). Male SHR were uninephrectomized and fed 4% high-salt diet (HS-UNX-SHR). Animals were divided into groups, as follows, and observed from 9 to 27 weeks of age: 1) vehicle (n = 14), 2) vehicle plus renal-denervation (n = 15), 3) cilnidipine (50 mg/kg per day, p.o.; n = 10), and 4) cilnidipine plus renal-denervation (n = 15). Renal denervation attenuated elevations in blood pressure, but failed to suppress urinary protein excretion and podocyte injury in HS-UNX-SHR. Cilnidipine in both innervated and denervated HS-UNX-SHR similarly induced significant antihypertensive effects, as well as suppressing the urinary protein excretion and podocyte injury, compared to vehicle-treated HS-UNX-SHR. These data indicate that renal nerves have a limited contribution to the cilnidipine-induced reno-protective effects in HS-UNX-SHR.

Cilnidipine Lowers Plasma Leptin of Patients with Obese Hypertension Associated with Cerebrovascular Disorder

Background: Since cilnidipine suppresses not only the L-type but also N-type calcium channels found on peripheral sympathetic nerve endings which control noradrenaline release, it is thought to be a Ca antagonist with low sympathetic nerve activation when lowering blood pressure (dual blocking action). As activation of sympathetic nervous system is suggested to contribute to hypertension in obesity, dual blocking action of cilnidipine may contribute to patients with obesity-hypertension. Methods: The effects of cilnidipine on plasma leptin levels and blood pressure were studied. Twenty three patients with obesity-hypertension associated with a past history of stroke or ischemic changes confirmed by brain magnetic resonance imaging were enrolled. Cilnidipine (10 mg/day) was administered orally once a day after breakfast. The duration of the study treatment was 12 weeks. Retroperitoneal adipose tissues around the kidney of both fat and lean cadaver and neuronal and non-neuronal tissues of rat were used for immunohistochemical examination. Result: The mean circulating leptin level decreased from 11.8 ng/ml to 10.8 ng/ml that reached statistical significance. Multiple regression analysis revealed no significant effects of covariates except for baseline leptin level. An immunohistochemical study revealed that N-type calcium channel protein was expressed on the cell membrane of adipocytes. We speculate that a blockade of calcium current through the N-type channel, instead of the L-type channel may suppress leptin secretion. Conclusion: The dual blocking action of cilnidipine may help control both arterial hypertension and leptininduced atherosclerosis in patients with obese hypertension associated with cerebrovascular disorder.

Renin-Angiotensin and Sympathetic Nervous System Interactions in the Control of Blood Pressure in Fructose-Induced Metabolic Syndrome

Activation of the sympathetic nervous system (SNS) stimulates renin release from the juxtraglomerular cells of the kidneys that leads to the generation of angiotensin I, which is then converted to angiotensin II (Ang II), the major effector peptide of the renin-angiotensin system (RAS). The formed Ang II can facilitate noradrenaline release from the renal sympathetic nerve endings in addition to its effect in the anterior hypothalamus and rostral ventrolateral medulla (RVLM) [1,2]. At RVLM neurons, Ang II acts either postsynaptically, by decreasing K

Evaluation of the Inhibitory Effect of Dihydropyridines on N-type Calcium Channel by Virtual Three-dimensional Pharmacophore Modeling

Currently, a new type of calcium channel blockers, which can inhibit not only L-type calcium channels abundantly expressed in vascular smooth muscles, but also N-type calcium channels that abound in the sympathetic nerve endings, have been developed. In this study, analysis on a like-for-like basis of the L- and N-type calcium channel-inhibitory activity of typical dihydropyridine-type calcium-channel blockers (DHPs) was performed. Moreover, to understand the differences of N-type calcium channel inhibition among DHPs, the binding of DHPs to the channel was investigated by means of hypothetical three-dimensional pharmacophore modeling using multiple calculated low-energy conformers of the DHPs. All of the tested compounds, i.e. cilnidipine (CAS 132203-70-4), efonidipine (CAS 111011-76-8), amlodipine (CAS 111470-99-6), benidipine (CAS 85387-35-5), azelnidipine (CAS 123524-52-7) and nifedipine (CAS 21829-25-4), potently inhibited the L-type calcium channel, whereas only cilnidipine inhibited the N-type calcium channel (IC50 value: 51.2 nM). A virtual three-dimensional structure of the N-type calcium channel was generated by using the structure of the peptide omega-conotoxin GVIA, a standard inhibitor of the channel, and cilnidipine was found to fit well into this pharmacophore model. Lipophilic potential maps of omega-conotoxin GVIA and cilnidipine supported this finding. Conformational overlay of cilnidipine and the other DHPs indicated that amlodipine and nifedipine were not compatible with the pharmacophore model because they did not contain an aromatic ring that was functionally equivalent to Tyr13 of omega-conotoxin GVIA. Azelnidipine, benidipine, and efonidipine, which have this type of aromatic ring, were not positively identified due to intrusions into the excluded volume. Estimation of virtual three-dimensional structures of proteins, such as ion channels, by using standard substrates and/or inhibitors may be a useful method to explore the mechanisms of pharmacological and toxicological effects of substrates and/or inhibitors, and to discover new drugs.

Reciprocal sympatho-sensory control: functional role of nucleotides and calcitonin gene-related peptide in a peripheral neuroeffector junction

The rat vas deferens has scattered sensory afferens plus a dense network of sympathetic motor efferens; these fibers are not known to interact functionally. We ascertained whether sensory fibers modulate the release of sympathetic transmitters through the release of calcitonin gene-related peptide (CGRP) and reciprocally assessed whether sympathetic transmitters modulate the overflow of ir-CGRP from sensory fibers. The tissue overflow of electrically evoked sympathetic co-transmitters (ATP/metabolites, noradrenaline (NA), and immunoreactive neuropeptide tyrosine (ir-NPY)) and the motor responses elicited were quantified following either exogenous CGRP or capsaicin application to elicit peptide release. Conversely, the outflow of ir-CGRP was examined in the presence of sympathetic transmitters. Exogenous CGRP reduced in a concentration-dependent manner the electrically evoked outflow of ATP/metabolites, NA, and ir-NPY with EC50 values of 1.3, 0.18, and 1.9 nM, respectively. CGRP also reduced the basal NA overflow. The CGRP-evoked modulation was blocked by CGRP8–37 or H-89. Release of endogenous CGRP by capsaicin significantly reduced the basal overflow of NA, ir-NPY, and the electrically evoked sympathetic transmitter release. ADP, 2-methylthioadenosine-5′-O-diphosphate (2-MeSADP), or UTP decreased the electrically evoked ir-CGRP overflow, whereas clonidine, α,β-methyleneadenosine 5′-triphosphate (α,β-mATP), or adenosine (ADO) were inactive. CGRP acting postjunctionally also reduced the motor responses elicited by exogenous NA, ATP, or electrically evoked contractions. We conclude that CGRP exerts a presynaptic modulator role on sympathetic nerve endings and reciprocally ATP or related nucleotides influence the release of ir-CGRP from sensory fibers, highlighting a dynamic sympatho-sensory control between sensory fibers and sympathetic nerve ending. Postjunctional CGRP receptors further contribute to reduce the tissue sympathetic motor tone implying a pre and postjunctional role of CGRP as a sympathetic tone modulator.

Salivary chromogranin A, but not α-amylase, correlates with cardiovascular parameters during high-intensity exercise

Several studies have shown that activation of the sympathetic nervous system results in the increased secretion of α-amylase (sAA), an enzyme produced by salivary glands. Recently, chromogranin A (CgA), a soluble protein costored and coreleased with catecholamines from the adrenal medulla and sympathetic nerve endings, has been proposed as a marker of sympathoadrenal medullary system (SAM) activity. The aim of this study was to investigate the behaviour of salivary chromogranin A (sCgA) and sAA during high-intensity exercise and to analyse their possible correlation with cardiovascular and psychological parameters. Before and during a standardized treadmill stress test, and at 5, 15 and 30 min during the recovery phase, sCgA and sAA were monitored in 21 healthy men. The double product (DP) of blood pressure and heart rate responses, and the product of the subjective ratings of perceived exertion recorded at the final step (RPE) and the exercise duration were used as indices of cardiovascular and exercise intensity, respectively. With respect to baseline, significant (P < 0·001) increases in peak sCgA (median 64%) and sAA (median 86%) were observed at the end of exercise. During the recovery phase, sAA levels fell abruptly, whereas sCgA remained elevated (P < 0·001). Significant correlations emerged only for sCgA with respect to %DP (r = 0·84; P < 0·001) and last step-RPE (r = 0·82; P = 0·024). These data suggest sCgA as a reliable marker of SAM activation. Furthermore, the relationship between sCgA and exercise intensity highlights the potential use of this noninvasive parameter in monitoring the adrenergic response during intense physical stress.

Norepinephrine reduces ω-conotoxin-sensitive Ca2+ currents in renal afferent neurons in rats

Sympathetic efferent and peptidergic afferent renal nerves likely influence hypertensive and inflammatory kidney disease. Our recent investigation with confocal microscopy revealed that in the kidney sympathetic nerve endings are colocalized with afferent nerve fibers (Ditting T, Tiegs G, Rodionova K, Reeh PW, Neuhuber W, Freisinger W, Veelken R. Am J Physiol Renal Physiol 297: F1427-F1434, 2009; Veelken R, Vogel EM, Hilgers K, Amman K, Hartner A, Sass G, Neuhuber W, Tiegs G. J Am Soc Nephrol 19: 1371-1378, 2008). However, it is not known whether renal afferent nerves are influenced by sympathetic nerve activity. We tested the hypothesis that norepinephrine (NE) influences voltage-gated Ca(2+) channel currents in cultured renal dorsal root ganglion (DRG) neurons, i.e., the first-order neuron of the renal afferent pathway. DRG neurons (T11-L2) retrogradely labeled from the kidney and subsequently cultured, were investigated by whole-cell patch clamp. Voltage-gated calcium channels (VGCC) were investigated by voltage ramps (-100 to +80 mV, 300 ms, every 20 s). NE and appropriate adrenergic receptor antagonists were administered by microperfusion. NE (20 μM) reduced VGCC-mediated currents by 10.4 ± 3.0% (P < 0.01). This reduction was abolished by the α-adrenoreceptor inhibitor phentolamine and the α(2)-adrenoceptor antagonist yohimbine. The β-adrenoreceptor antagonist propranolol and the α(1)-adrenoceptor antagonist prazosin had no effect. The inhibitory effect of NE was abolished when N-type currents were blocked by ω-conotoxin GVIA, but was unaffected by other specific Ca(2+) channel inhibitors (ω-agatoxin IVA; nimodipine). Confocal microscopy revealed sympathetic innervation of DRGs and confirmed colocalization of afferent and efferent fibers within in the kidney. Hence NE released from intrarenal sympathetic nerve endings, or sympathetic fibers within the DRGs, or even circulating catecholamines, may influence the activity of peptidergic afferent nerve fibers through N-type Ca(2+) channels via an α(2)-adrenoceptor-dependent mechanism. However, the exact site and the functional role of this interaction remains to be elucidated.

Targeting Cardiac Mast Cells: Pharmacological Modulation of the Local Renin-Angiotensin System

Enhanced production of angiotensin II and excessive release of norepinephrine in the ischemic heart are major causes of arrhythmias and sudden cardiac death. Mast cell-dependent mechanisms are pivotal in the local formation of angiotensin II and modulation of norepinephrine release in cardiac pathophysiology. Cardiac mast cells increase in number in myocardial ischemia and are located in close proximity to sympathetic neurons expressing angiotensin AT1- and histamine H3-receptors. Once activated, cardiac mast cells release a host of potent pro-inflammatory and pro-fibrotic cytokines, chemokines, preformed mediators (e.g., histamine) and proteases (e.g., renin). In myocardial ischemia, angiotensin II (formed locally from mast cell-derived renin) and histamine (also released from local mast cells) respectively activate AT1- and H3-receptors on sympathetic nerve endings. Stimulation of angiotensin AT1-receptors is arrhythmogenic whereas H3-receptor activation is cardioprotective. It is likely that in ischemia/reperfusion the balance may be tipped toward the deleterious effects of mast cell renin, as demonstrated in mast cell-deficient mice, lacking mast cell renin and histamine in the heart. In these mice, no ventricular fibrillation occurs at reperfusion following ischemia, as opposed to wild-type hearts which all fibrillate. Preventing mast cell degranulation in the heart and inhibiting the activation of a local renin-angiotensin system, hence abolishing its detrimental effects on cardiac rhythmicity, appears to be more significant than the loss of histamine-induced cardioprotection. This suggests that therapeutic targets in the treatment of myocardial ischemia, and potentially congestive heart failure and hypertension, should include prevention of mast cell degranulation, mast cell renin inhibition, local ACE inhibition, ANG II antagonism and H3-receptor activation.

Epinephrine and its Role in the Development of Obesity and Hypertension

Epinephrine accounts for 80%, while norepinephrine accounts for 20% of the total hormone secreted from the adrenal medulla. Further, in certain situations epinephrine may be released as a co-transmitter with norepinephrine from postganglionic sympathetic nerves. Epinephrine is known as a prime mover in the “fight or flight” response with epinephrine elevating heart rate, augmenting neurogenic vasoconstriction, reducing blood flow to the skin and the kidneys, increasing the production of sweat, and widening the smaller bronchioles in the lungs. Its action raises blood-sugar levels by stimulating glucose production in the liver, and blood fatty-acid levels in adipose tissue. These effects on the cardiovascular system could perhaps play an important role in the onset and maintenance of hypertension, obesity and the metabolic syndrome (type 2 diabetes). The “epinephrine hypothesis” proposes that circulating epinephrine is taken up by sympathetic nerves, thereby promoting norepinephrine release during sympathetic nervous system stimulation. It is suggested that binding of co-released epinephrine to pre-synaptic β-adrenoceptors augments exocytotic release of norepinephrine and contribute to high blood pressure (hypertension). Thus, the “epinephrine hypothesis” might explain how the adreno-medullary hormonal system could contribute to the development of essential hypertension by augmenting sympathoneuroral norepinephrine release. There is evidence that the sympathetic nerves of hypertensive patients do release epinephrine as a co-transmitter. In this review, results will be presented which suggest that epinephrine is synthesized in situ in sympathetic nerve endings via the action of phenylethanolamine-N-methyltransferase (PNMT), which is induced by chronic mental stress exposure. Accordingly, this represents a biomarker of chronic mental stress, rather than a specific mechanism of hypertension, as proposed in the “epinephrine hypothesis”.

Dopamine Regulates Angiogenesis in Normal Dermal Wound Tissues

Cutaneous wound healing is a normal physiological process and comprises different phases. Among these phases, angiogenesis or new blood vessel formation in wound tissue plays an important role. Skin is richly supplied by sympathetic nerves and evidences indicate the significant role of the sympathetic nervous system in cutaneous wound healing. Dopamine (DA) is an important catecholamine neurotransmitter released by the sympathetic nerve endings and recent studies have demonstrated the potent anti-angiogenic action of DA, which is mediated through its D2 DA receptors. We therefore postulate that this endogenous catecholamine neurotransmitter may have a role in the neovascularization of dermal wound tissues and subsequently in the process of wound healing. In the present study, the therapeutic efficacy of D2 DA receptor antagonist has been investigated for faster wound healing in a murine model of full thickness dermal wound. Our results indicate that treatment with specific D2 DA receptor antagonist significantly expedites the process of full thickness normal dermal wound healing in mice by inducing angiogenesis in wound tissues. The underlined mechanisms have been attributed to the up-regulation of homeobox transcription factor HoxD3 and its target α5β1 integrin, which play a pivotal role in wound angiogenesis. Since D2 DA receptor antagonists are already in clinical use for other disorders, these results have significant translational value from the bench to the bedside for efficient wound management along with other conventional treatment modalities.

Effect of acute and chronic treatment with practolol on cardiovascular responses in the pithed rat.

Abstract Chronic administration of practolol to the pithed rat produced a reduction in the pressor responses to electrical stimulation of the spinal cord and potentiation of pressor responses to high doses of (—)-noradrenaline compared to control animals. Acute administration of practolol caused an increase in the pressor responses to both electrical stimulation and high doses of noradrenaline. Heart rate responses to both forms of stimulation were less than control values after both acute and chronic dosage with practolol. It is possible that practolol reduces the release of noradrenaline at the sympathetic nerve ending after chronic administration.

Test the Heart Nerves: True Grit for Prognosis?

Introduction: Meta-iodobenzylguanidine (mIBG) is an analogue of guanethidine, a false neurotransmitter. Similarly to norepinephrine (NE), mIBG undergoes active uptake into the presynaptic sympathetic nerve endings through the NE transporter mechanism and is stored in citoplasmatic vesicles. In contrast to norepinephrine, mIBG is not catabolized by either monoamine oxidase or catechol-o-methyltransferase in the synaptic cleft, so that the molecule is kept intact in sympathetic vesicles. This favorable tracer kinetics provides the physiological basis for the scintigraphy imaging using the iodine-123–labeled compound (I-mIBG) that permits the quantitative assessment of the structural and functional integrity of the myocardial sympathetic nerve fibers [1]. Derangements of the cardiac sympathetic nervous system have been documented in the failing heart. Increased sympathetic activity is an early consequence of the reflex neuro-hormonal activation that occurs in heart failure (HF). As left ventricular (LV) dysfunction progresses, the chronic increase of sympathetic activity is associated with more marked changes in the cardiac adrenergic neurotransmission, leading to reduced reuptake of NE by the presynaptic fiber and reduced myocardial content of NE. The intensity of sympathetic activation correlates with the progression of LV dysfunction, symptom severity, and mortality [2]. This pathophysiological background constitutes the basis for the use of I-mIBG scintigraphy for risk stratification in HF [3]. Until recently, the evidence supporting the use of I-mIBG as a prognostic tool in HF consisted of only small singlecenter studies. More recently, the body of evidence showing the correlation of I-mIBG imaging with prognosis was reinforced by the positive results of a systematic review [4] and a retrospective multicenter European study [5]. The ADMIRE-HF trial, reported by Jacobson et al., is the first multicenter prospective trial to test the use of I-mIBG to risk-stratify patients with HF.

Mechanism of the indirect adrenergic effect of histamine in cat cerebral arteries.

KCl (50 mM), tyramine (10(-7) M), and histamine (10(-4) M) induced an increase in tritium release from cat cerebral arteries preincubated with [3H]noradrenaline, this increase being due in part to noradrenaline. When calcium was absent from the superfusion medium, only tyramine (10(-7) M) enhanced the tritium outflow. Colchicine (10(-3) M) partially inhibited the increase in radioactivity brought about by 10(-4) M histamine. KCl (50 mM) also evoked release of radioactivity from cerebral arteries preloaded with [3H]histamine; this release was unaffected by reserpine pretreatment or removal of both superior cervical sympathetic ganglia. Neither tyramine (10(-7) M) nor compound 48/80 (300 micrograms ml-1) altered the spontaneous tritium outflow from cerebral blood vessels preincubated with [3H]histamine. These results suggest that histamine is not accumulated by sympathetic nerve endings and elicits its noradrenaline-releasing effect by means of an exocytotic process.

The effects of calcium on adrenergic neuron blockade.

Abstract The effects of increasing extracellular calcium were investigated on the responses to sympathetic nerve stimulation of three isolated organs; rabbit ileum, guinea-pig vas deferens and rabbit ear artery. A rise in the calcium concentration increased the responses of the ileum to low frequency stimulation, the maximum increase being obtained at 8.8 mM calcium. After partial blockade by guanethidine of the responses of the ileum to high frequency stimulation, raised calcium concentrations again increased the responses. The increase was similar in guanethidine-treated and untreated preparations and the maximum increase in both was obtained using 8.8 mM calcium. In the vas deferens and rabbit ear artery preparations an increase in extracellular calcium did not antagonize the blocking action of guanethidine. These experiments do not therefore support the theory that guanethidine acts by preventing the entry of calcium into the sympathetic nerve endings.

Presynaptic changes promoted by alloxan diabetes in the cat isolated heart.

Adrenergic presynaptic functions were evaluated in the cat isolated perfused heart preparation. The sympathetic nerve endings were labelled with [3H]noradrenaline ([3H]NA) and the effect of electric neural stimulation was determined in the presence of drugs which inhibit neuronal or extraneuronal uptake, or which antagonize alpha-adrenoceptors. [3H]NA overflow was measured in control and diabetic cats and was significantly increased by electric neural stimulation on both conditions. Perfusion with 0.1 microM phentolamine increased transmitter overflow in control hearts but failed to do so on organs obtained from alloxan-treated cats. The data provide evidence that in alloxan diabetic cats there is an abnormality of the adrenergic synapse.

A comparison of the effects of 6-hydroxydopamine immunosympathectomy and reserpine on the cardiovascular reactivity in the rat.

Abstract In the conscious rat, 6-hydroxydopamine, or reserpine (5 mg/kg) pretreatment produced a marked fall in the mean systolic blood pressure whilst immunosympathectomized rats had resting blood pressures just below that of control animals. In pithed preparations, 6-hydroxydopamine treatment or immunosympathectomy potentiated the pressor responses to injected noradrenaline; reserpine pretreatment did not potentiate the noradrenaline response to the same degree. Tyramine responses were abolished after 6-hydroxydopamine or reserpine pretreatment but were unaffected by immunosympathectomy. Stimulation of the sympathetic outflow by the Gillespie &amp; Muir (1967) preparation was abolished after 6-hydroxydopamine and reserpine pretreatment, and reduced after immunosympathectomy. It is concluded that 6-hydroxydopamine produces a destruction of the sympathetic nerve endings, abolishing the physiological uptake process and, therefore, producing supersensitivity to injected noradrenaline. Immunosympathectomy, although showing a marked reduction in sympathetic nerve supply leaves a functional uptake process. Reserpine (5 mg/kg), given 6 h previously, depletes endogenous catecholamines without significantly altering the sensitivity to injected noradrenaline, the uptake process remaining functional.

Involvement of presynaptic dopamine receptors in the antihypertensive response to 2-NN-dimethylamino-5,6-dihydroxy-1,2,3,4,-tetrahydronaphthalene (M-7).

M-7, 1 and 3 mg kg-1 s.c., elicits an antihypertensive response and bradycardia in conscious spontaneously hypertensive rats (SHR) and causes inhibition of stimulation-evoked pressor response and tachycardia in pithed SHR. Metoclopramide (30 mg kg-1 i.p.), but not piperoxan (5 mg kg-1 i.p.), abolished the antihypertensive effect and inhibition of stimulation-evoked pressor responses produced by M-7 (1 mg kg-1 s.c.) in SHR. Conversely, piperoxan, but not metoclopramide, reduces the bradycardia and inhibition of stimulation-evoked tachycardia produced by M-7. Metoclopramide (30 mg kg-1 i.p.) did not affect the cardiovascular responses elicited by intracerebroventricular administration of either clonidine (1 microgram) of M-7 (3 micrograms). These results suggest that the antihypertensive effect of M-7 may be mediated by stimulation of presynaptic dopamine receptors on sympathetic nervous to the vasculature and is independent of the bradycardia, which is probably due to stimulation of presynaptic alpha 2-adrenoceptors on cardiac sympathetic nerve endings.