Regulation Of Sympathetic Tone Research Articles

Renalase: a novel regulator of cardiometabolic and renal diseases.

Renalase is a ~38 kDa flavin-adenine dinucleotide (FAD) domain-containing protein that can function as a cytokine and an anomerase. It is emerging as a novel regulator of cardiometabolic diseases. Expressed mainly in the kidneys, renalase has been reported to have a hypotensive effect and may control blood pressure through regulation of sympathetic tone. Furthermore, genetic variations in the renalase gene, such as a functional missense polymorphism (Glu37Asp), have implications in the cardiovascular and renal systems and can potentially increase the risk of cardiometabolic disorders. Research on the physiological functions and biochemical actions of renalase over the years has indicated a role for renalase as one of the key proteins involved in various disease states, such as diabetes, impaired lipid metabolism, and cancer. Recent studies have identified three transcription factors (viz., Sp1, STAT3, and ZBP89) as key positive regulators in modulating the expression of the human renalase gene. Moreover, renalase is under the post-transcriptional regulation of two microRNAs (viz., miR-29b, and miR-146a), which downregulate renalase expression. While renalase supplementation may be useful for treating hypertension, inhibition of renalase signaling may be beneficial to patients with cancerous tumors. However, more incisive investigations are required to unravel the potential therapeutic applications of renalase. Based on the literature pertaining to the function and physiology of renalase, this review attempts to consolidate and comprehend the role of renalase in regulating cardiometabolic and renal disorders.

Neuronal Nitric Oxide Synthase expression in brain from male spontaneously hypertensive rats. Implication in the control of cardiovascular function

Neuronal nitric oxide synthase (nNOS) in brain has been implicated in the regulation of sympathetic tone and control of cardiovascular functions, then in this study it was determined the nNOS expression and nitrites levels in brain from spontaneously hypertensive rats (SHR). Male Wistar Kyoto (WKY) and (SHR) strains at 4 months old were used, half of the experimental animals were administered with reserpine (R), (1 mg/kg of weight, for two weeks) and the others received vehicle (V) administration (dimethyl sulfoxide). Four experimental groups (WK+V, WKY+R, SH+V, SH+R) were followed and after cardiovascular parameters determination, brain was obtained. The expression of nNOS through western blot in frontal cortex‐FC, occipital cortex‐OC, cerebellum‐CB, medulla oblongata‐MO, spinal cord‐EC was determined and nitrites levels in tissue homogenate from the same brain regions were measured through Griess reaction. Heart rate (HR), systolic arterial blood pressure (SABP) and body weight, were analyzed. The results show that reserpine decrease significantly the body weight in g (WK+V 335.2±17.6 versus WK+R 280.4±9.87; SH+V 334.8±9.01 versus SH+R 269.3±8.65), the HR in beat/min (WK+V 302.2±11.6 versus WK+R 264±9.13; SH+V 354±17 versus SH+R 224±16), SABP in mmHg (WK+V: 165.8±4,964, versus WK+R 118.2±7.52; SH+V 215.4±5,074 versus SH+R 139.6±3.75), in both WKY and SHR (P<0.05 for all parameters). nNOS protein expression was high in WK+V in comparison with the SH+V, in FC and CB, whereas in the groups with reserpine administration the nNOS expression was higher in SH+R versus SH+V in FC, CB and MO. Tissue nitrites levels from different regions of the brain were reduced significantly in the SHR in comparison with WKY, particularly in FC (WK+V‐5.11 ±0.60 versus SH+V 3.53±0.53) and MO (WK+V 7.84±0.84 versus SH+V 3.24±0.48), however in the groups SHR+R a significantly increased of nitrites levels was observed in comparison with their own control, particularly in CB (SH+V 3.91±1.04 versus SH+R 7.53±0.83) and MO (SH+V 3.72±0.44 versus SH+R 5.8±0.39) (P<0.05 for all parameters). Increased nNOS expression in frontal cortex and cerebellum produces a significant decrease in the heart rate and systemic arterial blood pressure suggesting a key role of nNOS in the regulation of cardiovascular function in the SHR.

Human carotid bodies as a therapeutic target: new insights from a clinician's perspective.

From the physiological point of view, carotid bodies are mainly responsible for the ventilatory response to hypoxia; however, they also take part in the regulation of sympathetic tone. According to preclinical data, these structures likely contribute to the development and progression of sympathetically mediated diseases. Moreover, carotid body deactivation in animal models improved blood pressure control in hypertension and reduced mortality in heart failure, along with reducing sympathetic activity. On this basis, two first-in-man studies have been recently performed to investigate the safety and feasibility of such an approach in humans. In this review we summarise the current knowledge regarding the function of carotid bodies, the prevalence of their abnormalities, and the consequences of their excision in human hypertension and heart failure.

Relationship between microRNA-146a expression and plasma renalase levels in hemodialyzed patients.

BackgroundmicroRNA (miRNA) belongs to the non-coding RNAs family responsible for the regulation of gene expression. Renalase is a protein composed of 342 amino acids, secreted by the kidneys and possibly plays an important role in the regulation of sympathetic tone and blood pressure. The aim of the present study was to investigate plasma renalase concentration, and explore the relationship between miRNA-146a-5p expression and plasma renalase levels in hemodialyzed patients.MethodsThe study population comprised 55 subjects who succumbed to various cardiac events, 27 women and 28 men, aged 65–70 years. The total RNA including miRNA fraction was isolated using QiagenmiRNEasy Serum/Plasma kit according to the manufacturer’s protocol. The isolated miRNAs were analyzed using a quantitative polymerase chain reaction (qRT-PCR) technique. The plasma renalase levels were measured using a commercial ELISA kit.ResultsIn the group of patients with high levels of renalase, higher miRNA-146a expression was found, compared with those with low concentration of renalase. Patients with simultaneous low miRNA-146a expression and high level of renalase were confirmed to deliver a significantly longer survival time compared with other patients.ConclusionsmiRNA-146a and plasma renalase levels were estimated as independent prognostic factors of hemodialyzed patients’ survival time. Patients with low miRNA-146a expression demonstrated a significantly longer survival time in contrast to the patients with a high expression level of miRNA-146a. Moreover, a significantly longer survival time was found in patients with high renalase activity compared with patients with low activity of the enzyme.

Levels of renalase and advanced oxidation protein products with regard to catecholamines in haemodialysed patients.

The main mediators of the sympathetic nervous system in the effectors part are catecholamines (CA). An increased sympathetic nerve activity observed in chronic kidney disease (CKD), is due to a raised level of CA in plasma. Renalase is a protein secreted by the kidneys, composed of 342 amino acids, which is able to metabolize the circulating CA and possibly play an important role in the regulation of sympathetic tone and blood pressure. Also, oxidative stress, defined as a disruption of the equilibrium between the generation of oxidants, is a crucial factor in the development of the inflammatory syndrome associated with CKD. The advanced oxidation protein products (AOPP) represent exquisite markers of phagocyte-derived oxidative stress. The aim of the study was to investigate the concentration of renalase and explore the associations between AOPP with regards to CA in haemodialysis (HD) patients. The study was conducted among 50 residents of the municipality and neighbouring villages in the province of Lublin, central-eastern Poland. In the studied patients, it was found that an average concentration of renalase was 44.8 ± 6.5 μg/mL, whereas of AOPP plasma levels - 57.5 ± 21.5 μmol/L. The results demonstrated the correlation between levels of renalase and AOPP in the HD patients. Indeed, elevated levels of renalase and AOPP in HD may be due to the presence of uremic toxins in blood. The concentration of urea affects the plasma concentrations of AOPP and renalase causing a direct relationship between renalase and AOPP. However, there is no clear relationship between renalase and circulating catecholamines in HD patients.

Lack of type VI adenylyl cyclase (AC6) leads to abnormal sympathetic tone in neonatal mice

Visceral functions are regulated by a basal sympathetic nerve discharge (SND), also known as ‘sympathetic tone’. We demonstrate herein that AC6 existed in tyrosine hydroxylase-positive rostral ventrolateral medulla neurons in the brainstem. Adenylyl cyclase (AC) assays showed lower basal and pituitary adenylate cyclase-activating peptide-evoked AC activities in the brainstem of AC6-null mice, indicating that AC6 is a prominent AC isozyme in the brainstem. Furthermore, two independent lines of AC6-null mice exhibited a much higher SND, recorded from splanchnic sympathetic nerves of neonatal brainstem–spinal cord preparations, than wildtype mice. An assay of urine noradrenaline confirmed this observation. Collectively, AC6 plays a critical role in the regulation of sympathetic tone.

Hypertension and kidney disease

Most patients on dialysis are hypertensive and their blood pressure (BP) control is often poor. Renalase is preferentially expressed in proximal tubules, but it is also present in glomeruli and distant tubules, as well as in cardiomyocytes, liver, and skeletal muscle. It had been proposed that renalase had a flavin adenine dinucleotide (FAD)-binding domain and that FAD was an essential cofactor for its stability and monoamine oxidase activity. It was reported that renalase, secreted by the kidney and circulating in the blood, degraded catecholamines and might play a role in the regulation of sympathetic tone and BP. It has been also proposed that renalase-coding gene is a novel susceptibility gene for essential hypertension and its variations may influence BP. In addition, polymorphisms of the renalase gene in hemodialysed patients were associated with hypertension. However, several unresolved and controversial issues still remain such as how to measure renalase and its physiological activity. Furthermore, there are few data on possible activators and/or inhibitors of renalase. We are at the very beginning of solving the problem of whether renalase is a causative factor of hypertension in kidney disease or just an innocent bystander. Therefore, more research is needed to establish whether renalase can become a useful therapeutic target.

Renalase, a Novel Enzyme Involved in Blood Pressure Regulation, Is Related to Kidney Function but Not to Blood Pressure in Hemodialysis Patients

Renalase, secreted by the kidney, degrades catecholamines and may play a role in the regulation of sympathetic tone and blood pressure. The aim of this study was to assess serum renalase levels in hemodialysis patients and their relationship to blood pressure control, type of antihypertensive therapy and the presence of residual renal function. Results: The mean serum renalase in the study cohort was significantly higher than in the control group (27.53 ± 7.18 vs. 3.86 ± 0.73 µg/ml, p < 0.001). The serum renalase concentration was significantly lower in patients with residual renal function when compared to the anuric patients. The type of hypotensive treatment (β-blockers, ACE inhibitors or AT1 receptor blockers) did not affect renalase levels. There was a significant inverse correlation between the serum renalase and age (r = –0.28, p = 0.023) and residual renal function (r = –0.327, p = 0.001). Renalase was not related to blood pressure, heart rate or hemodialysis vintage. Conclusion: Elevated renalase levels in HD patients may be due to impaired kidney function. Further studies are needed to prove or disprove the possible role of renalase in the pathogenesis of hypertension in patients with kidney diseases.

Chronic infusion of angiotensin receptor antagonists in the hypothalamic paraventricular nucleus prevents hypertension in a rat model of sleep apnea

Sleep apnea is characterized by increased sympathetic activity and is associated with systemic hypertension. Angiotensin (Ang) peptides have previously been shown to participate in the regulation of sympathetic tone and arterial pressure in the hypothalamic paraventricular nucleus (PVN) neurons. We investigated the role of endogenous Ang peptides within the PVN to control blood pressure in a rat model of sleep apnea-induced hypertension. Male Sprague–Dawley rats (250 g), instrumented with bilateral guide cannulae targeting the PVN, received chronic infusion of Ang antagonists (A-779, Ang-(1–7) antagonist; losartan and ZD7155, AT 1 antagonists; PD123319, AT 2 receptor antagonist, or saline vehicle). A separate group received an infusion of the GABA A receptor agonist (muscimol) to inhibit PVN neuronal activity independent of angiotensin receptors. After cannula placement, rats were exposed during their sleep period to eucapnic intermittent hypoxia (IH; nadir 5% O 2; 5% CO 2 to peak 21% O 2; 0% CO 2) 20 cycles/h, 7 h/day, for 14 days while mean arterial pressure (MAP) was measured by telemetry. In rats receiving saline, IH exposure significantly increased MAP (+ 12 ± 2 mm Hg vs. Sham −2 ± 1 mm Hg P < 0.01). Inhibition of PVN neurons with muscimol reversed the increase in MAP in IH rats (MUS: −9 ± 4 mm Hg vs. vehicle + 12 ± 2 mm Hg; P < 0.01). Infusion of any of the Ang antagonists also prevented the rise in MAP induced by IH (A-779: −5 ± 1 mm Hg, losartan: -9 ± 4 mm Hg, ZD7155: -11 ± 4 mm Hg and PD123319: -4 ± 3 mm Hg; P < 0.01). Our results suggest that endogenous Ang peptides acting in the PVN contribute to IH-induced increases in MAP observed in this rat model of sleep apnea-induced hypertension.

Cardiovascular effects of leptin

A wealth of investigations, ranging from clinical and animal model studies to in vitro analyses, have generated great interest in the cardiovascular effects of leptin. Accordingly, many studies have examined the contribution of leptin to cardiac remodeling in heart failure and whether the effects of leptin on metabolism, apoptosis, extracellular matrix remodeling, and hypertrophy could explain the so-called obesity paradox. Furthermore, obesity and hyperleptinemia have often been associated with hypertension, and regulation of sympathetic tone or direct effects of leptin on contributors such as atherosclerosis, endothelial dysfunction, and thrombosis have been documented. Unfortunately, translating basic research studies in vitro, or in animal models, to human physiology has proven difficult. The degree of leptin resistance in obesity is one intriguing issue that must be resolved. Furthermore, the importance of autocrine and paracrine effects of leptin derived from the heart and perivascular adipose tissue must be further studied. Carefully planned and executed research to conclusively establish distinct effects of leptin on the cardiovascular system in normal and diseased states will be essential to harness any therapeutic potential associated with leptin's effects.

Renalase deficiency in chronic kidney disease, and its contribution to hypertension and cardiovascular disease

Recent experimental data shed light on the regulation of renalase, a secreted amine oxidase, which circulates in an inactive form (prorenalase). Abnormalities in the renalase pathway are evident not only in animal models of chronic kidney disease, but also during the development of hypertension, at a time when kidney function appears normal. Prorenalase is rapidly (30-60 s) activated by increased plasma catecholamines and systolic blood pressure. Catecholamine administration promotes the secretion of preformed renalase within 5 min. Plasma renalase is markedly reduced in patients with chronic kidney disease and end-stage renal disease, and in animal models of chronic kidney disease and salt-dependent hypertension. Rats subjected to subtotal nephrectomy develop hypertension and chronic kidney disease, and exhibit low plasma and cardiac renalase, and abnormal renalase activation. The renalase pathway is a previously unrecognized mechanism for regulating circulating catecholamines, cardiac function and blood pressure. In this pathway, prorenalase is rapidly activated by increased catecholamines and converted to renalase, which in turn degrades catecholamines. Abnormalities in the renalase pathway are evident in animal models of chronic kidney disease and hypertension. Collectively, these data suggest that renalase plays a key role in the regulation of sympathetic tone, blood pressure and cardiac function.

Total sleep deprivation inhibits the neuronal nitric oxide synthase and cytochrome oxidase reactivities in the nodose ganglion of adult rats

Sleep disorders are a form of stress associated with increased sympathetic activity, and they are a risk factor for the occurrence of cardiovascular disease. Given that nitric oxide (NO) may play an inhibitory role in the regulation of sympathetic tone, this study set out to determine the NO synthase (NOS) reactivity in the primary cardiovascular afferent neurons (i.e. nodose neurons) following total sleep deprivation (TSD). TSD was performed by the disc-on-water method. Following 5 days of TSD, all experimental animals were investigated for quantitative nicotinamine adenine dinucleotide phosphate-diaphorase (NADPH-d, a co-factor of NOS) histochemistry, neuronal NOS immunohistochemistry and neuronal NOS activity assay. In order to evaluate the endogenous metabolic activity of nodose neurons, cytochrome oxidase (COX) reactivity was further tested. All the above-mentioned reactivities were objectively assessed by computerized image analysis. The clinical significance of the reported changes was demonstrated by alterations of mean arterial blood pressure (MAP). The results indicated that in normal untreated rats, numerous NADPH-d/NOS- and COX-reactive neurons were found in the nodose ganglion (NG). Following TSD, however, both the labelling and staining intensity of NADPH-d/NOS as well as COX reactivity were drastically reduced in the NG compared with normal untreated ganglions. MAP was significantly higher in TSD rats (136+/-4 mmHg) than in normal untreated rats (123+/-2 mmHg). NO may serve as an important sympathoinhibition messenger released by the NG neurons, and decrease of NOS immunoexpression following TSD may account for the decrease in NOS content. In association with the reduction of NOS activity, a defect in NOS expression in the primary cardiovascular afferent neurons would enhance clinical hypertension, which might serve as a potential risk factor in the development of TSD-relevant cardiovascular disturbances.

Regulation of sympathetic tone and arterial pressure by the rostral ventrolateral medulla after depletion of C1 cells in rats.

This review describes experiments designed to determine the role of bulbospinal (BS) C1 cells in regulating the sympathetic outflow and blood pressure. This goal was achieved by analyzing the physiological consequences of destroying BS C1 cells. These cells were destroyed by suicide transport of an anti-dopamine-beta-hydroxylase antibody conjugated to saporin (anti-D beta H-SAP). Two to 3 weeks after spinal cord injection (T2-T6), the toxin destroyed 75-85% of BS C1 and C3 cells along with > 95% of BS noradrenergic neurons (A5, A6, A7). The toxin spared BS noncatecholaminergic cells. Under anesthesia, toxin-treated rats had a normal blood pressure and an apparently normal sympathetic nerve discharge (SNA, splanchnic), and intravenous clonidine caused a normal degree of sympathoinhibition. Inhibition of rostral ventrolateral medulla (RVLM) neurons by bilateral injection of muscimol caused the same hypotension and sympathoinhibition as in control rats. The baroreflex range was 41% attenuated by the toxin, but the MAP50 was unchanged. Sympathoexcitatory responses to stimulation of peripheral chemoreceptors with cyanide or to electrical stimulation of RVLM were severely depressed (60% to 80%) in toxin-treated rats. Rats in which A5 neurons were selectively destroyed had no deficit in the parameters tested. Unit recordings of BS RVLM neurons indicated that the toxin destroyed most barosensitive C1 neurons, but spared noncatecholaminergic lightly myelinated BS cells. In summary, the integrity of C1 neurons is not essential for the generation of SNA and the maintenance of BP under resting conditions, perhaps because these functions are performed primarily by noncatecholaminergic BS neurons. However, the deficits caused by treatment with anti-D beta H-SAP indicate that BS C1 neurons play a crucial role in several sympathoexcitatory responses mediated by the RVLM.

Catecholamine levels in practitioners of the transcendental meditation technique

With the aim of evaluating the sympathetic–adrenal medulla system in subjects practicing transcendental meditation (TM), their plasma catecholamine levels were determined at two different times of day. The study group consisted of 19 subjects who regularly practice either TM or Sidhi-TM technique, with a control group made up of 16 healthy subjects who had not previously used any relaxation technique. Catecholamine plasma levels were determined by high performance liquid chromatography, at 0900 and 2000 h. Morning and evening norepinephrine (NE) levels and morning epinephrine (E) levels were significantly lower in the TM group than in the control subjects (morning NE levels, pg/ml, mean±S.E.: TM group 136.6±13.0, control 236.8±21.0, P=.0001; evening NE levels: TM group 119.7±10.8, control 175.6±17.4, P=.009; morning E levels, pg/ml: TM group 140.2±10.6, control 196.7±23.8, P=.019). No differences were recorded for evening E levels and dopamine (DA) levels. No significant differences were found for catecholamine levels measured at different times of day in the TM group, demonstrating a lack of daily hormonal rhythm. Anxiety levels were similar in both groups. Based on the results obtained, it can be considered that the regular practice of TM has a significant effect on the sympathetic–adrenal medulla system. A low hormonal response to daily stress caused by sympathetic tone regulation through regular TM could explain our results, as well as the physiological and other effects related to the field of health described in those who practice meditation.

Regulation of sympathetic tone and arterial pressure by rostral ventrolateral medulla after depletion of C1 cells in rat.

1. In this study we examined whether the rostral ventrolateral medulla (RVLM) maintains resting sympathetic vasomotor tone and activates sympathetic nerve activity (SNA) after the depletion of bulbospinal C1 adrenergic neurones. 2. Bulbospinal C1 cells were destroyed ( approximately 84% loss) by bilateral microinjections (spinal segments T2-T3) of an anti-dopamine-beta-hydroxylase antibody conjugated to the ribosomal toxin saporin (anti-DH-SAP). 3. Extracellular recording and juxtacellular labelling of bulbospinal barosensitive neurones in the RVLM revealed that treatment with anti-DH-SAP spared the lightly myelinated neurones with no tyrosine hydroxylase immunoreactivity. 4. In rats treated with anti-DH-SAP, inhibition of RVLM neurones by bilateral microinjection of muscimol eliminated splanchnic SNA and produced the same degree of hypotension as in control rats. 5. Following treatment with anti-DH-SAP the sympathoexcitatory (splanchnic nerve) and pressor responses to electrical stimulation of the RVLM were reduced. 6. Treatment with anti-DH-SAP also eliminated the majority of A5 noradrenergic neurones. However, rats with selective lesion of A5 cells by microinjection of 6-hydroxydopamine into the pons showed no deficits to stimulation of the RVLM. 7. In summary, the loss of 84% of bulbospinal adrenergic neurones does not alter the ability of RVLM to maintain SNA and arterial pressure at rest in anaesthetized rats, but this loss reduces the sympathoexcitatory and pressor responses evoked by RVLM stimulation. The data suggest sympathoexcitatory roles for both the C1 cells and non-C1 cells of the RVLM and further suggest the C1 cells are critical for the full expression of sympathoexcitatory responses generated by the RVLM.

Genetic alteration of the alpha2-adrenoceptor subtype c in mice affects the development of behavioral despair and stress-induced increases in plasma corticosterone levels.

alpha2-Adrenoceptors (alpha2-AR) modulate many central nervous system functions, such as regulation of sympathetic tone, vigilance, attention, and reactivity to environmental stressors. Three alpha2-AR subtypes (alpha2A, alpha2B, and alpha2C) with distinct tissue-distribution patterns are known to exist, but the functional significance of each subtype is not clear. Since specific, alpha2-AR subtype-selective pharmacological probes are not available, mice with genetically altered alpha2C-AR expression were studied in order to investigate the possible involvement of the alpha2C-AR in physiological and behavioral responses to acute and repeated stress. A modified version of Porsolt's forced swimming test was used to assess the possible effects of altered alpha2C-AR expression on the development of behavioral despair. alpha2C-Overexpression increased and the lack of alpha2C-AR (alpha2C-KO) decreased the immobility of mice in the forced swimming test, ie alpha2C-AR expression appeared to promote the development of behavioral despair. In addition, alpha2C-KO was associated with attenuated elevation of plasma corticosterone after different stressors, and overexpression of alpha2C-ARs was linked with increased corticosterone levels after repeated stress. Moreover, the brain dopamine and serotonin balance, but not norepinephrine turnover, was dependent on alpha2C-AR expression, and the expression of c-fos and junB mRNA was increased in alpha2C-KO mice. Since alpha2C-KO produced stress-protective effects, and alpha2C-AR overexpression seemed to promote the development of changes related to depression, it is suggested that a yet-to-be developed subtype-selective alpha2C-AR antagonist might have therapeutic value in the treatment of stress-related neuropsychiatric disorders.

Involvement of imidazoline-preferring receptors in regulation of sympathetic tone

We examined the contribution of imidazoline-preferring receptors (IPR) and α 2-adrenoceptors at different levels of the central nervous system in the antihypertensive and sympathoinhibitory actions of rilmenidine in 2 conscious animal models, the spontaneously hypertensive rat (SHR) and the normotensive rabbit. In conscious SHRs, we compared the potency of rilmenidine and clonidine administered intravenously into the lateral cerebral ventricle, the cisterna magna, and into the subarachnoidal space of the thoracolumbar spinal cord. In SHRs, we found that rilmenidine was more potent and more effective by the intrathecal than the intracisternal route. By contrast, clonidine was most effective after administration into the cisterna magna. Intravenous administration of rilmenidine or clonidine induced dose-dependent and prolonged decreases in blood pressure and heart rate. Neither rilmenidine nor clonidine altered mean arterial pressure or heart rate when given into the lateral cerebral ventricle. These data suggest that in SHRs the spinal cord may be an important site for the antihypertensive action of rilmenidine. We therefore characterized the receptor type involved. We observed in conscious SHRs that intrathecal post-treatment with idazoxan, a mixed α 2-adrenoceptor and IPR antagonist, abolished the antihypertensive effect of rilmenidine, whereas 2-methoxyidazoxan, a selective α 2-adrenoceptor antagonist, caused only a partial reversal of the blood pressure effects of rilmenidine. These results suggest that rilmenidine acts mainly through IPR rather than α 2-adrenoceptors in the spinal cord. In view of these findings, we compared the hypotensive actions of rilmenidine and clonidine, administered into the lateral cerebral ventricle, the cisterna magna, and the subarachnoid space of the thoracolumbar spinal cord in conscious normotensive rabbits. Both drugs were less potent and effective when administered intrathecally than intracisternally. These experiments suggest that the hypotensive action of rilmenidine and clonidine in the rabbit is mediated through receptors mainly located in the brainstem. Further, we found that idazoxan reversed the hypotensive action of rilmenidine more readily than 2-methoxyidazoxan. Surprisingly, both idazoxan and 2-methoxyidazoxan completely reversed the depressor effects of clonidine. Therefore, in the rabbit, rilmenidine acts through IPR located in the brainstem and clonidine acts predominantly through α 2-adrenoceptors. In conclusion, our studies demonstrate that IPR are involved in the vasodepressor action of rilmenidine in both conscious SHRs and rabbits. However, although the main site of action of rilmenidine in SHRs may be located in the thoracolumbar spinal cord, in the rabbit it appears to be in the brainstem. The IPR selectivity for rilmenidine and the limited locations of this novel receptor may account for its good acceptability as a second-generation centrally acting antihypertensive agent.

Inhibition of Norepinephrine Release From Vascular Adrenergic Neurons by Oral Administration of β-Blocker in DOCA-Salt Hypertension

The ability of a beta-blocker to inhibit vascular sympathetic nerve activity associated with hypertension was studied in DOCA-salt hypertension in rats. A seven week treatment of DOCA and salt resulted in a significant increase in the systolic blood pressure of the uninephrectomized rats. The administration of propranolol (40 mg/L and 80 mg/L in drinking water) had little effect on the development of hypertension. After a three week administration of propranolol, perfused mesenteric vasculatures were prepared in vitro, and endogenous norepinephrine release as well as vascular responsiveness were examined. Endogenous norepinephrine and pressor responses during periarterial nerve stimulation were greater in the untreated DOCA-salt hypertensive rats than in the normotensive rats. In the DOCA-salt hypertensive rats treated with propranolol, the stimulation-evoked norepinephrine release and pressor responses were significantly attenuated, at both doses, compared with the untreated DOCA-salt hypertensive rats. These results demonstrate that propranolol inhibited the vascular sympathetic nerve activity in DOCA-salt hypertensive rats. This occurrence suggests a possible role of presynaptic beta-adrenoceptors in the regulation of sympathetic tone in DOCA-salt hypertension.