MELANOMA AND DYSPLASTIC NEVI DEVELOPMENT AFTER RANITIDINE/RILMENIDINE/МOXONIDINE, LERCANIDIPINE, ROSUVASTATIN AND VERAPAMIL/TRANDOLAPRIL - NEW DATA/CASE SERIES. THE POTENTIAL ROLE OF NITROSAMINE/NDSRIS CONTAMINATION IN POLYMEDICATION AS SUBSTANTIAL SKIN CANCER TRIGGERING FACTOR.

The idea of drug-induced/exogenic Nitrosogenesis is driven by the possibility of prolonged exposure of the human body to the influence of nitrosamines within the drug intake - substances or contaminants that have been proven to be carcinogenic or mutagenic one.Until recently, there was a complete lack of data in the scientific literature on the relationship between cancer, polymedication and polycontamination with nitrosamines. In the last decade, melanoma has been described repeatedly in the medical literature as a possible side-effect within the intake of possibly with nitrosamines contaminated medications such as: Valsartan, Hydrochlorothiazide, Amlodipine, Nebivolol, Bisoprolol and Perindopril. However, the contribution of the currently presented new data (5 new patients) is also due to the establishment of the possible pathogenetic role (with respect to melanoma) of several completely new drugs, previously unknown to the scientific community (potentially/actually contaminated with carcinogens/nitrosamines), such as: Ranitidine, Rosuvastatin, Lercanidipine, Rilmenidine, Trandolapril, Moxonidine and Verapamil.The leading and connecting link in shared new and old drug combinations of heterogeneous drug classes (polymedication) and melanoma development and progression remains again one and the same: the possible availability of nitroso component in the frame of exogenous nitrosogenesis according to the official FDA lists of 2023.The number of drugs shared as contaminated with nitrosamines after whose intake melanomas occur is increasing. Nitrosogenesis remains a new beginning, a new understanding and new interpretation of the carcinogenesis concerning melanoma, but probably also of cancer in general. Its further elucidation looks more than promising and is yet to come. More than worrying at the moment remains the fact that the scientific community has to clarify if: 1) peak concentrations of nitrosamines or NDSRIs within the framework of monomedication or 2) normal concentrations within the polymedication (catalogued in the list of FDA/ 2023 as potentially contaminated with hypothetical carcinogens), could hide relatively short-term risk of the development of real tumors: cutaneous melanomas and/or their precursor lesions. The validation of the concept of Nitrosogenesis and its relationship to Сarcinogenesis, is achieved in practice on the basis of the following facts: that it is the occurrence of the same monomorphic clinical pattern (melanoma/dysplastic nevi), developing after the intake of drugs with different mechanism of action, contaminated with nitrosamines/NDSRIs. The unifying link between the intake of certain drugs and the development of certain tumours remains the presence of nitrosamines. Ingredients that are present in drug preparations, identified as availability and as carcinogenic potency, but not yet reflected in packaging or prescriptions. The question remains: why?

Stimulation of mTOR-independent autophagy and mitophagy by rilmenidine exacerbates the phenotype of transgenic TDP-43 mice.

Autophagy, which mediates the delivery of cytoplasmic substrates to the lysosome for degradation, is essential for maintaining proper cell homeostasis in physiology, ageing, and disease. There is increasing evidence that autophagy is defective in neurodegenerative disorders, including motor neurons affected in amyotrophic lateral sclerosis (ALS). Restoring impaired autophagy in motor neurons may therefore represent a rational approach for ALS. Here, we demonstrate autophagy impairment in spinal cords of mice expressing mutant TDP-43Q331K or co-expressing TDP-43WTxQ331K transgenes. The clinically approved anti-hypertensive drug rilmenidine was used to stimulate mTOR-independent autophagy in double transgenic TDP-43WTxQ331K mice to alleviate impaired autophagy. Although rilmenidine treatment induced robust autophagy in spinal cords, this exacerbated the phenotype of TDP-43WTxQ331K mice, shown by truncated lifespan, accelerated motor neuron loss, and pronounced nuclear TDP-43 clearance. Importantly, rilmenidine significantly promoted mitophagy in spinal cords TDP-43WTxQ331K mice, evidenced by reduced mitochondrial markers and load in spinal motor neurons. These results suggest that autophagy induction accelerates the phenotype of this TDP-43 mouse model of ALS, most likely through excessive mitochondrial clearance in motor neurons. These findings also emphasise the importance of balancing autophagy stimulation with the potential negative consequences of hyperactive mitophagy in ALS and other neurodegenerative diseases.

Synergism of myocardial ß-adrenoceptor blockade and I1-imidazoline receptor-driven signaling: Kinase-phosphatase switching.

Recently identified imidazoline receptors of the first type (I1Rs) on the cardiomyocyte's sarcolemma open a new field in calcium signaling research. In particular, it is interesting to investigate their functional interaction with other well-known systems, such as ß-adrenergic receptors. Here we investigated the effects of I1Rs activation on L-type voltage-gated Ca2+-currents under catecholaminergic stress induced by the application of ß-agonist, isoproterenol. Pharmacological agonist of I1Rs (I1-agonist), rilmenidine, and the putative endogenous I1-ligand, agmatine, have been shown to effectively reduce Ca2+-currents potentiated by isoproterenol. Inhibitory analysis shows that the ability to suppress voltage-gated Ca2+-currents by rilmenidine and agmatine is fully preserved in the presence of the protein kinase A blocker (PKA), which indicates a PKA-independent mechanism of their action. The blockade of NO synthase isoforms with 7NI does not affect the intrinsic effects of agmatine and rilmenidine, which suggests NO-independent signaling pathways triggered by I1Rs. A nonspecific serine/threonine protein phosphatase (STPP) inhibitor, calyculin A, abrogates effects of rilmenidine or agmatine on the isoproterenol-induced Ca2+-currents. Direct measurements of phosphatase activity in the myocardial tissues showed that activation of the I1Rs leads to stimulation of STPP, which could be responsible for the I1-agonist influences. Obtained data clarify peripheral effects that occur during activation of the I1Rs under endogenous catecholaminergic stress, and can be used in clinical practice for more precise control of heart contractility in some cardiovascular pathologies.

Disturbance of I1-imidazoline receptor signal transduction in cardiomyocytes of Spontaneously Hypertensive Rats.

Imidazoline receptor of the first type (I1R) in addition to the established inhibition of sympathetic neurons may mediate the direct control of myocellular functions. Earlier, we revealed that I1-mediated signaling in the normotensive rat cardiomyocytes suppresses the nitric oxide production by endothelial NO synthase, impairs sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity, and elevates intracellular calcium in the cytosol. Also, I1-agonists counteract ß-adrenoceptor stimulation effects in respect to voltage-gated calcium currents. This study ascertains the I1R signal transduction in the normotensive Wistar and SHR cardiomyocytes. Reduction of Ca2+-currents by rilmenidine, a specific agonist of I1R, ensued from the phosphatidylcholine-specific phospholipase C-mediated activation of protein kinase C. There is a stimulation of serine/threonine phosphatase activity. In SHR cardiomyocytes, both the rilmenidine, and putative endogenous ligand, agmatine, almost twofold less effectively reduced L-type of Ca2+-currents. Average mRNA level of Nischarin, established functional component of I1R, is slightly decreased in SHR, as well as the intracellular Nischarin pool immunolabeled in the cytosol of SHR cardiomyocytes. Disturbance of I1R signal transduction in SHR may aggravate the development of this cardiovascular pathology.

Mitochondrial dysfunction is associated with long-term cognitive impairment in an animal sepsis model.

Background: Several different mechanisms have been proposed to explain long-term cognitive impairment in sepsis survivors. The role of persisting mitochondrial dysfunction is not known. We thus sought to determine whether stimulation of mitochondrial dynamics improves mitochondrial function and long-term cognitive impairment in an experimental model of sepsis.Methods: Sepsis was induced in adult Wistar rats by cecal ligation and perforation (CLP). Animals received intracerebroventricular injections of either rosiglitazone (biogenesis activator), rilmenidine, rapamycin (autophagy activators), or n-saline (sham control) once a day on days 7-9 after the septic insult. Cognitive impairment was assessed by inhibitory avoidance and object recognition tests. Animals were killed 24 h, 3 and 10 days after sepsis with the hippocampus and prefrontal cortex removed to determine mitochondrial function.Results: Sepsis was associated with both acute (24 h) and late (10 days) brain mitochondrial dysfunction. Markers of mitochondrial biogenesis, autophagy and mitophagy were not up-regulated during these time points. Activation of biogenesis (rosiglitazone) or autophagy (rapamycin and rilmenidine) improved brain ATP levels and ex vivo oxygen consumption and the long-term cognitive impairment observed in sepsis survivors.Conclusion: Long-term impairment of brain function is temporally related to mitochondrial dysfunction. Activators of autophagy and mitochondrial biogenesis could rescue animals from cognitive impairment.

Central Sympathetic Modulation Reverses Microvascular Alterations in a Rat Model of High-Fat Diet-Induced Metabolic Syndrome.

OBJECTIVES: The objective of this study was to investigate the role of the SNS on hemodynamic, metabolic, and microvascular alterations in a rat model of HFD-induced MS with salt supplementation. METHODS: In total, 40 adult male Wistar rats were fed normal chow (n = 10) or a HFD (n = 30) for 20 weeks. Thereafter, the HFD group received the centrally acting sympatho-modulatory drugs clonidine (0.1 mg/kg) or rilmenidine (1 mg/kg) or vehicle (n = 10/group) orally by gavage. FCD was evaluated using intravital video microscopy, and the SCD was evaluated using histochemical analysis. RESULTS: The pharmacological modulation of the SNS induced concomitant reductions in SBP, HR and plasma catecholamine levels. These effects were accompanied by a reversal of functional and structural capillary rarefaction in the skeletal muscle in both treated groups and an increase in SCD in the left ventricle only in the rilmenidine group. Improvement of the lipid profile and of glucose intolerance was also obtained only with rilmenidine treatment. CONCLUSIONS: Modulation of sympathetic overactivity results in the reversal of microvascular rarefaction in the skeletal muscle and left ventricle and improves metabolic parameters in an experimental model of MS in rats.

A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin.

The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I1-type imidazoline receptors (I1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from α2-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine-derived compounds with anticancer potential and devoid of α2-adrenoceptor effects by means of ligand- and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to α2-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers.

Improvement of obesity by activation of I1-imidazoline receptors in high fat diet-fed mice.

Imidazoline I1-receptor (I1R) is known to regulate the blood pressure, and rilmenidine, as the agonist, is used to treat hypertension in clinics. However, the role of I1R in obesity is still unclear. In the present study, we investigated the changes of obesity by activation of I1R in high fat diet (HFD)-fed mice. Chronic administration of rilmenidine into HFD-fed mice for 8 weeks significantly reduced body weight, which was reversed by efaroxan at the dose sufficient to block I1R. Also, rilmenidine significantly decreased the energy intake of HFD-fed mice. This reduction of energy intake was abolished by efaroxan at the same dosing for blockade of I1R. However, hypothalamic I1R protein expression in HFD-fed mice was markedly lower than that in normal chow-fed mice. In addition, epididymal white adipose tissue (eWAT) cell size in HFD-fed mice was decreased by rilmenidine via the activation of I1R. Moreover, effect of rilmenidine on appetite disappeared in db/db mice. Taken together, we suggest that rilmenidine can improve obesity in HFD-fed mice through an activation of I1R to ameliorate energy intake and eWAT accumulation.

Rilmenidine extends lifespan and healthspan in Caenorhabditis elegans via a nischarin I1-imidazoline receptor.

Repurposing drugs capable of extending lifespan and health span has a huge untapped potential in translational geroscience. Here, we searched for known compounds that elicit a similar gene expression signature to caloric restriction and identified rilmenidine, an I1-imidazoline receptor agonist and prescription medication for the treatment of hypertension. We then show that treating Caenorhabditis elegans with rilmenidine at young and older ages increases lifespan. We also demonstrate that the stress-resilience, health span, and lifespan benefits of rilmenidine treatment in C. elegans are mediated by the I1-imidazoline receptor nish-1, implicating this receptor as a potential longevity target. Consistent with the shared caloric-restriction-mimicking gene signature, supplementing rilmenidine to calorically restricted C. elegans, genetic reduction of TORC1 function, or rapamycin treatment did not further increase lifespan. The rilmenidine-induced longevity required the transcription factors FOXO/DAF-16 and NRF1,2,3/SKN-1. Furthermore, we find that autophagy, but not AMPK signaling, was needed for rilmenidine-induced longevity. Moreover, transcriptional changes similar to caloric restriction were observed in liver and kidney tissues in mice treated with rilmenidine. Together, these results reveal a geroprotective and potential caloric restriction mimetic effect by rilmenidine that warrant fresh lines of inquiry into this compound.

Autophagy and anti-inflammation ameliorate diabetic neuropathy with Rilmenidine.

PURPOSE: To evaluate the neuroprotective effects of Rilmenidine on diabetic peripheral neuropathy (DPN) in a rat model of diabetes induced by streptozotocin (STZ). METHODS: STZ (60 mg/kg) was administered to adult Sprague-Dawley rats to induce diabetes. On the 30th day after STZ administration, electromyography (EMG) and motor function tests confirmed the presence of DPN. Group 1: Control (n = 10), Group 2: DM + 0.1 mg/kg Rilmenidine (n = 10), and Group 3: DM + 0.2 mg/kg Rilmenidine (n = 10) were administered via oral lavage for four weeks. EMG, motor function test, biochemical analysis, and histological and immunohistochemical analysis of sciatic nerves were then performed. RESULTS: The administration of Rilmenidine to diabetic rats substantially reduced sciatic nerve inflammation and fibrosis and prevented electrophysiological alterations. Immunohistochemistry of sciatic nerves from saline-treated rats revealed increased perineural thickness, HMGB-1, tumor necrosis factor-α, and a decrease in nerve growth factor (NGF), LC-3. In contrast, Rilmendine significantly inhibited inflammation markers and prevented the reduction in NGF expression. In addition, Rilmenidine significantly decreased malondialdehyde and increased diabetic rats' total antioxidative capacity. CONCLUSIONS: The findings of this study suggest that Rilmenidine may have therapeutic effects on DNP by modulating antioxidant and autophagic pathways.

Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a polyglutamine expansion in huntingtin. There are no treatments that are known to slow the neurodegeneration caused by this mutation. Mutant huntingtin causes disease via a toxic gain-of-function mechanism and has the propensity to aggregate and form intraneuronal inclusions. One therapeutic approach for HD is to enhance the degradation of the mutant protein. We have shown that this can be achieved by upregulating autophagy, using the drug rapamycin. In order to find safer ways of inducing autophagy for clinical purposes, we previously screened United States Food and Drug Administration-approved drugs for their autophagy-stimulating potential. This screen suggested that rilmenidine, a well tolerated, safe, centrally acting anti-hypertensive drug, could induce autophagy in cell culture via a pathway that was independent of the mammalian target of rapamycin. Here we have shown that rilmenidine induces autophagy in mice and in primary neuronal culture. Rilmenidine administration attenuated the signs of disease in a HD mouse model and reduced levels of the mutant huntingtin fragment. As rilmenidine has a long safety record and is designed for chronic use, our data suggests that it should be considered for the treatment of HD and related conditions.

Improvement of hyperphagia by activation of cerebral I(1)-imidazoline receptors in streptozotocin-induced diabetic mice.

Imidazoline I1-receptors (I1R) are known to regulate blood pressure and rilmenidine, an agonist, is widely used as antihypertensive agent in clinic. However, the role of I1R in feeding behavior is still unclear. In the present study, we used the agonist of I1R to investigate the effect on hyperphagia in streptozotocin (STZ)-induced diabetic mice. Rilmenidine decreased the food intake of STZ-diabetic mice in a dose-dependent manner. The reduction of food intake was abolished by pretreatment with efaroxan at the dose sufficient to block I1R. Intracerebroventricular (icv) administration of rilmenidine into STZ-diabetic mice also significantly reduced hyperphagia, which was reversed by icv administration of efaroxan. In addition, similar results were observed in STZ-diabetic mice, which received chronic treatment with rilmenidine 3 times daily (t.i.d.) for 7 days. Moreover, the hypothalamic neuropeptide Y (NPY) level was reduced by rilmenidine that was also reversed by pretreatment with efaroxan. In conclusion, the obtained results suggest that rilmenidine can decrease food intake in STZ-diabetic mice through an activation of I1R to lower hypothalamic NPY level.

Development and Validation of Two New Methods for the Determination of Rilmenidine in Bulk and Pharmaceutical Preparation.

In the present study, two new methods were developed and validated for the determination of rilmenidine in bulk and pharmaceutical preparation. Both methods are based on a derivatization reaction using 4-chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) as a fluorogenic substance. The drug reagent derivatives were formed by the reaction of rilmenidine with NBD-Cl at pH 9.0 at 70°C for 40 min. The reaction mixtures were analyzed by spectrofluorimetry in the first method and high performance liquid chromatography (HPLC) in the second method. Derivatives were determined at λex 493 nm and at λem 536 nm in the spectrofluorimetric method. The separation was performed place on a Phenomenex, C18 column (250 × 4.6 mm, 5 µm i.d) using a mobile phase comprising 0.2% formic acid and acetonitrile gradient elution mode in the HPLC method. Analytes were detected by a fluorescence detector at the same wavelength. The methods were validated for limit of quantitation, linearity, robustness, recovery, limit of detection, precision and accuracy. Calibration curves for the first and second methods were found to be linear in the range of 2.0-12.0 and 250-2000 ng/mL, respectively. Detection limits for the spectrofluorimetric and HPLC methods were calculated as 0.16 and 18.28 ng/mL, respectively. The validated methods were applied successfully to the determination of rilmenidine in bulk and pharmaceutical preparation.

A novel mechanism for decreasing plasma lipid level from imidazoline I-1 receptor activation in high fat diet-fed mice.

The imidazoline I-1 receptor (I-1 R) agonists are widely used to lower blood pressure, but their effects on hyperlipidemia are still obscure. The present study is aimed to evaluate the possible mechanism(s) of I-1 R in the regulation of lipid homeostasis. Farnesoid X receptor (FXR) plays an important role in blood lipid homeostasis; however, the role of FXR in rilmenidine-induced blood lipid lowering action is still unknown. Thus, we administered rilmenidine, a selective agonist of I-1 R, into high fat diet-fed (HFD) mice showing hypertriglyceridemia and hypercholesterolemia. Rilmenidine significantly ameliorated hyperlipidemia in HFD mice after 7 days of administration. Pretreatment with efaroxan, at a dose sufficient to inhibit I-1 R activation, blocked the effects of rilmenidine. Also, in cultured HepG2 cells, rilmenidine dose-dependently induced the expression of farnesoid X receptor (FXR). The rilmenidine-induced FXR expression and FXR-related genes were blocked by efaroxan. However, rilmenidine treatment did not affect the expression of enzymes related to ß-oxidation. In conclusion, activation of I-1 R may activate FXR to lower plasma lipids, suggesting I-1 R as a new target for the treatment of hyperlipidemia.

Investigation of the effects of the chronic administration of some antihypertensive drugs on enzymatic and non-enzymatic oxidant/antioxidant parameters in rat ovarian tissue.

OBJECTIVE: In this study, effects of chronic antihypertensive drug (clonidine, methyldopa, amlodipine, ramipril, and rilmenidine) treatment on antioxidant-oxidant parameters were investigated in rat ovarian tissue. STUDY DESIGN: Chronic drug administration for 30 days and at the end, biochemical examinations (total glutathione (tGSH), glutathione peroxidase (GPO), glutathione reductase (GR), glutathione s-transferase (GST), superoxide dismutase (SOD), nitric oxide (NO), catalase (CAT), malondialdehyde (MDA), and myeloperoxidase (MPO) analyses) were performed. RESULTS: The levels of glutathione (GSH) and NO, and the activities of GPO, GR, GST, SOD, and CAT were measured the lowest in ramiprile group. Also in ramiprile group, the level of MDA and the activity of MPO was the highest. CONCLUSION: We divided the drugs into four groups according to their biochemical side effect potentials in ovarian tissue: (I) Drugs which have no clear negative effect on ovarian tissue: clonidine, rilmenidine; (II) Drugs which have mild negative effect on ovarian tissue: methyldopa; (III) Drugs which have moderate negative effect on ovarian tissue: amlodipine; (IV) Drugs which have severe negative effect on ovarian tissue: ramipril. These data might be useful in the selection of the least toxic antihypertensive drug in pregnant and/or normal females.

Centrally acting antihypertensives change the psychogenic cardiovascular reactivity.

Clonidine (CL) and Rilmenidine (RI) are among the most frequently prescribed centrally acting antihypertensives. Here, we compared CL and RI effects on psychogenic cardiovascular reactivity to sonant, luminous, motosensory, and vibrotactile stimuli during neurogenic hypertension. The femoral artery and vein of Wistar (WT - normotensive) and spontaneously hypertensive rats (SHR) were catheterized before (24 h interval) i.p. injection of vehicle (NaCl 0.9%, control - CT group), CL (10 µg/kg), or RI (10 µg/kg) and acute exposure to luminous (5000 lm), sonant (75 dB sudden tap), motor (180° cage twist), and air-jet (10 L/min - restraint and vibrotactile). Findings showed that: (i) CL or RI reduced the arterial pressure of SHR, without affecting basal heart rate in WT and SHR; (ii) different stimuli evoked pressor and tachycardic responses; (iii) CL and RI reduced pressor response to sound; (iv) CL or RI reduced pressor responses to luminous stimulus without a change in peak tachycardia in SHR; (v) cage twist increased blood pressure in SHR, which was attenuated by CL or RI; (vi) air-jet increased pressure and heart rate; (vii) CL or RI attenuated the pressor responses to air-jet in SHR while RI reduced the chronotropic reactivity in both strains. Altogether, both antihypertensives relieved the psychogenic cardiovascular responses to different stimuli. The RI elicited higher cardioprotective effects through a reduction in air-jet-induced tachycardia.

Microvascular effects of centrally acting antihypertensive drugs in spontaneously hypertensive rats.

We investigated the effects of oral long-term antihypertensive treatment using centrally acting sympathoinhibitory drugs on capillary density in the skin, skeletal muscle, and heart in the spontaneously hypertensive rat (SHR). Wistar Kyoto rats (WKY) were used as normotensive control groups. Functional capillary density was assessed using intravital fluorescence videomicroscopy and structural capillary density with histochemical analysis. Groups of 10 SHRs were orally treated over 28 days with clonidine (0.1 mg x kg x d), rilmenidine (1 mg x kg x d), or moxonidine (10 mg x kg x d). A group of WKY was also treated with clonidine (0.1 mg x kg x d). Treatment with all antihypertensive drugs induced a normalization of arterial pressure accompanied by a reversion of functional capillary rarefaction in the skeletal muscle and skin of SHR. Clonidine treatment also reduced arterial pressure and increased functional capillary density in the skin and skeletal muscle of WKY. Histochemical analysis showed that SHR had a lower capillary to fiber ratio in the skeletal muscle (P < 0.0001), which was normalized by all treatments. The capillary volume density to fiber volume density ratio in the left ventricle of SHR was also significantly reduced (P < 0.0001). However, myocardial capillary rarefaction was not altered by the different treatments. In conclusion, the results showed that long-term antihypertensive treatment with centrally acting drugs enhanced tissue perfusion and reversed capillary rarefaction in the skeletal muscle of SHRs.

Cardiac and renal baroreflex control during stress in conscious renovascular hypertensive rabbits: effect of rilmenidine.

OBJECTIVE: We examined whether renal sympathetic nerve activity (RSNA) and heart rate (HR) baroreflexes in conscious rabbits were altered by exposure to a combination of stress and hypertension and determined how this was modified by acute and chronic treatment with the sympathoinhibitory agent rilmenidine. METHODS: Rabbits were made hypertensive with a renal-artery clip and a renal nerve recording electrode was implanted 4-5 weeks later. After recovery, baroreflexes were measured before and during airjet stress and again after receiving rilmenidine (either acutely or by infusion for 3 weeks). RESULTS: Renal clipping increased mean arterial pressure (MAP) and shifted baroreflex RSNA and HR curves rightward. The HR and RSNA upper plateaus were similar to those of normotensive animals but HR baroreflex sensitivity was reduced in the hypertensive group. Airjet stress lowered HR baroreflex sensitivity in sham but not in hypertensive rabbits. By contrast, stress increased the baroreflex-induced maximum RSNA in hypertensive animals but not in normotensive rabbits. MAP variability was greater in the hypertensive group but was unaffected by airjet stress. Acute and chronic rilmenidine lowered MAP to close to normotensive levels, markedly reduced MAP variability and RSNA but did not prevent the RSNA baroreflex facilitation produced by airjet stress. CONCLUSION: Baroreflex control of HR was diminished by either hypertension or acute airjet stress but the effects were not additive. Although the baroreflex-induced RSNA maximum was increased by stress only in hypertensive animals, rilmenidine was effective in minimizing the reflex autonomic disturbances produced by hypertension and stress.