High-dose IV magnesium in mesothelioma patients receiving surgery with hyperthermic intraoperative cisplatin: Pilot studies and design of a phase II randomized clinical trial.

INTRODUCTION: Hyperthermic intraoperative cisplatin (HIOC) is associated with acute kidney injury (AKI). Administration of high-dose magnesium attenuates cisplatin-induced AKI (CP-AKI) in animal models but has not been rigorously examined in humans. METHODS: We tested the feasibility and safety of different doses of magnesium in mesothelioma patients receiving HIOC. In Pilot Study 1, we administered a 36-h continuous infusion of magnesium at 0.5 g/h, targeting serum magnesium levels between 3 and 4.8 mg/dL. In Pilot Study 2A, we administered a 6 g bolus followed by an infusion starting at 2 g/h, titrated to achieve levels between 4 and 6 mg/dL. We eliminated the bolus in Pilot Study 2B. RESULTS: In Pilot Study 1, all five patients enrolled completed the study; however, median postoperative Mg levels were only 2.4 mg/dL. In Pilot Study 2A, two of four patients (50%) were withdrawn due to bradycardia during the bolus. In Pilot Study 2B, two patients completed the study whereas two developed postoperative bradycardia attributed to the magnesium. CONCLUSIONS: A 0.5 g/h infusion for 36 h did not achieve therapeutic magnesium levels, while an infusion at 2 g/h was associated with bradycardia. These studies informed the design of a randomized clinical trial testing whether intravenously Mg attenuates HIOC-associated AKI.

Low-dose steroid-induced bradyarrhythmias and treatment refractory hypokalaemia: a case report.

Corticosteroid therapy has become an important modality of treatment for diseases in which rapid control of immunoinflammatory processes is required. However, one of the serious, but less known adverse effect of this therapy is cardiac arrhythmias. This includes both tachyarrhythmias and bradyarrhythmias. Corticosteroid use may also be associated with electrolyte imbalances like hypokalaemia by its mineralocorticoid activity. Those side effects are mainly seen with high-dose intravenous methyl-prednisolone or oral pulse dose prednisolone therapy. Here we report our experience in a child with warm idiopathic autoimmune haemolytic anaemia who developed sinus bradyarrhythmias and treatment refractory hypokalaemia during low-dose steroid therapy with reduction in heart rate by 60% of baseline.

Persistent Hyperinsulinemia Following High-Dose Insulin Therapy: A Case Report.

INTRODUCTION: Overdoses of beta-adrenergic antagonists and calcium channel antagonists represent an uncommonly encountered but highly morbid clinical presentation. Potential therapies include fluids, calcium salts, vasopressors, intravenous lipid emulsion, methylene blue, and high-dose insulin. Although high-dose insulin is commonly used, the kinetics of insulin under these conditions are unknown. CASE REPORT: We present a case of a 51-year-old male who sustained a life-threatening overdose after ingesting approximately 40 tablets of a mixture of amlodipine 5 mg and metoprolol tartrate 25 mg. Due to severe bradycardia and hypotension, he was started on high-dose insulin (HDI) therapy; this was augmented with epinephrine. Despite the degree of his initial shock state, he ultimately recovered, and HDI was discontinued. Insulin was infused for a total of approximately 37 hours, most of which was dosed at 10 U/kg/hour; following discontinuation, serial serum insulin levels were drawn and remained at supraphysiologic levels for at least 24 hours and well above reference range for multiple days thereafter. CONCLUSION: The kinetics of insulin following discontinuation of high-dose insulin therapy are largely unknown, but supraphysiologic insulin levels persist for some time following therapy; this may allow for simple discontinuation rather than titration of insulin at the end of therapy. Dextrose replacement is frequently needed; although the duration is often difficult to predict, prolonged infusions may not be necessary.

Direct evidence of bradycardic effect of omega-3 fatty acids acting on nucleus ambiguus.

Docosahexaenoic acid (DHA) an omega-3 polyunsaturated fatty acid, is an agonist of FFA1 receptor. DHA administration reduces the heart rate via unclear mechanisms. We examined the effect of DHA on neurons of nucleus ambiguus that provide the parasympathetic control of heart rate. DHA produced a dose-dependent increase in cytosolic Ca2+ concentration in cardiac-projecting nucleus ambiguus neurons; the effect was prevented by GW1100, a FFA1 receptor antagonist. DHA depolarized cultured nucleus ambiguus neurons via FFA1 activation. Bilateral microinjection of DHA into nucleus ambiguus produced bradycardia in conscious rats. Our results indicate that DHA decreases heart rate by activation of FFA1 receptor on cardiac-projecting nucleus ambiguus neurons.

BRASH Syndrome: Bradycardia, Renal Failure, AV Blockade, Shock, and Hyperkalemia.

BACKGROUND: BRASH syndrome, or Bradycardia, Renal Failure, AV blockade, Shock, and Hyperkalemia, has recently become recognized as a collection of objective findings in a specific clinical context pertaining to emergency medicine and critical care. However, there is little emergency medicine and critical care literature specifically evaluating this condition. OBJECTIVE: We sought to define and review BRASH syndrome and identify specific management techniques that differ from the syndromes as they present individually. DISCUSSION: BRASH syndrome is initiated by synergistic bradycardia due to the combination of hyperkalemia and medications that block the atrioventricular (AV) node. The most common precipitant is hypovolemia or medications promoting hyperkalemia or renal injury. Left untreated, this may result in deteriorating renal function, worsening hyperkalemia, and hemodynamic instability. Patients can present with a variety of symptoms ranging from asymptomatic bradycardia to multiorgan failure. BRASH syndrome should be differentiated from isolated hyperkalemia and overdose of AV-nodal blocking medications. Treatment includes fluid resuscitation, hyperkalemia therapies (intravenous calcium, insulin/glucose, beta agonists, diuresis), management of bradycardia (which may necessitate epinephrine infusion), and more advanced therapies if needed (lipid emulsion, glucagon, or high-dose insulin infusion). Understanding and recognizing the pathophysiology of BRASH syndrome as a distinct entity may improve patient outcomes. CONCLUSIONS: BRASH syndrome can be a difficult diagnosis and is due to a combination of hyperkalemia and medications that block the AV node. Knowledge of this condition may assist emergency and critical care providers.

Preclinical investigation of the cardiovascular actions induced by aqueous extract of Pimpinella anisum L. seeds in rats.

ETHNOPHARMACOLOGY RELEVANCE: Pimpinella anisum is used in traditional medicine because of its pharmacological properties which include cardiovascular action. However, no scientific information supports this use. AIM OF THE STUDY: This study investigated the effects of Pimpinella on arterial blood pressure (BP) and its pharmacological mechanism of action. MATERIAL AND METHODS: Pimpinella seeds were extracted with water, concentrated and freeze-dried yielding the aqueous extract (AE). A non-invasive BP assessment method was used (via the caudal artery) on Wistar, Wistar Kyoto, SHRs and rats that were submitted to high intake of dietary salt. Direct BP and heart rate were evaluated in Wistar rats in the absence or presence of atropine, L-NAME and angiotensin II. Spontaneous diuresis and the effect of AE on depolarized portal vein of Wistar rats was also examined. RESULTS: The data revealed that AE reduced BP in all groups evaluated and its effects were not due to diuretic, sympatholytic or parasympathomimetic actions. Additionally, it was shown that AE does not act as an angiotensin receptor blocker and does not induce hypotension by reducing vascular resistance induced by oxide nitric. In the depolarized portal vein, AE inhibited calcium influx, which indicates that AE acts as calcium channel blocker. CONCLUSION: This study validates the cardiovascular actions of Pimpinella and characterizes the hypotensive effects of Pimpinella that are related to the blockade of calcium channels.

[Bradycardia and Hypotension from Improper Use of Aconite Root: A Case Report and Brief Review].

BACKGROUND: Adverse reactions associated with Chinese herbal medicines (CHMs) are usually the result of unpredictable active/toxic ingredients, inaccurate or mistaken beliefs, or poor supervision. The herb that most commonly induces severe adverse effects in Hong Kong and China is aconite root. More than 200 species of Aconitum plants are used for medicinal purposes, with aconite roots producing analgesic, anti-inflammatory, cardiotonic, and anti-tumor effects. The active components are alkaloids; these can be toxic, but CHM processing methods lower their toxicity and increase the pharmacological efficacy. However, aconite poisoning can result from inadequate decoction time or exceeding the recommended dose. CASE REPORT: Here we report the case of a 92-year-old woman who presented with life-threatening bradycardia and hypotension. This started 1 h after she inappropriately consumed a herbal decoction containing Fuzi for mood fluctuation and health maintenance; Fuzi, an aconite root, has known cardiotoxicity. Electrocardiography showed supraventricular abnormalities, including sinus bradycardia and low-amplitude P waves. After an infusion of normal saline and inotropic agents for 25 h, the clinical manifestations subsided, her sinus rhythm returned to normal, and she was discharged. At follow-up 2 weeks later, she was in good health and had ceased taking any CHM. CONCLUSIONS: Standardized processing methods, stringent regulations, and cooperation between health professions can ensure medication safety and establish a fully-fledged operating process for these valuable drugs. We hope this report will help establish correct attitudes toward CHM and will assist Traditional Chinese Medicine practitioners to become more familiar with Aconitum plants.

Clinical judgement perplexed by initially undisclosed use of herbal medicine and unexpected cross-reactivity of immunoassay.

We report a case of symptomatic bradycardia caused by consumption of a Chinese herbal medicine which was initially undisclosed to the attending emergency physician. The scientific name of the herb is Panax japonicus. Electrocardiogram revealed sinus bradycardia. Laboratory tests were normal except for the detection of a high serum digoxin level. Further interrogation of the patient eventually disclosed ingestion of the herb which, however, did not contain any digoxin. Other active ingredients in the herb include various types of ginsenoside. These are digoxin-like substances that had caused the observed false-positive detection of digoxin by fluorescence polarization immunoassay due to cross-reactivity. Our case-report provides an important insight about a blind-spot in the field of laboratory medicine (clinical pathology), namely, the false positive detection of digoxin due to crossreactivity in the immunoassay when we come across digoxin-like substances in clinical scenarios, which has barely received attention in the medical literature. It also conveys a clear educational message that with full understanding of the laboratory methodology and its mechanistic rationale there are actually some tricks-of-the-trade that allow us to optimize the specificity of the biochemical tests and the treatment of digoxin-like substances overdose.

Impact of Age and Polytherapy on Fingolimod Induced Bradycardia: a Preclinical Study.

Fingolimod is a an oral disease modifying drug for relapsing remitting multiple sclerosis (MS) preventing egress of B and T cells from lymph nodes. Relevant first dose adverse events include bradycardia and atrioventricular conduction slowing. Cardiac side effects of fingolimod and combinational pharmacotherapy including duloxetine and tolterodine were monitored in mice of different age using implantable ECG telemetric systems. Cardiac tissue was assessed for S1P-receptor subtype (1 and 3), and for GIRK1 expression. Fingolimod led to a significant heart rate reduction within 60 min, which returned to baseline values within 24 h. In older mice bradycardia was more pronounced compared to younger mice. Atrioventricular conduction was not affected. Older mice showed a higher S1PR3 expression in a naïve state and receptor expression was reduced after fingolimod administration. Combination with duloxetine or tolterodine alleviated fingolimod induced heart rate decrease. Our data provide preclinical evidence that negative chronotropic effects of fingolimod might be age dependent, possibly due to an altered expression and internalization of cardiac S1PR3 in older animals. This data could be relevant for future clinical monitoring and patient selection in the aging MS population. Combinational therapies of fingolimod and duloxetine or tolterodine are well tolerated and safe without an increased risk for pronounced bradycardia or arrhythmia.

Central mechanism of the cardiovascular responses caused by L-proline microinjected into the paraventricular nucleus of the hypothalamus in unanesthetized rats.

Previously, we reported that microinjection of L-proline (L-Pro) into the paraventricular nucleus of the hypothalamus (PVN) caused vasopressin-mediated pressor responses in unanesthetized rats. In the present study, we report on the central mechanisms involved in the mediation of the cardiovascular effects caused by the microinjection of L-Pro into the PVN. Microinjection of increasing doses of L-Pro (3-100nmol/100nL) into the PVN caused dose-related pressor and bradycardic responses. No cardiovascular responses were observed after the microinjection of equimolar doses (33nmol/100nL) of its isomer D-Proline (D-Pro) or Mannitol. The PVN pretreatment with either a selective non-NMDA (NBQX) or selective NMDA (LY235959 or DL-AP7) glutamate receptor antagonists blocked the cardiovascular response to L-Pro (33nmol/100nL). The dose-effect curve for the pretreatment with increasing doses of LY235959 was located at the left in relation to the curves for NBQX and DL-AP7, showing that LY235959 is more potent than NBQX, which is more potent than DL-AP7 in inhibiting the cardiovascular response to L-Pro. The cardiovascular response to the microinjection of L-Pro into the PVN was not affected by local pretreatment with Nω-Propyl-l-arginine (N-Propyl), a selective inhibitor of the neuronal nitric oxide synthase (nNOS), suggesting that NO does not mediate the responses to L-Pro in the PVN. In conclusion, the results suggest that ionotropic receptors in the PVN, blocked by both NMDA and non-NMDA receptor antagonists, mediate the pressor response to L-Pro that results from activation of PVN vasopressinergic magnocellular neurons and vasopressin release into the systemic circulation.

Lidocaine Toxicity During Attempted Epistaxis Cautery.

BACKGROUND: Epistaxis is a common problem that occurs in up to 60% of the general population, and is a common emergency department (ED) complaint. The use of lidocaine for analgesia is common when cauterization is required for bleeds that are refractory to manual compression. Although the use of lidocaine is generally thought of as a benign intervention, it is not completely without risk. CASE REPORT: We present the case of a 19-year-old man who presented to the ED with persistent anterior epistaxis. He developed severe lidocaine toxicity resulting from topical anesthesia applied prior to intranasal cautery for the epistaxis. This toxicity, which manifested as seizures, bradycardia, hypotension, nausea, and emesis, was rapidly recognized and appropriately treated, with a good clinical outcome for the patient. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We present this case to increase awareness among emergency physicians of the potential complications of the intranasal use of topical lidocaine, something that is generally considered a benign intervention. We also discuss the pathophysiology and management of lidocaine toxicity.

Near Death Experience from Placement of an Intrathecal Catheter.

UNLABELLED: The management of pain due to cancer is challenging and often requires invasive therapy in addition to medication management. Intrathecal drug delivery is a form of advanced therapy that delivers medication locally in the intrathecal space while reducing systemic side effects associated with high doses of opioids. Although risks associated with intrathecal drug delivery are low, some common complications include dislodgement, kinking, or fracture of the catheter, bleeding, neurological injury, infection, and cerebrospinal leaks. We present a case of a 38-year-old woman with a medical history significant for stage IV breast cancer, L2 metastatic lesion, opioid tolerance, and chronic neck and low back pain who was admitted to the hospital for intractable pain. She had failed multiple interventional procedures in the past including lumbar medial nerve radiofrequency ablation, epidural steroid injection, and trigger point injections as well as a kyphoplasty at the L2 level. Failing both oral and parenteral opioid treatments, the decision was made to place an intrathecal pump in the patient. After placement of the intrathecal catheter and prior to any bolus of medication being given, the patient became bradycardic with a heart rate in the 20s and experienced a 10 second pause. The patient had intermittent bradycardia over the following days and symptoms resolved only after removal of the intrathecal catheter itself. To our knowledge, this is the first reported case with a complication of recurrent bradycardic and asystolic episodes prior to the administration of intrathecal opioid but shortly after placement of the intrathecal catheter itself. KEY WORDS: Intrathecal drug delivery, complications, cancer pain, intrathecal analgesia, bradycardia, opioids.

Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies.

Management of cardiovascular instability resulting from calcium channel antagonist (CCB) or beta-adrenergic receptor antagonist (BB) poisoning follows similar principles. Significant myocardial depression, bradycardia and hypotension result in both cases. CCBs can also produce vasodilatory shock. Additionally, CCBs, such as verapamil and diltiazem, are commonly ingested in sustained-release formulations. This can also be the case for some BBs. Peak toxicity can be delayed by several hours. Provision of early gastrointestinal decontamination with activated charcoal and whole-bowel irrigation might mitigate this. Treatment of shock requires a multimodal approach to inotropic therapy that can be guided by echocardiographic or invasive haemodynamic assessment of myocardial function. High-dose insulin euglycaemia is commonly recommended as a first-line treatment in these poisonings, to improve myocardial contractility, and should be instituted early when myocardial dysfunction is suspected. Catecholamine infusions are complementary to this therapy for both inotropic and chronotropic support. Catecholamine vasopressors and vasopressin are used in the treatment of vasodilatory shock. Optimizing serum calcium concentration can confer some benefit to improving myocardial function and vascular tone after CCB poisoning. High-dose glucagon infusions have provided moderate chronotropic and inotropic benefits in BB poisoning. Phosphodiesterase inhibitors and levosimendan have positive inotropic effects but also produce peripheral vasodilation, which can limit blood pressure improvement. In cases of severe cardiogenic shock and/or cardiac arrest post-poisoning, extracorporeal cardiac assist devices have resulted in successful recovery. Other treatments used in refractory hypotension include intravenous lipid emulsion for lipophilic CCB and BB poisoning and methylene blue for refractory vasodilatory shock.

Electrophysiological, haemodynamic, and mitochondrial alterations induced by levobupivacaine during myocardial ischemia in a pig model: protection by lipid emulsions?

Accidental intravascular or high-dose injection of local anesthetics (LA) can result in serious, potentially life-threatening complications. Indeed, adequate supportive measures and the administration of lipid emulsions are required in such complications. The study's objectives were threefold: (i) evaluate the myocardial toxicity of levobupivacaine when administered intravenously; (ii) investigate levobupivacaine toxicity on cardiomyocytes mitochondrial functions and cellular structure; (iii) assess the protective effects of a lipid emulsion in the presence or absence of myocardial ischemia. Domestic pigs randomized into two groups of 24 animals each, with either preserved coronary circulation or experimental myocardial ischemia. Six animals from each group received either: (i) single IV injection of saline, (ii) lipid emulsion (Intralipid(®) ), (iii) levobupivacaine, (iv) combination levobupivacaine-Intralipid(®) . Serially measured endpoints included: heart rate, duration of the monophasic action potentials (dMAP), mean arterial pressure, and peak of the time derivative of left ventricular pressure (LV dP/dtmax ). In addition, the following cardiomyocytes mitochondrial functions were measured: reactive oxygen species (ROS) production, oxidative phosphorylation, and calcium retention capacity (CRC) as well as the consequences of ROS production on lipids, proteins, and DNA. IV injection of levobupivacaine induced sinus bradycardia and reduced dMAP and LV dP/dtmax . At the mitochondrial level, oxygen consumption and CRC were decreased. In contrast, ROS production was increased leading to enhanced lipid peroxidation and structural alterations of proteins and DNA. Myocardial ischemia was associated with global worsening of all changes. Intralipid(®) quickly improved haemodynamics. However, beneficial effects of Intralipid(®) were less clear after myocardial ischemia.

Transient A-V dissociation and severe hypotension due to consumption of Ayurvedic medicine--Vatsanabha (aconitum ferox).

A 24 year old married, well educated, female patient presented with complaints of giddiness and blackouts. On evaluation, patient had hypotension and bradycardia. ECG findings were suggestive of complete A-V dissociation. On detailed history patient revealed consumption. of Ayurvedic medicine Vatsanabha for arthritis. This study impresses upon the need for complete history talking and generating awareness regarding the correct and observed use of any drug including alternative medicines.

[Severe poisoning by plants used for traditional medicine in Mayotte]. / Intoxications graves lors de traitements traditionnels par les plantes à Mayotte.

The authors describe three cases of severe accidental poisoning by plants used as part of a traditional treatment in Mayotte. The established, or suspected, toxicity of Thevetia peruviana (Yellow oleander), Cinchona pubescens (Red quinine-tree), Melia azaderach (Persian lilac, also called china berry) and Azadirachta indica (Neem), is discussed. The clinical presentation is cardiac (atrioventricular block) and well known for Thevetia and Cinchona intoxications. Neurological signs and multi-organ failure are found for Azadirachta and Melia. The identification of the plants is never easy, nor is the evidence of their accountability. In the three cases reported, no other cause than the traditional treatment has been found to explain the clinical presentation. The outcome was favorable in all cases. The authors emphasize the difficulties to investigate these accidents, the poor medical knowledge of these practices in tropical areas, and in Mayotte particularly. The need for cooperation with local botanists, familiar with traditional medicine, is also underlined.

Management of a mixed overdose of calcium channel blockers, ß-blockers and statins.

We describe a case of extreme mixed overdose of calcium channel blockers, ß-blockers and statins. The patient was successfully treated with aggressive resuscitation including cardiac pacing and multiorgan support, glucagon and high-dose insulin for toxicity related to calcium channel blockade and ß-blockade, and ubiquinone for treating severe presumed statin-induced rhabdomyolysis and muscle weakness.

Linalool-rich rosewood oil induces vago-vagal bradycardic and depressor reflex in rats.

Cardiovascular effects of the linalool-rich essential oil of Aniba rosaeodora (here named as EOAR) in normotensive rats were investigated. In anesthetized rats, intravenous (i.v.) injection of EOAR induced dose-dependent biphasic hypotension and bradycardia. Emphasis was given to the first phase (phase 1) of the cardiovascular effects, which is rapid (onset time of 1-3 s) and not observed in animals submitted to bilateral vagotomy or selective blockade of neural conduction of vagal C-fibre afferents by perineural treatment with capsaicin. Phase 1 was also absent when EOAR was directly injected into the left ventricle injection, but it was unaltered by i.v. pretreatment with capsazepine, ondansetron or HC030031. In conscious rats, EOAR induced rapid and monophasic hypotensive and bradycardiac (phase 1) effects that were abolished by i.v. methylatropine. In endothelium-intact aortic rings, EOAR fully relaxed phenylephrine-induced contractions in a concentration-dependent manner. The present findings reveal that phase 1 of the bradycardiac and depressor responses induced by EOAR has a vago-vagal reflex origin resulting from the vagal pulmonary afferents stimulation. Such phenomenon appears not to involve the recruitment of C-fibre afferents expressing 5HT3 receptors or the two chemosensory ion channels TRPV1 and TRPA1 . Phase 2 hypotensive response appears resulting from a direct vasodilatory action.

The protein Ocular albinism 1 is the orphan GPCR GPR143 and mediates depressor and bradycardic responses to DOPA in the nucleus tractus solitarii.

BACKGROUND AND PURPOSE: L-DOPA is generally considered to alleviate the symptoms of Parkinson's disease by its conversion to dopamine. We have proposed that DOPA is itself a neurotransmitter in the CNS. However, specific receptors for DOPA have not been identified. Recently, the gene product of ocular albinism 1 (OA1) was found to exhibit DOPA-binding activity. Here, we have investigated whether OA1 is a functional receptor of DOPA in the nucleus tractus solitarii (NTS). EXPERIMENTAL APPROACH: We examined immunohistochemical expression of OA1 in the NTS, and the effects of DOPA microinjected into the depressor sites of NTS on blood pressure and heart rate in anaesthetized rats, with or without prior knock-down of OA1 in the NTS, using shRNA against OA1. KEY RESULTS: Using a specific OA1 antibody, OA1-positive cells and nerve fibres were found in the depressor sites of the NTS. OA1 expression in the NTS was markedly suppressed by microinjection into the NTS of adenovirus vectors carrying the relevant shRNA sequences against OA1. In animals treated with OA1 shRNA, depressor and bradycardic responses to DOPA, but not those to glutamate, microinjected into the NTS were blocked. Bilateral injections into the NTS of DOPA cyclohexyl ester, a competitive antagonist against OA1, suppressed phenylephrine-induced bradycardic responses without affecting blood pressure responses. CONCLUSION AND IMPLICATIONS: OA1 acted as a functional receptor for DOPA in the NTS, mediating depressor and bradycardic responses. Our results add to the evidence for a central neurotransmitter role for DOPA, without conversion to dopamine.

Cardiovascular effects of the essential oil of Croton zehntneri leaves in DOCA-salt hypertensive, conscious rats.

This study investigated the cardiovascular effects of the essential oil of Croton zehntneri (EOCZ) in deoxycorticosterone-acetate (DOCA)-salt hypertensive rats. Furthermore, in vitro experiments using isolated thoracic aortic rings were performed to assess the vascular effects of the EOCZ. In conscious hypertensive rats, intravenous (i.v.) injections of EOCZ (1-20 mg/kg) induced rapid (2-4 s) and dose-dependent hypotension and bradycardia (phase 1). The hypotension was followed by a significant pressor effect that was more evident at the higher doses (10 and 20 mg/kg) of EOCZ. Hypotension and bradycardia of EOCZ (phase 1) were abolished and respectively reversed into pressor and tachycardiac effects by methylatropine (1 mg/kg, i.v.) pretreatment. In isolated endothelium-intact aortic preparations, increasing concentrations (1-1000 microg/mL) of EOCZ relaxed the potassium-induced contraction in a concentration-dependent manner with an IC50 (geometric mean [95% confidence interval]) value of 202.0 [92.0-443.7] microg/mL. This vasorelaxant effect remained unaffected by either mechanical removal of functional vascular endothelium (IC50 = 189.0 [159.4-224.7] microg/mL) or the addition of atropine (1 microM) (IC50 = 158.6 [79.8-316.2] microg/mL) in the perfusion medium. These data show that i.v. administration of EOCZ in DOCA-salt hypertensive rats induces a vago-vagal reflex decreases in heart rate and blood pressure (phase 1). EOCZ may induce a second and delayed hypotension due to its direct endothelium-independent vasorelaxant effects, but it seems to be buffered by the pressor component (subsequent to phase 1) of EOCZ. This pattern of blood pressure and heart rate responses to EOCZ seems unaltered by DOCA-salt hypertension, as was similar to that previously reported in conscious normotensive rats.