Bradycardiac Responses Research Articles

Subacute Exposure to Gaseous Pollutants from Diesel Engine Exhaust Attenuates Capsaicin-Induced Cardio-Pulmonary Reflex Responses Involving Oxidant Stress Mechanisms in Adult Wistar Rats.

Intravenous injection of capsaicin produces vagal-mediated protective cardio-pulmonary (CP) reflexes manifesting as tachypnea, bradycardia, and triphasic blood pressure (BP) response in anesthetized rats. Particulate matter from diesel engine exhaust has been reported to attenuate these reflexes. However, the effects of gaseous constituents of diesel exhaust are not known. Therefore, the present study was designed to investigate the effects of gaseous pollutants in diesel exhaust, on capsaicin-induced CP reflexes in rat model. Adult male rats were randomly assigned to three groups: Non-exposed (NE) group, filtered diesel exhaust-exposed (FDE) group and N-acetyl cysteine (NAC)-treated FDE group. FDE group of rats (n = 6) were exposed to filtered diesel exhaust for 5 h a day for 5days (D1-D5), and were taken for dissection on day 6 (D6), while NE group of rats (n = 6) remained unexposed. On D6, rats were anesthetized, following which jugular vein was cannulated for injection of chemicals, and femoral artery was cannulated to record the BP. Lead II electrocardiogram and respiratory movements were also recorded. Results show that intravenous injection of capsaicin (0.1ml; 10µg/kg) produced immediate tachypneic, hyperventilatory, hypotensive, and bradycardiac responses in both NE and FDE groups of rats. However, these capsaicin-induced CP responses were significantly attenuated in FDE group as compared to the NE group of rats. Further, FDE-induced attenuation of capsaicin-evoked CP responses were diminished in the N-acetyl cysteine-treated FDE rats. These findings demonstrate that oxidant stress mechanisms could possibly be involved in inhibition of CP reflexes by gaseous pollutants in diesel engine exhaust.

Subthreshold Doses of Inflammatory Mediators potentiate One Another to Elicit Reflex Cardiorespiratory Responses in Anesthetized Rats.

Reflex cardio-vascular and respiratory (CVR) alterations evoked by intraarterial instillation of nociceptive agents are termed vasosensory reflexes. Such responses elicited by optimal doses of inflammatory mediators have been described in our earlier work. The present study was designed to evaluate the interactions between subthreshold doses of inflammatory mediators on perivascular nociceptive afferents in urethane anesthetized rats. Healthy male adult rats (Charles-Foster strain) were anesthetized with an intraperitoneal injection of urethane. After anesthesia, the right femoral artery was cannulated. Respiratory movements, blood pressure, and electrocardiogram were recorded. The interactions between subthreshold doses of algogens in the elicitation of vasosensory reflex responses were studied by instillation of bradykinin (1 nM) and histamine (100 μM) into the femoral artery one after the other, in either temporal combination in separate groups of rats. The CVR responses obtained in these groups were then compared with the responses produced by 100 μM histamine and 1 nM bradykinin in saline-pretreated groups, which served as control. Subthreshold doses of histamine elicited transient tachypnoeic, hyperventilatory, hypotensive, and bradycardiac responses, in rats pretreated with subthreshold doses of bradykinin [p < 0.01, two-sided Dunnett's test] but not in saline pretreated groups [p > 0.05, two-sided Dunnett's test]. Similar responses were elicited by bradykinin after histamine pretreatment compared to the saline-pretreated group. Furthermore, CVR responses produced by histamine in the bradykininpretreated group were greater in magnitude as compared to bradykinin-induced responses in the histamine-pretreated group [p < 0.05, two-sided Dunnett's test]. The present study demonstrates that both bradykinin and histamine potentiate one another in the elicitation of vasosensory reflex responses, and bradykinin is a better potentiator than histamine at the level of perivascular nociceptive afferents in producing reflex CVR changes.

Perivascular histamine receptors mediate vasosensory reflex responses elicited by thermal nociceptive stimuli in anaesthetised rat models

Objectives: Reflex responses elicited by intra-arterial (i.a) instillation of nociceptive agents are known as vasosensory reflex responses. The present study was designed to demonstrate the vasosensory reflex responses evoked by thermal nociceptive stimuli in anaesthetised rat models and to examine the role of perivascular histamine receptors in mediating these responses. Materials and Methods: In this study, saline at different temperatures (0°C/30°C/55°C) was instilled retrogradely into the femoral artery to stimulate the perivascular nociceptive terminals and the respiratory movements, BP and ECG were recorded for 10 min. Experiments were performed in four groups of rats. Two groups were dedicated to study the temperature-induced reflex cardiorespiratory (CVR) responses after i.a instillation of cold (0°C) and warm saline (55°C). The responses in these groups were compared with the responses after instillation of normal saline at room temperature (30°C) in a separate group of rats that served as time matched control group. Another group of rats was pre-treated with pheniramine and the responses elicited by warm saline were studied. Results: Instillation of warm saline produced immediate (2–6 s) hyperventilatory, hypotensive and bradycardiac responses which were short-lived, while equivolume of normal saline at room temperature did not. Cold saline also elicited the CVR changes of similar quality as that of warm saline but of lesser quantity which were not significantly different from the control group. Pre-treatment with pheniramine significantly attenuated the warm saline-induced reflex responses. Conclusion: Activation of perivascular sensory nerve terminals by thermal nociceptive stimuli elicits vasosensory reflex responses altering CVR parameters. Perivascular histamine receptors play a significant role in mediating the temperature-induced vasosensory reflex responses.

Ipsilateral somatic nerves mediate histamine-induced vasosensory reflex responses involving perivascular afferents in rat models

Reflex cardiorespiratory alterations elicited after instillation of nociceptive agents intra-arterially (i.a) are termed as ‘vasosensory reflex responses’. The present study was designed to evaluate such responses produced after i.a. instillation of histamine (1 mM; 10 mM; 100 mM) and to delineate the pathways i.e. the afferents and efferents mediating these responses. Blood pressure, electrocardiogram and respiratory excursions were recorded before and after injecting saline/histamine, in a local segment of femoral artery in urethane anesthetized rats. Paw edema and latencies of responses were also estimated. Separate groups of experiments were conducted to demonstrate the involvement of somatic nerves in mediating histamine-induced responses after ipsilateral femoral and sciatic nerve sectioning (+NX) and lignocaine pre-treatment (+Ligno). In addition, another set of experiments was performed after bilateral vagotomy (+VagX) and the responses after histamine instillation were studied. Histamine produced concentration-dependent hypotensive, bradycardiac, tachypnoeic and hyperventilatory responses of shorter latencies (2–7 s) favouring the neural mechanisms in eliciting the responses. Instillation of saline (time matched control) in a similar fashion produced no response, excluding the possibilities of ischemic/stretch effects. Paw edema was absent in both hind limbs indicating that the histamine did not reach the paws and did not spill out into the systemic circulation. +NX, +VagX, +Ligno attenuated histamine-induced cardiorespiratory responses significantly. These observations conclude that instillation of 10 mM of histamine produces optimal vasosensory reflex responses originating from the local vascular bed; afferents and efferents of which are mostly located in ipsilateral somatic and vagus nerves respectively.

Intra-arterial Instillation of a Nociceptive Agent Modulates Cardiorespiratory Parameters Involving 5-HT3 and TRPV1 Receptors in Anesthetized Rats.

Since long back, it has been a matter of discussion regarding the role of peripheral blood vessels in the regulation of cardiorespiratory (CVR) system. The role of 5-HT3 and TRPV1 receptors present on perivascular nerves in elicitation of CVR reflexes was examined after intra-arterial instillation of bradykinin in urethane anesthetized rats. Femoral artery was cannulated retrogradely and was utilized for the instillation of saline/agonist/antagonist and recording of blood pressure (BP), using a double ported 24G cannula. BP, respiration and ECG were recorded for 30 min after bradykinin (1 μM) in the absence or presence of antagonists. Instillation of bradykinin produced immediate hypotensive (40%), bradycardiac (17%), tachypnoeic (45%) and hyperventilatory (96%) responses of shorter latencies (5-8 s) favoring the neural mechanisms in producing the responses. In lignocaine (2%) pretreated animals, bradykinin- induced hypotensive (10%), bradycardiac (1.7%), tachypnoeic (13%) and hyperventilatory (13%) responses attenuated significantly. Pretreatment with ondansetron (100 μg/kg), 5-HT3-antagonist attenuated the hypotensive (10%), bradycardiac (1.7%), tachypnoeic (11%) and hyperventilatory (11%) responses significantly. Pretreatment with capsazepine (1 mg/kg), transient receptor potential vanilloid 1- antagonist blocked the hypotensive (5%), bradycardiac (1.2%), tachypnoeic (6%) and hyperventilatory (6%) responses significantly. In conclusion, presence of a nociceptive agent in the local segment of an artery evokes vasosensory reflex responses modulating CVR parameters involving TRPV1 and 5-HT3 receptors present on the perivascular sensory nerve terminals in anesthetized rats.

Intra-arterial injection of bradykinin produces reflex cardiorespiratory changes involving histamine receptors in anesthetized rats

Objectives: It is well known that intra-arterial injection of nociceptive agent produces vasosensory reflex responses altering cardiorespiratory parameters. The role of various inflammatory mediators is also implicated in the regulation of these reflex responses. However, the role of histamine in this regard is not clear. This study was performed to understand the role of H1 and H2 receptors in modulating the cardiorespiratory responses evoked after i.a. injection of bradykinin (BK). Materials and Methods: Male albino rats were anesthetized with an intra-peritoneal injection of urethane (1.5 g/kg). Tracheostomy was performed to keep the respiratory tract patent. The femoral artery was cannulated proximally by pediatric i.v. cannula (24 G, double ported). This cannulation was used for the blood pressure (BP) recording as well as for the drugs instillation as it contains double port with injection valve. The effect of BK (1 µM) on BP, electrocardiographic, and respiration was recorded for 30 min. The respiratory frequency, respiratory minute volume, mean arterial pressure, and heart rate were computed from the original tracings and the data were presented as mean ± SEM. Results: Intra-arterial injection of BK produced immediate hyperventilatory (50% from initial), hypotensive (40% from initial), and bradycardiac responses (17% from initial) of shorter latency (5–8 s) indicating the neural mechanisms in producing the responses. Pre-treatment with pheniramine maleate significantly attenuated the BK-induced hyperventilatory (11% from initial), hypotensive (8% from initial), and bradycardiac responses (2% from initial). Conclusion: Our data provide evidences for the involvement of H1 and H2 receptors in producing the BK-induced vasosensory reflex responses modulating the cardiovascular parameters in anesthetized rats.

Instillation of bradykinin into femoral artery elicits cardiorespiratory reflexes involving perivascular afferents in anesthetized rats.

The physiology of baroreceptors and chemoreceptors present in large blood vessels of the heart is well known in the regulation of cardiorespiratory functions. Since large blood vessels and peripheral blood vessels are of the same mesodermal origin, therefore, involvement of the latter in the regulation of cardiorespiratory system is expected. The role of perivascular nerves in mediating cardiorespiratory alterations produced after intra-arterial injection of a nociceptive agent (bradykinin) was examined in urethane-anesthetized male rats. Respiratory frequency, blood pressure, and heart rate were recorded for 30 min after the retrograde injection of bradykinin/saline into the femoral artery. In addition, paw edema was determined and water content was expressed as percentage of wet weight. Injection of bradykinin produced immediate tachypneic, hypotensive and bradycardiac responses of shorter latency (5-8 s) favoring the neural mechanisms involved in it. Injection of equi-volume of saline did not produce any responses and served as time-matched control. Paw edema was observed in the ipsilateral hind limb. Pretreatment with diclofenac sodium significantly attenuated the bradykinin-induced responses and also blocked the paw edema. Ipsilateral femoral and sciatic nerve sectioning attenuated bradykinin-induced responses significantly, indicating the origin of responses from the local vascular bed. Administration of bradykinin in the segment of an artery produced reflex cardiorespiratory changes by stimulating the perivascular nociceptors involving prostaglandins. This is a novel study exhibiting the role of peripheral blood vessels in the regulation of the cardiorespiratory system.

Involvement of CRF1 receptors in bed nucleus of stria terminalis (BNST) on baroreflex responses in chronically stressed rats

INTRODUCTIONStudies suggest the involvement of CRF receptors in bed nucleus of the stria terminalis (BNST) on cardiovascular responses in acute stress. Data from our group had demonstrated that the expression of CRF1 receptors within the BNST is decreased in animals exposed to chronic variable stress (CVS). Nevertheless, an involvement of BNST CRF neurotransmission on cardiovascular changes evoked by CVS has never been investigated.AIMTo evaluate the involvement of CRF1 receptor in the BNST on baroreflex changes evoked by CVS in rats.METHODOLOGYMale Wistar rats (250g) were submitted to stereotaxic surgery for implantation of cannulas into the BNST. After 4 days of recovery, the animals were exposed to a CVS protocol for 10 days. After the last session, the rats had the femoral artery and vein cannulated for cardiovascular record and drug infusion, respectively. Twenty‐four hours later, the experiments were performed. Baroreflex function was assessed by evoking changes on arterial pressure throughout intravenous infusions of phenylephrine and sodium nitroprusside, which evoke pressor and depressor effects, respectively. Baroreflex activity was evaluated in both control rats and animals subjected to ECV protocol before and after bilateral microinjection of the selective CRF1 antagonist CP376395 (5nmol/100nL) into the BNST.RESULTSComparison of values before BNST treatment revealed that ECV decreased the bradycardiac response evoked by blood pressure increase (−48±10 vs −114±23 bpm, P&lt;0.03). Moreover, bilateral microinjection of CP376395 into the BNST decreased reflex bradycardia in control group (−51±13 vs −114±23 bpm, P&lt;0.02), but not in animals subjected to ECV (−51±10 vs −48±10 bpm, P&gt;0.05). The tachycardia evoked by blood pressure decrease was also decreased following ECV (57±5 vs 97±11 bpm, P&lt;0.05). The BNST treatment with CP376395 decreased the tachycardiac response in control animals (50±9 vs 97±11 bpm, P&lt;0.001), but without affecting this response in CVS rats (52±5 vs 57±5 bpm, P&gt;0.05).CONCLUSIONThe impairment of baroreflex function evoked by CVS is related to decreased control of this reflex cardiovascular by CRF1 receptor in the BNST.Support or Funding InformationFINANCIAL SUPPORT: FAPESPThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

CRF1 and CRF2 receptors in the bed nucleus of stria terminalis differently modulate the baroreflex function in unanesthetized rats.

The baroreflex is an important blood pressure regulating mechanism. The bed nucleus of stria terminalis (BNST) modulates the baroreflex function. However, the local BNST neurochemical mechanisms involved in control of baroreflex responses are not completely understood. Therefore, in this study, we investigated the involvement of corticotropin-releasing factor (CRF) receptors within the BNST in baroreflex control of heart rate in unanesthetized rats. For this, we evaluated effects of bilateral microinjection into the BNST of either the selective CRF1 receptor antagonist CP376395 (5nmol/100nL) or the selective CRF2 receptor antagonist antisauvagine-30 (5nmol/100nL) in bradycardiac response evoked by blood pressure increases caused by intravenous infusion of phenylephrine as well as tachycardiac response to blood pressure decrease caused by intravenous infusion of sodium nitroprusside. Bilateral microinjection of CP376395 into the BNST decreased the baroreflex bradycardiac response without affecting the reflex tachycardia. Conversely, BNST treatment with antisauvagine-30 decreased heart rate response during blood pressure drop without affecting the reflex bradycardia. Overall, these findings provide evidence of an involvement of CRF neurotransmission within the BNST in baroreflex activity. Nevertheless, data indicate that local CRF1 and CRF2 receptors differently modulate the baroreflex control of heart rate.

Interaction of GABA and norepinephrine in the lateral division of the bed nucleus of the stria terminals in anesthetized rat, correlating single-unit and cardiovascular responses

The bed nucleus of the stria terminalis (BST) consists of multiple anatomically distinct nuclei. The lateral division, which receives dense noradrenergic innervation, has been implicated in cardiovascular regulation and modulation of responses to stress. This study is performed to identify the cardiovascular and single-unit responses of the lateral BST to norepinephrine (NE), involved adrenoceptors, and possible interaction with GABAergic system of the BST in urethane-anesthetized rats. NE, adrenoreceptor antagonists, and GABAA antagonist were microinjected into the lateral division of BST, while arterial pressure (AP), heart rate (HR), and single-unit responses were simultaneously recorded.NE microinjected into the lateral division of BST produced depressor and bradycardic responses. The decrease in AP and HR to NE was blocked by prazosin, an α1-adrenoreceptor antagonist, but not by yohimbine, an α2 antagonist.Furthermore, injections of the GABAA receptor antagonist, bicuculline methiodide (BMI), into the lateral BST abolished the NE-induced depressor and bradycardic responses. We also observed single-unit responses consisting of excitatory and inhibitory responses correlated with cardiovascular function to the microinjection of NE. In conclusion, these data provide the first evidence that microinjection of NE in the lateral division of BST produces depressor and bradycardic responses in urethane-anesthetized rat. The depressor and bradycardiac response are mediated by local α1- but not α2-adrenoceptors. α1-AR activates the GABAergic system within the BST, which in turn produces depressor and bradycardic responses.

High‐calorie Diet Induces Vascular and Hemodynamic Abnormalities in Absence of Change in Blood Glucose or Insulin Levels: Modulation by Oral Anti‐hyperglycemic Drugs

While the effect of hyperglycemia associated with diabetes on vascular function is well‐established by experimental and clinical evidence, few studies examined the early onset vascular changes occurring within the context of diabetes development before the establishment of frank hyperglycemia. Moreover, recent clinical evidence suggests a vasculoprotective effect for anti‐hyperglycemic drugs that is not a direct consequence of their effect on blood glucose level. Thus, an early intervention with diabetic vascular complications, be it through anti‐hyperglycemic drugs or otherwise, requires an adequate understanding of the underlying pathophysiological mechanism. In this study, we used a high calorie‐fed rat model, known to develop stable fasting hyperglycemia on long‐term feeding, to study changes in vascular function prior to the development of diabetes. Rats were fed a high fat (15% saturated fat), high fructose (20%) diet for 12 weeks, at which point there was no increase in fasting serum glucose, serum insulin, nor mean arterial pressure (MAP). Aortic rings from these rats showed an increased contractile response to phenylephrine (PE) compared to rings from age‐matched control animals, with an increased sensitivity (reduced EC50). The PE‐induced contractions were resistant to Ca‐free physiological solution and appeared to be more sensitive to Rho kinase inhibition. In parallel, the hypercontractile phenotype was manifested as an increase in the pressor effect of PE upon administration in vivo with a poor reflex bradycardiac response, despite the absence of a change in basal MAP. On the other hand, aortic rings from the high‐calorie fed rats showed an impaired endothelium‐dependent relaxation in response to acetylcholine (ACh), with increased constriction with higher ACh concentrations. Cyclo‐oxygenase‐mediated relaxation appeared to be most affected in these vessels, whereas nitric oxide donor‐mediated relaxations were not affected. Both ACh‐mediated relaxation and constriction were abolished in denuded rings from high‐calorie fed rats or upon treatment with a nitric oxide synthase inhibitor. Again, the altered dilatory effect was reflected in a reduced in vivo depressor response. Histopathology and immunohistochemistry showed an increased intimal thickness of aorta from these rats together with increased TGF‐β1 and Smad 3 expression. A two‐week treatment with either pioglitazone or metformin reversed the increased contractility to PE, increased intimal thickness, and increased TGF‐β1 expression with no change in fasting serum glucose. Our results suggest that early vascular dysfunction associated with high calorie intake involve inflammatory changes that could be linked to adipose inflammation. Anti‐hyperglycemic drugs showed a possible vascular anti‐inflammatory effect that is distinct from their effect on glycemic control.Support or Funding InformationFaculty of Medicine Bridge Fund, American University of Beirut

N-methyl-D-aspartate receptors mediate Mesobuthus tamulus venominduced vasosensory reflex responses in anesthetized rats

Background: The autonomic changes and cardiorespiratory changes seen in vascular disorders are suggested to be mediated reflexly by the activation of perivascular nociceptors. The role of prostaglandins, vanilloid receptor 1, 5-hydroxytryptamine type 3, and kinin receptors is well established. Aims and Objectives: This study was conducted to understand the role of N-methyl-D-aspartate (NMDA) receptor in modulating vasosensory reflex responses evoked by Mesobuthus tumulus venom. Materials and Methods: Healthy male albino rats were anesthetized with an intra-peritoneal injection of urethane (1.5 g/kg). Tracheostomy was performed to keep the airway patent. Femoral artery was cannulated proximally as well as distally to record the blood pressure (BP) and to inject the chemicals, respectively. The effect of venom on BP, heart rate (HR), respiratory rate, and minute ventilation was recorded for 60 min at every 5 min and presented as mean ± standard error of mean. Results: Intra-arterial injection of venom produced immediate hyperventilatory response (increase of 41.6%), followed by hypoventilatory response (decrease of 40.1%), and finally sustained hyperventilatory response (increase of 53%) which was observed up to 60 min. The hypertensive response started at 40 s, peaking at 5 min (increase of 48%), and remained above the initial level subsequently. The bradycardiac response began around 5 min, peaking at 25 min (decrease of 50% in HR), and remained at that level up to 60 min. In 2-amino 5-phosphonovaleric acid (NMDA receptor antagonist) pre-treated group, the venom-induced cardiovascular responses (mean arterial pressure and HR) were markedly attenuated in comparisons to the venom only group but not the respiratory responses. Conclusions: The data provide evidence for the involvement of NMDA receptors in producing the venom-induced vasosensory reflex responses modulating the cardiovascular parameters in anesthetized rats.

Impact of Restless Legs Syndrome on Cardiovascular Autonomic Control.

To examine whether patients with restless legs syndrome demonstrate specific alterations in cardiovascular autonomic control. Patients with moderate-severe restless legs syndrome (n = 20, 80% female) and controls (n = 20) matched for age, sex, body mass index, and free of hypertension and cardiovascular disease were enrolled. We assessed cardiovagal baroreflex gain via the modified Oxford technique, sympathetically mediated vascular responses to isometric exercise to fatigue, bradycardiac response to Valsalva maneuver, and respiratory sinus arrhythmia during paced breathing. Standard electrocardiography, beat-by-beat arterial pressure, respiration, and popliteal blood flow velocity were recorded continuously. Resting blood pressure and heart rate were similar between groups. However, baroreflex gain averaged 14.3 ± 1.4 msec/mm Hg in restless legs syndrome and was lower than in controls (22.6 ± 3.5 msec/mm Hg, P = 0.04). Hemodynamic responses to isometric exercise were similar between groups, though participants with restless legs syndrome had lower leg blood flow (P < 0.001), with greater leg vascular resistance (P < 0.0001), before and during isometric exercise. Respiratory sinus arrhythmia and Valsalva ratios were similar between groups. Neither baroreflex gain nor vascular resistance was correlated with sleep duration, sleep quality, or symptom duration. Patients with restless legs syndrome demonstrate compromised cardiovagal control, specific to the arterial baroreflex, with greater peripheral vascular resistance, potentially due to heightened sympathetic outflow. These autonomic alterations may directly relate to the higher prevalence of cardiovascular disease in restless legs syndrome.

Morphine blocks the Mesobuthus tamulus venom-induced augmentation of phenyldiguanide reflex and pulmonary edema in anesthetized rats.

Objective:Pulmonary edema, a manifestation of scorpion envenomation syndrome, is attributed to cardiogenic or noncardiogenic factors. Morphine is a drug used for cardiogenic pulmonary edema and its effect on Mesobuthus tamulus (MBT) venom-induced changes is not known. Therefore, we hypothesized that morphine blocks the MBT venom-induced augmentation of phenyldiguanide (PDG) reflex and pulmonary edema.Materials and Methods:Experiments were performed on anesthetized adult female rats. Trachea and jugular vein were cannulated, and the electrocardiographic potentials were recorded by connecting needle electrodes in limb lead II configuration. PDG (10 ΅g/kg, IV, bolus injection) responses were elicited by bolus injection initially, after saline/morphine (1 mg/kg) and after injecting MBT venom (100 μg/kg). The time-response area of the PDG-induced bradycardiac response after treatment was calculated as % of the initial PDG response area. At the end of experiments, lungs were excised for determination of pulmonary water content.Results:PDG produced bradycardiac response that lasted for >60 s. MBT venom augmented the PDG reflex response by 2.5 times. In morphine pretreated group, augmentation of bradycardiac response induced by MBT venom was absent. MBT venom increased the pulmonary water content, and the increase was absent in morphine pretreated animals.Conclusion:The results reveal that morphine prevents the MBT venom-induced augmentation of PDG reflex response and pulmonary edema. Thus, morphine can be useful in scorpion envenomation syndrome associated with pulmonary edema.

B1-kinin receptors modulate Mesobuthus tamulus venom-induced vasosensory reflex responses in anesthetized rats.

Objective:Intra-arterial injection of Mesobuthus tamulus (BT) venom produces reflex vasosensory responses modulating cardiorespiratory parameters in albino rats. The present study was conducted to understand the role of kinin receptors in modulating vasosensory reflexes evoked by BT venom.Materials and Methods:In urethane-anesthetized rats, tracheostomy was performed to keep the airway patent. The femoral artery was cannulated proximally, as well as distally, to record the blood pressure (BP) and to inject the chemicals, respectively. Electrocardiographic and respiratory excursions were recorded to compute the heart rate (HR) and respiratory rate (RR). A group of animals was pretreated with saline/kinin receptor antagonists intra-arterially (B1/B2 receptor antagonists) before the injection of venom.Results:After intra-arterial injection of BT venom (1 mg/kg), there was an immediate increase in RR, which reached to 40% within 30 s, followed by a decrease of 40%. Further, there was sustained increase in RR (50%) up to 60 min. The BP started to increase at 40 s, peaking at 5 min (50%), and remained above the initial level up to 60 min. The bradycardiac response started after 5 min which peaked (50% of initial) at 25 min and remained at that level up to 60 min. In B1 receptor antagonist (des-Arg) pretreated animals, venom-induced cardiovascular responses were attenuated (by 20–25% in mean arterial pressure and HR) significantly but not in B2 receptor antagonist (Hoe-140) pretreated animals. Either of the antagonists failed to alter the RR responses.Conclusions:BT venom-induced vasosensory reflex responses modulating cardiovascular parameters are mediated via B1-kinin receptors in anesthetized rats.

Time course of muscle sympathetic nerve activity to active muscle during mild isometric contractions in humans

Ethanol consumption is associated with several cardiovascular dysfunctions. Studies indicate that exercise and testosterone can alter the ethanol consumption. However, the influence of these factors in ethanol-evoked cardiovascular changes is unknown. Here we investigated the influence of physical training and testosterone treatment in changes on blood pressure, heart rate (HR), and baroreflex activity evoked by ethanol consumption. For this, sedentary and trained animals were randomly assigned to 4 experimental groups treated with etanol (20%) and/or testosterone (10 mg/kg, s.c.). The training protocol was performed on a treadmill and consisted of a continuous 60-min session 5 days/week for 6 weeks. Rats had free access to ethanol 20% and water bottles 3 times a week during the entire training protocol. During the last 2 weeks, testosteronewas administrated daily concurrentlywith exercise and ethanol access. Analysis of arterial pressure did not indicate effect of either physical training (P N 0.05) or treatments (P N 0.05). However, testosterone treatment (alone or in combination with ethanol) reduced HR (P b 0.05). Physical training did not affect HR (P N 0.05). Neither physical training nor ethanol/testosterone affected bradycardiac response to blood pressure increase evoked by intravenous phenylephrine infusion (P N 0,05) and tachycardiac responses to blood pressure decrease evoked by intravenous infusion of sodium nitroprusside (P N 0.05). These results did not indicate an impact of intermittent ethanol consumption in a free-choice model on cardiovascular function, contrasting with previous results using continuous access to ethanol solution as the sole fluid source. Nevertheless, testosterone treatment evoked resting bradycardia, which was not affected by either ethanol consumption or physical training. Financial support: FAPESP, PADC/FCF-UNESP.

Mechanism of the cardiovascular responses caused by l-proline microinjected into the supraoptic nucleus of the hypothalamus in unanesthetized rats

In the present study, we report on the cardiovascular effects caused by the microinjection of L-proline (L-Pro) into the supraoptic nucleus (SON) in unanesthetized rats: the possible involvement of ionotropic glutamate receptors in the SON, as well as the peripheral mechanisms involved in the mediation of its cardiovascular effects. We compared the L-Pro effects with those caused by the injection of L-glutamate (L-Glu) into the SON. Microinjection of increasing doses of L-Pro into the SON caused dose-related cardiovascular responses in unanesthetized rats that were similar to those observed after the injection of L-Glu. Pretreatment of the SON with either a selective non-NMDA (NBQX) or a selective NMDA (LY235959) glutamate receptor antagonist blocked the cardiovascular response to L-Pro. The dose-effect curve for the pretreatment with increasing doses of LY235959 was shifted to the left in relation to the curve for NBQX, showing that LY235959 is more potent than NBQX in inhibiting the cardiovascular response to L-Pro. On the other hand, the cardiovascular response to L-Glu was only significantly reduced by pretreatment with NBQX (2nmol/100nL), but not affected by LY235959 (2nmol/100nL). The pressor response to L-Pro was not affected by intravenous pretreatment with the ganglion blocker pentolinium, but it was blocked by intravenous pretreatment with the V1-vasopressin receptor antagonist dTyr(CH2)5(Me)AVP. In conclusion, these results suggest that L-Pro has a selective receptor that is sensitive to ionotropic glutamate receptor antagonists. Its activation in the SON results in vasopressin release into the systemic circulation, causing pressor and bradycardiac responses.

Possible mechanisms of action of the aqueous extract of Artocarpus altilis (breadfruit) leaves in producing hypotension in normotensive Sprague–Dawley rats

Context and objectives: Artocarpus altilis (Parkinson) Fosberg (Moraceae) (breadfruit) leaves are used as an antihypertensive remedy. We investigated the possible mechanisms of action of its aqueous extract and its effect on cytochromes P450 (CYP) enzyme activities.Materials and methods: Intravenous administration of an aqueous leaf extract (20.88–146.18 mg/kg) of A. altilis on mean arterial pressure and heart rate were recorded via cannulation of the carotid artery on anaesthetized normotensive Sprague–Dawley rats. Recordings of the contractile activity of the aortic rings to the extract (0.71–4.26 mg/mL) were studied using standard organ bath techniques. Inhibitions of human CYP3A4 and CYP2D6 enzyme activities were evaluated by means of a fluorometric assay in 96 well plates using heterologously expressed microsomes.Results: A. altilis caused significant (p < 0.05) hypotensive and bradycardiac responses unaffected by atropine (2 mg/kg) and mepyramine (5 mg/kg), but attenuated by propranolol (1 mg/kg) and N(G)-nitro-l-arginine methyl ester (5 mg/kg). The extract (0.71–4.26 mg/mL) significantly (p < 0.05) relaxed phenylephrine (10−9–10−4 M) and 80 mM KCl-induced contractions in endothelium intact and denuded aortic rings; and caused a significant (p < 0.05) rightward shift of the Ca2+ dose-response curves in Ca2+-free Kreb’s solution. Moderate inhibitions of cytochrome P450s (CYP3A4 and CYP2D6) enzyme activities with IC50 values of 0.695 ± 0.187 and 0.512 ± 0.131 mg/mL, respectively, were produced.Conclusion: A. altilis exhibits negative chronotropic and hypotensive effects through α-adrenoceptor and Ca2+ channel antagonism. Drug adversity effects are unlikely if the aqueous leaf extract is consumed with other medications reliant on CYP3A4 and CYP2D6 metabolism. This study thus provides scientific evidence for the use of the breadfruit in the treatment of hypertension.

Cardiovascular effects of the microinjection of L‐proline into the third ventricle or the paraventricular nucleus of the hypothalamus in unanesthetized rats

We investigated the cardiovascular effects of the microinjection of L-proline (L-Pro) into the third ventricle (3V) and its peripheral mechanisms. Different doses of L-Pro into the 3V caused dose-related pressor and bradycardiac responses. The pressor response to L-Pro injected into the 3V was potentiated by intravenous pretreatment with the ganglion blocker pentolinium (5 mg/kg), thus excluding any significant involvement of the sympathetic nervous system. Because the response to the microinjection of L-Pro into the 3V was blocked by intravenous pretreatment with the V1-vasopressin receptor antagonist dTyr(CH(2) )(5) (Me)AVP (50μg/kg), it is suggested that these cardiovascular responses are mediated by a vasopressin release. The pressor response to the microinjection of L-Pro into the 3V was found to be mediated by circulating vasopressin, so, given that the paraventricular nucleus of the hypothalamus (PVN) is readily accessible from the 3V, we investigated whether the PVN could be a site of action for the L-Pro microinjected in the 3V. The microinjection of L-Pro (0.033 μmoles/0.1 μl) into the PVN caused cardiovascular responses similar to those of injection of the 3V and were also shown to be mediated by vasopressin release. In conclusion, these results show that the microinjection of L-Pro into the 3V causes pressor and bradycardiac responses that could involve stimulation of the magnocellular cells of the PVN and release of vasopressin into the systemic circulation. Also, because the microinjection of L-Pro into the PVN caused a pressor response, this is the first evidence of cardiovascular effects caused by its injection in a supramedullary structure.

Cardiovascular responses to glutamate microinjection in the dorsomedial periaqueductal gray of unanesthetized rats

The periaqueductal gray area (PAG) is a mesencephalic area involved in cardiovascular modulation. Glutamate (L-Glu) is an abundant excitatory amino acid in the central nervous system (CNS) and is present in the rat PAG. Moreover, data in the literature indicate its involvement in central blood pressure control. Here we report on the cardiovascular effects caused by microinjection of L-Glu into the dorsomedial PAG (dmPAG) of rats and the glutamatergic receptors as well as the peripheral mechanism involved in their mediation. The microinjection of L-Glu into the dmPAG of unanesthetized rats evoked dose-related pressor and bradycardiac responses. The cardiovascular response was significantly reduced by pretreatment of the dmPAG with a glutamatergic M-methyl-D-aspartate (NMDA) receptor antagonist (LY235959) and was not affected by pretreatment with a non-NMDA receptor antagonist (NBQX), suggesting a mediation of that response by the activation of NMDA receptors. Furthermore, the pressor response was blocked by pretreatment with the ganglion blocker pentolinium (5 mg/kg, intravenously), suggesting an involvement of the sympathetic nervous system in this response. Our results indicate that the microinjection of L-Glu into the dmPAG causes sympathetic-mediated pressor responses in unanesthetized rats, which are mediated by glutamatergic NMDA receptors in the dmPAG.