Decrease In Mean Arterial Blood Pressure Research Articles

Concomitant administration of sGC stimulators with common classes of anti-hypertensive agents results in increased efficacy in spontaneously hypertensive rats

Background Soluble guanylate cyclase (sGC) stimulators demonstrate smooth muscle relaxation and vasodilation via the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway. A novel class of sGC stimulators, the pyrazole-pyrimidines, was synthesized with the objective of creating a potent, once-a-day (QD) oral treatment for cardiovascular diseases. Several compounds from this class were identified as potent stimulators of sGC in vitro (EC50 = 40-287 nM). These compounds were evaluated in pharmacokinetic (PK) and blood pressure pharmacodynamics (PD) in vivo rat and dog models and were shown to exhibit sustained compound exposure (Thalf = >7 hours in preclinical species) after oral dosing, predicting QD dosing in humans. Further, they significantly decreased mean arterial blood pressure (MAP (≥ 10mmHg) after oral dosing. The potential for sGC stimulators to work in combination with reference antihypertensive therapies was assessed in an in vivo PD assay in a spontaneous hypertensive rat (SHR) model. Doses of losartan, atenolol, amlodipine, and our sGC stimulators that induced an effect (< 30mmHg) on MAP were chosen. IWP-121, a representative sGC stimulator, was shown to provide additional MAP lowering effects when combined with losartan, atenolol, or amlodipine, resulting in an increase in overall blood pressure effects between 5-50%. By linking compound concentration to blood pressure change for each compound alone and in combination, we were able to assess the PK/PD relationships for the individual and combined effects.

Cerebral oxygenation in the beach chair position before and during general anesthesia in patients with and without cardiovascular risk factors

Study ObjectivesTo evaluate changes in cerebral tissue oxygen index (TOI) values under the beach chair position before and during general anesthesia in surgical patients with or without cardiovascular risk factors. DesignProspective study. SettingOperating room in the university hospital. PatientsNinety-one patients undergoing surgery, including healthy patients (n = 28), patients with 1 cardiovascular risk factor (n = 33), and those with more than 1 risk factor (n = 30). Interventions and MeasurementsCerebral TOI the day before and during general anesthesia was evaluated using a near-infrared spectroscopy NIRO-200 (Hamamatsu Photonics, Hamamatsu, Japan) for each patient. The initial TOI measurement in the supine position after a 10-minute rest or 10 minute after the endotracheal intubation was followed by measurements in 30° and subsequent 60° upright position for 5 minutes. Phenylephrine 0.1 mg and/or ephedrine 4 mg was administered intravenously to maintain mean blood pressure above 60 mm Hg accordingly. Main ResultsThe beach chair position decreased mean arterial blood pressure and heart rate under general anesthesia, although patients with more than 1 cardiovascular risk factor needed significantly more phenylephrine doses to maintain mean blood pressure above 60 mm Hg. Values of TOI were within the normal range of about 70% before and during anesthesia in all groups. ConclusionsThe beach chair position under general anesthesia did not alter cerebral oxygenation in patients with or without cardiovascular risk factors showing normal preoperative cerebral TOI values when the mean blood pressure was maintained above 60 mm Hg. The careful management using the cerebral oxygenation monitoring appears to maintain cerebral perfusion in the beach chair position during general anesthesia.

Chronic Losartan Treatment Up-Regulates AT1R and Increases the Heart Vulnerability to Acute Onset of Ischemia and Reperfusion Injury in Male Rats.

Inhibition of angiotensin II type 1 receptor (AT1R) is an important therapy in the management of hypertension, particularly in the immediate post-myocardial infarction period. Yet, the role of AT1R in the acute onset of myocardial ischemia and reperfusion injury still remains controversial. Thus, the present study determined the effects of chronic losartan treatment on heart ischemia and reperfusion injury in rats. Losartan (10 mg/kg/day) was administered to six-month-old male rats via an osmotic pump for 14 days and hearts were then isolated and were subjected to ischemia and reperfusion injury in a Langendorff preparation. Losartan significantly decreased mean arterial blood pressure. However, heart weight, left ventricle to body weight ratio and baseline cardiac function were not significantly altered by the losartan treatment. Of interest, chronic in vivo losartan treatment significantly increased ischemia-induced myocardial injury and decreased post-ischemic recovery of left ventricular function. This was associated with significant increases in AT1R and PKCδ expression in the left ventricle. In contrast, AT2R and PKCε were not altered. Furthermore, losartan treatment significantly increased microRNA (miR)-1, -15b, -92a, -133a, -133b, -210, and -499 expression but decreased miR-21 in the left ventricle. Of importance, addition of losartan to isolated heart preparations blocked the effect of increased ischemic-injury induced by in vivo chronic losartan treatment. The results demonstrate that chronic losartan treatment up-regulates AT1R/PKCδ and alters miR expression patterns in the heart, leading to increased cardiac vulnerability to ischemia and reperfusion injury.

Anti Hypertensive Activity of the Ethanolic Extract of Lantana camara leaves on high salt loaded wistar albino rats

Background: Hypertension is the most common and major cardiovascular disease. There is an urgent need for treament of hypertension by exploration of several medicinal plants having potent anti hypertensive activity as the modern medicines are having many side effects. Objective: The study focus on scientific evaluation of antihypertensive activity of ethanolic extract of Lantana camara leaves (EELC) in different experimental models. Material & methods: Antihypertensive activity was conducted on wister albino rats by determining serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), creatinine and Sodium levels by using Semi Autoanalyser and Flame photometer; chick mean arterial blood pressure by using condon’s mercury manometer and isolated frog heart for recording cardic responses using student kymograph. Results: EELC produced negative inotropic and negative chronotropic effect, antagonised by atropine on isolated frog heart. EELC shows dose dependent (p<0.05) decreased mean arterial blood pressure (MABP) in anaesthetic chick. Salt treated rats displayed significant (p<0.05) increase in blood level of SGOT, SGPT, Creatinine and sodium, decrease in pottassim levels in comparision with normal rats. Treatment with EELC (200 and 400 mg/kg) significantly balanced the ionic levels such as lower the sodium and elevate the potassium levels. Creatinine levels were signifi-cantly (p<0.05) reduced by the treatment with EELC. There are no significant changes occurred in serum SGOT and SGPT upon EELC administration. The present study suggests that treatment of salt hypertensive rats with EELC protects against renal injuries. Conclusion: It was concluded that ethanolic extract of Lantana camara leaves reduces work load of heart, maintain inotonic levels by negative chronotropic effect, relaxes the smooth muscles in chick and salt hypertensive rats against renal and vascular injuries is proved.

The Effect of Decreasing Flow Rate on Cerebral Hemodynamics During Veno-Arterial Extracorporeal Membrane Oxygenation in Piglets.

To explore the influence of decreasing flow rate on cerebral hemodynamics during veno-arterial extracorporeal membrane oxygenation (va-ECMO), six normoxemic and six hypoxemic piglets were put on va-ECMO. The ECMO flow rate was decreased from the maximal achievable level to 50 mL min1 with steps of 50 mL min1 every 2 minutes. Changes in mean arterial blood pressure (MABP), left common carotid artery blood flow (Qcar), and other physiologic variables were continuously measured. Changes in concentrations of oxyhemoglobin and deoxyhemoglobin were measured using near infrared spectrophotometry (NIRS). Changes in difference between cerebral oxygen hemoglobin and deoxyhemoglobin concentration (ΔcHbD) and total hemoglobin concentration (ΔctHb) were calculated. ΔcHbD represents changes in cerebral blood flow (CBF), and ΔctHb reflects changes in cerebral blood volume (CBV). Data analysis was performed using mixed models and demonstrated a significant positive correlation between ECMO flow and, respectively, MABP (r = 0.7, p < 0.001), Qcar (r = 0.7, p < 0.001), cHbD (r = 0.8, p < 0.001), and ctHb (r = 0.7, p < 0.001). There was no significant relation between oxygenation state preceding ECMO and Qcar, cHbD, and ctHb during decreasing ECMO flow rate. We conclude that decreasing ECMO flow rate ultimately leads to concurrent decrease in MABP, CBF, and CBV.

Tissue inflammation and nitric oxide-mediated alterations in cardiovascular function are major determinants of endotoxin-induced insulin resistance.

BackgroundEndotoxin (i.e. LPS) administration induces a robust inflammatory response with accompanying cardiovascular dysfunction and insulin resistance. Overabundance of nitric oxide (NO) contributes to the vascular dysfunction. However, inflammation itself also induces insulin resistance in skeletal muscle. We sought to investigate whether the cardiovascular dysfunction induced by increased NO availability without inflammatory stress can promote insulin resistance. Additionally, we examined the role of inducible nitric oxide synthase (iNOS or NOS2), the source of the increase in NO availability, in modulating LPS-induced decrease in insulin-stimulated muscle glucose uptake (MGU).MethodsThe impact of NO donor infusion on insulin-stimulated whole-body and muscle glucose uptake (hyperinsulinemic-euglycemic clamps), and the cardiovascular system was assessed in chronically catheterized, conscious mice wild-type (WT) mice. The impact of LPS on insulin action and the cardiovascular system were assessed in WT and global iNOS knockout (KO) mice. Tissue blood flow and cardiac function were assessed using microspheres and echocardiography, respectively. Insulin signaling activity, and gene expression of pro-inflammatory markers were also measured.ResultsNO donor infusion decreased mean arterial blood pressure, whole-body glucose requirements, and MGU in the absence of changes in skeletal muscle blood flow. LPS lowered mean arterial blood pressure and glucose requirements in WT mice, but not in iNOS KO mice. Lastly, despite an intact inflammatory response, iNOS KO mice were protected from LPS-mediated deficits in cardiac output. LPS impaired MGU in vivo, regardless of the presence of iNOS. However, ex vivo, insulin action in muscle obtained from LPS treated iNOS KO animals was protected.ConclusionNitric oxide excess and LPS impairs glycemic control by diminishing MGU. LPS impairs MGU by both the direct effect of inflammation on the myocyte, as well as by the indirect NO-driven cardiovascular dysfunction.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-015-0223-2) contains supplementary material, which is available to authorized users.

Bacillus anthracis edema but not lethal toxin challenge in rats is associated with depressed myocardial function in hearts isolated and tested in a Langendorff system

Although direct myocardial depression has been implicated in the lethal effects of Bacillus anthracis lethal toxin (LT), in hearts isolated from healthy rats and perfused under constant pressure, neither LT or edema toxin (ET) in typically lethal concentrations depressed myocardial function. In the present study, we challenged rats with LT and ET and performed in vivo and ex vivo heart measures. Sprague-Dawley rats infused over 24 h with LT (n = 94), ET (n = 99), or diluent (controls; n = 50) were studied at 8, 24, or 48 h. Compared with control rats (all survived), survival rates with LT (56.1%) and ET (37.3%) were reduced (P < 0.0001) similarly (P = 0.66 for LT vs. ET). LT decreased mean arterial blood pressure from 12 to 20 h (P ≤ 0.05), whereas ET decreased it progressively throughout (P < 0.05). On echocardiography, LT decreased left ventricular (LV) ejection fraction at 8 and 48 h but increased it at 24 h and decreased cardiac output (P ≤ 0.05 for the time interaction or averaged over time). ET decreased systolic and diastolic volumes and increased LV ejection fraction at 24 h (P ≤ 0.05). In isolated hearts perfused for 120 min under constant pressure, LT did not significantly alter LV systolic or developed pressures at any time point, whereas ET decreased both of these at 24 h (P < 0.0001 initially). ET but not LT progressively increased plasma creatine phosphokinase and cardiac troponin levels (P < 0.05). In conclusion, despite echocardiographic changes, in vivo lethal LT challenge did not produce evidence of myocardial depression in isolated rat hearts. While lethal ET challenge did depress isolated heart function, this may have resulted from prior hypotension and ischemia.

SGC Stimulation Results in Potent Anti‐hypertensive Effects as a Stand‐alone or Combination Therapy in the Rat

Soluble guanylate cyclase (sGC) stimulators have the potential to treat a variety of cardiovascular diseases via the nitric oxide (NO)‐sGC‐cyclic guanosine monophosphate (cGMP) pathway. Ironwood Pharmaceuticals has synthesized a number of novel sGC stimulators with the objective of creating a once‐a‐day oral anti‐hypertensive.A screening paradigm that evaluated sGC enzyme stimulation, pharmacokinetics (PK), and pharmacodynamics (PD) identified three novel sGC stimulators that induce sustained cardiovascular effects after oral dosing. Potency against sGC was evaluated using an in vitro cell based assay that measured cGMP production. Compounds were subsequently evaluated in PK and blood pressure PD in vivo rat models. All compounds were potent stimulators of sGC in vitro (EC50 = 40‐220nM), had sustained compound exposure in vivo (Thalf 7‐12 hours) after oral dosing, and significantly decreased mean arterial blood pressure (MABP) in vivo (蠅 10mmHg) after oral dosing.The potential for sGC stimulators to work in combination with reference anti‐hypertensive therapies was assessed in our in vivo PD assay. Doses of Losartan, Atenolol, Amlodipine or each of our sGC stimulators that induced a decrease in MABP (蠅 10mmHg) when dosed alone were chosen. Combining sGC stimulators with anti‐hypertensives resulted in an additional 5‐50% decrease in MABP over either therapy given alone. These data indicate that IWP sGC stimulators possess potent anti‐hypertensive effects in the rat and that their efficacy increases when dosed in combination with standard anti‐hypertensive agents.This research was funded by Ironwood Pharmaceuticals.

Acute and chronic temperature effects on cardiovascular regulation in the red-eared slider (Trachemys scripta).

Acute and chronic changes in ambient temperature alter several aspects of reptilian physiology. We investigated the effects of each type of temperature change on reptilian cardiovascular regulation in red-eared slider turtles (Trachemys scripta), a species known to experience marked seasonal changes in ambient temperature. Turtles were instrumented with occlusive catheters in the femoral artery and vein. Following an acclimation period of 10 days at 13 °C (13(1)), cardiovascular responses to adrenaline, and the cardiac limb of the baroreflex were quantified. Ambient temperature was then reduced 1 °C day(-1) until 3 °C was reached (3(1)). Turtles were maintained at this temperature for 1-week before cardiovascular responses were reassessed. Turtles were then gradually (1 °C day(-1)) returned to an ambient temperature of 13 °C, (13(2)). After a 1-week re-acclimation period, cardiovascular responses were again determined. Finally, 1-week post-pharmacological manipulation of turtles in the 13(2) treatment, ambient temperature was reduced to 3 °C over 24 h (3(2)), and cardiovascular responses were again assessed. Temperature reduction from 13(1) to 3(1) decreased mean arterial blood pressure (P(m)) and heart rate (f(H)) by ~38 and ~63%, respectively. Acute temperature reduction, from 13(2) to 3(2), decreased f(H) similarly, ~66%; however, while P(m) decreased ~28%, this was not significantly different than P(m) at 13(2). The adrenaline injections increased f(H) ranging from 90 to 170% at 13 °C which was a greater change than that observed at 3 °C ranging from a 40 to 70% increase. The increase in P m at the lowest dose of adrenaline did not differ across the temperature treatment groups. The operational point (set-point) P(m) of the baroreflex was decreased similarly by both methods of temperature reduction (3(1) or 3(2)). Further, a hypertensive cardiac baroreflex was absent in the majority of the animals studied independent of temperature. Baroreflex gain and normalized gain based on individual estimates of the relationship were decreased by temperature reduction similarly. Collectively, the data suggest that red-eared slider turtles modulate (down-regulate) some cardiovascular control mechanisms during reduced ambient temperature.

Atorvastatin reduces endotoxin-induced microvascular inflammation via NOSII.

In a lipopolysaccharide (LPS)-induced rat model of sepsis (endotoxaemia), we previously demonstrated that pravastatin reduced microvascular inflammation via increased endothelial nitric oxide synthase III (NOSIII). This study aimed to determine whether atorvastatin, the most commonly used statin for lowering cholesterol, exerted beneficial pleiotropic effects via a similar mechanism. The mesenteric microcirculation of anaesthetised male Wistar rats (308 ± 63g, n = 54) was prepared for fluorescent intravital microscopy. Over 4h, animals received intravenous (i.v.) administration of either saline, LPS (150μgkg(-1)h(-1)) or LPS + atorvastatin (200μgkg(-1)s.c., 18 and 3h before LPS), with/without the non-specific NOS inhibitor L-NG-Nitroarginine Methyl Ester (L-NAME) (10μgkg(-1)h(-1)) or NOSII-specific inhibitor 1400W (20μgkg(-1)min(-1)). LPS decreased mean arterial blood pressure (MAP) (4h, control 113 ± 20mmHg; LPS 70 ± 23mmHg), being reversed by atorvastatin (105 ± 3mmHg) (p < 0.05). LPS also increased macromolecular leak measured after 100mgkg(-1) of i.v FITC-BSA (arbitrary grey level adjacent to venules), which again was attenuated by atorvastatin (control 1.9 ± 4.0; LPS 12.0 ± 2.4; LPS + atorvastatin 4.5 ± 2.2) (p < 0.05). Furthermore, immunohistochemistry identified that atorvastatin decreased LPS-induced upregulation of endothelial cell NOSII expression, but NOSIII was unchanged in all groups. Atorvastatin improved MAP and reduced microvascular inflammation during endotoxaemia, associated with a reduction of pro-inflammatory NOSII. This differs from previous studies, whereby pravastatin increased expression of NOSIII. Thus preoperative statins have beneficial anti-inflammatory effects during endotoxaemia, but careful consideration must be given to the specific statin being used.

Abstract 526: Blood Pressure in the SHR Following Renal Denervation or Etamicastat, a Novel Dopamine-β-Hydroxylase Inhibitor

Overactivity of the sympathetic nervous system plays an important role in the development and progression of hypertension. Catheter-based renal nerve ablation for treatment of drug-resistant hypertension has been recently developed. An alternative strategy for modulation of sympathetic nerve function is to reduce the biosynthesis of norepinephrine (NE) via inhibition of dopamine β-hydroxylase (DβH), the enzyme that catalysis the conversion of dopamine to NE in sympathetic nerves. Renal denervation (RDN) was performed in spontaneously hypertensive rats (SHR) to evaluate the effect of RDN on NE levels and blood pressure throughout a 28-day period. Chronic oral treatment with the peripheral selective DβH inhibitor etamicastat (30 mg/kg/day) was performed in another cohort of SHR. RDN and chronic oral treatment with etamicastat did not affect renal function, as assessed by urinary protein, creatinine and urea levels. RDN significantly decreased mean arterial blood pressure (MAP, in mm Hg) 7 days post-surgery (139±6, P&lt;0.01) versus baseline values (158±6). A gradual MAP return to high baseline levels was observed overtime; 139±7 at day 14, 151±12, at day 21 and 155±12 at day 28 after RDN. Treatment with etamicastat decreased baseline MAP (150±5) in a sustained and significant (P&lt;0.01) manner at all-time points: 141±5 at day 7, 139±5 at day 14, 138±5 at day 21 and 143±5 at day 28. At day 28, NE levels (in pmol/mg tissue) in renal tissue were significantly decreased in both RDN (0.12±0.08, P=0.001) and etamicastat-treated group (0.48±0.04, P=0.01) as compared to vehicle group (0.88±0.13). On the other hand, left ventricle NE levels were decreased only after treatment with etamicastat (1.24±0.12, P=0.04) but not in the RDN group (2.53±0.24, P=0.9) when compared to controls (2.59±0.58). It is concluded that RDN produces transitory decreases in MAP, whereas prolonged down regulation of sympathetic drive with the DβH inhibitor etamicastat results in sustained decreases in MAP.

The guanosine-adenosine interaction exists in vivo.

In cultured renal cells and isolated perfused kidneys, extracellular guanosine augments extracellular adenosine and inosine (the major renal metabolite of adenosine) levels by altering the extracellular disposition of these purines. The present study addressed whether this "guanosine-adenosine mechanism" exists in vivo. In rats (n = 15), intravenous infusions of adenosine (1 µmol/kg per minute) decreased mean arterial blood pressure (MABP) from 114 ± 4 to 83 ± 5 mm Hg, heart rate (HR) from 368 ± 11 to 323 ± 9 beats/min), and renal blood flow (RBF) from 6.2 ± 0.5 to 5.3 ± 0.6 ml/min). In rats (n = 15) pretreated with intravenous guanosine (10 µmol/kg per minute), intravenous adenosine (1 µmol/kg per minute) decreased MABP (from 109 ± 4 to 58 ± 5 mm Hg), HR (from 401 ± 10 to 264 ± 20 beats/min), and RBF (from 6.2 ± 0.7 to 1.7 ± 0.3). Two-factor analysis of variance (2F-ANOVA) revealed a significant interaction (P < 0.0001) between guanosine and adenosine for MABP, HR, and RBF. In control rats, the urinary excretion rate of endogenous inosine was 211 ± 103 ng/30 minutes (n = 9); however, in rats treated with intravenous guanosine (10 µmol/kg per minute), the excretion rate of inosine was 1995 ± 300 ng/30 minutes (n = 12; P < 0.0001 versus controls). Because adenosine inhibits inflammatory cytokine production, we also examined the effects of intravenous guanosine on endotoxemia-induced increases in tumor necrosis factor-α (TNF-α). In control rats (n = 7), lipopolysaccharide (LPS; Escherichia coli 026:B6 endotoxin; 30 mg/kg) increased plasma TNF-α from 164 ± 56 to 4082 ± 730 pg/ml, whereas in rats pretreated with intravenous guanosine (10 µmol/kg per minute; n = 6), LPS increased plasma TNF-α from 121 ± 45 to 1821 ± 413 pg/ml (2F-ANOVA interaction effect, P = 0.0022). We conclude that the guanosine-adenosine mechanism exists in vivo and that guanosine may be a useful therapeutic for reducing inflammation.

Exogenous hydrogen sulfide causes different hemodynamic effects in normotensive and hypertensive rats via neurogenic mechanisms

BackgroundIncreasing evidence suggests that disturbances in H2S homeostasis may participate in the development of hypertension. In this study we compared hemodynamic responses to intracerebroventricular (ICV) infusions of sodium hydrosulfide (NaHS), a H2S donor, between normotensive rats (WKY), spontaneously hypertensive rats (SHR) and angiotensin II – induced hypertensive rats (WKY-Ang II). MethodsWe tested the effects of NaHS on mean arterial blood pressure (MABP) and heart rate (HR) in 12–14-week-old, male rats. MABP and HR were continuously recorded at baseline and during ICV infusion of either vehicle (Krebs–Henseleit buffer) or NaHS. ResultsICV infusions of the vehicle did not affect MABP and HR. WKY rats infused with 30nmol/h of NaHS showed a mild decrease in MABP and HR. ICV infusion of 100nmol/h produced a biphasic response i.e. mild hypotension and bradycardia followed by an increase in MABP and HR, whereas, the infusion of 300nmol/h of the H2S donor caused a monophasic increases in MABP and HR. In contrast, SHR rats as well as WKY-Ang II rats showed a decrease in MABP and HR during ICV infusions of NaHS. ConclusionsThe results provide further evidence for the involvement of H2S in the neurogenic regulation of the circulatory system and suggest that alterations in H2S signaling in the brain could be associated with hypertension.

Comparison of the cardiorespiratory effects of a combination of ketamine and propofol, propofol alone, or a combination of ketamine and diazepam before and after induction of anesthesia in dogs sedated with acepromazine and oxymorphone

To evaluate the cardiorespiratory effects of IV administration of propofol (4 mg/kg), ketamine hydrochloride and propofol (2 mg/kg each; K-P), or ketamine hydrochloride (5 mg/kg) and diazepam (0.2 mg/kg; K-D) before and after induction of anesthesia (IoA) in dogs sedated with acepromazine maleate and oxymorphone hydrochloride. 10 healthy adult Beagles. Each dog was randomly allocated to receive 2 of 3 treatments (1-week interval). For instrumentation prior to each treatment, each dog was anesthetized with isoflurane. After full recovery, acepromazine (0.02 mg/kg) and oxymorphone (0.05 mg/kg) were administered IV. Fifteen minutes later (before IoA), each dog received treatment IV with propofol, K-P, or K-D. Cardiorespiratory and arterial blood gas variables were assessed before, immediately after, and 5 minutes after IoA. Compared with findings before IoA, dogs receiving the K-P or K-D treatment had increased cardiac output, oxygen delivery, and heart rate 5 minutes after IoA; K-P administration did not change mean arterial blood pressure or stroke volume and decreased systemic vascular resistance. Propofol decreased mean arterial blood pressure and systemic vascular resistance immediately after IoA but did not change heart rate, cardiac output, or oxygen delivery. All treatments caused some degree of apnea, hypoventilation, and hypoxemia (Pao2 < 80 mm Hg). In dogs, K-P treatment maintained mean arterial blood pressure better than propofol alone and increased heart rate, cardiac output, or oxygen delivery, as did the K-D treatment. Supplemental 100% oxygen should be provided during IoA with all 3 treatments.

Comparison of pharmacological activity of macitentan and bosentan in preclinical models of systemic and pulmonary hypertension

AimsThe endothelin (ET) system is a tissular system, as the production of ET isoforms is mostly autocrine or paracrine. Macitentan is a novel dual ETA/ETB receptor antagonist with enhanced tissue distribution and sustained receptor binding properties designed to achieve a more efficacious ET receptor blockade. To determine if these features translate into improved efficacy in vivo, a study was designed in which rats with either systemic or pulmonary hypertension and equipped with telemetry were given macitentan on top of maximally effective doses of another dual ETA/ETB receptor antagonist, bosentan, which does not display sustained receptor occupancy and shows less tissue distribution. Main methodsAfter establishing dose–response curves of both compounds in conscious, hypertensive Dahl salt-sensitive and pulmonary hypertensive bleomycin-treated rats, macitentan was administered on top of the maximal effective dose of bosentan. Key findingsIn hypertensive rats, macitentan 30mg/kg further decreased mean arterial blood pressure (MAP) by 19mmHg when given on top of bosentan 100mg/kg (n=9, p<0.01 vs. vehicle). Conversely, bosentan given on top of macitentan failed to induce an additional MAP decrease. In pulmonary hypertensive rats, macitentan 30mg/kg further decreased mean pulmonary artery pressure (MPAP) by 4mmHg on top of bosentan (n=8, p<0.01 vs. vehicle), whereas a maximal effective dose of bosentan given on top of macitentan did not cause any additional MPAP decrease. SignificanceThe add-on effect of macitentan on top of bosentan in two pathological models confirms that this novel compound can achieve a superior blockade of ET receptors and provides evidence for greater maximal efficacy.

Patient-controlled sedation with propofol/remifentanil versus propofol/alfentanil for patients undergoing outpatient colonoscopy, a randomized, controlled double-blind study.

Context:Many techniques are used for sedation of colonoscopies. Patient-controlled sedation (PCS) is utilizing many drugs or drug combinations.Aims:The aim of this study is to compare the safety and feasibility of propofol/remifentanil versus propofol/alfentanil given to sedate patients undergoing outpatient colonoscopies through a patient-controlled technique.Settings and Design:Controlled randomized and double-blind study.Materials and Methods:A total of 80 patients were randomly divided into two groups; PA group received a combination of propofol/alfentanil and PR group received propofol/remifentanil combination. Patients were monitored for heart rate (HR), blood pressure (BP), oxygen saturation, and Ramsay sedation scale (RSS). Times of the following events were recorded; initiation of sedation, insertion and removal of the colonoscope, recovery and discharge. Five intervals were calculated; time to sedation, procedure time, postprocedure time, procedure room time, and postanesthesia care unit (PACU) time. Endoscopist and patient satisfaction scores were obtained.Statistical Analysis Used:Unpaired Student's t-test was used to compare between the two groups. Paired Student's t-test was used to compare baseline readings with readings after 30 min of sedation in the same group when needed.Results:Both groups showed slowing of the HR and decrease in mean arterial BP. HR and mean arterial BP were significantly lower 5 and 10 min after initiation of sedation in PR group when compared with PA group. Both HR and mean arterial BP returned to presedation readings 30 min after initiation of sedation in PR group but not in PA group. No differences between the two groups concerning oxygen saturation, RSS, endoscopist and patient satisfaction scores. Postprocedure and PACU times were significantly prolonged in PA group.Conclusion:PCS with either remifentanil/propofol or alfentanil/propofol for patients undergoing outpatient colonoscopy is safe and feasible. Remifentanil/proofol has more beneficial advantages in this setting secondary to its more rapid clearance.

Amlodipine Increased Endothelial Nitric Oxide and Decreased Nitroxidative Stress Disproportionately to Blood Pressure Changes

Clinical trials have shown that amlodipine reduces cardiovascular events at a rate that is not predicted by changes in brachial arterial pressure alone. These findings may be explained, in part, by the pleiotropic effects of amlodipine on endothelial cell (EC) function. In this study, we elucidated the effect of amlodipine on nitric oxide (NO) bioavailability and cytotoxic peroxynitrite (ONOO(-)) and blood pressure (BP). Spontaneously hypertensive rats (SHRs) were treated with vehicle or amlodipine (5 mg/kg/day) for 8 weeks and compared with untreated, baseline rats. NO and ONOO(-) release from aortic and glomerular ECs were measured ex vivo using amperometric nanosensors following maximal stimulation with calcium ionophore. BP was measured using the tail-cuff method. As compared with baseline, vehicle treatment had reduced aortic endothelial NO release from 157 ± 11 nM to 55 ± 6 nM and increased ONOO(-) from 69 ± 7 nM to 156 ± 19 nM. The NO/ONOO(-) ratio, a comprehensive measurement of eNOS function, decreased from 2.3 ± 0.3 to 0.3 ± 0.1. Compared with vehicle, amlodipine treatment restored NO to 101 ± 3 nM, decreased ONOO(-) to 50 ± 4 nM, and increased the NO/ONOO(-) ratio to 2.0 ± 0.2, a level similar to baseline. Similar changes were observed for glomerular ECs. Mean arterial blood pressure increased from 149 ± 3 mm Hg (baseline) to 174 ± 1 mm Hg (vehicle). Amlodipine slightly, but significantly, decreased mean arterial blood pressure to 167 ± 3 mm Hg vs. vehicle treatment. Amlodipine increased NO bioavailability and decreased nitroxidative stress in SHRs with EC dysfunction disproportionately to BP changes. These direct, vascular effects of amlodipine on EC function may contribute to reduced risk for atherothrombotic events as observed in clinical trials.

Abstract 413: Renal Cyclooxygenase-2 Expression And Hemodynamic Role During Angiotensin II-dependent Hypertension

Intrarenal cyclooxygenase-2 (COX-2) activity is increased during activation of the renin-angiotensin-system (RAS) increasing synthesis of prostaglandin E2 (PGE2) and buffering the vasoconstrictor and antinatriuretic effects of angiotensin II (AngII). While AngII upregulates intrarenal COX-2 expression, it remains unclear if this occurs in a time-dependent manner, thereby impacting renal hemodynamics differently during the early and late phases of the development of high blood pressure in AngII-induced hypertension. Male Sprague-Dawley rats were infused with AngII (0.4 μg/min/kg). Systolic blood pressure (SBP), COX-2 expression and PGE2 tissue content and urinary excretion were evaluated at day 3, 7 and 14 of the AngII infusions. In acute studies we evaluated the effects of COX-2 inhibition at day 5-7 and day 14 on renal hemodynamic parameters. Chronic AngII infusions increased SBP from day 7 through 14: 162 ± 5 mmHg; and 198 ± 15 mmHg versus controls: 114 ± 10 mmHg; P&lt;0.05. COX-2 mRNA and protein levels were high in kidney cortex only at day 3 (mRNA: 241 ± 56%, protein: 160 ± 21%, P&lt;0.05 versus controls). Medullary COX-2 mRNA and protein were increased on days 3 (mRNA: 176 ± 20%, protein: 185 ± 32%, P&lt;0.05 versus controls), 7 (mRNA: 189 ± 23%, protein: 158 ± 15%, P&lt;0.05 versus controls) and 14 (mRNA: 148 ± 15%, protein: 135 ± 13%, P&lt;0.05 versus controls). Urinary and medullary PGE2 increased by day 3 and remained elevated during days 7 and 14. COX-2 inhibition decreased GFR and renal blood flow in AngII infused rats during both the early and late phases. Interestingly, COX-2 inhibition decreased mean arterial blood pressure at day 14 of AngII-infusion (COX-2 inhibition: 124 ± 9 versus 140 ± 7 mmHg, P&lt;0.05) but not during the early normotensive phase (COX-2 inhibition: 110 ± 4 versus 115± 4 mmHg, P=NS). These results indicate that enhanced medullary COX-2 expression and PGE2 production during both the early and late phases attenuates the effects of AngII on renal hemodynamics. However COX-2 inhibition at day 14 reduced blood pressure, suggesting that a vasoconstrictor COX-2 metabolite contributes to the hypertension during the late phase.

Potent antihypertensive activity of Thai-Lanna medicinal plants and recipes from “MANOSROI III” database

Context: Traditional medicines have long been used by Thai practitioners for the treatment of many diseases including hypertension. The antihypertensive recipes and plants were searched and selected by a computer program from Thai/Lanna medicinal plant recipe database “MANOSROI III” using hypertensive symptoms as keywords.Objectives: To evaluate the antihypertensive potential of 30 recipes and 10 Thai-Lanna medicinal plants selected from “MANOSROI III” database using l-NAME induced hypertensive rat model.Materials and methods: Extracts from the selected recipes and plants were prepared according to the traditional indications. Antihypertensive activities including the decrease of the mean arterial blood pressure (MABP) and heart rate (HR) of the extracts as well as duration of action were investigated by intra-arterial assessment technique. All extracts were screened for phytochemicals including anthraquinone, glycoside, xanthone, tannin, carotenoid, flavones and alkaloids using standard methods.Results and conclusions: All 12 of the 30 selected recipes (40%) demonstrated antihypertensive activity with the maximum decrease of MABP at 27.17 ± 3.17% that was 2.41-fold of prazosin hydrochloride. Most recipes exhibiting antihypertensive activity contained plants in the families of Zingiberaceae and Piperaceae. The top five antihypertensive recipes showed the presence of glycosides, xanthones and alkaloids. Ten single plants from these recipes were extracted and evaluated for antihypertensive activity. The cassumunar ginger extract exhibited the maximum decrease of MABP at 39.83 ± 3.92%, which was 3.54-times that of prazosin hydrochloride. This study demonstrated the potent antihypertensive activity of Thai medicinal plants and recipes that can be further developed as antihypertensive agents.

Abstract 524: Extracellular Guanosine Regulates Extracellular Adenosine Levels

Extracellular adenosine modulates cardiovascular and renal function. While measuring extracellular purines in biological samples, we observed a correlation between levels of adenosine and guanosine. This observation led us to test the hypothesis that extracellular guanosine regulates extracellular adenosine levels in the cardiovascular and renal systems. Rat preglomerular vascular smooth muscle cells in culture were incubated with adenosine and/or guanosine. In the absence of added adenosine, exogenous guanosine (30 μmol/L) had little effect on extracellular adenosine levels, indicating that extracellular guanosine does not trigger the release or production of adenosine. Without added guanosine and 1 hour after adding 3 μmol/L of exogenous adenosine, extracellular adenosine levels were only 0.125 ± 0.020 μmol/L, indicating rapid disposition of extracellular adenosine by a monolayer of cells. In contrast, extracellular adenosine levels 1 hour after adding 3 μmol/L of adenosine plus guanosine (30 μmol/L) were 1.173 ± 0.061 μmol/L (9-fold higher; p&lt;0.0001), indicating slow disposition of extracellular adenosine in the presence of extracellular guanosine. Extracellular guanosine impeded the disposition of extracellular adenosine not only in preglomerular vascular smooth muscle cells, but also in rat preglomerular vascular endothelial cells, mesangial cells, cardiac fibroblasts and kidney epithelial cells, as well as in human aortic vascular smooth muscle cells, coronary artery vascular smooth muscle cells and coronary artery endothelial cells. In rats, infusions of guanosine per se had little effect on cardiovascular/renal variables, yet markedly enhanced the effects of co-infusions of adenosine. For example, in control rats, adenosine (0.3 μmol/kg/min) only modestly decreased mean arterial blood pressure (from 114 ± 4 to 100 ± 4 mm Hg). In contrast, in guanosine-treated rats (10 μmol/kg/min), adenosine profoundly decreased blood pressure (from 109 ± 4 to 79 ± 3 mm Hg; p&lt;0.0001 vs non-guanosine treated group). Conclusion: Extracellular guanosine powerfully regulates extracellular adenosine levels by altering adenosine disposition and this occurs in many, perhaps most, cell types in the cardiovascular system and kidneys.