Effects Of Phenylephrine Research Articles

Abstract 20118: Defining the Sufficiency of Atg7 to Suppress Phenylephrine-induced Cardiac Hypertrophy

Introduction: Macroautophagy is a process of bulk protein degradation. Our prior work showed that Atg7 expression is sufficient to induce autophagic flux in vitro and in vivo . When Atg7 was co-expressed with CryAB R120G in the heart, cardiac hypertrophy was blunted in heart weight/body weight ratios and fetal gene expression markers. To determine if Atg7 expression is sufficient to limit hypertrophic growth in another model, we tested the effects of Atg7 overexpression with phenylephrine-induced hypertrophy both in vitro and in vivo . Hypothesis: Atg7 will blunt the hypertrophic effects of phenylephrine. Methods: Rat neonatal cardiomyocytes were infected with adenoviruses expressing either LacZ or Atg7 and treated with phenylephrine to induce cardiomyocytes hypertrophy. Osmotic pumps were surgically implanted into control mice and mice with cardiac-specific expression of Atg7 to infuse phenylephrine (PE) or vehicle (saline) for four weeks. Results: PE treatment significantly increased neonatal cardiomyocyte areas in LacZ-expressing cells, while Atg7-expressing cardiomyocytes showed no growth. In mice, all genotypes responded to PE treatment with significantly increased heart weight/body weight ratios and increased fiber size. However, Atg7-expressing hearts differed significantly from control hearts in normalized heart mass following PE delivery. Vehicle treated Atg7-expressing hearts had 17% smaller myofiber cross-sectional areas than those from control genotypes and had a reduced hypertrophic response to PE, relative to controls. Echocardiography showed that Atg7-expressing hearts had significantly elevated cardiac function (% fractional shortening) prior to and throughout the experiment over control hearts (33% vs. 29%). PE significantly increased fractional shortening) from 29% to 36% in control hearts, but failed to significantly elevate cardiac function in Atg7-expressing hearts further (33% vs 35%). Additional assays are underway to understand the Atg7-dependent adaptations to PE. Conclusion: Atg7 expression yields modestly smaller hearts with enhanced cardiac function which may protect them from hypertrophic stresses like phenylephrine.

Gender-specific differences in the in situ cardiac function of endotoxemic rats detected by pressure-volume catheter.

The aim of the present study was to investigate the existence of gender-related differences in the profile of changes that occur in cardiac functionality during endotoxic shock. For this, both male and female Wistar rats received a single injection of lipopolysaccharide (LPS; 10 mg/kg, i.p.) at 6 h (LPS 6-h group) or 24 h (LPS 24-h group) before the induction of anesthesia and insertion of a pressure-volume catheter using the closed-chest method. Control animals received sterile saline. Hemodynamic parameters were recorded under basal conditions and during the peak of the pressor effect of phenylephrine (30 nmol/kg i.v.). Body temperature, hematologic parameters, blood glucose, and diuresis were also evaluated. There were unremarkable differences between male and female rats in the general aspects of sepsis evaluated in our study. Both male and female rats from the LPS 6-h group presented hypotension, depressed left ventricular ejection fraction, decreased stroke work, reduced dP/dtmax (maximal rate of left ventricle pressure change), P@dP/dtmax (pressure value at the maximum dP/dtmax), dP/dtmin (minimal rate of left ventricle pressure change), and preload-recruitable stroke work indices, as well as increased end-systolic volume. Nevertheless, only male rats from the LPS 24-h group still presented decreased stroke work and reduced dP/dtmax, P@dP/dtmax, and preload-recruitable stroke work indices. The end-systolic volume presented slight changes during the pressor effects of phenylephrine in all groups of male rats, as well as in females from the control and LPS 6-h groups, but it was significantly increased in females from the LPS 24-h group. These findings suggest that after induction of endotoxic shock female rats may recover the inotropic cardiac function earlier than males, as well as present improved adaptation of their left ventricle to the pressure-loading effects of phenylephrine.

Prophylactic effects of elastin peptide derived from the bulbus arteriosus of fish on vascular dysfunction in spontaneously hypertensive rats

AimsTo determine the prophylactic effects of an elastin peptide derived from the bulbus arteriosus of bonitos and prolylglycine (PG), a degradation product of elastin peptide, on vascular dysfunction in spontaneously hypertensive rats (SHRs). Main methodsMale 15-week-old SHR/Izm rats were fed without (control group) or with elastin peptide (1g/kg body weight) for 5weeks (EP group), or were infused via an osmotic mini-pump for 4weeks with PG (PG group) or saline (control group). Using thoracic aortas, we assessed endothelial changes by scanning electron microscopy. Vascular reactivity (contraction and relaxation) and pressure-induced distension was compared. mRNA production levels of endothelial nitric oxide synthase (eNOS) and intercellular adhesion molecule-1 (ICAM-1) were investigated by real-time-polymerase chain reaction. Key findingsAortas of the EP group displayed limited endothelial damage compared with that in the control group. Under treatment of SHRs with elastin peptide, the effect of phenylephrine returned closer to the normal level observed in normotensive Wistar–Kyoto (WKY/Izm) rats. mRNA production of eNOS (but not ICAM-1) was greater in the EP group than in the control group. Endothelial damage was suppressed and pressure-induced vascular distension was greater in the PG group than in the corresponding control group. SignificanceThese results suggest that elastin peptide from bonitos elicits prophylactic affects hypertension-associated vascular dysfunction by targeting the eNOS signaling pathway. PG may be a key mediator of the beneficial effects of elastin peptide.

External carotid artery flow maintains near infrared spectroscopy-determined frontal lobe oxygenation during ephedrine administration

Phenylephrine and ephedrine affect frontal lobe oxygenation ([Formula: see text]) differently when assessed by spatially resolved near infrared spectroscopy. We evaluated the effect of phenylephrine and ephedrine on extra- vs intra-cerebral blood flow and on [Formula: see text]. In 10 healthy males (age 20-54 yr), phenylephrine or ephedrine was infused for an ∼20 mm Hg increase in mean arterial pressure. Cerebral oxygenation (SavO₂) was calculated from the arterial and jugular bulb oxygen saturations. Blood flow in the internal carotid artery (ICAf) and blood flow in the external carotid artery (ECAf) were assessed by duplex ultrasonography. Invos-5100c (SinvosO₂) and Foresight (SforeO₂) determined [Formula: see text] while forehead skin oxygenation (SskinO₂) was assessed. Phenylephrine reduced SforeO₂ by 6.9% (95% confidence interval: 4.8-9.0%; P<0.0001), SinvosO₂ by 10.5 (8.2-12.9%; P<0.0001), and ECAf (6-28%; P=0.0001), but increased ICAf (5-21%; P=0.003) albeit with no consequence for SskinO₂ or SavO₂. In contrast, SforeO₂ was maintained with administration of ephedrine while SinvosO₂ and SavO₂ decreased [by 3.1 (0.7-4.5%; P=0.017) and 2.1 (0.5-3.3%; P=0.012)] as arterial carbon dioxide pressure decreased (P=0.003). ICAf was stable and ECAf increased by 11 (4-18%; P=0.005) with administration of ephedrine while SskinO₂ did not change. The effect of phenylephrine on ScO₂ is governed by a decrease in external carotid blood flow since it increases cerebral blood flow as determined by flow in the internal carotid artery. In contrast, ScO₂ is largely maintained with administration of ephedrine because blood flow to extracerebral tissue increases.

Effects of α1-adrenoceptor agonist phenylephrine on swelling-activated chloride currents in human atrial myocytes.

Swelling-activated chloride currents (ICl.swell) play an important role in cardiac electrophysiology and arrhythmogenesis. However, the regulation of these currents has not been clarified to date. In this research, we focused on the function of phenylephrine, an α1-adrenoceptor agonist, in the regulation of I(Cl.swell) in human atrial myocytes. We recorded I(Cl.swell) evoked by a hypotonic bath solution with the whole-cell patch-clamp technique. We found that I(Cl.swell) increased over time, and it was difficult to achieve absolute steady state. Phenylephrine potentiated I(Cl.swell) from -1.00 ± 0.51 pA/pF at -90 mV and 2.58 ± 1.17 pA/pF at +40 mV to -1.46 ± 0.70 and 3.84 ± 1.67 pA/pF, respectively (P < 0.05, n = 6), and the upward trend in ICl.swell was slowed after washout. This effect was concentration-dependent, and the α1-adrenoceptor antagonist prazosin shifted the dose-effect curve rightward. Addition of prazosin or the protein kinase C (PKC) inhibitor bisindolylmaleimide (BIM) attenuated the effect of phenylephrine. The PKC activator phorbol 12,13-dibutyrate (PDBu) activated I(Cl.swell) from -1.69 ± 1.67 pA/pF at -90 mV and 5.58 ± 6.36 pA/pF at +40 mV to -2.41 ± 1.95 pA/pF and 7.05 ± 6.99 pA/pF, respectively (P < 0.01 at -90 mV and P < 0.05 at +40 mV; n = 6). In conclusion, the α1-adrenoceptor agonist phenylephrine augmented I(Cl.swell), a result that differs from previous reports in other animal species. The effect was attenuated by BIM and mimicked by PDBu, which indicates that phenylephrine might modulate I(Cl,swell) in a PKC-dependent manner.

Effect of intracameral phenylephrine on systemic blood pressure

Sir, A culture of caution pervades in the perioperative use of intracameral phenylephrine (I/C PE) for patients with cardiovascular comorbidities. We sought to assess its safety by investigating whether it confers any clinically significant cardiovascular effect, specifically on blood pressure.

Bupivacaine-induced Vasodilation Is Mediated by Decreased Calcium Sensitization in Isolated Endothelium-denuded Rat Aortas Precontracted with Phenylephrine.

BackgroundA toxic dose of bupivacaine produces vasodilation in isolated aortas. The goal of this in vitro study was to investigate the cellular mechanism associated with bupivacaine-induced vasodilation in isolated endotheliumdenuded rat aortas precontracted with phenylephrine.MethodsIsolated endothelium-denuded rat aortas were suspended for isometric tension recordings. The effects of nifedipine, verapamil, iberiotoxin, 4-aminopyridine, barium chloride, and glibenclamide on bupivacaine concentration-response curves were assessed in endothelium-denuded aortas precontracted with phenylephrine. The effect of phenylephrine and KCl used for precontraction on bupivacaine-induced concentration-response curves was assessed. The effects of verapamil on phenylephrine concentration-response curves were assessed. The effects of bupivacaine on the intracellular calcium concentration ([Ca2+]i) and tension in aortas precontracted with phenylephrine were measured simultaneously with the acetoxymethyl ester of a fura-2-loaded aortic strip.ResultsPretreatment with potassium channel inhibitors had no effect on bupivacaine-induced relaxation in the endothelium-denuded aortas precontracted with phenylephrine, whereas verapamil or nifedipine attenuated bupivacaine-induced relaxation. The magnitude of the bupivacaine-induced relaxation was enhanced in the 100 mM KCl-induced precontracted aortas compared with the phenylephrine-induced precontracted aortas. Verapamil attenuated the phenylephrine-induced contraction. The magnitude of the bupivacaine-induced relaxation was higher than that of the bupivacaine-induced [Ca2+]i decrease in the aortas precontracted with phenylephrine.ConclusionsTaken together, these results suggest that toxic-dose bupivacaine-induced vasodilation appears to be mediated by decreased calcium sensitization in endothelium-denuded aortas precontracted with phenylephrine. In addition, potassium channel inhibitors had no effect on bupivacaine-induced relaxation. Toxic-dose bupivacaine- induced vasodilation may be partially associated with the inhibitory effect of voltage-operated calcium channels.

CD73-TNAP crosstalk regulates the hypertrophic response and cardiomyocyte calcification due to α1 adrenoceptor activation.

Cluster of differentiation 73 (CD73) is an ecto-5' nucleotidase which catalyzes the conversion of AMP to adenosine. One of the many functions of adenosine is to suppress the activity of tissue nonspecific alkaline phosphatase (TNAP), an enzyme important in regulating intracellular calcification. Since myocardial calcification is associated with various cardiac disease states, we studied the individual roles and crosstalk between CD73 and TNAP in regulating myocyte responses to the α1 adrenoceptor agonist phenylephrine in terms of calcification and hypertrophy. Cultured neonatal rat cardiomyocytes were treated with 10 µM phenylephrine for 24 h in the absence or presence of the stable adenosine analog 2-chloro-adenosine, the TNAP inhibitor tetramisole or the CD73 inhibitor α,β-methylene ADP. Phenylephrine produced marked hypertrophy as evidenced by significant increases in myocyte surface area and ANP gene expression, as well as calcification determined by Alizarin Red S staining. These responses were associated with reduced CD73 gene and protein expression and CD73 activity. Conversely, TNAP expression and activity were significantly increased although both were suppressed by 2-chloro-adenosine. CD73 inhibition alone significantly reduced myocyte-derived adenosine levels by >50 %, and directly induced hypertrophy and calcification in the absence of phenylephrine. These responses and those to phenylephrine were abrogated by TNAP inhibition. We conclude that TNAP contributes to the hypertrophic effect of phenylephrine, as well as its ability to produce cardiomyocyte calcification. These responses are minimized by CD73-dependent endogenously produced adenosine.

Effect of Phenylephrine on Hemodynamic State and Cerebral Oxygen Saturation During Anesthesia in the Upright Position

*Cardiovascular Therapeutics Unit, Department of Pharmacology, University of Melbourne, Parkville, Australia; †Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Parkville, Australia; ‡School of Medicine, University of Melbourne, Parkville, Melbourne, Australia; and §Melbourne Orthopaedic Group, Windsor, Australia.

A Decrease in Spatially Resolved Near-Infrared Spectroscopy-Determined Frontal Lobe Tissue Oxygenation by Phenylephrine Reflects Reduced Skin Blood Flow

Spatially resolved near-infrared spectroscopy-determined frontal lobe tissue oxygenation (ScO2) is reduced with administration of phenylephrine, while cerebral blood flow may remain unaffected. We hypothesized that extracranial vasoconstriction explains the effect of phenylephrine on ScO2. We measured ScO2 and internal and external carotid as well as vertebral artery blood flow in 7 volunteers (25 [SD 4] years) by duplex ultrasonography during IV infusion of phenylephrine, together with middle cerebral artery mean blood velocity, forehead skin blood flow, and mean arterial blood pressure. During phenylephrine infusion, mean arterial blood pressure increased, while ScO2 decreased by -19% ± 3% (mean ± SE; P = 0.0005). External carotid artery (-27.5% ± 3.0%) and skin blood flow (-25.4% ± 7.8%) decreased in response to phenylephrine administration, and there was a relationship between ScO2 and forehead skin blood flow (Pearson r = 0.55, P = 0.042, 95% confidence interval [CI], = 0.025-0.84; Spearman r = 0.81, P < 0.001, 95% CI, 0.49-0.94) and external carotid artery conductance (Pearson r = 0.62, P = 0.019, 95% CI, 0.13 to 0.86; Spearman r = 0.64, P = 0.012, 95% CI, 0.17-0.88). These findings suggest that a phenylephrine-induced decrease in ScO2, as determined by INVOS-4100 near-infrared spectroscopy, reflects vasoconstriction in the extracranial vasculature rather than a decrease in cerebral oxygenation.

Hemodynamic consequences of spatially‐dependent sympathetic regulation in skeletal muscle arteriolar trees (678.14)

The sympathetic nervous system (SNS) elicits vasoconstriction on skeletal muscle arterioles via release of neurotransmitters norepinephrine (NE; acting on α1‐ and α2R), neuropeptide Y (NPY; acting on Y1R), and adenosine‐triphosphate (ATP; acting on P2X1R). Previous studies have shown that the level of α‐adrenoreceptor modulation is dependent on vessel branch order. However, to date, no studies have investigated the integrated roles of α1R, α2R, Y1R, and P2X1R modulation on arteriolar network hemodynamics. Thus, we evaluated the effects of phenylephrine (PE; α1R agonist), UK 14,304 (UK; α2R agonist), NPY, and ATP on arteriolar diameters in continuously branching arteriolar trees (1st order to 5th order; 1A‐5A). In male rats, concentration‐response curves (PE and ATP: 10‐9‐10‐4M; UK: 10‐9‐10‐5M; NPY: 10‐13‐10‐8M) of arteriolar diameter changes were evaluated in the gluteus maximus muscle (n蠅5 rats/group). Like others, we observed that α1R and α2R control is greatest at large (1A‐2A) arterioles, with declining sensitivity in subsequent branch orders approaching capillaries. Beyond this, we have observed that NPY and ATP elicit the greatest constrictor effects in arterioles closest to capillaries, with declining effects in descending branch orders approaching feed arterioles. Using our theoretical flow model, simulations assessed total flow and red blood cell (RBC) flow heterogeneity within the network using our experimental pharmacological data. Using our experimental inputs, we are the first to illustrate that spatial differences in ligand sensitivity enable the SNS to modify bulk tissue blood flow and RBC distribution differentially in branching networks.Grant Funding Source: NSERC

Changes during development of COX 1 and 2 in heart, abdominal and thoracic aorta (837.11)

Cyclooxigenase 1 and 2 have been related in the release of prostanoids that regulate the effect of various agonists as in the case of phenylephrine, but its unknown that how this enzyme is involved in the contractile response to phenylephrine age‐dependent. The aim of this paper is to analyze changes of COX 1 and 2 involvements in the contractile response to phenylephrine in the thoracic and abdominal aorta and coronary artery of pubescent, young and old rats. It has been describe that during development there are changes in the activity of some enzymatic pathways, in this work we analyze the change in the involvement of cyclooxygenase and PGs in the contractile effect of phenylephrine with age. Methods: we used male rats of 6, 16 weeks and 1 year of age. Rats were anesthetized with pentobarbital (50 mg / kg), after that we proceeded to obtain the thoracic aorta and abdominal aorta and the heart and they were placed in an isolated organ system where we proceeded to make concentration response curves to phenylephrine. On the other hand we obtain heart and aorta for the western blot analysis and the immunohistochemistry assay of COX 1 and COX 2. Conclusions: COX1 increase during development. On the other hand COX2 decrease in the elderly stage only in thoracic aorta.Grant Funding Source: COFAA / IPN

The mechanism of change in the rate of agglutination of human erythrocytes under the influence of adrenaline

In the study of red blood cells of 80 men found that adrenaline (10(-10) - 10(-6) g/mL) and phenylephrine (10-(10) - 10(-6) g/mL) dose-dependently increase the speed of agglutination of red blood cells, according to the decrease in agglutination of the start time and ginipral (10(-10) - 10(-7) g/mL), on the contrary, decreases it. The effect of adrenaline and phenylephrine is blocked by nicergoline (10(-6) g/mL), increased obzidan (10(-6) g/mL) and does not change under the action ofyohimbine (10(-6) g/mL) and atenolol (10(-6) g/mL). These data indicate that the speed of agglutination increases with activation alpha1-adrenergic receptor (AR) and decreases in the activation of beta2-AR, while the activation of alpha2- and beta1-AR does not affect it. Trifluoperazine (10(-6) g/mL) as the calmodulin antagonist, barium chloride (10(-6) g/mL) as a blocked of Ca(2+)-dependent K(+)-channels and indomethacine (10(-6) g/mL) as an inhibitor of cyclooxygenase and phospholipase A2 inhibit the ability of adrenaline to increases the speed of agglutination of red blood cells. This suggests that the effect of adrenaline caused an increase in erythrocyte entry of Ca2+, activation of calmodulin, cyclooxygenase, phospholipase A2 and the release of K+ from red blood cell through the Ca(2+)-dependent K+ channels, which is regarded as a manifestation of eryptosis. Indirectly, this means that more efficient activation of alpha1-AR and beta2-AR, respectively, increases or, conversely, decreases the rate of eryptosis.

Adrenergic regulation of GABA release from presynaptic terminals in rat cerebral cortex.

The α1-adrenoceptor agonist phenylephrine and the β-adrenoceptor agonist isoproterenol have opposite effects on evoked EPSPs (eEPSPs) in the cerebral cortex. The suppressive effects of phenylephrine on eEPSPs are mediated by modulation of postsynaptic glutamate receptors, whereas enhancement of eEPSPs by isoproterenol is due to facilitation of glutamate release from presynaptic terminals. The present study used whole-cell patch-clamp recordings from layer V pyramidal neurons in visuocortical slice preparations to assess the effects of phenylephrine and isoproterenol on the release probability of γ-aminobutyric acid (GABA). The present study recorded evoked inhibitory postsynaptic potentials (eIPSCs) by repetitive electrical stimulation (duration, 100 μs; 10 stimuli at 33 Hz) and miniature IPSCs (mIPSCs). The effects of phenylephrine (100 μM) depended on the amplitude of eIPSCs: phenylephrine decreased the paired-pulse ratios (PPRs) of eIPSCs with smaller amplitudes (<~600 pA) but increased PPRs of eIPSCs with larger amplitude. Phenylephrine also exhibited amplitude-dependent modulation of mIPSCs, i.e., an increase in the frequency of smaller mIPSC events (<~20 pA) and a decrease in the frequency of larger events. These findings suggest that α1-adrenoceptor activation facilitates GABA release from a subpopulation of GABAergic terminals that induce smaller-amplitude IPSCs in postsynaptic neurons. In contrast, isoproterenol (100 μM) consistently decreased the PPR of eIPSCs and increased the frequency of mIPSCs, suggesting that presynaptic β-adrenoceptors increase release probability from most GABAergic terminals. The complexity of adrenoceptor modulations in GABAergic synaptic transmission by α1-adrenoceptor and β-adrenoceptor activation may be due to the presence of pleiotropic subtypes of GABAergic interneurons in the cerebral cortex.

Effect of phenylephrine vs. ephedrine on frontal lobe oxygenation during caesarean section with spinal anesthesia: an open label randomized controlled trial

Background: During caesarean section spinal anesthesia may provoke maternal hypotension that we prevent by administration of phenylephrine and/or ephedrine. Phenylephrine is however reported to reduce the near infrared spectroscopy-determined frontal lobe oxygenation (ScO2) but whether that is the case for patients exposed to spinal anesthesia is not known.Objectives: To evaluate the impact of phenylephrine vs. ephedrine on ScO2during caesarean section with spinal anesthesia in a single center, open-label parallel-group study with balanced randomization of 24 women (1:1). Secondary aims were to compare the effect of the two drugs on maternal hemodynamics and fetal heart rate.Intervention: Ephedrine (0.8–3.3 mg/min) vs. phenylephrine infusion (0.02–0.07 mg/min).Results: For the duration of surgery, administration of ephedrine maintained ScO2 (compared to baseline +2.1 ± 2.8%; mean ± SE, while phenylephrine reduced ScO2 (−8.6 ± 2.8%; p = 0.005) with a 10.7% difference in ScO2between groups (p = 0.0106). Also maternal heart rate was maintained with ephedrine (+3 ± 3 bpm) but decreased with phenylephrine (−11 ± 3 bpm); difference 14 bpm (p = 0.0053), but no significant difference in mean arterial pressure (p = 0.1904) or CO (p = 0.0683) was observed between groups. The two drugs also elicited an equal increase in fetal heart rate (by 19 ± 3 vs. 18 ± 3 bpm; p = 0.744).Conclusion: In the choice between phenylephrine and ephedrine for maintenance of blood pressure during caesarean section with spinal anesthesia, ephedrine maintains frontal lobe oxygenation and maternal heart rate with a similar increase in fetal heart rate as elicited by phenylephrine.Trial registration: Clinical trials NCT 01509521 and EudraCT 2001 006103 35.

Haemodynamic effects of phenylephrine commenced prior to induction of anaesthesia in older patients undergoing high-risk vascular surgery

Fall in mean arterial blood pressure (MAP) during anaesthetic induction is common and may result in profound hypotension. Using the LiDCORapid (LiDCO Ltd, UK), we previously demonstrated that the fall in MAP is usually driven by a reduction in stroke volume (SV) that was presumed due to venodilation. Low- dose phenylephrine (PE), a venoconstrictor, commenced immediately prior to induction ameliorated these effects to a significant degree [1]. However, it is important that the pre-induction administration of PE should not cause any marked changes in MAP and CO. We retrospectively studied a group of 40 high-risk patients about to undergo major peripheral vascular surgery where PE was commenced immediately pre-induction. The haemodynamic effects of this dose of PE on MAP, SV and CO were analysed.

Phenylephrine postconditioning increases myocardial injury: are alpha-1 sympathomimetic agonist cardioprotective?

We studied effects of phenylephrine (PHE) on postischemic functional recovery and myocardial injury in an ischemia-reperfusion (I-R) experimental model. Rat hearts were Langendorff-perfused and subjected to 30 min zero-flow ischemia (I) and 60 min reperfusion (R). During R PHE was added at doses of 1 μM (n = 10) and 50 μM (n = 12). Hearts (n = 14) subjected to 30 and 60 min of I-R served as controls. Contractile function was assessed by left ventricular developed pressure (LVDP) and the rate of increase and decrease of LVDP; apoptosis by fluorescent imaging targeting activated caspase-3, while myocardial injury by lactate dehydrogenase (LDH) released during R. Activation of kinases was measured at 5, 15, and 60 min of R using western blotting. PHE did not improve postischemic contractile function. PHE increased LDH release (IU/g); 102 ± 10.4 (Mean ± standard error of mean) control versus 148 ± 14.8 PHE (1), and 145.3 ± 11 PHE (50) hearts, (P < 0.05). PHE markedly increased apoptosis. Molecular analysis showed no effect of PHE on the activation of proapoptotic c-Jun N-terminal kinase signaling; a differential pattern of p38 mitogen activated protein kinase (MAPK) activation was found depending on the PHE dose used. With 1 μM PHE, p-p38/total-p38 MAPK levels at R were markedly increased, indicating its detrimental effect. With PHE 50 μM, no further changes in p38 MAPK were seen. Activation of Akt kinase was decreased implying involvement of different mechanisms in this response. PHE administration during reperfusion does not improve postischemic recovery due to exacerbation of myocardial necrosis and apoptosis. This finding may be of clinical and therapeutic relevance.

Orchidectomy enhances the expression of endothelin-1 and ETB receptors in rat portal vein.

Functional studies have shown that orchidectomy increases the effects of phenylephrine on rat portal veins, but that it is completely prevented in the presence of both ETA and ETB receptor antagonists. Although it suggests the involvement of endothelin-1 (ET-1), the local production of this vasoactive peptide has not been directly quantified in portal veins. Therefore, the aim of the present study was to verify if orchidectomy increases the local expression of ET-1 as well as ETA and ETB receptors in the rat portal vein. Indeed, the genic expression of ET-1, ETA and ETB receptors in rat portal veins taken from control (CONT), orchidectomized (ORX) and ORX plus testosterone-replacement therapy (ORX + T) animals were determined by Real Time RT-PCR. The results showed that orchidectomy induced a significant increment in genic expression of ET-1and ETB receptors in the rat portal veins, which was completely reversed by testosterone replacement treatment. In conclusion, the results suggest that orchidectomy increases the production of ET-1 in the rat portal vein and that, at least partially, it may be related to the previously reported elevation of responses to phenylephrine.

Ephedrine versus phenylephrine effects on fetal outcome and hemodynamics of pre-eclamptic mothers undergoing cesarean section under spinal anesthesia

Background This randomized double-blind study was started with an objective of comparing two commonly used vasopressors (phenylephrine and ephedrine) as intravenous bolus injection to reduce hypotension in elective cesarean section in mothers with pre-eclampsia and estimating their impact on fetal outcome. Place of the study The study was conducted in Woman Health Hospital, Assiut University, Egypt. Patients and methods We studied 40 pre-eclamptic patients undergoing elective cesarean section under spinal anesthesia who developed hypotension after subarachnoid block. They were randomly allocated to one of the two groups to receive an intravenous bolus of the following drugs: group P, phenylephrine (75 μg, n = 20) or group E, ephedrine (6 mg, n = 20). Hypotension was defined as a decrease in systolic pressure to more than 25% of baseline values or systolic blood pressure of less than 90 mmHg. Results There were significant differences in systolic and diastolic blood pressure and pulse rate for the two studied drugs, which were less affected in the ephedrine group as compared with the phenylephrine group. Neonatal Apgar scores were within normal range in both groups. With respect to arterial and venous blood gases, there was significant difference in base excess and nonsignificant difference in pH and PO 2 between the two groups. Conclusion Both vasopressors phenylephrine (75 μg) and ephedrine (6 mg) were given as a bolus dose to pre-eclamptic candidates receiving spinal anesthesia, causing hemodynamic stability to mothers. However, the usage of phenylephrine was safer for fetal outcome than epinephrine in high-risk cesarean sections (pre-eclampsia) under spinal anesthesia.

Treatment with an extract of Terminalia superba Engler & Diels decreases blood pressure and improves endothelial function in spontaneously hypertensive rats

Ethnopharmacological relevanceThe stem bark of Terminalia superba (TS) is widely used as a decoction by Cameroonian folk medicine for the treatment of hypertension. The aim of the present study was to evaluate the effect of a chronic treatment with a TS extract on spontaneously hypertensive rats (SHR) with respect to efficacy, biochemical mechanisms and safety. Materials and methodsEleven-week-old SHR and normotensive Wistar Kyoto rats (WKY) were daily treated by gavage with a methylene chloride extract of stem bark of Terminalia superba (TMSE, 150mg/kg) or with the vehicle for 5 weeks. Systolic blood pressure (SBP) was measured weekly using the tail-cuff method. At the end of the treatment period, vascular function was assessed on isolated thoracic rings, urinary 8-iso-PGF2α levels were measured and cytochrome P-450 3A (CYP 3A) activity was evaluated in liver microsomes. ResultsTMSE reduced SBP (P<0.001) in SHR but not in WKY rats. In SHR, the vasorelaxant response to acetylcholine was significantly improved by TMSE as a result of increased nitric oxide synthase (NO) activity and decreased superoxide anion production. In addition, TMSE reduced the vasoconstrictive effect of phenylephrine and improved the sensitivity of smooth muscle cells to NO. TMSE dramatically decreased 8-iso-PGF2α levels in SHR. By contrast, TMSE did not affect all these parameters in WKY rats. Neither diuresis nor the hepatic CYP 3A activity was modified in both animal groups. ConclusionsThis study demonstrated that Terminalia superba has a potent antihypertensive activity in SHR which is partly due to endothelium-dependent and endothelium-independent effects as well as decreased oxidative stress. The data also provide evidence for the lack of herb-drug interaction through hepatic CYP 3A.