Studying the effect of vasopressors on therapeutic drug monitoring of two local anesthetics using hybrid micelle liquid chromatography as an analysis tool.

A hybrid micelle based mobile phase was used to develop and validate a liquid chromatographic method for the separation and quantification of two local anesthetics namely; lidocaine hydrochloride (LID), and bupivacaine hydrochloride (BPV) in presence of the frequently co administered vasopressors phenyl ephrine (PHR) and ephedrine (EPH). Optimization of chromatographic separation conditions was performed applying experimental one factor at a time tool, and design of experiment, where the retention behavior of all analytes using both optimization protocols was in accordance. Chromatographic separation was carried on a C8 column operating at 40 °C at a flow rate of 1.5 mL/min. using a mobile phase consisting of 0.18 M sodium dodecyl sulphate, 10% acetonitrile, containing 0.3% triethyl amine and adjusted to pH 7 using 2 M ortho phosphoric acid, adopting UV detection at 230 nm. The proposed method was fully validated and applied to both in vitro and in vivo analysis of rat blood samples. The pharmacokinetics of both LID and BPV was followed when they were solitary injected or when co administered with either PHR or EPH. Moreover, the in vitro spiked experiment was also subjected to documented bio-analytical validation procedures.

Contrast-Enhanced Ultrasound to Detect Early Microvascular Changes in Skeletal Muscle after High-Dose Radiation Treatment.

The biological response of normal tissue to high-dose radiation treatment remains poorly understood. Alterations to the microenvironment, specifically the microvasculature, have been implicated as a significant contributor to tumoral cytotoxicity. We used contrast-enhanced ultrasound (CEU) perfusion imaging, which is uniquely suited to assess functional status of the microcirculation, to measure microvascular blood flow after high-dose irradiation to normal skeletal muscle tissue in a murine model. Proximal hindlimbs of wild-type C57Bl/6 mice were irradiated with a single fraction using 6 MV photons, 1 cm bolus and a dynamic wedge. Quantitative perfusion CEU imaging of the skeletal muscle was performed at days 1 and 8 postirradiation in three different regions of interest (ROIs): 1. 15 Gy external-beam irradiated leg; 2. 12 Gy irradiated 5 mm proximal area; 3. single ROI in the nonirradiated contralateral (CL) hindlimb. Perfusion imaging was also performed in the hindlimb of nonirradiated mice. CEU time-intensity data were analyzed to measure microvascular blood flow (MBF, also referred to as perfusion), and its parametric components of microvascular flux rate and functional microvascular blood volume (MBV). Plasma measurements of two potent vasoconstrictors, endothelin-1 and angiotensin II, were also performed to assess systemic response. CEU perfusion imaging values for the 12 and 15 Gy irradiated limb regions were pooled. At day 1, MBF in the irradiated limb was significantly lower than in the CL limb (P = 0.016) but quite similar to the nonirradiated mice. At day 8, both limbs of irradiated mice exhibited a trend towards lower MBF than the limbs of nonirradiated mice (28% decrease in mean MBF, P = 0.149 for CL; 39% decrease, P = 0.065 for irradiated limb). Compared to nonirradiated animals, the reduction in perfusion in irradiated limbs at day 8 may have been more influenced by the microvascular flux rate (25% decrease in the mean, P = 0.079) than the MBV (12% decrease in the mean, P = 0.328). Examination of vasoactive compounds revealed that the average plasma concentration for endothelin-1 at day 8 postirradiation was significantly higher in 14 irradiated animals than in 4 nonirradiated animals (3.07 pg/ ml vs. 2.51 pg/ml; P = 0.011). Up to day 8 after high-dose irradiation, flow deficits in irradiated muscle appear to be a consequence of increased vascular resistance more so than loss or functional de-recruitment of microvascular units.

A Prospective, Randomized, Double-Blinded Study of the Effect of Intravenous Ondansetron on the Effective Dose in 50% of Subjects of Prophylactic Phenylephrine Infusions for Preventing Spinal Anesthesia-Induced Hypotension During Cesarean Delivery.

BACKGROUND: Ondansetron has been shown to reduce the incidence of hypotension and vasopressor requirement during spinal anesthesia for obstetric and nonobstetric surgery. However, the magnitude of this effect has not been fully quantified. In this parallel-group, randomized, double-blinded study, we determined the effective dose in 50% of subjects (ED50) of a prophylactic phenylephrine infusion for preventing hypotension in patients who received a single dose of intravenous ondansetron 4 mg or saline control before combined spinal-epidural anesthesia for elective cesarean delivery. ED50 values obtained were compared to estimate the effect of ondansetron versus placebo on vasopressor requirement. METHODS: Sixty parturients were randomly assigned to receive ondansetron (group O) or saline control (group C) 10 minutes before positioning for induction of spinal anesthesia. A prophylactic phenylephrine infusion was used to prevent hypotension. The first patient in each group received a phenylephrine infusion at the rate of 0.5 µg/kg/min. The infusion rate for each subsequent patient was varied with increments or decrements of 0.05 µg/kg/min based on the response of the previous patient, and the effective dose of the phenylephrine infusion for preventing hypotension in 50% of patients (ED50) was calculated for each group and compared using up-down sequential analysis. Probit regression was applied as a backup and sensitivity analysis was used to compare ED50 values for phenylephrine between groups by comparing calculated relative mean potency. RESULTS: The ED50 (mean [95% confidence interval (CI)]) of the rate of phenylephrine infusion was lower in group O (0.24 µg/kg/min [0.10-0.38 µg/kg/min]) compared with group C (0.32 µg/kg/min [0.14-0.47 µg/kg/min]) (P < .001). The total consumption of phenylephrine (mean ± standard deviation [SD]) until delivery was lower in group O (316.5 ± 25.9 µg) than in group C (387.7 ± 14.7 µg, P = .02). The estimate of relative median potency for phenylephrine for group O versus group C was 0.74 (95% CI, 0.37-0.95). CONCLUSIONS: Under the conditions of this study, intravenous ondansetron 4 mg reduced the ED50 of a prophylactic phenylephrine infusion by approximately 26% in patients undergoing cesarean delivery under combined spinal-epidural anesthesia.

Hormonal Neuroendocrine and Vasoconstrictor Peptide Responses of Ball Game and Cyclic Sport Elite Athletes by Treadmill Test.

OBJECTIVE: Our objective was to evaluate complex hormonal response in ball game and cyclic sport elite athletes through an incremental treadmill test, since, so far, variables in experimental procedures have often hampered comparisons of data. METHODS: We determined anthropometric data, heart rate, maximal oxygen uptake, workload, plasma levels of lactate, adrenaline, noradrenaline, dopamine, cortisol, angiontensinogen and endothelin in control (n = 6), soccer (n = 8), handball (n = 12), kayaking (n = 9) and triathlon (n = 9) groups based on a Bruce protocol through a maximal exercise type of spiroergometric test. RESULTS: We obtained significant increases for adrenaline, 2.9- and 3.9-fold by comparing the normalized means for soccer players and kayakers and soccer players and triathletes after/before test, respectively. For noradrenaline, we observed an even stronger, three-time significant difference between each type of ball game and cyclic sport activity. CONCLUSIONS: Exercise related adrenaline and noradrenaline changes were more pronounced than dopamine plasma level changes and revealed an opportunity to differentiate cyclic and ball game activities and control group upon these parameters. Normalization of concentration ratios of the monitored compounds by the corresponding maximal oxygen uptake reflected better the differences in the response level of adrenaline, noradrenaline, dopamine and cortisol.

Maternal plasma levels of interleukin-6, C-reactive protein, vitamins C, E and A, 8-isoprostane and oxidative status in women with preterm premature rupture of membranes.

OBJECTIVE: Preterm premature rupture of membranes (PPROM) is associated with significant maternal and perinatal morbidity. This study examined maternal oxidative stress in PPROM. METHODS: This was a prospective cross-sectional study conducted in a university hospital. A total of 72 pregnant women were recruited into two groups, those with PPROM (38 cases) and those without PPROM (34 controls) matched for gestational age. Plasma interleukin-6, C-reactive protein, vitamins C, E and A, 8-isoprostane, total oxidant status (TOS) and antioxidant status (TAS) were determined for all study participants and the data were compared between the PPROM and control groups. RESULTS: Both case and control groups were comparably matched in age, parity, gestational age and smoking status. There was a significant association between low 8-isoprostane, low vitamin C and high total oxidant status and the occurrence of PPROM (p < 0.001). CONCLUSIONS: Plasma vitamin C and 8-isoprostane levels were lower and TOS higher in women with PPROM. Further research is needed to identify robust biological markers for the prevention and also prognosis of PPROM.

Endogenous cardiotonic steroids in chronic renal failure.

BACKGROUND: Previous reports demonstrated that digitalis-like cardiotonic steroids (CTS) contribute to the pathogenesis of end-stage renal disease. The goal of the present study was to define the nature of CTS in patients with chronic kidney disease (CKD) and in partially nephrectomized (PNx) rats. METHODS: In patients with CKD and in healthy controls, we determined plasma levels of marinobufagenin (MBG) and endogenous ouabain (EO) and erythrocyte Na/K-ATPase activity in the absence and in the presence of 3E9 anti-MBG monoclonal antibody (mAb) and Digibind. Levels of MBG and EO were also determined in sham-operated Sprague-Dawley rats and in rats following 4 weeks of PNx. RESULTS: In 25 patients with CKD plasma, MBG but not EO was increased (0.86 ± 0.07 versus 0.28 ± 0.02 nmol/L, P < 0.01) and erythrocyte Na/K-ATPase was inhibited (1.24 ± 0.10 versus 2.80 ± 0.09 µmol Pi/mL/h, P < 0.01) as compared to that in 19 healthy subjects. Ex vivo, 3E9 mAb restored Na/K-ATPase in erythrocytes from patients with CKD but did not affect Na/K-ATPase from control subjects. Following chromatographic fractionation of uremic versus normal plasma, a competitive immunoassay based on anti-MBG mAb detected a 3-fold increase in the level of endogenous material having retention time similar to that seen with MBG. A similar pattern of CTS changes was observed in uremic rats. As compared to sham-operated animals, PNx rats exhibited 3-fold elevated levels of MBG but not that of EO. CONCLUSIONS: In chronic renal failure, elevated levels of a bufadienolide CTS, MBG, contribute to Na/K-ATPase inhibition and may represent a potential target for therapy.

Angiotensin (1-7) receptor antagonism equalizes angiotensin II-induced hypertension in male and female spontaneously hypertensive rats.

Females are less sensitive to the hypertensive effects of angiotensin II compared with males, although the molecular mechanisms responsible are unknown. We hypothesize that differential activation of angiotensin II, angiotensin (1-7), angiotensin II type 1, angiotensin II type 2, and mas levels in the renal cortex of male and female spontaneously hypertensive rats contribute to sex differences in the blood pressure response to angiotensin II infusion. Males had a greater increase in blood pressure after angiotensin II infusion than females (males: 150±2 to 186±3 mm Hg; females: 137±3 to 160±4 mm Hg; P<0.05). Angiotensin II infusion resulted in comparable increases in plasma and renal cortical angiotensin II levels in both sexes. Renal cortical angiotensin (1-7) levels were higher in female rats under basal conditions (195±10 versus 67±11 ng/g of cortex; P<0.05) and after angiotensin II infusion (281±25 versus 205±47 ng/g of cortex; P<0.05) compared with male rats. In the renal cortex of male rats, angiotensin II infusion decreased angiotensin II type 1 protein expression and increased angiotensin II type 2 expression with no change in mas expression. In female rats there was an increase in mas receptor protein expression with angiotensin II infusion, although angiotensin II type 1 and angiotensin II type 2 expressions were unchanged. Male and female rats were then treated with the angiotensin (1-7) mas receptor antagonist A-779 in the absence and presence of angiotensin II. A-779 equalized the blood pressure response to angiotensin II in males and females (blood pressure at the end of treatment: males, 166±4 mm Hg; females, 164±5 mm Hg). In conclusion, angiotensin (1-7) contributes to the sex difference in angiotensin II-induced increases in blood pressure in spontaneously hypertensive rats.

Emerging role of the bufadienolides in cardiovascular and kidney diseases.

The bufadienolides are a group of steroid hormones that circulate in blood and are excreted in urine. They have the ability to inhibit the adenosine triphosphatase sodium-potassium pump (Na(+)-K(+)-ATPase), with predilection for its alpha1 isoform. This capability enables them to share with other cardiac glycosides the facility to cause an increase in sodium excretion, produce vasoconstriction resulting in hypertension, and act as cardiac inotropes. Bufadienolides have been implicated in instances of volume expansion-mediated hypertension, syndromes in which they are considered capable of causing a vascular leak, interfering with cellular proliferation, and inhibiting cellular maturation. An antagonist to the most well-studied bufadienolide, marinobufagenin, is resibufogenin, a compound that provides promise for the treatment of disorders in which excessive levels of marinobufagenin are present and are etiopathogenetic.

Effects of nasal application of an epinephrine and lidocaine mixture on the hemodynamics and nasal mucosa in oral and maxillofacial surgery.

PURPOSE: Our purpose was to investigate the influences of nasal pretreatment with a mixed solution of epinephrine and lidocaine (E-L pretreatment) on the systemic hemodynamics and the mucosa of the inferior nasal concha, which is carried out for expansion of the nasal cavity and the prevention of mucosal injury before nasotracheal intubation. PATIENTS AND METHODS: Subjects included 29 adult patients undergoing oral and maxillofacial surgery. This study consisted of 2 parts. In part 1 (n = 18), the effects of E-L pretreatment on the systemic hemodynamics were studied before (pre-Anesth group, n = 10) and after (post-Anesth group, n = 8) induction of anesthesia. Changes of the mucosal volume and the blood flow of the inferior nasal concha also were observed by optic bronchoscopy and noncontact type laser-Doppler flowmetry, respectively. In part 2 (n = 11), changes in the serum concentrations of epinephrine and lidocaine after the E-L pretreatment were determined by high performance liquid chromatography and enzyme immunoassay, respectively. RESULTS: The heart rate increased at 2 and 3 min after E-L pretreatment in pre-Anesth group (P < .05), but not in post-Anesth group. The cross section of the nasal cavity decreased from 66% to 42% (n = 8, P < .05). The mucosal blood flow decreased from 60 to 22 AU (n = 8, P < .01). The serum epinephrine concentration increased from 24 to 185 pg/mL. CONCLUSIONS: The E-L pretreatment provided characteristic evidence for useful expansion of the nasal cavity and for reduction of the nasal mucosal blood flow with less systemic hemodynamic effects, although further investigation is needed for the determination of the proper epinephrine concentration in E-L pretreatment.

Adenosine 5'-tetraphosphate is a highly potent purinergic endothelium-derived vasoconstrictor.

Besides serving as a mechanical barrier, the endothelium has important regulatory functions. The discovery of nitric oxide revolutionized our understanding of vasoregulation. In contrast, the identity of endothelium-derived vasoconstrictive factors still remains uncertain. The supernatant from mechanically stimulated human microvascular endothelial cells elicited a potent vasoconstrictive response in the isolated perfused rat kidney. Whereas a nonselective purinoceptor blocker blocked this vasoactivity most potently, the inhibition of the endothelin receptor by BQ123 weakly affected that vasoconstrictive response. As a compound responsible for that vasoconstrictive effect, we have isolated from HMECs and identified the mononucleotide adenosine 5'-tetraphosphate (AP4). This nucleotide proved to be the most potent vasoactive purinergic mediator identified to date, exerting the vasoconstriction predominantly through activation of the P2X1 receptor. The intraarterial application of AP4 in a Wistar-Kyoto rat induced a strong increase of the mean arterial pressure. The plasma concentration of AP4 is in the nanomolar range, which, in vivo, induces a significant change in the mean arterial pressure. To our knowledge, AP4, which exerts vasoactive effects, is the most potent endogenous mononucleotide identified to date in mammals. The effects of AP4, the plasma concentration of AP4, and its release suggest that this compound functions as an important vasoregulator.

Enhanced water and salt intake in transgenic mice with brain-restricted overexpression of angiotensin (AT1) receptors.

To address the relative contribution of central and peripheral angiotensin II (ANG II) type 1A receptors (AT(1A)) to blood pressure and volume homeostasis, we generated a transgenic mouse model [neuron-specific enolase (NSE)-AT(1A)] with brain-restricted overexpression of AT(1A) receptors. These mice are normotensive at baseline but have dramatically enhanced pressor and bradycardic responses to intracerebroventricular ANG II or activation of endogenous ANG II production. Here our goal was to examine the water and sodium intake in this model under basal conditions and in response to increased ANG II levels. Baseline water and NaCl (0.3 M) intakes were significantly elevated in NSE-AT(1A) compared with nontransgenic littermates, and bolus intracerebroventricular injections of ANG II (200 ng in 200 nl) caused further enhanced water intake in NSE-AT(1A). Activation of endogenous ANG II production by sodium depletion (10 days low-sodium diet followed by furosemide, 1 mg sc) enhanced NaCl intake in NSE-AT(1A) mice compared with wild types. Fos immunohistochemistry, used to assess neuronal activation, demonstrated sodium depletion-enhanced activity in the anteroventral third ventricle region of the brain in NSE-AT(1A) mice compared with control animals. The results show that brain-selective overexpression of AT(1A) receptors results in enhanced salt appetite and altered water intake. This model provides a new tool for studying the mechanisms of brain AT(1A)-dependent water and salt consumption.

The renin-angiotensin system contributes to renal fibrosis through regulation of fibrocytes.

BACKGROUND: The renin-angiotensin system is a major pathway in the pathogenesis of cardiovascular and renal diseases. Bone marrow-derived fibrocytes, which are dual positive for CD45 and type I collagen, are now considered to contribute to the pathogenesis of various fibrotic diseases. We hypothesized that fibrocytes might contribute to renal fibrosis by an angiotensin II dependent pathway. RESULTS: In murine models of renal fibrosis, angiotensin II type 2 receptor (AT2R)-deficient mice, when compared with wild-type mice, showed increased renal fibrosis and fibrocyte infiltration with a concomitant upregulation of renal transcripts of procollagen type I (alpha) (COL1A1). Fibrocyte numbers in the bone marrow also were increased in AT2R-deficient mice. By contrast, pharmacological inhibition of angiotensin II type 1 receptor (AT1R) with valsartan reduced the degree of renal fibrosis and the number of fibrocytes in both the kidney and the bone marrow. In isolated human fibrocytes, inhibition of AT2R signaling increased the angiotensin II-stimulated expression of type I collagen, whereas inhibition of AT1R decreased collagen synthesis. These results suggest that AT1R/AT2R signaling may contribute to the pathogenesis of renal fibrosis by at least two mechanisms: by regulating the number of fibrocytes in the bone marrow, and by activation of fibrocytes.

[Hemodynamic effects of local anesthetics with adrenaline during septal surgery]. / Nazal cerrahide adrenalinli lokal anestetiklerin hemodinamik etkileri.

OBJECTIVES: We investigated the hemodynamic effects of local anesthetics with adrenaline used before septal surgery. PATIENTS AND METHODS: In a prospective, controlled design, administration of local anesthetics was performed with and without adrenaline in 39 patients and 10 patients, respectively, undergoing septal surgery. Plasma adrenaline concentrations were measured before anesthesia, and after 2, 5, and 10 minutes from anesthesia. The patients were monitored with respect to pulse rate, electrocardiographic findings, and blood pressure. RESULTS: Preoperative plasma adrenaline levels were similar in patients receiving local anesthetics with or without adrenaline (0.8 nmol/l vs 0.7 nmol/l). Following adrenaline administration, adrenaline levels showed significant increases to 2.2, 1.9, and 1.7 nmol/l after 2, 5, and 10 minutes, respectively (p<0.001), whereas they remained similar in the control group. No side effects related to adrenaline use were detected. CONCLUSION: Despite systemic absorption of local injections, adrenaline-related side effects during septal surgery are extremely rare when the patients are closely monitored.

Reduced circulating levels of angiotensin-(1--7) in systemic sclerosis: a new pathway in the dysregulation of endothelial-dependent vascular tone control.

OBJECTIVE: Systemic sclerosis (SSc) impairs endothelium-dependent vasodilatation. Among angiotensin I (Ang I)-derived compounds, vasoconstrictor angiotensin II (Ang II) and vasodilator angiotensin-(1-7) (Ang-(1-7)), cleaved from ACE and neutral endopeptidase (NEP) 24.11, respectively, play an important role in vascular tone regulation. Ang-(1-7) may act independently or by activating other vasodilating molecules, such as nitric oxide (NO) or prostaglandin I2 (PGI2). Our aim was to assess, in patients with SSc, circulating levels of Ang I, Ang II and Ang-(1-7), with their metabolising enzymes ACE and NEP, and levels of NO and PGI2, and to correlate them to the main characteristics of SSc. METHODS: Levels of Ang I, Ang II, Ang-(1-7), NEP, ACE, NO and PGI2 were measured in 32 patients with SSc, who were also assessed for humoral and clinical characteristics, and 55 controls. RESULTS: Plasma Ang I, Ang II and Ang-(1-7) levels were lower in patients with SSc than in controls (p<0.001in all cases). When Ang II and Ang-(1-7) levels were expressed as a function of the available Ang I, lower Ang-(1-7) levels in patients with SSc than in controls were confirmed (p<0.001), while no difference was found for Ang II levels. In patients with SSc, the Ang II/Ang-(1-7) ratio indicated a prevalence of Ang II over Ang-(1-7), while in controls Ang-(1-7) was prevalent (p<0.001). Levels of ACE, NEP, NO and PGI2 were lower in patients with SSc than in controls (p<0.05 in all cases). CONCLUSION: In patients with SSc, prevalence of the vasoconstricting Ang II over the vasodilator Ang-(1-7) suggests a dysfunction of the angiotensin-derived cascade that may contribute to dysregulation of vascular tone.

[Tumescent anaesthesia for dermatological surgery. Plasma concentrations of lidocaine and prilocaine]. / Tumeszenzlokalanästhesie bei dermatologischen Eingriffen. Plasmakonzentrationen von Lidocain und Prilocain.

BACKGROUND: Tumescent anaesthesia is currently used for several dermatological procedures. The objective of this study was to determine the plasma concentrations of local anaesthetics under real operating conditions with this anaesthetic technique. METHODS: A total of 31 patients received 3 different anaesthetic solutions with prilocaine and lidocaine for several surgical procedures. The concentrations of local anaesthetics, methemoglobin, epinephrine as well as the occurrence of adverse reactions were determined 30 min, 1 h, 3 h, 6 h, 12 h and 24 h after administration RESULTS: Maximum plasma concentrations of prilocaine were measured predominantly after 3 and 6 h, for lidocaine after 6 h. In two patients maximum plasma levels occurred 24 h after infiltration. Although toxic concentrations were not exceeded, side-effects could be observed in four patients. CONCLUSIONS: Even if the measured concentrations of local anaesthetics appeared to be safe, slight and moderate side-effects could be observed in 12.9% of cases. Maximum plasma levels of local anaesthetics may still occur 24 h after administration.

Blood leukocyte mRNA expression for IL-10, IL-1Ra, and IL-8, but not IL-6, increases after exercise.

The primary purpose of this project was to study exercise-induced leukocyte cytokine mRNA expression. Changes in plasma cytokine levels and blood leukocyte mRNA expression for interleukin-6 (IL-6), IL-8, IL- 10, and IL-1 receptor antagonist (IL-1Ra) were measured in 12 athletes following 2 h of intensive cycling ( approximately 64% Watts(max)) while ingesting a carbohydrate or placebo beverage (randomized and double blinded). Blood samples were collected 30 min preexercise and immediately and 1 h postexercise. Carbohydate compared with placebo ingestion attenuated exercise-induced changes in plasma cortisol (8.8% vs. 62%, respectively), epinephrine (-9.2% vs. 138%), IL-6 (10-fold vs. 40-fold), IL-10 (8.9-fold vs. 26-fold, and IL-1Ra (2.1-fold vs. 5.6-fold). Significant time effects were measured for blood leukocyte IL-8 (2.4-fold increase 1 h postexercise), IL-10 (2.7-fold increase), IL-1Ra (2.2-fold increase), and IL-6 (0.8-fold decrease) mRNA content, with no significant differences between Cho and Pla test conditions. In summary, gene expression for IL-8, IL-10, and IL-1Ra, but not IL-6, is increased in blood leukocytes taken from athletes following 2 h of intensive cycling and is not influenced by carbohydrate compared with placebo ingestion. mRNA expression was high enough to indicate a substantial contribution of blood leukocytes to plasma levels of IL-8, IL-10, and IL-1Ra during prolonged exercise.

Angiotensin II, interstitial inflammation, and the pathogenesis of salt-sensitive hypertension.

Transient administration of ANG II causes persistent salt-sensitive hypertension associated with arteriolopathy, interstitial inflammation, and cortical vasoconstriction; blocking the vascular and inflammatory changes with mycophenolate mofetil (MMF) prevents vasoconstriction. While infiltrating leukocytes during the salt-sensitive hypertension phase express ANG II, the functional role of ANG II during this phase is not known. We examined the acute effect of candesartan on renal hemodynamics during the established salt-sensitive hypertensive phase and related these findings to direct measurement of intrarenal ANG II and inflammatory cells in rats previously exposed to ANG II with or without MMF treatment. Sham controls were also examined. The administration of ANG II, followed by exposure to high-salt diet, resulted in hypertension, cortical vasoconstriction, an increase in interstitial inflammatory cells (44.8 +/- 1.3 lymphocytes/mm2, and 30.8 +/- 1.2 macrophages/mm2 ANG II vs. 19.6 +/- 2 lymphocytes/mm2, and 22 +/- 0.7 macrophages/mm2 Sham), and increase in renal ANG II levels (1,358 +/- 74.6 pg/ml ANG II vs. 194 +/- 9.28 pg/ml Sham). Treatment with MMF during the administration of exogenous ANG II resulted in reduction in renal interstitial inflammation (19.7 +/- 0.9 lymphocytes/mm2 and 15.9 +/- 0.8 machophages/mm2), ANG II levels (436.9 +/- 52.29 pg/ml), cortical vasoconstriction, and stable blood pressure levels during the subsequent challenge with a high-salt diet. Acute administration of candesartan similarly reduced renal vasoconstriction and blood pressure. We conclude that the cortical vasoconstriction occurring with salt-sensitive hypertension following exposure to ANG II is mediated by intrarenal ANG II, related, at least in part, to the interstitial inflammation.

Antioxidant N-acetylcysteine restores systemic nitric oxide availability and corrects depressions in arterial blood pressure and heart rate in diabetic rats.

Increased oxidative stress and reduced nitric oxide (NO) bioactivity are key features of diabetes mellitus that eventually result in cardiovascular abnormalities. We assessed whether N-acetylcysteine (NAC), an antioxidant and glutathione precursor, could prevent the hyperglycaemia induced increase in oxidative stress, restore NO availability and prevent depression of arterial blood pressure and heart rate in vivo in experimental diabetes. Control (C) and streptozotocin-induced diabetic (D) rats were treated or not treated with NAC in drinking water for 8 weeks, initiated 1 week after induction of diabetes. At termination, plasma levels of free 15-F2t-isoprostane, a specific marker of oxygen free radical induced lipid peroxidation, was increased while the plasma total antioxidant concentration was decreased in untreated diabetic rats as compared to control rats (P<0.05). This was accompanied by a significant reduction of plasma levels of nitrate and nitrite, stable metabolites of NO, (P<0.05, D vs. C) and a reduced endothelial NO synthase protein expression in the heart and in aortic and mesenteric artery tissues. Systolic, diastolic and mean arterial blood pressures (SBP, DBP and MAP) and heart rate (HR) were reduced in diabetic rats (P<0.05 vs. C) and NAC normalised the changes that occurred in the diabetic rats. The protective effects may be attributable to restoration of NO bioavailability in the circulation.

Plasma catecholamine concentrations and hemodynamic responses to vasoconstrictor during conventional or Gow-Gates mandibular anesthesia.

OBJECTIVE: The literature supports that systemic responses to injected vasoconstrictors depend on the volume and concentration administered, patient's age and health status, as well as site of injection. Thus, the influence of mandibular anesthesia technique on hemodynamic and plasma responses to epinephrine-containing local anesthetics was investigated. STUDY DESIGN: Conventional or Gow-Gates anesthesia with 2% lidocaine and epinephrine, 1:100,000, was performed in 18 subjects who required third molar extraction. A control group of 9 subjects was submitted to conventional anesthesia with plain 3% mepivacaine. Blood pressure, heart rate, and plasma catecholamines were measured. RESULTS: Analysis of variance showed that plasma epinephrine level after conventional lidocaine anesthesia was significantly elevated (P < .01), while there was no difference between the Gow-Gates and control groups. The hemodynamic parameters did not demonstrate correlation to the injection technique. CONCLUSION: Presumably, there was less exogenous epinephrine absorption in the Gow-Gates technique than in the conventional mandibular anesthesia injection.