Thalidomide Attenuates Epileptogenesis and Seizures by Decreasing Brain Inflammation in Lithium Pilocarpine Rat Model.

Thalidomide (TAL) has shown potential therapeutic effects in neurological diseases like epilepsy. Both clinical and preclinical studies show that TAL may act as an antiepileptic drug and as a possible treatment against disease development. However, the evidence for these effects is limited. Therefore, the antiepileptogenic and anti-inflammatory effects of TAL were evaluated herein. Sprague Dawley male rats were randomly allocated to one of five groups (n = 18 per group): control (C); status epilepticus (SE); SE-TAL (25 mg/kg); SE-TAL (50 mg/kg); and SE-topiramate (TOP; 60mg/kg). The lithium-pilocarpine model was used, and one day after SE induction the rats received pharmacological treatment for one week. The brain was obtained, and the hippocampus was micro-dissected 8, 18, and 28 days after SE. TNF-α, IL-6, and IL-1ß concentrations were quantified. TOP and TAL (50 mg/kg) increased the latency to the first of many spontaneous recurrent seizures (SRS) and decreased SRS frequency, as well as decreasing TNF-α and IL-1ß concentrations in the hippocampus. In conclusion, the results showed that both TAL (50 mg/kg) and TOP have anti-ictogenic and antiepileptogenic effects, possibly by decreasing neuroinflammation.

Potential Mechanisms Involved in Palmitoylethanolamide-Induced Vasodepressor Effects in Rats.

Palmitoylethanolamide is an endogenous lipid that exerts complex vascular effects, enhances the effects of endocannabinoids and induces a direct hypotension, but the mechanisms involved have been poorly explored. Hence, this study investigated in Wistar pithed rats the role of CB1, CB2, TRPV1 and GPR55 receptors in the inhibition by palmitoylethanolamide of the vasopressor responses produced by sympathetic stimulation or exogenous noradrenaline. Frequency- and dose-dependent vasopressor responses were analysed before and during intravenous (i.v.) continuous infusions of palmitoylethanolamide in animals receiving i.v. bolus of the antagonists NIDA41020 (CB1), AM630 (CB2), capsazepine (TRPV1), and/or cannabidiol (GPR55). Palmitoyletha-nolamide (0.1-3.1 µg/kg/min) dose-dependently inhibited the sympathetically induced and noradrenaline-induced vasopressor responses. Both inhibitions were: (i) partially blocked by 100 µg/kg NIDA41020, 100 µg/kg capsazepine, or 31 µg/kg cannabidiol; (ii) unaffected by 310 µg/kg AM630; and (iii) abolished by the combination NIDA41020 + capsazepine + cannabidiol (100, 100, and 31 µg/kg, respectively). The resting blood pressure was decreased by palmitoylethanolamide (effect prevented by NIDA41020, capsazepine or cannabidiol, but not by AM630). These results suggest that: (i) palmitoylethanolamide inhibits the vasopressor responses to sympathetic stimulation and exogenous noradrenaline and that it induces hypotension; and (ii) all these effects are mediated by prejunctional and vascular CB1, TRPV1 and probably GPR55, but not by CB2, receptors.

Anticoagulant proteins in a population of Mexican mestizo donors.

BACKGROUND: To determine the activity of antithrombin (AT), protein C (PC), and protein S (PS), as well as the frequency of deficiencies of these proteins in a population of healthy Mexican mestizo blood donors. METHODS: AT, PC, and PS were determined from 1,502 plasma samples of healthy blood donors by using commercial kits in a coagulometer 4 STA (Diagnostica Stago, Asnières, France). RESULTS: A total of 741 women and 761 men were under study. They were divided into age range groups (18-24, 25-34, 35-44, 45-54, and 55-64 years). Activity of AT, PC, and PS was determined. For AT, activity values were specific for each age group according to gender when it had to do with PS, as well as when PC was determined. Frequencies of AT, PC, PS, and activated PC resistance activity deficiencies were obtained from reference levels (RLs) and average levels of this study. Differences were found between both frequencies for AT, PC, and PS, and the average levels obtained were used in this study. The frequencies of the activity deficiencies obtained through the values gotten in this population were: AT, 0.6%; PC, 1.06% (which is higher than the one obtained using the RLs described by commercial kits 0.33% and 0.66%, respectively); and PS, 1% (which is less than 4.5%). CONCLUSIONS: It is necessary to know the characteristics and biological behavior of the coagulation proteins in the Mexican population because the RLs used have been established for populations that are genetically different.

[Reference values for blood coagulation factor activity in the Mexican population].

INTRODUCTION: During the fluid phase of hemostasis, fibrinogen is converted into fibrin, but other hemostatic factors are required. Reference values of hemostatic factors are established by manufacturers producing reagents using individuals with a specific genetic background. OBJECTIVE: To establish reference values for hemostatic factors in the Mexican indigenous and Mestizo populations. MATERIAL AND METHODS: We carried out a cross-sectional, descriptive study of healthy adult Mexicans. Clotting activity was evaluated using coagulometric assays. Blood donors were informed about the nature of the study and informed consent was obtained prior to blood being drawn. The protocol was approved by the Ethics Committee of our institution. RESULTS: One hundred and twenty samples were assayed (60 females and 60 males). Fibrinogen was higher in mestizos and in females. Reference values for factor XII ranged from 40-170% in indigenous subjects and from 36-159% in mestizos. Factor VIII ranged from 57-160% in indigenous subjects and from 51-209% in mestizo subjects. Reference values for the other hemostatic factors were also clearly different from the commercial reference values. Reference values for hemostatic factors in the Mexican population are different from traditionally used commercial reference values. There were significant differences between indigenous and mestizo Mexicans in the concentration of hemostatic factors with a tendency among mestizos to have higher factor concentrations. Low levels of plasma factor XII are frequent and perhaps may represent a risk factor for thrombotic events. Using these reference values may individualize the reposition of factors in Mexican hemophiliac patients.

Immunotoxic damage in floriculturists exposed to pesticide mixtures.

The aim of the present work was to determine if the use of pesticide mixtures produced alterations in immunotoxicity biomarkers. The study was undertaken in three groups: the first group consisted of 38 floriculturists, the second comprised 38 vendors of the local market, and the last comprised 33 non-exposed persons from another locality. The determinations included haematocrit, mean cellular volume, hemoglobin, number of erythrocytes and leukocytes, immunoglobulins (IgA, IgG, IgM, and IgE), percentage of T-lymphocytes, and mitotic index from lymphocyte cultures with and without phytohaemagglutinin (PHA). The obtained results indicated the following: (i) in the level of the studied immunoglobulins, the results were within the reference values; (ii) there was a reduction in the amount of T-lymphocytes in the floriculturists in comparison with the determined in the other two groups; (iii) there was a decrease in the mitotic index of PHA-stimulated lymphocyte cultures of floriculturists and vendors in relation to the value of the control group; (iv) there was an increase in the mitotic index of unstimulated lymphocytes of floriculturists compared with the lymphocytes of the other two groups; and (v) there was no correlation between the results and the personal characteristics of the studied individuals. Our results established an immunotoxic effect in the floriculturists exposed to pesticides.

Enantiomeric N-substituted phthalimides with excitatory amino acids protect zebrafish larvae against PTZ-induced seizures.

Epilepsy is a chronic neurological disease with high prevalence and adverse impacts on the quality of life of patients and caregivers. Up to one-third of individuals with epilepsy do not respond to current pharmacotherapy, underscoring the importance of identifying new molecules for epilepsy control. Thalidomide, the first synthetized phthalimide, is a neuroactive molecule with anti-seizure drug properties. The phthalimide group has been studied in some N-phthaloyl amino acids due to its pharmacological properties. Here we examine enantiomers of phthaloyl aspartate (R and S) and phthaloyl glutamate (R and S) for anti-seizure effects using zebrafish as a model. The zebrafish model is rapidly growing in use as a preclinical screening tool for drug discovery in epilepsy. Pentylenetetrazol (PTZ) exposure was used to produce convulsive behavior in 7- and 10-days post-fertilization (dpf) zebrafish larvae; these ages correspond to before and after the blood-brain-barrier (BBB) is fully developed. Larvae were pre-treated for 60 min with: control, valproic acid sodium salt (SVP) 3 mM, or one of two concentrations of N-phthaloyl-R-glutamic acid (R-TGLU; 100, 316 µM) prior to PTZ addition. R-TGLU modified the locomotor phenotype and protected against PTZ in 7 and 10 dpf larvae at 316 µM, suggesting it crossed the BBB. We next tested the per se and anticonvulsant effect of the glutamate and aspartate phthalimides were tested at 237.1 and 316 µM concentration in 10dpf zebrafish. The four tested molecules produced an anticonvulsant effect at 237.1 µM concentration, however the behavioral changes that they induce suggest that they might act by different mechanisms.

NPY-Y1 receptors in dorsal periaqueductal gray modulate anxiety, alcohol intake, and relapse in Wistar rats.

Neuropeptide Y (NPY) is likely the main endogenous anxiolytic neuromodulator involved in alcohol intake. NPY-Y1, a receptor for NPY, is highly expressed in the periaqueductal gray (PAG), a mesencephalic structure involved in integrating nervous activity to the performance of active and passive defensive behaviors related to fear and anxiety. Interestingly, anxiety and fear are some of the prevailing emotional negative states during alcohol abstinence. Moreover, an inverse relationship between NPY activity and alcohol consumption has been frequently reported, mainly in the extended amygdala. Nevertheless, both the roles of NPY and that of the receptor involved in these actions have been scarcely studied. Thus, the aim of this study was to analyze the pharmacological effect of NPY and NPY-Y1 receptor blockade into the dorsal periaqueductal gray (D-PAG) in an alcohol consumption and relapse paradigm in adult male Wistar rats. Ninety-six rats at postnatal day 42 (PND-42) were classified as having low and high anxiety (LA and HA), respectively, through the elevated plus maze test (EPM). Then, those animals were randomly divided into alcohol naïve (AN) and forced alcohol consumption (FAC) groups. A cannula was implanted in D-PAG to microinject vehicle (VEH), NPY, or BIBP-3226 (a selective NPY-Y1 receptor antagonist). A defensive burying behavior test (DBB) was performed to assess the anxiety-like state during withdrawal, followed by a 24-hour free choice voluntary alcohol intake test. Under our experimental conditions, NPY microinjection decreased alcohol consumption in HA rats, whereas NPY-Y1 receptor blockade in D-PAG produced a notably anxiogenic effect and higher alcohol intake and relapse. In conclusion, NPY in the D-PAG, most likely acting on NPY-Y1 receptors, induced a significant anxiolytic effect and prominently inhibited alcohol consumption and relapse in Wistar rats.

Antidepressant effects of acupoint stimulation and fluoxetine by increasing dendritic arborization and spine density in CA1 hippocampal neurons of socially isolated rats.

Given the importance of depression and the adverse effects of conventional treatment, it is necessary to seek complementary therapies. In a rat model of depression, this study aimed to assess the behavioral and morphological effects of embedding absorbable thread in acupoints (acu-catgut), and compare the results to those of fluoxetine treatment and the corresponding control groups. Therefore, depressive-like behavior was evaluated with the forced swimming test, and dendritic morphology (in the CA1 hippocampal region) with the Golgi-Cox technique and Sholl analysis. After weaning, male Sprague-Dawley rats were housed in social isolation for 8 weeks to induce depressive-like behavior. They were then given a 21-day treatment by stimulating acupoints with acu-catgut (AC) or fluoxetine (FX) (2 mg/kg). Rats were divided into six groups: Control (socially housed), social isolation (SI), SI + AC, SI + Sham (sham embedding of thread), SI + FX and SI + VH (vehicle). Compared to fluoxetine, acu-catgut treatment was more effective in reversing depressive-like behavior elicited by SI. The SI-induced reduction in dendritic length and spine density in hippocampal CA1 pyramidal neurons was attenuated after prolonged treatment with acu-catgut or fluoxetine. Hence, both treatments proved capable of reversing depressive-like alterations caused by SI, likely due to dendritic remodeling in the hippocampus.

Effect of parathyroidectomy on cardiac fibrosis and apoptosis: possible role of aldosterone.

BACKGROUND/AIM: It has been demonstrated that parathyroidectomy prevents left ventricular hypertrophy in uremic animals. Although this effect may be mediated by direct actions of parathormone (PTH), it may also be exerted through regulation of profibrotic factors such as aldosterone. In adrenal cortex cell cultures, PTH increases aldosterone release. The objective of this work is to assess the effect of parathyroidectomy on aldosterone levels and on cardiac fibrosis and apoptosis in uremic rats. METHODS: Four groups of rats were studied: C, control; 5/6Nx, 5/6 nephrectomy; PTx, parathyroidectomy, and 5/6NxPTx, 5/6 nephrectomy plus parathyroidectomy. Thirty days after the last surgical procedure the animals were sacrificed. Serum creatinine, ionized calcium, aldosterone, PTH, cardiac weight, fibrosis and apoptosis were measured. RESULTS: Serum creatinine levels were significantly higher in 5/6Nx and 5/6NxPTx groups (1.62 +/- 0.21 and 1.38 +/- 0.15 mg/dl) than in C and PTx groups (0.66 +/- 0.02 and 0.47 +/- 0.01 mg/dl, p < 0.001). Potassium levels were significantly higher in the 5/6Nx and 5/6NxPTx groups (5.2 +/- 0.3 and 5.4 +/- 0.3 mg/dl) than in the C group (4.3 +/- 0.06 mg/dl, p < 0.05). Values in 5/6Nx and 5/6NxPTx groups were not significantly different from each other. PTH levels were significantly higher in the 5/6Nx group (470.5 +/- 156.3 microg/ml) than in the controls (102.3 +/- 14.3 microg/ml). PTH levels in the PTx group (1.78 +/- 0.52 microg/ml) and in the 5/6NxPTx group (81.64 +/- 32.15 microg/ml) were similar to control values. Ionized calcium was lower in PTx and 5/6NxPTx groups (0.80 +/- 0.07 and 0.89 +/- 0.07 mmol/l) as compared with C and 5/6Nx groups (1.14 +/- 0.01 and 0.96 +/- 0.01 mmol/ l, p < 0.01). The heart weight as percentage of the body weight increased significantly in 5/6Nx animals (4.20 +/- 0.15%) compared to the C group (3.41 +/- 0.27%, p < 0.05); parathyroidectomy reversed the heart weight increment in the 5/6NxPTx animals (3.58 +/- 0.16%). Myocardial fibrosis was significantly higher in the 5/6Nx group (12.5 +/- 1.1%) than in the C group (7.3 +/- 1.5%, p < 0.001); in the 5/6NxPTx animals fibrosis returned towards control values (8.9 +/- 0.2%). Myocardial apoptosis rose significantly in 5/6Nx animals (24.3 +/- 1.2%) compared to the C group (6.7 +/- 0.83%, p < 0.001); parathyroidectomy reversed the apoptosis in the 5/6NxPTx animals (10.4 +/- 0.49%). Aldosterone levels increased significantly in the 5/6Nx group (2,461 +/- 257 pg/ml) compared to the C group (703 +/- 81 pg/ml, p < 0.001); in the 5/6NxPTx animals aldosterone levels were below control values (509 +/- 99 pg/ml). CONCLUSIONS: Uremia was associated to myocardial hypertrophy, fibrosis and apoptosis. Surgically induced hypoparathyroidism prevented the development of these disorders. Our results suggest that in the remnant kidney rat model myocardial hypertrophy, fibrosis, and apoptosis are mediated by high circulating aldosterone levels. Aldosterone, in turn, may be regulated by PTH.

Involvement of opioid and GABA systems in the ventrolateral periaqueductal gray on analgesia associated with tonic immobility.

Ventrolateral periaqueductal gray (VL-PAG) contains key neuronal circuits related to the analgesic effect involved in integrated defensive behaviors such as immobility response (IR). The latter is characterized by a reversible state of motor inhibition that can be elicited in rats under several conditions including restriction of movements (tonic immobility: TI). It is known that IR-induced analgesia can be elicited by manipulations or drugs acting on the central nervous system (CNS) at different levels. The aim of this study was to assess the role of the opioid and the GABA systems in TI-elicited analgesia. After inducing TI in naïve rats by neck clamping, the analgesic effect was evaluated by the tail-flick (TF) test. Compared to the control group, rats with TI had increased TF latency evidencing an analgesic effect. An opioid receptor agonist and antagonist were injected systemically, as well as microinjected locally in VL-PAG, as well as GABAA receptor agonist and antagonist were microinjected into VL-PAG. Under both injection schemes, morphine increased TF latency and TI duration, while naloxone blocked TI-induced analgesia. Muscimol reduced TF latency and TI duration while bicuculline increased TF latency but not TI duration. This suggests that TI-elicited analgesia was mediated by opioids at different levels of the CNS especially in the VL-PAG by inhibition of intrinsic tonic GABAergic activity. There were no additive analgesic effects of morphine or bicuculline with tonic immobility, which probably means reach a certain upper limit under such conditions.

Development of a UPLC-MS/MS method for the quantification of sildenafil by DBS, and its use on pediatric pulmonary hypertension.

BACKGROUND: Sildenafil is used for the treatment of pediatric pulmonary hypertension. A dried blood spot (DBS)-based LC-MS method for sildenafil quantitation was developed and applied to a group of patients. RESULTS: DBS showed high portability and stability of samples, and the method was selective and linear for quantitation of sildenafil (5-3,000 ng/ml) and N-desmethyl-sildenafil (3-1,500 ng/ml). After a single oral dose of sildenafil (1 mg/kg), method evidenced poor metabolism in these patients. CONCLUSION: The method was successfully applied in peripheral blood and can be used for both pharmacokinetics and therapeutic drug monitoring. DBS proved to have advantages during sample translation and preservation of analytes. Data suggest that hazardous blood sildenafil levels may be reached in this population.

The long-term ingestion of a diet high in extra virgin olive oil produces obesity and insulin resistance but protects endothelial function in rats: a preliminary study.

BACKGROUND: It has been hypothesized that fatty acids derived from a diet high in saturated fat may negatively affect endothelial function more significantly than a diet high in unsaturated fat; nevertheless, the effects of the long-term ingestion of monounsaturated fatty acids on endothelial function have been poorly studied. METHODS: To examine the chronic effects of monounsaturated (e.g., extra virgin olive oil (EVOO)) or saturated (e.g., margarine (M)) fatty acid-rich diets on the development of insulin resistance and endothelial dysfunction in rats, three groups of rats were fed control, high-EVOO or high-M diets for 20 weeks. Body weight, energy consumption, insulin resistance, lipid peroxidation and in vitro vascular reactivity with and without metformin were assessed during the study period. RESULTS: Both high-fat diets produced obesity and insulin resistance. EVOO-fed rats showed smaller increases in total cholesterol and arterial lipid peroxidation when compared with M-fed rats. Vascular reactivity to phenylephrine and sodium nitroprusside was not modified, but the vasodilating effect of carbachol was especially reduced in the M-fed rats compared with the EVOO-fed or control groups. Metformin addition to the incubation media decreased the vascular response to phenylephrine; decrease that was lower in rats fed with both high fat diets, and increased the carbachol and nitroprusside effects, but the metformin-enhanced response to carbachol was lower in the M group. CONCLUSIONS: Our results suggest that feeding rats with high quantities of EVOO, despite producing obesity and insulin resistance, produces low levels of circulating cholesterol and arterial lipoperoxidation compared to M fed rats and shows a preserved endothelial response to carbachol, effect that is significantly enhanced by metformin only in rats fed with control and EVOO diets.

Comparison of fasting bioavailability among 100-mg commercial, 100-mg generic, and 50-mg chewable generic sildenafil tablets in healthy male Mexican volunteers: a single-dose, 3-period, crossover study.

BACKGROUND: Sildenafil citrate (SIL) was the first oral drug registered in Mexico for the treatment of erectile dysfunction. However, succinct pharmacokinetic data are available in the Mexican population. OBJECTIVE: The goals of the present work were: (1) to design a specific method to quantify SIL plasma levels by using UPLC-MS/MS; (2) to compare oral SIL bioavailability in Mexican men with pharmacokinetic data in other populations; (3) to fulfill local regulatory requests; and (4) to describe the relative tolerability of a new 50-mg chewable tablet. METHODS: This was a randomized, single-dose, 3-period, 6-sequence crossover study in healthy male volunteers. In each period, subjects received single oral doses of 100 mg of sildenafil (1 commercial [reference(⁎)], 1 generic [test 1(†)], or 2 chewable generic tablets [test 2(‡)]), with a 4-day washout period between each dose. Serial blood samples were collected for up to 24 hours. SIL was measured in heparinized plasma by using a validated UPLC-MS/MS method. Pharmacokinetic parameters included C(max), T(max), AUC(0-24), and AUC(0-∞). Bioequivalence was established if 90% CIs for mean test:reference ratios of log-transformed C(max) and AUC fell within the range of 0.80 to 1.25. Tolerability was assessed on the basis of a clinical interview with the subject and monitoring of vital signs. RESULTS: Demographic data showed a homogeneous population. Validation of analytical method proved to be linear within the range of 1 to 1000 ng/mL, with selectivity, accuracy, and precision. 90% CIs for test 1:reference ratios were 86.52 to 113.56, 94.75 to 108.84, and 94.97 to 108.82 for the logarithm parameters C(max), AUC(0-24), and AUC(0-∞), respectively. The 90% CIs for the test 2:reference ratios were 82.14 to 107.24, 98.26 to 112.56, and 99.19 to 113.34 for C(max), AUC(0-24), and AUC(0-∞). Regarding relative tolerability, slight cephalea was the most common adverse effect. CONCLUSIONS: The developed analytical method was validated in compliance with local requirements and was useful for sildenafil measurement. This single-dose study under fasting conditions suggests that both test products met the Mexican regulatory criteria for assuming bioequivalence in these healthy, male Mexican volunteers. The clinical data suggest that the chewable tablets were well tolerated by volunteers.

Activation of 5-HT1B receptors inhibits the vasodepressor sensory CGRPergic outflow in pithed rats.

The importance of calcitonin gene-related peptide (CGRP) in the regulation of vascular tone has been widely documented. Indeed, stimulation of the perivascular sensory outflow in pithed rats results in vasodepressor responses, which are mediated by CGRP release. These vasodepressor responses are inhibited by clonidine via prejunctional alpha(2A/2C)-adrenoceptors, but no study has yet reported the role of prejunctional 5-hydroxytryptamine (5-HT) receptors in this experimental model. Since activation of prejunctional 5-HT(1) receptors results in inhibition of neurotransmitter release, this study sets out to investigate as an initial approach the role of 5-HT(1B) receptors in the inhibition of the vasodepressor sensory outflow in pithed rats. Male Wistar pithed rats were pretreated with hexamethonium (2mg/kg.min) followed by i.v. continuous infusions of methoxamine (20 microg/kg min), and then by saline (0.02 ml/min) or CP-93,129 (a rodent 5-HT(1B) receptor agonist; 0.1, 1 and 10 microg/kg min). Under these conditions, electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the spinal cord (T(9)-T(12)) resulted in frequency-dependent decreases in diastolic blood pressure. The infusions of CP-93,129, as compared to those of saline, inhibited the vasodepressor responses induced by electrical stimulation without affecting those to i.v. bolus injections of exogenous alpha-CGRP (0.1, 0.18, 0.31, 0.56 and 1 microg/kg). This inhibition by CP-93,129 was abolished by the antagonists GR127935 (5-HT(1B/1D)) or SB224289 (5-HT(1B)), but not by BRL15572 (5-HT(1D)). The above results suggest that CP-93,129-induced inhibition of the vasodepressor (perivascular) sensory outflow in pithed rats is mainly mediated by activation of prejunctional 5-HT(1B) receptors.

Activity and residual effect of two formulations of lambdacyhalothrin sprayed on palm leaves to Rhodnius prolixus.

The insecticidal activity and residual effect of two formulations of lambdacyhalothrin were evaluated with Rhodnius prolixus; laboratory and field tests were conducted in the State of Chiapas, Mexico. The results indicate that the lethal concentrations of the active ingredient of SC (LC50 = 2.37 and LC90 = 8.5 mg, a.i./m2) were 4-8 times than those with the insecticide WP applied on R. prolixus bugs in palm leaves, a common building material for thatched roofs. Other investigators in South America recommended applying 30 mg a.i./m2 in porous materials; we obtained that the products WP and SC were 3.5 and 16 times more effective on palm leaves. Regarding the evaluation of the residual effects in field spraying, there was up to 15 months persistence after the application of WP in two doses (8.6 mg a.i./m2 and 3.752 mg a.i./m2) with SC. We consider R. prolixus highly susceptible to the employed pyrethroids; they could be used to control this vector in the state of Chiapas, Mexico.

Pharmacological profile of the vascular responses to dopamine in the canine external carotid circulation.

The present study investigated the effects of dopamine on the canine external carotid circulation. One min. intracarotid artery (i.c.) infusions of dopamine (10-310 microg min.-1) produced dose-dependent decreases in the canine external carotid conductance without affecting blood pressure or heart rate. This effect was mimicked by the D1/2-like receptor agonist apomorphine (1-310 microg min-1), but not by the D2-like receptor agonist, bromocriptine (31-310 microg min.-1). In contrast, fenoldopam (1-310 microg min.-1, intracarotid), a D1-like receptor agonist, produced dose-dependent increases in external carotid conductance. The vasoconstrictor response to dopamine was abolished after intravenous administration of the antagonists, phentolamine (alpha1/2; 2000 microg kg-1) or rauwolscine (alpha2; 100 microg kg-1), but remained unaffected after prazosin (alpha1; 100 microg kg-1) or haloperidol (D2-like; 1000 microg kg-1). Interestingly, after phentolamine not only were the vasoconstrictor responses to dopamine abolished, but even a dose-dependent vasodilator component was unmasked. These vasodilator responses to dopamine remained unchanged after intravenous haloperidol or propranolol (1000 microg kg-1 each). On the other hand, the vasodilator responses to fenoldopam, which remained unchanged after intravenous saline (0.1 ml kg-1), propranolol (1000 microg kg-1) or vagosympathectomy, were abolished by the D1-like receptor antagonist, SCH-23390 (10 microg kg-1). Lastly, the responses to dopamine and fenoldopam were not significantly altered after intraperitoneal pretreatment with reserpine (5 mg kg-1; -24 hr). The above results suggest that the canine external carotid vasoconstrictor responses to dopamine: (i) are mainly mediated by alpha2-adrenoceptors; and (ii) overshadow a vasodilator component, which involves vascular D1-like receptors.

Activity and Residual Effect of Two Formulations of Lambdacyhalothrin Sprayed on Palm Leaves to Rhodnius prolixus

The insecticidal activity and residual effect of two formulations of lambdacyhalothrin were evaluated with Rhodnius prolixus;laboratory and field tests were conducted in the State of Chiapas, Mexico. The results indicate that the lethal concentrations of the active ingredient of SC (LC50 = 2.37 and LC90 = 8.5 mg, a.i./mý) were 4-8 times than those with the insecticide WP applied on R. prolixus bugs in palm leaves, a common building material for thatched roofs. Other investigators in South America recommended applying 30 mg a.i./mý in porous materials; we obtained that the products WP and SC were 3.5 and 16 times more effective on palm leaves. Regarding the evaluation of the residual effects in field spraying, there was up to 15 months persistence after the application of WP in two doses (8.6 mg a.i./mý and 3.752 mg a.i./mý) with SC. We consider R. prolixus highly susceptible to the employed pyrethroids; they could be used to control this vector in the state of Chiapas, Mexico

Comparación de los efectos de la serotonina, 2-(2-aminoetil)-quinolina (D-1997) y sumatriptan sobre el flujo sanguíneo carotídeo externo del perro / D-1997 and external carotid blood flow

La 2-(2-aminoetil)-quinolina (D-1997) es un derivado quinolínico capaz de mimetizar el efecto contráctil de la serotonina (5-hidroxitriptamina; 5HT) en la vena safena y la arteria basilar del perro. Debido a la similitud que parece existir en el tipo de receptor serotónergico presente en estas preparaciones y el que media la vasoconstricción de la cirulación carotídea del perro, el presente estudio analiza el perfil hemodinámico del D-1997 en el lecho arterial carotídeo externo de perros vago simpatectomizados anestesiados con pentobarbital. Los efectos del D-1997 se compararon con aquellos producidos por la 5-HT y el agente antimigrañoso, sumatriptan. Las infusiones intracarotídeas (i.c.), durante 1 min, de D-1997 (10, 30, 100, 300 y 1000 µg/min), 5HT (0.3, 1, 3, 10, 30 y 100 µg/min), y sumatriptan (3, 10, 30 y 100 µg/min), produjeron decrementos del flujo sanguíneo carotídeo externo (FSCE) dependientes de la dosis empleada. Debido a que estos efectos no se vieron acompañados de modificaciones en la presión arterial, los agonistas produjeron incrementos dosis-dependientes de la resitencia carotídea externa (RCE). Las respuestas vasoconstrictoras inducidas por el D-1997 y la 5-HT fueron de corta duración (hasta 10 min), mientras que aquellas producidas por el sumatriptan fueron de larga duración (hasta 40 min). Los cambios hemodinámicos producidos por el D-1997 y la 5-HT y el sumatriptan en la carótida externa no modificaron los valores basales de resitencia en el lecho arterial de la carótida común contralateral, hecho que indica un efecto local. El orden de potencia agonista aparente fue 5-HT>sumatriptan>D-1997, mientras que el orden de eficacia, representada aquí como la respuesta máxima observada, siguió un patrón diferente, es decir, D-1997 ò sumatriptan > 5-HT. La administración repetida o la administración previa de 5-HT y sumatriptan no modificó las respuestas inducidas por este nuevo agonista; en consecuencia, el D-1997 se comportó como un agonista completo sin inducción de taquifilaxia. Los resultados de este estudio indican que, al igual que en la arteria basilar y en la vena safena del perro, el D-1997 es capaz de producir contracción del músculo liso vascular en el lecho arterial carotídeo externo del perro

Influence of 5-hydroxytryptamine on the pressor responses induced by norepinephrine and electrical sympathetic stimulation in the pithed rat

Serotonin (5-hydroxytryptamine; 5-HT) modifies the responses to several vasoconstrictor stimuli prejunctionally and/or postjunctionally. The pressent study analyzed the effects of 5-HT on the pressor responses induced by norepinephrine (NE) or electrical sympathetic stimulation in pithed rats. Responses to intravenous (i.v.) NE (0.03-3 µg/kg) or electrical stimulation at increasing frequencies (0.1 - 3 Hz) were evaluated before and during continous i.v. infusions of physiological saline (0.01 ml/min) or 5-HT (1 - 10 µg/kg x min). The effects of 5-HT on the tachycardic responses to NE and sympathetic stimulation were studied in parallel. The increases in diastolic blood pressure and heart rate produced by NE were not modified by 5-HT. In contrast, 5-HT significantly and dose-dependently inhibited the increases in diastolic blood pressure but not those in heart rate - produced by stimulation of the appropriate spinal segments. Theses effects of 5-HT were more prononced on the responses to lower frequencies of stimulation. It is suggested that 5-HT inhibits the electrically induced pressor responses by a prejunctional mechanism which would lead to a reduction of neurotransmitter release from the sympathetic nerves supplying the systemic vasculature. The selective stimulation of this inhibitory mechanism might represent a new approach for the development of novel antihypertensive agents