scholarly journals Systemic and portal hemodynamic effects of anandamide

2001 ◽  
Vol 280 (1) ◽  
pp. G14-G20 ◽  
Author(s):  
Nelson Garcia ◽  
Zoltán Járai ◽  
Faridoddin Mirshahi ◽  
George Kunos ◽  
Arun J. Sanyal
Keyword(s):  
Vascular Resistance ◽  
Nordihydroguaiaretic Acid ◽  
Hemodynamic Effects ◽  
Venous Flow ◽  
Portal Hemodynamics ◽  
Sr 141716A ◽  
Dose Dependent Decrease ◽  
Endogenous Cannabinoid ◽  
Dose Dependent ◽  
Mesenteric Vascular Resistance

The endogenous cannabinoid anandamide causes hypotension and mesenteric arteriolar dilation. A detailed analysis of its effects on systemic and portal venous hemodynamics had not yet been performed. We assessed the effects of anandamide (0.4–10 mg/kg) on systemic and portal hemodynamics with and without prior treatment with various antagonists. The specific antagonists used included SR-141716A, N ω-nitro-l-arginine methyl ester, indomethacin, and nordihydroguaiaretic acid. Anandamide produced a dose-dependent decrease in mean arterial pressure due to a drop in systemic vascular resistance (SVR) that was accompanied by a compensatory rise in cardiac output. Anandamide also elicited an increase in both portal venous flow and pressure, along with a decline in mesenteric vascular resistance (MVR). Pretreatment with 3 mg/kg SR-141716A, a CB1 antagonist, prevented the decline of SVR and MVR from the lower dose of anandamide. Antagonism of nitric oxide synthetase, cyclooxygenase, or 5-lipoxygenase did not prevent the systemic nor the portal hemodynamic effects of anandamide. Furthermore, the use of R-methanandamide, a stable analog of anandamide, produced similar hemodynamic effects on the mesenteric vasculature, thereby implying that the effects of anandamide are not related to its breakdown products. Anandamide produced profound, dose-dependent alterations in both the systemic and portal circulations that could be at least partially blocked by pretreatment with SR-141716A.

scholarly journals Characterization and cardiovascular actions of endothelin-1 and endothelin-3 from the American alligator

2002 ◽  
Vol 282 (2) ◽  
pp. R594-R602 ◽  
Author(s):  
Björn Platzack ◽  
Yuqi Wang ◽  
Dane Crossley ◽  
Valentine Lance ◽  
James W. Hicks ◽  
...  
Keyword(s):  
Blood Flow ◽  
Vascular Resistance ◽  
Biological Activities ◽  
Systemic Blood Pressure ◽  
Second Phase ◽  
Systemic Blood ◽  
Cardiovascular Actions ◽  
Dose Dependent Decrease ◽  
Alligator Mississipiensis ◽  
Dose Dependent

The structures and biological activities of the isoforms of endothelin (ET) in a reptile are unknown. ET-3, whose primary structure is identical to human ET-3 except for the substitution Phe4 → Tyr, and a peptide identical to human ET-1 were isolated from an extract of the lung of the alligator, Alligator mississipiensis. Bolus intravenous injections of alligator ET-3 (10, 30, and 100 pmol/kg) into anesthetized alligators produced dose-dependent decreases in systemic blood pressure (Psys) and systemic vascular resistance (Rsys) without change in heart rate (HR), systemic blood flow (Qsys), pulmonary pressure (Ppul), pulmonary vascular resistance (Rpul), or pulmonary blood flow (Qpul). At a dose of 300 pmol/kg, the initial vasodilatation was followed by an increase in Rsys and decreases in Qsys and Ppul. The response to intravenous human/alligator ET-1 (10, 30, 100, and 300 pmol/kg) was biphasic at all doses with initial decreases in Psys and Rsys being followed by sustained increases in these parameters. In the pulmonary circulation, ET-1 produced a dose-dependent decrease in Qpul and an increase in Rpul during the first phase of the response but no significant change during the second phase. There was no change in HR in response to ET-1. The vasodilatator action of arginine, but not ET-1, was attenuated by N ω-nitro-l-arginine methyl ester, indicating that the effect of the peptide is probably not mediated through increased synthesis of nitric oxide. The data demonstrate that the structure of the ET isoforms has been strongly conserved during the evolution of vertebrates but that cardiovascular actions differ significantly between the alligator and mammals, especially in the magnitude and duration of the hypotensive response.

Adrenoceptor function in the bovine pulmonary circulation

1986 ◽  
Vol 64 (6) ◽  
pp. 689-693 ◽  
Author(s):  
Kevin J. Greenlees ◽  
Robert Gamble ◽  
Peter Eyre
Keyword(s):  
Arterial Pressure ◽  
Vascular Resistance ◽  
Pulmonary Arteries ◽  
Systemic Arterial Pressure ◽  
Venous Circulation ◽  
Arterial Ph ◽  
Pulmonary Arterial ◽  
Dose Dependent Decrease ◽  
Dose Dependent ◽  
Arteries And Veins

The bovine pulmonary vascular response to α- and β-agonists was studied using an awake intact calf model. Pulmonary arterial pressure, pulmonary arterial wedge pressure, left atrial pressure, systemic arterial pressure, and cardiac output were measured in response to 3 min infusions of isoproterenol (β-agonist; 0.12, 0.24, 0.48, 0.9, and 1.8 μg∙kg−1∙min−1) and phenylephrine (α-agonist, 0.15, 0.30, 0.60, 1.15, and 2.30 μg∙kg−1∙min−1). Phenylephrine caused an increase in vascular resistance in the pulmonary arterial and venous compartments. The slope of the resistance in response to phenylephrine was greater in the pulmonary arterial than pulmonary venous circulation. Isoproterenol resulted in a dose-dependent decrease in vascular resistance in the pulmonary arteries and veins. The vascular resistance was decreased to the same level in the pulmonary arteries and veins although the arteries showed a greater percent change. In addition, isoproterenol infusion resulted in a transient decrease in arterial pH and increase in values for packed cell volume and haemoglobin.

Analysis of adrenergic responses in the mesenteric vascular bed of the cat; evidence that vascular beta2-adrenoceptors are innervated

1984 ◽  
Vol 62 (12) ◽  
pp. 1470-1478 ◽  
Author(s):  
William M. Armstead ◽  
Howard L. Lippton ◽  
Albert L. Hyman ◽  
Philip J. Kadowitz
Keyword(s):  
Vascular Resistance ◽  
Nerve Stimulation ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Stimulation ◽  
Beta Adrenergic ◽  
Vascular Bed ◽  
Alpha Receptors ◽  
Mesenteric Vascular Bed ◽  
Dose Dependent ◽  
Mesenteric Vascular Resistance

Responses to sympathetic nerve stimulation and pressor hormones were investigated in the feline mesenteric vascular bed under conditions of controlled blood flow. Sympathetic nerve stimulation and norepinephrine produced frequency- and dose-dependent increases in mesenteric vascular resistance. However, when alpha-receptors were blocked with the non-equilibrium alpha-receptor antagonist, phenoxybenzamine, nerve stimulation and norepinephrine produced frequency- and dose-dependent decreases in mesenteric vascular resistance. These reductions in mesenteric vascular resistance were unchanged after indomethacin or atropine, whereas propranolol converted the mesenteric vasodilator responses to small vasoconstrictor responses. In these studies, responses to a variety of vasoconstrictor agents were enhanced after administration of propranolol. Sotalol, a nonselective beta blocker with little membrane stabilizing activity, also enhanced vasoconstrictor responses. The present data suggest that both alpha- and beta-adrenergic receptors are innervated in the feline mesenteric vascular bed, and that vasodilator responses to norepinephrine and sympathetic nerve stimulation are independent of activation of muscarinic receptors or formation of products in the cyclooxygenase pathway. These data also demonstrate that there is a nonspecific potentiation of intestinal vasoconstrictor responses after beta-adrenergic receptor blockade that is independent of a membrane-stabilizing or receptor-mediated mechanism.

Insulin secretion and substrate homeostasis in prolonged hypothermia in rats

1988 ◽  
Vol 255 (6) ◽  
pp. R1035-R1040
Author(s):  
R. Hoo-Paris ◽  
M. L. Jourdan ◽  
L. C. Wang ◽  
R. Rajotte
Keyword(s):  
Insulin Secretion ◽  
Plasma Glucose ◽  
Low Temperatures ◽  
Plasma Insulin ◽  
Glucose Utilization ◽  
Exogenous Insulin ◽  
Metabolic Substrate ◽  
Endogenous Insulin ◽  
Dose Dependent Decrease ◽  
Dose Dependent

In hypothermia, impairment of metabolic substrate mobilization and utilization may be a factor limiting survival. By use of a newly developed technique, substrate profiles and their regulation by insulin were examined in hypothermic rats (body temperature 19 degrees C) over 24 h. Plasma glucose concentrations increased to approximately 300 mg/dl during cooling and remained high throughout the period of hypothermia. Free fatty acid (FFA) concentration was not altered during cooling or during the first 10 h of hypothermia (approximately 700 mu eq/l) but progressively decreased thereafter, reaching 420 mu eq/l by 20 h. Plasma insulin decreased dramatically during cooling and remained very low (9 +/- 2 microU/ml) during the whole period of hypothermia, reflecting the suppression of insulin secretion by isolated islets at low temperatures. To test he hypothesis that suppression of endogenous insulin secretion may hamper glucose utilization and thus limit survival in hypothermia, exogenous insulin was administered. At doses of 0.1, 0.5, and 1 U/kg intravenously, insulin slowly decreased plasma glucose and FFA. However, at 0.1 and 1 U/kg intraperitoneally, insulin resulted in a dose-dependent decrease in survival time in the hypothermic rat. It is possible that the antilipolytic effect of insulin may have outweighed any beneficial effect of improving glucose utilization in hypothermia.

scholarly journals A Reversible Shift of Driver Dependence from EGFR to Notch1 in Non-Small Cell Lung Cancer as a Cause of Resistance to Tyrosine Kinase Inhibitors

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2022
Author(s):  
Francesca Iommelli ◽  
Viviana De Rosa ◽  
Cristina Terlizzi ◽  
Rosa Fonti ◽  
Rosa Camerlingo ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Epithelial Mesenchymal Transition ◽  
Parental Cell ◽  
Egfr Inhibitors ◽  
Simultaneous Increase ◽  
Adherent Cells ◽  
Binding Assays ◽  
Mesenchymal Transition ◽  
Dose Dependent Decrease ◽  
Dose Dependent

Notch1 plays a key role in epithelial-mesenchymal transition (EMT) and in the maintenance of cancer stem cells. In the present study we tested whether high levels of activated Notch1 in oncogene-driven NSCLC can induce a reversible shift of driver dependence from EGFR to Notch1, and thus causing resistance to EGFR inhibitors. Adherent cells (parental) and tumor spheres (TS) from NSCLC H1975 cells and patient-derived CD133-positive cells were tested for EGFR and Notch1 signaling cascade. The Notch1-dependent modulation of EGFR, NCID, Hes1, p53, and Sp1 were then analyzed in parental cells by binding assays with a Notch1 agonist, DLL4. TS were more resistant than parental cells to EGFR inhibitors. A strong upregulation of Notch1 and a concomitant downregulation of EGFR were observed in TS compared to parental cells. Parental cell exposure to DLL4 showed a dose-dependent decrease of EGFR and a simultaneous increase of NCID, Hes1, p53, and Sp1, along with the dislocation of Sp1 from the EGFR promoter. Furthermore, an enhanced interaction between p53 and Sp1 was observed in TS. In NSCLC cells, high levels of active Notch1 can promote a reversible shift of driver dependence from EGFR to Notch1, leading to resistance to EGFR inhibitors.

Inhibitory Effects of Purple Sweet Potato Leaf Extract on the Proliferation and Lipogenesis of the 3T3-L1 Preadipocytes

2015 ◽  
Vol 43 (05) ◽  
pp. 915-925 ◽  
Author(s):  
Shou-Lun Lee ◽  
Hsien-Kuang Lee ◽  
Ting-Yu Chin ◽  
Ssu-Chieh Tu ◽  
Ming-Hsun Kuo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Sweet Potato ◽  
Early Stage ◽  
Water Extract ◽  
Potato Leaf ◽  
Purple Sweet Potato ◽  
Pre Treatment ◽  
Dose Dependent Decrease ◽  
Dose Dependent

Purple sweet potato leaves (PSPLs) are healthy vegetable that is rich in anti-oxidants. A solution of boiling water extract of PSPL (PSPLE) is believed to be able to prevent obesity and metabolic syndrome in the countryside of Taiwan, but its efficacy has not yet been verified. The purpose of this study was to investigate the possible anti-adipogenesis effect of PSPLE in vitro. PSPLE was used to treat the 3T3-L1 cells, and the effects on cell proliferation and adipogenesis were investigated. The results showed that PSPLE caused a dose-dependent decrease in the cell proliferation of 3T3-L1 preadipocytes, but did not alter the cell viability. In addition, PSPLE induced ERK inactivation in the 3T3-L1 preadipocytes. Furthermore, pre-treatment of confluent 3T3-L1 cells with PSPLE led to reduced lipid accumulation in differentiated 3T3-L1 cells. The inhibition of lipogenesis could result from the PSPLE-induced down-regulation of the expression of the C/EBPα and SREBP-1 transcription factors during 3T3-L1 adipocyte differentiation. These results suggest that PSPLE not only inhibits cell proliferation at an early stage but also inhibits adipogenesis at a later stage of the differentiation program.

scholarly journals Comparative Drug Disposition, Urinary Pharmacokinetics, and Renal Effects of Multilamellar Liposomal Nystatin and Amphotericin B Deoxycholate in Rabbits

2003 ◽  
Vol 47 (12) ◽  
pp. 3917-3925 ◽  
Author(s):  
Andreas H. Groll ◽  
Diana Mickiene ◽  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Raul M. Alfaro ◽  
...  
Keyword(s):  
Total Dose ◽  
Amphotericin B ◽  
Drug Disposition ◽  
Fungal Infections ◽  
Standard Dose ◽  
Concentration Data ◽  
Drug Concentrations ◽  
Amphotericin B Deoxycholate ◽  
Dose Dependent Decrease ◽  
Dose Dependent

ABSTRACT The comparative drug dispositions, urinary pharmacokinetics, and effects on renal function of multilamellar liposomal nystatin (LNYS; Nyotran) and amphotericin B deoxycholate (DAMB; Fungizone) were studied in rabbits. Drug concentrations were determined by high-performance liquid chromatography as total concentrations of LNYS and DAMB. In comparison to a standard dose of 1 mg of DAMB/kg of body weight, therapeutic dosages of LNYS, i.e., 2, 4, and 6 mg/kg, resulted in escalating maximum concentrations (C max) (17 to 56μ g/ml for LNYS versus 3.36 μg/ml for DAMB; P< 0.001) and values for the area under the concentration-time curve from 0 to 24 h (AUC0-24) (17 to 77μ g · h/ml for LNYS versus 12μ g · h/ml for DAMB; P < 0.001) in plasma but a significantly faster total clearance from plasma (0.117 to 0.080 liter/h/kg for LNYS versus 0.055 liter/h/kg for DAMB; P = 0.013) and a ≤8-fold-smaller volume of distribution at steady state (P = 0.002). Urinary drug concentration data revealed a ≥10-fold-higher C max (16 to 10 μg/ml for LNYS versus 0.96μ g/ml for DAMB; P = 0.015) and a 4- to 7-fold-greater AUC0-24 (63 to 35μ g · h/ml for LNYS versus 8.9μ g · h/ml for DAMB; P = 0.015) following the administration of LNYS, with a dose-dependent decrease in the dose-normalized AUC0-24 in urine (P= 0.001) and a trend toward a dose-dependent decrease in renal clearance. Except for the kidneys, the mean concentrations of LNYS in liver, spleen, and lung 24 h after dosing were severalfold lower than those after administration of DAMB (P,<0.002 to <0.001). Less than 1% each of the total dose of LNYS was recovered from the kidneys, liver, spleen, and lungs; in contrast, a quarter of the total dose was recovered from the livers of DAMB-treated animals. LNYS had dose-dependent effects on glomerular filtration and distal, but not proximal, renal tubular function which did not exceed those of DAMB at the highest investigated dosage of 6 mg/kg. The results of this experimental study demonstrate fundamental differences in the dispositions of LNYS and DAMB. Based on its enhanced urinary exposure, LNYS may offer a therapeutic advantage in systemic fungal infections involving the upper and lower urinary tracts that require therapy with antifungal polyenes.

Pressure-induced smooth muscle cell depolarization in pulmonary arteries from control and chronically hypoxic rats does not cause myogenic vasoconstriction

2005 ◽  
Vol 98 (3) ◽  
pp. 1119-1124 ◽  
Author(s):  
Jay S. Naik ◽  
Scott Earley ◽  
Thomas C. Resta ◽  
Benjimen R. Walker
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Cell Membrane ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Arteries ◽  
Barometric Pressure ◽  
Cell Membrane Potential ◽  
Intraluminal Pressure ◽  
Dose Dependent

Chronic obstructive pulmonary diseases, as well as prolonged residence at high altitude, can result in generalized airway hypoxia, eliciting an increase in pulmonary vascular resistance. We hypothesized that a portion of the elevated pulmonary vascular resistance following chronic hypoxia (CH) is due to the development of myogenic tone. Isolated, pressurized small pulmonary arteries from control (barometric pressure ≅ 630 Torr) and CH (4 wk, barometric pressure = 380 Torr) rats were loaded with fura 2-AM and perfused with warm (37°C), aerated (21% O2-6% CO2-balance N2) physiological saline solution. Vascular smooth muscle (VSM) intracellular Ca2+ concentration ([Ca2+]i) and diameter responses to increasing intraluminal pressure were determined. Diameter and VSM cell [Ca2+]i responses to KCl were also determined. In a separate set of experiments, VSM cell membrane potential responses to increasing luminal pressure were determined in arteries from control and CH rats. VSM cell membrane potential in arteries from CH animals was depolarized relative to control at each pressure step. VSM cells from both groups exhibited a further depolarization in response to step increases in intraluminal pressure. However, arteries from both control and CH rats distended passively to increasing intraluminal pressure, and VSM cell [Ca2+]i was not affected. KCl elicited a dose-dependent vasoconstriction that was nearly identical between control and CH groups. Whereas KCl administration resulted in a dose-dependent increase in VSM cell [Ca2+]i in arteries taken from control animals, this stimulus elicited only a slight increase in VSM cell [Ca2+]i in arteries from CH animals. We conclude that the pulmonary circulation of the rat does not demonstrate pressure-induced vasoconstriction.

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