Intestinal microvascular responsiveness to norepinephrine in chronic portal hypertension

1991 ◽  
Vol 260 (4) ◽  
pp. H1135-H1143 ◽  
Author(s):  
T. Joh ◽  
D. N. Granger ◽  
J. N. Benoit
Keyword(s):  
Blood Flow ◽  
Portal Hypertension ◽  
Dose Response ◽  
Vessel Diameter ◽  
Maximal Response ◽  
Hypertensive Rats ◽  
Response Curves ◽  
Cross Sectional ◽  
On Line

Effects of chronic prehepatic portal hypertension on intestinal microvascular sensitivity to norepinephrine (NE) were studied. Normal and portal hypertensive rats were anesthetized, and the intestine was prepared for in vivo microscopic observation. The preparation was transferred to a video microscope and a first-, second-, or third-order submucosal arteriole (i.e., 1A, 2A, or 3A, respectively) selected for study. Microvascular diameter and arteriolar erythrocyte velocity were measured on-line, and arteriolar blood flow was subsequently calculated as the product of velocity and vessel cross-sectional area. Once steady-state conditions were reached, the preparation was exposed to incremental doses of NE and microvessel responses were recorded. Cumulative log dose-response curves relating the change in arteriolar blood flow and vessel diameter to NE concentration were constructed for each group of arterioles and the ED50 for maximal response obtained from each dose-response relationship. NE ED50 for 1A blood flow was significantly higher in portal hypertensive rats (2.57 +/- 0.25 microM) compared with control rats (1.48 +/- 0.19 microM). Analysis of the diameter responses of 1A, 2A, and 3A indicated that the loss of vascular NE sensitivity in chronic portal hypertension was localized to the terminal submucosal arterioles (2A and 3A). No differences in the diameter response of 1A were observed between normal and portal hypertensive rats. Separate experiments were conducted to test if glucagon, a known mediator of the hyperdynamic intestinal circulation in portal hypertension, could acutely alter NE responsiveness in normal animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Endogenous vasoconstrictor tone in intestine of normal and portal hypertensive rats

1993 ◽  
Vol 264 (1) ◽  
pp. H171-H177 ◽  
Author(s):  
T. Joh ◽  
D. N. Granger ◽  
J. N. Benoit
Keyword(s):  
Blood Flow ◽  
Portal Hypertension ◽  
Adrenergic Receptors ◽  
Adrenergic Blockade ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Alpha Adrenergic Receptors ◽  
Control Plasma ◽  
Arteriolar Diameter

The purpose of the present study was to determine the effects of endogenous norepinephrine, vasopressin (AVP), and angiotensin II (ANG II) on normal intestinal microvascular dimensions and to determine whether endogenous vasoconstrictor tone was altered in chronic portal hypertension. The intestine of normal and portal hypertensive rats was prepared for in vivo microscopic observation, and an arteriole (1A, 2A, or 3A) was selected for study. Arteriolar diameter and erythrocyte velocity were continuously monitored and used in the calculation of arteriolar blood flow. Once steady-state conditions were established, specific antagonists to alpha-adrenergic, AVP, or ANG II receptors were applied locally to remove the influences of each of these systems. In normal animals, blockade of alpha-adrenergic receptors produced a 1.3, 1.5, and 14.7% increase in the diameter of 1A, 2A, and 3A, respectively. AVP blockade in normal animals produced an 8.7, 1.6, and 1.5% increase in the diameter of 1A, 2A, and 3A, respectively; ANG II blockade only produced an increase in 3A diameter (5.8%). alpha-Adrenergic blockade produced a smaller increase in portal hypertensive 3A diameter (2.3%) compared with normal rats. AVP and ANG II blockade produced a significantly larger dilation of 3A (AVP, 4.8%) and 1A (ANG II, 3.8%), respectively, compared with control. Plasma AVP and ANG II levels were higher in portal hypertensive (AVP, 9.1 pg/ml; ANG II, 8.6 pg/ml) than in normal rats (AVP, 5.5 pg/ml; ANG II, 6.6 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Cutaneous blood flow and sweat rate responses to exogenous administration of acetylcholine and methacholine

2007 ◽  
Vol 102 (5) ◽  
pp. 1856-1861 ◽  
Author(s):  
Kenichi Kimura ◽  
David A. Low ◽  
David M. Keller ◽  
Scott L. Davis ◽  
Craig G. Crandall
Keyword(s):  
Blood Flow ◽  
Dose Response ◽  
Sweat Rate ◽  
Molar Concentration ◽  
Maximal Response ◽  
Cutaneous Blood Flow ◽  
Response Curves ◽  
Forearm Skin ◽  
Dose Response Curves ◽  
Cutaneous Blood

The aim of this study was to evaluate cutaneous vasodilation and sweating responses to exogenous administration of acetylcholine (ACh) and methacholine (MCh), which have different sensitivities to endogenous cholinesterase. Four intradermal microdialysis probes were placed in dorsal forearm skin: two sites were perfused with ACh (1 × 10−7–1 M) and the other two with the same molar concentrations of MCh. Sweat rate (SR) and cutaneous blood flow were simultaneously assessed directly over each microdialysis membrane. Dose-response curves were constructed, and the effective concentration of the drug resulting in 50% of the maximal response (EC50) was identified. For SR and cutaneous vascular conductance (CVC), there were no significant differences in EC50 between sites receiving the same drug: −1.52 ± 0.18 and −1.19 ± 0.09 log-molar concentration of ACh at distal and proximal sites, respectively, and −2.35 ± 0.24 and −2.42 ± 0.23 log-molar concentration of MCh at distal and proximal sites, respectively, for SR ( P > 0.05) and −3.87 ± 0.32 and −3.97 ± 0.27 log-molar concentration of ACh at distal and proximal sites, respectively, and −4.78 ± 0.17 and −4.46 ± 0.16 log-molar concentration of MCh at distal and proximal sites, respectively, for CVC ( P > 0.05). However, the EC50 for CVC and SR was significantly lower at the MCh than at the ACh sites. A second procedure was performed to confirm that differences in responses between ACh and MCh could be attributed to different cholinesterase sensitivities. Similarly, four microdialysis membranes were placed in dorsal forearm skin: two sites were perfused with ACh and other two with MCh. However, one of each of the ACh and MCh sites was also perfused with 10 μM neostigmine (an acetylcholinesterase inhibitor). Neostigmine at the ACh site induced a leftward shift (i.e., lower EC50) of the SR and CVC dose-response curves compared with the site treated with ACh alone, resulting in no difference in the EC50 for SR and CVC between the ACh + neostigmine and the MCh site. These results suggest that elevations in SR and CVC occur earlier with MCh than with ACh treatment because of differences in cholinesterase susceptibility between these drugs.

scholarly journals Geometric Features of the Pial Arteriolar Networks in Spontaneous Hypertensive Rats: A Crucial Aspect Underlying the Blood Flow Regulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Dominga Lapi ◽  
Martina Di Maro ◽  
Nicola Serao ◽  
Martina Chiurazzi ◽  
Maurizio Varanini ◽  
...  
Keyword(s):  
Blood Flow ◽  
Peripheral Resistance ◽  
Hypertensive Rats ◽  
Cross Sectional ◽  
Spontaneously Hypertensive ◽  
Adult Age ◽  
Cranial Window ◽  
Frequency Components ◽  
Geometric Arrangements

BackgroundSeveral studies indicate that hypertension causes major changes in the structure of the vessel wall by affecting the regulation of blood supply to the tissues. Recently, it has been observed that capillary blood flow is also considerably influenced by the structural arrangement of the microvascular networks that undergo rarefaction (reduction of the perfused vessel number). Therefore, this study aimed to assess the geometric arrangements of the pial arteriolar networks and the arteriolar rhythmic diameter changes in spontaneously hypertensive rats (SHRs).MethodsFluorescence microscopy was utilized to observe in vivo the pial microcirculation through a closed cranial window. Pial arterioles were classified according to Strahler’s method. The arteriolar rhythmic diameter changes were evaluated by a generalization short-time Fourier transform.ResultYoung SHRs showed four orders of vessels while the adult ones only three orders. The diameter, length, and branching number obeyed Horton’s law; therefore, the vessels were distributed in a fractal manner. Larger arterioles showed more asymmetrical branches than did the smaller ones in young SHRs, while in adult SHRs smaller vessels presented asymmetrical branchings. In adult SHRs, there was a significant reduction in the cross-sectional area compared with the young SHRs: this implies an increase in peripheral resistance. Young and adult age-matched normotensive rats did not show significant alterations in the geometric arteriolar arrangement with advancing age, both had four orders of arteriolar vessels, and the peripheral resistance did not change significantly. Conversely, the frequency components evaluated in arteriolar rhythmic diameter changes of young and adult SHRs showed significant differences because of a reduction in the frequency components related to endothelial activity detected in adult SHRs.ConclusionIn conclusion, hypertension progressively causes changes in the microarchitecture of the arteriolar networks with a smaller number of vessels and consequent reduced conductivity, characteristic of rarefaction. This was accompanied by a reduction in the formation and release of independent and dependent – endothelial nitric oxide components regulating arterial vasomotion.

Effects of inhaled substance P on airway responsiveness to methacholine in asthmatic subjects in vivo

1994 ◽  
Vol 77 (3) ◽  
pp. 1325-1332 ◽  
Author(s):  
D. Cheung ◽  
H. van der Veen ◽  
J. den Hartigh ◽  
J. H. Dijkman ◽  
P. J. Sterk
Keyword(s):  
Substance P ◽  
Dose Response ◽  
Forced Expiratory Volume ◽  
Maximal Response ◽  
Response Curves ◽  
Airway Narrowing ◽  
Dose Response Curves ◽  
High Doses

We tested the hypothesis that the inhaled tachykinin substance P (SP) can induce hyperresponsiveness to methacholine in asthmatic subjects in vivo. Nine atopic nonsmoking asthmatic males with normal forced expiratory volume in 1 s (FEV1; > 80% predicted) and increased methacholine sensitivity [provocative concn causing 20% fall in FEV1 (PC20) < 8 mg/ml] participated in a two-period placebo-controlled crossover study. Dose-response curves to SP (0.25–8 mg/ml) and placebo were recorded on 2 randomized days at least 1 wk apart, and methacholine tests were done 24 h before and 2 and 24 h after these challenges. The responses were measured by FEV1 (%fall from baseline). The position of the methacholine dose-response curves was expressed by the PC20 FEV1 and by the maximal response by the plateau level (MFEV1). SP caused a dose-dependent fall in FEV1 (P < 0.001). There was a slight increase in the PC20 FEV1 at 2 and 24 h, which was not significantly different between placebo and SP. Similarly, there was a reduction in MFEV1 at 2 h after both pretreatments. However, at 24 h after SP inhalation, MFEV1 increased compared with placebo. These changes in MFEV1 were significantly different between SP and placebo by 5.2 +/- 2.2% fall (SE) (P < 0.05). We conclude that 1) a bronchoconstrictive dose of SP, compared with placebo, enhances maximal airway narrowing to methacholine in asthma 24 h after inhalation and 2) tolerance develops to high doses of inhaled methacholine. These findings are suggestive of a role of SP in causing excessive airway narrowing in asthma by inflammatory mechanisms.

Effects of epinephrine on insulin-mediated glucose uptake in whole body and leg muscle in humans: role of blood flow

1992 ◽  
Vol 263 (2) ◽  
pp. E199-E204 ◽  
Author(s):  
M. Laakso ◽  
S. V. Edelman ◽  
G. Brechtel ◽  
A. D. Baron
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Glucose Uptake ◽  
Dose Response ◽  
Insulin Dose ◽  
Whole Body ◽  
Response Curves ◽  
Leg Muscle

In vivo insulin-mediated glucose uptake (IMGU) occurs chiefly in skeletal muscle, where it is determined by the product of arteriovenous glucose difference (delta AVG) and blood flow (BF) rate into muscle. Epinephrine (Epi) reduces the rate of IMGU in whole body. To examine whether this is due to a reduction in delta AVG across or BF into skeletal muscle we constructed insulin dose-response curves for whole body IMGU and leg muscle IMGU- using euglycemic clamp ((+)[3-3H]glucose infusion) and leg balance techniques during insulin infusions ranging from 10 to 1,200 mU.m-2.min-1. We studied six subjects [wt 70 +/- 2 (SE) kg] during an Epi infusion at a single rate of 0.002 mg.kg-1.min-1 and six subjects (70 +/- 3 kg) during a saline infusion alone. Maximum whole body glucose uptake (WBGU) was similar during Epi and saline infusions [71.4 vs. 73.6 mmol.kg-1.min-1, P = not significant (NS)]. Compared with saline, maximum delta AVG was decreased during Epi infusion (1.04 vs. 1.31 mM, P less than 0.01). Compared with saline alone maximum leg BF was increased (5.3 vs. 4.3 dl/min, P less than 0.01) during Epi infusion. Thus maximum leg glucose uptake (LGU) was similar (696 vs. 821 pmol.leg-1.min-1, P = NS) during infusion of Epi and saline, respectively. Half-maximal effective dose for insulin's effect to stimulate WBGU, delta AVG, BF, and LGU was increased two- to threefold during Epi vs. saline infusions (P less than 0.01 for all values).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Physiologically based kinetic modelling based prediction of in vivo rat and human acetylcholinesterase (AChE) inhibition upon exposure to diazinon

2021 ◽  
Author(s):  
Shensheng Zhao ◽  
Sebastiaan Wesseling ◽  
Bert Spenkelink ◽  
Ivonne M. C. M. Rietjens
Keyword(s):  
Dose Response ◽  
Kinetic Modelling ◽  
Ache Inhibition ◽  
Response Curves ◽  
Alternative Testing ◽  
Dose Response Curves ◽  
Physiologically Based Kinetic Modelling ◽  
Point Of Departure

AbstractThe present study predicts in vivo human and rat red blood cell (RBC) acetylcholinesterase (AChE) inhibition upon diazinon (DZN) exposure using physiological based kinetic (PBK) modelling-facilitated reverse dosimetry. Due to the fact that both DZN and its oxon metabolite diazoxon (DZO) can inhibit AChE, a toxic equivalency factor (TEF) was included in the PBK model to combine the effect of DZN and DZO when predicting in vivo AChE inhibition. The PBK models were defined based on kinetic constants derived from in vitro incubations with liver fractions or plasma of rat and human, and were used to translate in vitro concentration–response curves for AChE inhibition obtained in the current study to predicted in vivo dose–response curves. The predicted dose–response curves for rat matched available in vivo data on AChE inhibition, and the benchmark dose lower confidence limits for 10% inhibition (BMDL10 values) were in line with the reported BMDL10 values. Humans were predicted to be 6-fold more sensitive than rats in terms of AChE inhibition, mainly because of inter-species differences in toxicokinetics. It is concluded that the TEF-coded DZN PBK model combined with quantitative in vitro to in vivo extrapolation (QIVIVE) provides an adequate approach to predict RBC AChE inhibition upon acute oral DZN exposure, and can provide an alternative testing strategy for derivation of a point of departure (POD) in risk assessment.

Histamine tachyphylaxis in canine airways despite prostaglandin synthesis inhibition

1988 ◽  
Vol 65 (5) ◽  
pp. 1944-1949 ◽  
Author(s):  
P. J. Antol ◽  
S. J. Gunst ◽  
R. E. Hyatt
Keyword(s):  
Smooth Muscle ◽  
Dose Response ◽  
Prostaglandin Synthesis ◽  
Response Curves ◽  
Synthesis Inhibition ◽  
High Concentrations ◽  
Alpha Chloralose ◽  
Prostaglandin Synthesis Inhibitors

Tachyphylaxis to aerosolized histamine was studied in dogs anesthetized with thiamylal after pretreatment with prostaglandin synthesis inhibitors. Three consecutive histamine dose-response curves were obtained in nine dogs pretreated with 5 mg/kg indomethacin; two of these nine were also pretreated with 10 mg/kg indomethacin. Seven of the nine dogs were pretreated with 4 mg/kg sodium meclofenamate; four of these seven were also pretreated with 12 mg/kg. All dogs had tachyphylaxis at high concentrations of histamine regardless of inhibitor used. Pretreatment with indomethacin while the dogs were under alpha-chloralose-urethan anesthesia gave similar results. Histamine tachyphylaxis was also studied both in the presence and in the absence of indomethacin in tracheal smooth muscle strips obtained from seven additional dogs. A decrease in the median effective dose to histamine was observed in the indomethacin-treated strips, but tachyphylaxis to histamine remained. We conclude that prostaglandin synthesis inhibition does not reverse histamine tachyphylaxis either in vivo or in vitro. Thus the mechanism of histamine tachyphylaxis remains unexplained.

Airway responses to inhaled ouabain and histamine in conscious guinea pigs

1986 ◽  
Vol 60 (6) ◽  
pp. 2089-2093 ◽  
Author(s):  
K. P. Agrawal ◽  
R. E. Hyatt
Keyword(s):  
Guinea Pigs ◽  
Airway Responsiveness ◽  
Maximal Response ◽  
Response Curves ◽  
Inhibiting Effect ◽  
Homeostatic Function ◽  
Positive Correlations ◽  
Airway Responses ◽  
Airway Conductance

Tracheal Na+-K+-ATPase activity is positively correlated with in vivo airway responsiveness to histamine. We wondered whether this were a chance association or whether it was directly related to the mechanism of hyperreactivity. Therefore, we obtained dose-response curves to aerosols of histamine and ouabain in guinea pigs to determine whether an in vivo relationship existed between the excitatory effects of histamine and the enzyme-inhibiting effect of ouabain. Airway responsiveness to ouabain was measured as the ouabain concentration producing a 30% decrease in specific airway conductance (ED30) or that producing a half-maximal response (ED50). Responsiveness to histamine was measured either as ED30 or as ED50. Significant positive correlations were noted between the log ED50 of ouabain and log histamine ED30 or ED50 (r = 0.81 and 0.83, respectively; P less than 0.001), and between log ouabain ED30 and log histamine ED30 and ED50 (r = 0.76 and 0.77, respectively; P less than 0.002). Pretreatment with ouabain increased airway responsiveness to histamine (P less than 0.05). We suggest that in hyperreactive airways Na+-K+-ATPase serves a homeostatic function of preventing Na+ and Ca2+ loading of the cell and that it is not directly responsible for the hyperreactivity.

Histamine H2-receptor of human and rabbit parietal cells

1987 ◽  
Vol 253 (4) ◽  
pp. G497-G501 ◽  
Author(s):  
R. Leth ◽  
B. Elander ◽  
U. Haglund ◽  
L. Olbe ◽  
E. Fellenius
Keyword(s):  
Dose Response ◽  
In Vivo Model ◽  
Response Curves ◽  
Gastric Glands ◽  
Histamine H2 Receptor ◽  
Receptor Affinity ◽  
H2 Receptor ◽  
Dose Response Curves

The histamine H2-receptor on the human parietal cell has been characterized by using dose-response curves and the negative logarithm of the molar concentration of an antagonist (pA2) analyses of cimetidine antagonism of betazole, histamine, and impromidine stimulation in isolated human and rabbit gastric glands. To evaluate the in vitro results, betazole-stimulated gastric acid secretion with and without cimetidine was also studied in healthy subjects. In the in vivo model, individual dose-response curves were shifted to the right with increasing cimetidine concentrations, but this was counteracted by increasing betazole doses, indicating competitive, reversible antagonism. The pA2 values ranged from 6.1 to 6.3. In isolated human gastric glands, impromidine was shown to be eight times more potent than histamine, indicating higher receptor affinity, but the maximally stimulated aminopyrine accumulation was the same as for histamine, and the pA2 values for cimetidine antagonism did not differ significantly, i.e., 5.7 (histamine) and 6.1 (impromidine). In isolated rabbit gastric glands, cimetidine inhibited the histamine- and impromidine-stimulated response with pA2 values of 6.0 and 7.3, respectively. Impromidine was shown to be approximately 100 times more potent than in human gastric glands, whereas histamine had the same potency. This confirms the role of the histamine H2-receptor and suggests a difference between the species concerning receptor affinity.

PAF-induced contraction of canine trachea mediated by 5-hydroxytryptamine in vivo

1989 ◽  
Vol 66 (2) ◽  
pp. 638-643 ◽  
Author(s):  
T. M. Murphy ◽  
N. M. Munoz ◽  
J. Moss ◽  
J. S. Blake ◽  
M. M. Mack ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Dose Response ◽  
Contractile Response ◽  
Platelet Activating Factor ◽  
Smooth Muscle Contraction ◽  
Active Tension ◽  
Response Curves ◽  
Arteriovenous Difference

We studied the secretory correlates of tracheal smooth muscle contraction caused by platelet-activating factor (PAF) in nine mongrel dogs in vivo. In five dogs, dose-response curves were generated by rapid intra-arterial injection of 10(-10) to 10(-6) mol PAF into the isolated tracheal circulation; tracheal contractile response was measured isometrically in situ. To examine the mechanism by which PAF elicits contraction of canine trachealis, concentrations of serotonin (5-HT) and histamine were assayed in the venous effluent as the arteriovenous difference (AVd) in mediator concentration across the airway for each level of contraction. PAF caused dose-related active tracheal tension to a maximum of 37.2 +/- 5.4 g/cm (10(-6) mol PAF). The AVd in 5-HT increased linearly from 0.20 +/- 0.05 (10(-9) mol PAF) to 3.5 +/- 0.3 ng/ml (10(-6) mol PAF) (P less than 0.005). In contrast, the AVd in histamine was insignificant and did not change with increasing doses of PAF. A positive correlation was obtained between the AVd in 5-HT and active tracheal tension (r = 0.92, P less than 0.001); there was no correlation between AVd in histamine and active tension (r = -0.16). PAF-induced parasympathetic activation was not mediated by 5-HT; contraction elicited by exogenous 5-HT was not affected by muscarinic blockade. We conclude that nonparasympathetically mediated contraction elicited acutely by PAF in dogs results at least in part from secondary release of serotonin and is not mediated by histamine.

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