Responses of airway rapidly adapting receptors to bradykinin before and after administration of enalapril in rabbits

1992 ◽  
Vol 83 (4) ◽  
pp. 399-407 ◽  
Author(s):  
M. Hargreaves ◽  
K. Ravi ◽  
M. P. J. Senaratne ◽  
C. T. Kappagoda
Keyword(s):  
Dose Response ◽  
Neural Activity ◽  
Response Curve ◽  
Enzyme Inhibitor ◽  
Dose Response Curve ◽  
Receptor Activity ◽  
Before And After ◽  
Resting Activity ◽  
Control State ◽  
Stimulation Of

1. The present study was performed in anaesthetized, artificially ventilated, open-chested rabbits to examine whether (a) the rapidly adapting receptors of the airways were stimulated by exogenously administered bradykinin, and (b) if this sensitivity could be enhanced by the angiotensin-converting-enzyme inhibitor, enalapril. 2. Rapidly adapting receptor activity (n = 8) was recorded from the cervical vagus. Bradykinin was injected intravenously (0.25–1.0 μg/kg) and a dose—response curve relating receptor activity to bradykinin was elicited. In the control state, the threshold dose of bradykinin required for stimulation of rapidly adapting receptors was 0.53 ± 0.11 μg/kg. Five minutes after the administration of enalapril maleate (2 mg intravenously), the dose—response curve was shifted to the left significantly (P<0.01). 3. In seven other rapidly adapting receptors, enalapril (2 mg) increased the resting activity significantly (P<0.05) over a period of 60 min. This increase was significantly different from the spontaneous variation in neural activity of rapidly adapting receptors (n = 7) recorded over a period of 60 min. 4. Bradykinin either alone (0.25–1.0 μg/kg) or in the presence of enalapril did not stimulate the slowly adapting receptors (n = 5) of the airways. 5. These results show that (a) exogenous bradykinin stimulates the rapidly adapting receptors, (b) the sensitivity of rapidly adapting receptors to bradykinin is enhanced by enalapril and (c) enalapril increases the resting activity of rapidly adapting receptors. It is suggested that the cough reported after the administration of enalapril may be due to stimulation of rapidly adapting receptors of the airways.

Effects of inhibitors of cyclic nucleotide phosphodiesterase on actions of cholecystokinin, bombesin, and carbachol on pancreatic acini

1983 ◽  
Vol 245 (5) ◽  
pp. G676-G680
Author(s):  
J. D. Gardner ◽  
V. E. Sutliff ◽  
M. D. Walker ◽  
R. T. Jensen
Keyword(s):  
Dose Response ◽  
Cyclic Nucleotide ◽  
Response Curve ◽  
Dose Response Curve ◽  
Cyclic Nucleotide Phosphodiesterase ◽  
Enzyme Secretion ◽  
Amylase Secretion ◽  
Pancreatic Acini ◽  
Rightward Shift ◽  
Stimulation Of

In dispersed acini from guinea pig pancreas two inhibitors of cyclic nucleotide phosphodiesterase, Ro 20-1724 and 3-isobutyl-1-methylxanthine (IBMX), augmented the increase in amylase secretion caused by supramaximal concentrations of cholecystokinin but did not alter the stimulation of enzyme secretion caused by bombesin. The augmentations of the action of cholecystokinin caused by Ro 20-1724 or IBMX could be reproduced by 8-bromo-cAMP. When tested alone or with theophylline, cholecystokinin did not alter cAMP in pancreatic acini; however, with Ro 20-1724 or IBMX, concentrations of cholecystokinin that were supramaximal for stimulating amylase secretion caused a significant increase in cellular cAMP. These findings indicate that Ro 20-1724 and IBMX augment the action of cholecystokinin on enzyme secretion by inhibiting cyclic nucleotide phosphodiesterase and allowing a significant cholecystokinin-induced increase in cellular cAMP. IBMX but not Ro 20-1724 caused a parallel rightward shift in the dose-response curve for the stimulation of amylase secretion caused by carbachol. IBMX also caused a parallel rightward shift in the dose-response curve for the stimulation of outflux of 45Ca caused by carbachol. These results indicate that IBMX, but not Ro 20-1724, can function as a muscarinic cholinergic antagonist.

VIP stimulation of β-naphthylamidase activity in guinea-pig thyroid sections

1985 ◽  
Vol 109 (4) ◽  
pp. 505-510 ◽  
Author(s):  
P. A. Ealey ◽  
N.J. Marshall ◽  
R. P. Ekins
Keyword(s):  
Dose Response ◽  
Response Curve ◽  
Receptor Site ◽  
Dose Response Curve ◽  
Tsh Receptor ◽  
Maximal Response ◽  
Cytochemical Bioassay ◽  
Order Of Magnitude ◽  
Specific Receptors ◽  
Stimulation Of

Abstract. Subsequent to the discovery of vasoactive intestinal peptide (VIP) in the thyroid gland, VIP has been shown to stimulate various thyroid functions. The site of interaction of VIP with the thyroid follicular cell is at present not known, and this study has used the ultrasensitive cytochemical bioassay (CBA) for thyroid stimulators to investigate this further. Exposure of thyroid sections for 3 min to VIP resulted in increased naphthylamidase activity, with half-maximal response observed at 3 × 10−13 m VIP. This response to such low doses of VIP is consistent with the CBA being ultrasensitive to other thyroid stimulators e.g. TSH, thyroid stimulating antibodies and forskolin. The response to VIP was abolished by rabbit anti-VIP antiserum. The dose-response curve to VIP was bell-shaped (as with the other stimulators), maximal stimulation occurring at 10−12 m VIP. In contrast, however, to other thyroid stimulators, namely TSH, LATS-B and 3 monoclonal stimulating antibodies, whose ascending limbs of the doseresponse curves extended over 3-4 orders of magnitude, the VIP curve rose rapidly from basal to maximal tissue stimulation from 10−13 to 10−12m VIP, i.e. one order of magnitude. This unusual dose-response curve to VIP was parallel to that produced by forskolin. 11E8, a monoclonal 'blocking' antibody which is a potent inhibitor of TSH stimulation, did not 'block' forskolin stimulation, consistent with the belief that forskolin acts at a post-receptor site. However, unlike forskolin, VIP was inhibited by monoclonal 11E8, which may imply a hitherto unexpected involvement of the TSH receptor in VIP stimulation of the thyroid or, alternatively, steric inhibition by 11E8 when bound to the TSH receptor of VIP interaction with adjacent VIP-specific receptors.

Forskolin stimulation of naphthylamidase in guinea pig thyroid sections detected with a cytochemical bioassay

1985 ◽  
Vol 108 (3) ◽  
pp. 367-371 ◽  
Author(s):  
Patricia A. Ealey ◽  
Leonard D. Kohn ◽  
Nicholas J. Marshall ◽  
Roger P. Ekins
Keyword(s):  
Guinea Pig ◽  
Dose Response ◽  
Response Curve ◽  
Thyroid Tissue ◽  
Receptor Site ◽  
Dose Response Curve ◽  
Cytochemical Bioassay ◽  
Surface Receptor ◽  
Stimulation Of ◽  
Endocrine Tissues

Abstract. Forskolin, from the roots of the Indian medicinal plant Coleus forskohlii, has recently been shown to be a potent stimulator of adenylate cyclase in many systems, including endocrine tissues such as the thyroid gland. We describe forskolin activation of β-naphthylamidase activity in guinea pig thyroid tissue using the cytochemical bioassay (CBA) for thyroid stimulators. This CBA is the most sensitive bioassay for TSH and LATS-B currently available, being able to detect stimulation by doses as low as 10−5 mU TSH/l and 10−9 mU LATS-B/l. The dose-response curve to forskolin was bell-shaped (as is seen with TSH and LATS-B) with the ascending limb of the curve produced by 10−13 m to 10−12 m forskolin after a 3 min exposure time. Maximal stimulation was observed with 10−12m forskolin. However, the dose-response curve to forskolin was not parallel to that given by TSH, the slope of the ascending limb being much greater. It has been suggested that stimulation of β-naphthylamidase activity in the CBA is via cAMP. We report that dibutyryl cAMP at doses from 10−16m to 10−11 m produces a bell-shaped dose-response curve with a very broad peak response, again not parallel to that produced by TSH. Forskolin activation of β-naphthylamidase in the CBA is unaffected by a 1:106 dilution of 11E8, a monoclonal antibody raised against solubilised TSH receptors, which binds to the TSH receptor and inhibits TSH stimulation. Although the precise location of forskolin action is not known, this is further evidence that forskolin acts at a post-surface receptor site.

Role of Endothelial K + Channels in NO-Dependent Vasorelaxant Responses to Acetylcholine in Rat Aorta.

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 698-698
Author(s):  
John Quilley ◽  
Yue Qiu
Keyword(s):  
Dose Response ◽  
Response Curve ◽  
Rat Aorta ◽  
Dose Response Curve ◽  
Response Curves ◽  
K Channels ◽  
Voltage Dependent ◽  
The Right ◽  
Stimulation Of

P30 Endothelium-dependent vasorelaxant responses to acetylcholine (Ach) in rat aorta are mediated solely by NO. Rings precontracted with U46619 were used to investigate the role of endothelial K + channels. Thus, any effect of K + channel inhibitors on Ach responses in the absence of an effect on those to nitroprusside (NP) can be attributed to interference with Ach-induced stimulation of NO. Vasorelaxant responses to Ach (log EC 50 -7.29M) were abolished by removal of the endothelium or inhibition of NO synthesis with nitroarginine (100μM) which potentiated responses to NP (log EC 50 -9.41M vs -8.47M for control). In the presence of TEA (10mM) to inhibit K + channels, the dose-response curve for Ach, but not NP, was shifted to the right (log EC 50 -6.06). Elevation of extracellular K + (25mM KCl)also shifted the dose-response curve for Ach to the right. Inhibitors of specific types of K + channels: BaCl 2 (30μM), apamin (100nM), glibenclamide (10μM), charybdotoxin (50nM) and iberiotoxin (100nM) were without effect on dose-response curves to either Ach or NP. However, the combination of apamin (100nM) and charybdotoxin (50nM) but not apamin plus iberiotoxin, reduced relaxant responses to Ach (log EC 50 -6.95M) without affecting those to NP.These results confirm that Ach-induced relaxation of rat aorta is mediated entirely by endothelium-derived NO, the release of which apparently involves hyperpolarization of the endothelium. This effect is dependent on activation of a K + channel that is blocked by a combination of apamin/charybdotoxin but neither agent alone, possibly indicating characteristics of both Ca 2+ - activated and voltage-dependent K + channels.

2-Chloroadenosine increases calcium mobilization from mouse calvaria in vitro

1982 ◽  
Vol 100 (2) ◽  
pp. 313-320 ◽  
Author(s):  
Ulf Lerner ◽  
Bertil B. Fredholm
Keyword(s):  
Bone Resorption ◽  
Cyclic Amp ◽  
Bone Tissue ◽  
Dose Response ◽  
Response Curve ◽  
Dose Response Curve ◽  
Cyclic Amp Accumulation ◽  
Adenosine Analogue ◽  
Stimulation Of

Abstract. The effect of 2-chloroadenosine on bone resorption and on cyclic AMP formation in murine calvarial bones in vitro was investigated. 2-Chloroadenosine increased the release of 45Ca from the cultured bones, but had no effect on dead bones, indicating that the effect is cell mediated. The adenosine analogue remained in the medium for 48 h and caused a transient stimulation of the formation of cyclic AMP. The dose-response curve for the stimulatory effect on cyclic AMP accumulation was linear up to 10−4m. The dose-response curve for 45Ca release was linear from 3 × 10−7 m to 3 × 10−5 m but then showed a decline in the response. 8-Bromo cyclic AMP inhibited the release of 45Ca in 24 h cultures. The initial stimulatory effect on bone resorption by 2-chloroadenosine may therefore not depend on cyclic AMP. The level of inosine increased during culture indicating that adenosine is formed by bone tissue.

A Screening Procedure for Substances Which Inhibit Dextran Edema in the Rat

1958 ◽  
Vol 193 (2) ◽  
pp. 275-282 ◽  
Author(s):  
Jacob C. Stucki ◽  
Charles R. Thompson
Keyword(s):  
Dose Response ◽  
Response Curve ◽  
Intraperitoneal Administration ◽  
Dose Response Curve ◽  
Screening Procedure ◽  
Adrenergic Agents ◽  
Adrenergic Drugs ◽  
Before And After ◽  
Quantitative Bioassay

Determination of foot volume by mercury displacement before and after the intraperitoneal administration of dextran to rats demonstrated that pronounced edema occurs one-half to three-fourths of an hour after dextran, reaches a maximum in 1 1/2 hours, and gradually subsides over the next several hours. Inhibiting substances prevent the edema entirely, reduce its severity or delay its appearance. A method was presented for screening compounds for ability to inhibit dextran edema. A dose-response curve developed for chlorpromazine suggests that the technique might also be suitable for quantitative bioassay. It was found that strongly vasoconstrictor adrenergic agents inhibited edema while adrenergic drugs with other predominating activities did not. Atropine, Dibenamine, morphine, reserpine, hydroxyzine and meprobamate were inactive. Chlorpromazine, the antihistaminics and anesthetic doses of phenobarbital were active. Cortisone and phenylbutazine were inactive but the salicylates were moderately active.

Secretagogue stimulation of [14C]aminopyrine accumulation by isolated canine parietal cells

1980 ◽  
Vol 238 (4) ◽  
pp. G366-G375 ◽  
Author(s):  
A. H. Soll
Keyword(s):  
Parietal Cell ◽  
Dose Response ◽  
Response Curve ◽  
Dissociation Constants ◽  
Receptor Site ◽  
Dose Response Curve ◽  
Cell Content ◽  
Parallel Displacement ◽  
Mucosal Cells ◽  
Stimulation Of

Isolated canine gastric mucosal cells accumulate [14C]aminopyrine (AP) when treated with histamine, gastrin, and carbachol. In fractions of varying parietal cell content, this accumulation of AP correlated with the parietal cell content. Cimetidine caused parallel displacement of the dose-response curve to histamine, but failed to alter the response to carbachol or gastrin. Atropine caused parallel displacement of the dose-response curve to carbachol, but failed to inhibit the response to histamine or gastrin. The dissociation constants (Kb) for cimetidine inhibition of histamine and for atropine inhibition of carbachol were found to be 1.0 micro M and 1.3 nM, respectively, values comparable to those reported for other tissues. Thus, the isolated parietal cell appears to have pharmacologically typical H2- and muscarinic receptors, with gastrin acting at a third receptor site. Isobutyl methylxanthine (IMX) and the cAMP analogues dibutyryl cAMP (DBcAMP) and 8-bromo cAMP (but not the same analogues of cGMP) also stimulated AP accumulation. Atropine failed to inhibit the responses to IMX or DBcAMP, whereas cimetidine did inhibit the response to IMX, but not to DBcAMP.

Effects of inhibitors of cyclic nucleotide phosphodiesterase on the actions of vasoactive intestinal peptide and secretin on pancreatic acini

1982 ◽  
Vol 242 (6) ◽  
pp. G547-G551
Author(s):  
J. D. Gardner ◽  
L. Y. Korman ◽  
M. D. Walker ◽  
V. E. Sutliff
Keyword(s):  
Vasoactive Intestinal Peptide ◽  
Dose Response ◽  
Cyclic Nucleotide ◽  
Response Curve ◽  
Phosphodiesterase Inhibitor ◽  
Dose Response Curve ◽  
Cyclic Nucleotide Phosphodiesterase ◽  
Amylase Secretion ◽  
Pancreatic Acini ◽  
Stimulation Of

Theophylline, 3-isobutyl-1-methylxanthine (IBMX), and Ro 20-1724 each augmented the increase in cAMP and the stimulation of amylase secretion caused by vasoactive intestinal peptide (VIP) or secretin. With IBMX the dose-response curve for the stimulation of amylase secretion caused by VIP or secretin spanned a range of lower concentrations than did that obtained with Ro 20-1724, which in turn spanned a range of lower concentrations than did that obtained with theophylline. The configuration of the dose-response curve for the action of VIP on cAMP differed with each phosphodiesterase inhibitor tested. With Ro 20-1724 the dose-response curve was monophasic, whereas with the two methylxanthines the dose-response curve was biphasic. With theophylline the magnitude of the second component of the dose-response curve was larger than the first; with IBMX the magnitude of the first component was larger than the second. The configuration of the dose-response curve for the action of secretin on cAMP also differed with each phosphodiesterase inhibitor tested. With theophylline the dose-response curve was monophasic, whereas with Ro 20-1724 and IBMX the dose-response curve was biphasic. With Ro-20-1724 the magnitude of the second component of the dose-response curve was larger than the first; with IBMX the magnitude of the first component was larger than the second. These results indicate that cAMP is compartmentalized in pancreatic acinar cells and that the different compartments of cAMP are affected differently by various inhibitors of cyclic nucleotide phosphodiesterase. These findings also suggest that the different compartments of cAMP are acted on by phosphodiesterases with different sensitivities to various inhibitors.

Enhanced airway responses to substance P after repeated challenge in guinea pigs

1989 ◽  
Vol 66 (2) ◽  
pp. 955-961 ◽  
Author(s):  
S. A. Shore ◽  
J. M. Drazen
Keyword(s):  
Substance P ◽  
Dose Response ◽  
Guinea Pigs ◽  
Response Curve ◽  
Enzyme Inhibitor ◽  
Dose Response Curve ◽  
Base Line ◽  
Response Curves ◽  
Dose Response Curves ◽  
Airway Responses

We performed three consecutive dose-response curves to rapid intravenous infusions of substance P (SP) in anesthetized, mechanically ventilated guinea pigs. The dose of SP required to decrease pulmonary conductance to 50% of its base-line value (ED50GL) decreased 2.8-fold (P less than 0.002) and 3.3-fold (P less than 0.001) on the second and third dose-response curves, respectively, compared with the first. SP did not alter airway responses to intravenous histamine but did cause a significant (3.7-fold) decrease in ED50GL for dose-response curves to intravenous capsaicin, an agent that causes bronchoconstriction by release of endogenous tachykinins. The neutral metalloendopeptidase inhibitor thiorphan (0.5 mg) and the angiotensin-converting enzyme inhibitor captopril (1.7 mg) both caused a marked enhancement of airway responses to SP observed on the first dose-response curve but did not alter the enhancement of SP-induced airway responses produced by repeated SP challenge. The anticholinergic atropine (5 mg/kg iv), the antihistamine mepyramine (8 mg/kg iv), and the cyclooxygenase inhibitor indomethacin (30 mg/kg ip) had no effect on the first SP dose-response curve. Atropine and mepyramine did not prevent the enhancement of SP responses observed with repeated challenge, but after pretreatment with either indomethacin or acetylsalicylic acid, dose-response curves to SP were reproducible. Our results indicate that airway responses to intravenous SP are enhanced with repeated SP challenge and suggest that cyclooxygenase products of arachidonic acid metabolism are involved in the mediation of this phenomenon.

scholarly journals Insulin, dexamethasone and their interactions in the control of glucose metabolism in adipose tissue from lactating and nonlactating sheep

1988 ◽  
Vol 256 (2) ◽  
pp. 509-514 ◽  
Author(s):  
R G Vernon ◽  
E Taylor
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Dose Response ◽  
Response Curve ◽  
Insulin Dose ◽  
Dose Response Curve ◽  
Acetate Uptake ◽  
Lactate Output ◽  
Acetate Utilization ◽  
Stimulation Of

1. Lactation results in decreased glucose and acetate utilization and increased lactate output by sheep adipose tissue. 2. The ability of insulin to stimulate acetate uptake was lost in adipose tissue from lactating sheep, whereas both the response and the sensitivity (ED50) for insulin for stimulation of glucose conversion into products other than lactate were decreased. These impairments were partly restored by prolonged incubation of adipose tissue for 48 h. 3. The ability of insulin to stimulate lactate output was not altered by lactation. 4. Dexamethasone inhibited glucose uptake, lactate output and glycerol output in adipose tissue from both non-lactating and lactating sheep, with an ED50 of about 1 nM. Dexamethasone inhibited acetate uptake by adipose tissue from non-lactating sheep, but this effect was not observed with adipose tissue from lactating sheep. 5. Dexamethasone inhibited the stimulation of glucose uptake at all concentrations of insulin used; the effect varied with insulin concentration and resulted in an accentuation of the insulin dose-response curve. The insulin dose-response curve in the presence of dexamethasone was muted during lactation. 6. The overall effect of these adaptations is to ensure that glucose and acetate utilization by adipose tissue after an insulin surge is diminished during lactation.

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