II. Pharmacology of Angiotensin Antagonists

1973 ◽  
Vol 51 (2) ◽  
pp. 114-121 ◽  
Author(s):  
D. Regoli ◽  
W. K. Park ◽  
F. Rioux
Keyword(s):  
Slow Rate ◽  
Response Curve ◽  
Receptor Site ◽  
Maximal Response ◽  
Pharmacological Properties ◽  
Response Curves ◽  
Onset Of Action ◽  
Competitive Antagonist ◽  
Long Acting ◽  
The Right

The pharmacological properties of three antagonists of angiotensin II (ATII) have been characterized on the rat isolated stomach strip.(8-Gly)-ATII, a newly synthesized antagonist of ATII, as well as (8-Leu)-ATII and (1-Sar-8-Leu)-ATII displace to the right the dose–response curve of ATII and the displacement is proportional to the dose of antagonist.Dose–response curves of ATII remain parallel to that of the control in the presence of (8-Gly)-ATII and (8-Leu)-ATII, while parallelism is lost with (1-Sar-8-Leu)-ATII. This antagonist also depresses the maximal response to ATII.All data presented in this paper indicate that (8-Gly)-ATII and (8-Leu)-ATII are competitive antagonists of ATII with different affinities for the receptors, (8-Gly)-ATII being about 12 times less potent than (8-Leu)-ATII. This compound competes with ATII on a one to one basis: pA2 of (8-Leu)-ATII has the same value as pD2 of ATII.(1-Sar-8-Leu)-ATII does not fulfil the criteria of a competitive antagonist. This compound is very potent and the onset of action is as rapid (5 min) as for the other two compounds. All data obtained with (1-Sar-8-Leu)-ATII are consistent with the assumption that this compound is competitive in the sense that it acts on the same receptor site as ATII, but owing probably to slow rate of inactivation by tissue aminopeptidases, it dissociates slowly from the receptors and it acts as a specific long-acting antagonist.

Effects of Lidocaine and Procaine on Canine Nasal Blood Vessels

1988 ◽  
Vol 97 (4) ◽  
pp. 409-413 ◽  
Author(s):  
Hsing-Won Wang ◽  
Richard T. Jackson
Keyword(s):  
Blood Vessels ◽  
Nasal Mucosa ◽  
Dose Response ◽  
Response Curve ◽  
Smooth Muscle Contraction ◽  
Dose Response Curve ◽  
Maximal Response ◽  
Field Stimulation ◽  
Response Curves ◽  
The Right

The effects of lidocaine and procaine on contractile responses of isolated canine nasal mucosal blood vessels to field stimulation and methoxamine were investigated. Analysis of cumulative dose-response curves showed that the two local anesthetics antagonized methoxamine and inhibited the field-stimulation response. The latter effect was interpreted as due to the blockade of Na+channels. This would inhibit nerve conduction induced by field stimulation. The former effect on methoxamine is probably caused by the effect of these anesthetics on the mobilization of Ca++ needed for smooth muscle contraction. Preincubation of the nasal mucosa with low doses of procaine or lidocaine shifts the methoxamine dose-response curve to the right. With higher doses, the maximal response is also reduced. The shift of the dose-response curve showed that procaine or lidocaine can change the α-adrenergic receptor affinity. Commercial 1% lidocaine with 1:100,000 epinephrine also inhibits field stimulation and antagonizes methoxamine contractions. Lidocaine can increase the basal tone of nasal mucosa, while procaine cannot. From these results, we conclude that procaine and lidocaine have common mechanisms in blocking Na+ channels but differ in their ability to modify Ca++ stores or channels.

Interaction between octapeptide-cholecystokinin, gastrin, and secretin on cat gallbladder in vitro

1975 ◽  
Vol 229 (5) ◽  
pp. 1311-1315 ◽  
Author(s):  
Chowdhury ◽  
JM Berkowitz ◽  
M Praissman ◽  
JW Fara
Keyword(s):  
Dose Response ◽  
Receptor Site ◽  
Isometric Tension ◽  
Maximal Response ◽  
Response Curves ◽  
Tension Development ◽  
Common Receptor ◽  
Secretin Receptor ◽  
The Right

Effects of OP-CCK, gastrin, and secretin were studied on isometric tension development in strips of cat gallbladder. Effective molar concentrations were 2.2 X 10(-10) to 5.3 X 10(-9) for OP-CCK, and 1.13 X 10(-7) to 1.5 X 10(-6) for gastrin. The maximal response to gastrin averaged 66% the maximal response to OP-CCK and effects were not blocked by atropine. Secretin was weakly stimulatory or ineffective by itself. Prior addition of submaximal doses of gastrin shifted the dose-response curve of OP-CCK to the right, but neither the slope nor the calculated maximal response (CMR) was significantly changed. This suggests that gastrin and OP-CCK compete for a common receptor on cat gallbladder. On the other hand, a background dose of secretin shifted the dose-response curves for both OP-CCK and gastrin to the left and increased the slopes significantly with increase in the respective CMRs. The combined action of OP-CCK (or gastrin) and secretin are supra-additive. These experiments suggest that OP-CCK and gastrin act at a common receptor site which is different from the secretin-receptor site.

Antagonist properties of arylaminopyridazine GABA derivatives at the Ascaris muscle GABA receptor

1991 ◽  
Vol 159 (1) ◽  
pp. 149-164
Author(s):  
A. H. Duittoz ◽  
R. J. Martin
Keyword(s):  
Gabaa Receptor ◽  
Binding Sites ◽  
Gaba Receptor ◽  
Dissociation Constants ◽  
Ascaris Suum ◽  
Antagonistic Activity ◽  
Maximal Response ◽  
Response Curves ◽  
Gaba Derivatives ◽  
The Right

1. In a previous study, it was shown that the potency order for two arylamino-pyridazine derivatives, SR95531 and SR95103, was different in Ascaris suum when compared to vertebrate preparations. SR95531, the most potent analogue at the vertebrate GABAA receptor, was found to be very weak at antagonizing GABA responses in Ascaris, but SR95103, approximately 20 times less potent than SR95531 in vertebrate preparations, was more potent than SR95531 in Ascaris. These results suggested the existence of different accessory binding sites at the Ascaris GABA receptor. 2. To test this hypothesis, the effects of a series of arylaminopyridazine derivatives of GABA on the GABA response in Ascaris suum muscle were investigated using a two-microelectrode current-clamp technique. 3. The results showed that SR42627, a potent antagonist at the GABAA receptor, was one of the weakest analogues in Ascaris muscle. In contrast, SR95132, virtually inactive in vertebrate preparations, was equipotent to SR95103, the most potent analogue of the series in Ascaris muscle. 4. The three most potent analogues in Ascaris, SR95103, SR95132 and SR42666, displace GABA dose-response curves to the right without decreasing the maximal response. The modified Schild plots for these compounds are consistent with a competitive mechanism involving two molecules of GABA and only one molecule of antagonist interacting with the receptor. The estimated dissociation constants for SR95103, SR95132 and SR42666 are, respectively, 64, 65 and 105 mumol l-1. 5. Structure-activity relationships for this series of compounds were examined in Ascaris and compared to those in vertebrates. Substitution on the pyridazine ring in the 4-position, while detrimental for the antagonist potency at the vertebrate GABAA receptor, appears to be a prerequisite for antagonistic activity on the Ascaris muscle GABA receptor. These results are interpreted in terms of the accessory binding site theory of Ariens, and suggest the existence of different accessory binding sites on the Ascaris GABA receptor.

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.

scholarly journals Early Effects of Tetraethylammonium Chloride on the Contractile Properties of Isolated Rabbit Basilar Arteries

1987 ◽  
Vol 7 (2) ◽  
pp. 237-247 ◽  
Author(s):  
A. R. Young ◽  
H. Säveland ◽  
J. D. Pickard ◽  
S. Perry ◽  
L. Brandt ◽  
...  
Keyword(s):  
Potassium Conductance ◽  
Cerebrovascular Reactivity ◽  
Maximal Response ◽  
Induced Response ◽  
Response Curves ◽  
Vascular Effects ◽  
Extracellular Medium ◽  
Tetraethylammonium Chloride ◽  
Basilar Arteries ◽  
The Right

The acute vascular effects of tetraethylammonium chloride (TEA) were examined on annular segments of rabbit basilar arteries, Contractions induced by the potassium channel blocker were compared with those obtained for potassium chloride, 5-hydroxytryptamine (5-HT) and norepinephrine (NE), The greater magnitude of the contractions was of the following order: [K+] > 5-HT> TEA> NK High concentrations of TEA alone (10−2 M) generated spontaneous oscillatory contractions in cerebral vessels that were normally quiescent, Low concentrations of TEA (10−8-10−6 M), which had no vasomotor properties per se, enhanced the contractile response of submaximal concentrations of 5-HT (10−7 M) and NE (3 × 10−6 M) and attenuated the contraction produced by 60 m M [K+], An increased vascular response to the amines was still evident up to 3 h after the addition of TEA despite frequent rinsing with fresh buffer solutions. On arteries precontracted with TEA (10−2 M), but not high [K +], the subsequent addition of 5-HT (10−7 M) still induced a powerful constriction. Repeated concentration-response curves for [K+] were reproducible and, in the presence of TEA (10−8 or 10−6 M), the curve was displaced to the right in a competitive manner. A higher concentration of TEA (10−4 M) was devoid of any blocking properties on the [K+]-induced response whereas, at 10−3 M TEA, the response was potentiated, as evidenced by a shift of the curve to the left. Interactions between TEA and the cumulative response to 5-HT were difficult to interpret. Repeated exposures of the artery to 5-HT resulted in an increased maximal response with each determination (EAm = 127 ± 9% and 149 ±: 14% of control values following the second and third applications, respectively). With TEA (10−6 M), the increase in the maximal contractile effect noted previously was not observed. Contractions induced by single concentrations of TEA (10−2 M) or [K+] (60 m M) were calcium dependent, were abolished completely in a calcium-free medium, and were depressed by the calcium antagonist nimodipine. 5-Hydroxytryptamine-induced contractions (10−5 M) were less sensitive to withdrawal of calcium from the extracellular medium (31 ± 6% relative to the maximal response at 4 m M calcium). Hence, an acute reduction in potassium conductance in cerebrovascular smooth muscle produced by TEA has complex, concentration-dependent effects and reproduces only part of the spectrum of effects of cisternal injection of blood on cerebrovascular reactivity.

Postsynaptic potentiation and desensitization in frog neuromuscular junction

1988 ◽  
Vol 66 (5) ◽  
pp. 624-629 ◽  
Author(s):  
M. I. Glavinqvić
Keyword(s):  
Neuromuscular Junction ◽  
Dose Response ◽  
Response Curve ◽  
Dose Response Curve ◽  
Maximal Response ◽  
Frog Neuromuscular Junction ◽  
Receptor Complexes ◽  
Fractional Increase ◽  
The Right ◽  
Postsynaptic Potentiation

The fractional increase in ACh responses that occurs at the beginning of each train of iontophoretically applied ACh pulses has been examined at the frog neuromuscular junction at room temperature, in the presence of active cholinesterase, during desensitization produced by a rapid sequence (every 20 s) of short (5 Hz, 5 s) iontophoretic trains of ACh. The fractional increase in ACh responses, which is used as an indicator of postsynaptic potentiation, becomes progressively greater with ACh application, often markedly (>100%), although ACh responses are greatly reduced (as much as 90%) owing to desensitization. Clearly postsynaptic potentiation can exist concomitantly with desensitization. In addition, the dose–response curve is shifted to the right and its maximal response is diminished. The shift in the dose–response curve to the right, which can explain greater postsynaptic potentiation, is unlikely to be caused by accumulation of "monoligand-bound ACh receptor complexes," since experiments were done with active cholinesterase. The shift probably results from a greater number of desensitized receptors which, because of their large affinity for ACh molecules, serve as "high affinity traps." A small decrease of the maximal dose–response suggests only a small fractional decrease in the number of activable receptors, whereas a large shift to the right indicates a large fractional increase in the number of desensitized receptors. It appears that prior to ACh application only a small fraction of all receptors are desensitized. Alternatively, the shift to the right occurs because the cooperative action of ACh on receptors increases during desensitization.

Desensitisation in Human and Rabbit Blood Platelets

1982 ◽  
Vol 47 (03) ◽  
pp. 278-284 ◽  
Author(s):  
T J Hallam ◽  
P A Ruggles ◽  
M C Scrutton ◽  
R B Wallis
Keyword(s):  
Dose Response ◽  
Response Curve ◽  
Blood Platelets ◽  
Human Platelets ◽  
Dose Response Curve ◽  
Maximal Response ◽  
Significant Shift ◽  
Type I ◽  
Rabbit Blood ◽  
The Right

Summary1. Exposure of human and rabbit blood platelets to all full agonists tested induces agonist-specific (or homologous) desensitisation except in the case of adrenaline and collagen in human platelets.2. Desensitisation to vasopressin and 5-hydroxytryptamine (5HT) develops rapidly and results from suppression of maximal responsiveness without significant shift in the dose/response curve (Type I). In rabbit platelets, maintenance of desensitisation to 5HT is correlated with the extracellular 5HT concentration. Responsiveness to other agonists is either unaffected, or is enhanced due to a shift in the dose/response curve to the left without change in maximal responsiveness.3. Homologous desensitisation to ADP, U-46619 and thrombin develops more slowly, is correlated with disaggregation and is associated with a shift in the dose/response curve to the right without suppression of maximal responsiveness (Type II). Responsiveness to most other agonists is either unaffected, or is enhanced due to a shift in the dose/response curve to the left without a change in maximal responsiveness. However, exposure to thrombin suppresses the maximal response to vasopressin without a shift in the dose/response curve, and exposure to U-46619 causes a shift in the dose/response curve for collagen to the right.4. In human platelets prolonged exposure to 5HT causes agonist non-specific (or heterologous) desensitisation in which responsiveness to all agonists except adrenaline is suppressed as a result of shifts in the dose/response curves to the right.5. We propose that Types I and II homologous desensitisation result respectively from prolonged receptor occupancy and from either activation of degradative mechanisms for the agonist or processing of the receptor to a lower affinity state.

Endothelium dependence of effects of high PCO2 on agonist-induced contractility of rat aorta

1993 ◽  
Vol 264 (2) ◽  
pp. H512-H519 ◽  
Author(s):  
S. Fukuda ◽  
M. Morioka ◽  
T. Tanaka ◽  
K. Taga ◽  
K. Shimoji
Keyword(s):  
Response Curve ◽  
Thromboxane A2 ◽  
Rat Aorta ◽  
Cyclooxygenase Inhibitors ◽  
High Pco2 ◽  
Maximal Response ◽  
Thromboxane A2 Receptor ◽  
Aortic Smooth Muscle ◽  
The Right ◽  
Time Contraction

To investigate the modulation of CO2 and endothelium of vascular contraction induced by various agonists, we studied the influence of high PCO2 (PCO2 = 91 mmHg, pH = 6.99) on the response of endothelium-intact and -rubbed rat aortic preparations to KCl, phenylephrine (PE), and human-porcine endothelin-1 (ET-1). Response of endothelium-intact aortic preparations to KCl was not influenced by both high PCO2 and the pH-matched acidotic solution (7.00) with normal PCO2, whereas that of endothelium-rubbed preparations was attenuated solely by high PCO2. With cyclooxygenase inhibitors or a thromboxane A2 receptor antagonist, high PCO2 attenuated the respose of both preparations to KCl. The dose-response curve of endothelium-intact and -rubbed preparations to PE was shifted to the right by both high PCO2 and the pH-matched acidotic solution with normal PCO2. The maximal response of endothelium-intact preparation to PE was attenuated by high PCO2. Indomethacin augmented the inhibitory action of high PCO2 on the PE-induced contraction. Contractile responses of endothelium-intact and -rubbed preparations to ET-1 were not influenced by high PCO2. With indomethacin, high PCO2 also had no influence on the ET-1-induced contraction of endothelium-intact preparations. Endothelium modified the high PCO2 effects on the time-contraction responses to the three agonists. CO2 and endothelium may variously modify the responses of rat aorta to different agonists. Cyclooxygenase-related eicosanoid(s) may be involved in the effects of high PCO2 on the response of rat aortic smooth muscle cells to KCl and PE.

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.

Histamine dose-response curves in guinea pigs

1985 ◽  
Vol 58 (2) ◽  
pp. 625-634 ◽  
Author(s):  
W. C. Hulbert ◽  
T. McLean ◽  
B. Wiggs ◽  
P. D. Pare ◽  
J. C. Hogg
Keyword(s):  
Dose Response ◽  
Guinea Pigs ◽  
Response Curve ◽  
Dynamic Compliance ◽  
Dose Response Curve ◽  
Base Line ◽  
Response Curves ◽  
Mechanically Ventilated ◽  
Dose Response Curves ◽  
The Right

Histamine dose-response curves were performed on anesthetized tracheostomized guinea pigs that were paralyzed and mechanically ventilated at a constant tidal volume and breathing frequency. The dose was calculated by generating an aerosol of known concentration and measuring the volume delivered to the lung. Increasing the dose was accomplished by increasing the number of breaths of aerosol delivered. The response to each dose was determined by measuring the change in airway resistance (RL) and dynamic compliance (Cdyn) using the method of Von Neergaard and Wirz (Z. Klin. Med. 105: 51–82, 1927). With increasing doses of histamine, RL increased and reached a plateau at approximately five times the base-line value and Cdyn fell to approximately 20% of its initial value. The variability in the base-line and maximum response as well as the calculated sensitivity and reactivity was less than that previously reported. Propranolol pretreatment increased resting RL and shifted the dose-response curve for RL to the left of the controls, increasing reactivity but not sensitivity. Atropine shifted the dose-response curve to the right of the control, decreasing sensitivity but without changing reactivity. The data for Cdyn showed that atropine pretreatment caused a higher resting value and propranolol pretreatment a lower value at the highest histamine dose but no differences in either sensitivity or reactivity.

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