Receptors for bradykinin in intestinal and uterine smooth muscle

1977 ◽  
Vol 55 (6) ◽  
pp. 1270-1285 ◽  
Author(s):  
J. Barabé ◽  
J.-N. Drouin ◽  
D. Regoli ◽  
W. K. Park
Keyword(s):  
Smooth Muscle ◽  
Direct Action ◽  
Rabbit Aorta ◽  
Maximum Effect ◽  
Academic Press ◽  
Response Curves ◽  
Rat Uterus ◽  
Hexyl Ester ◽  
Stimulus Effect ◽  
General Pharmacology

An attempt has been made to characterize receptors for bradykinin (BK) in two smooth muscle preparations (cat ileum and rat uterus) sensitive to BK. Studies have shown that contractions of the two isolated organs produced by BK result from a direct action of this peptide on specific receptors. Since (a) experimental dose–response curves of BK in the two preparations are superimposed to the theoretical ones calculated with the equation of Clark (Clark, A. J. 1937. General pharmacology. Verlag von J. Springer, Berlin), (b) ratios between doses producing 16 and 84% of maximum effect correspond to 1:28 (cat ileum) and 1:19 (rat uterus), and (c) relations stimulus–effect are linear and with a slope of 1.0 (cat ileum) and 1.1 (rat uterus), we choose to interpret these findings with the approach proposed by Clark (1937) and elaborated by Ariens (Ariens, E. J. 1964. Molecular pharmacology. Academic Press Inc., London).Studies on the structure–activity relationships performed with fragments and analogues of BK do not allow for a precise distinction of groups responsible for affinity or for the activation of receptors, and actually show that 1-Arg, 4-Gly, 5-Phe, 8-Phe, and 9-Arg are essential for the interaction. Analogues more potent than BK were obtained by replacing 8-Phe with Tyr(Me) and Trp, while 8-Cha BK keeps full activity. When tested for antagonism, all the analogues and the fragments are inactive; some of these compounds were found to potentiate the activity of BK in the rat uterus.Cyproheptadine (CH), dihydrochlorprothixene (DHCP), phenylalanine-octyl ester (POE), and β-phenylanaline-hexyl ester (β-PHE), as well as 5-Tyr(Me),8-Tyr(Me) BK, and 8-Leu-OMe Octa BK were tested for antagonism. CH, DHCP, POE, and β-PHE (at concentrations ranging from 10−6 to 10−5 M) reduce the myotropic effects of BK in the two preparations. The antagonism is nonspecific for BK, since the effects of other agonists acting on receptors different from those of BK are also reduced. Maximal responses to BK as well as to the other stimulants are significantly diminished, indicating that the antagonism is of the noncompetitive type. 5-Tyr(Me),8-Tyr(Me) BK and 8-Leu-OMe Octa BK did not exert any antagonistic action.Evidence is presented in favour of the interpretation that the receptors for BK in the two preparations are of the same type, and differ from the receptor of the rabbit aorta.

Characterization of receptors for angiotensin in the rat vas deferens

1979 ◽  
Vol 57 (4) ◽  
pp. 417-423 ◽  
Author(s):  
J. Magnan ◽  
D. Regoli
Keyword(s):  
Smooth Muscle ◽  
Vas Deferens ◽  
Proteolytic Enzymes ◽  
Rabbit Aorta ◽  
Rat Vas Deferens ◽  
Converting Enzyme ◽  
Response Curves ◽  
Sympathetic Nerve Stimulation ◽  
The Right

Experiments were performed in the rat vas deferens to characterize the receptor for angiotensin mediating the potentiation of the sympathetic nerve stimulation by this peptide. For this purpose we measured the order of potency of various angiotensins, the affinity of two specific and competitive antagonists, and we compared the effects of several angiotensins in tissues desensitized by angiotensin II.The potency of natural angiotensins follows the order: ATII > ATI > ATIII the relative potency of a few analogues which resist degradation by proteolytic enzymes as well as the potency of three L-Ala analogues of ATII show similar changes as those observed in other smooth muscle preparations (e.g. the rabbit aorta).Affinity of antagonists was evaluated by measuring pA2 and is higher for [Leu8]-ATII than for [des-Asp1, Leu8]-ATII. Both antagonists appear to be competitive since they displace the dose-response curves of ATII and ATIII to the right without changing the slope of the curves. Desensitization with ATII renders the tissues insensitive to ATIII and to other angiotensins without changing the response of the tissues to substance P.ATII does not modify the action of exogenous NA on nonstimulated tissues. ATI has no direct effect since its action is completely blocked in the presence of an inhibitor of the converting enzyme (SQ. 14225), while the responses of the vas deferens to ATII and substance P are unaltered.It is concluded that the receptor for ATII in the rat vas deferens is of the same type as the receptor mediating contraction of the rabbit aorta.

Metabolism of angiotensin II and some analogs in intact strips and in muscle preparations of rabbit aortae

1978 ◽  
Vol 56 (1) ◽  
pp. 39-47 ◽  
Author(s):  
J. Magnan ◽  
D. Regoli
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Smooth Muscle Cells ◽  
Rabbit Aorta ◽  
Muscle Preparation ◽  
Response Curves ◽  
Aortic Strip ◽  
Complete Relaxation ◽  
Maximal Tension ◽  
Apparent Diffusion

The purpose of this work was twofold: (a) to develop a muscle preparation of the rabbit aorta free of adventitia and endothelium, and (b) to measure the metabolism of angiotensin II (ATII) in this preparation. The muscle was prepared by 'shucking-off' the adventitia layer and by eliminating the endothelium. Concentration–response curves to ATII and noradrenaline (NA) measured in the muscle preparation provided pD2 values for ATII and NA not significantly different from those observed in the intact aortic strip. However, the maximal tension developed by the two agonists averaged 20–30% of the maximal tension of the intact strips. Apparent diffusion of ATII, in and out of the tissue, was faster in the muscle while NA diffusion was not significantly different. Metabolism of ATII was measured at the plateau of contraction and after complete relaxation in both the muscle and the intact strip. Ten percent of ATII was metabolized at the plateau of the contraction and 50% after complete relaxation. Heptapeptide 1–7 was the metabolite found in both preparations. 1-β-Asp ATII was also broken down to heptapeptide 1–7 while 1-β-Asp,8-Phe-OMe-ATII resisted the degradation and was found unchanged even after 90 min of incubation. It is suggested that the enzyme which inactivates ATII is located in the smooth muscle cells and that it is a carboxypeptidase.

Electrical and mechanical effects of molecular variants of CCK on antral smooth muscle.

1978 ◽  
Vol 235 (3) ◽  
pp. E324 ◽  
Author(s):  
K G Morgan ◽  
P F Schmalz ◽  
V L Go ◽  
J H Szurszewski
Keyword(s):  
Smooth Muscle ◽  
Action Potential ◽  
Direct Action ◽  
Single Cells ◽  
Circular Muscle ◽  
Molecular Forms ◽  
Organ Bath ◽  
Amino Acid Residues ◽  
Response Curves

Intracellular microelectrode and standard organ bath techniques were used to study in vitro the effects of three molecular forms of the peptide cholecystokinin on the electrical and mechanical activities of canine antral circular muscle. Three forms were studied: the carboxyl-terminal octapeptide of cholecystokinin (CCK-OP), the molecule containing 33 amino acid residues (CCK33), and the peptide termed "cholecystokinin variant" that contains 39 amino acids (CCK39). All three forms increased the force and frequency of spontaneous contractions. They also increased the frequency and the amplitude and duration of the plateau of the gastric action potential. Atropine did not block any of these effects, suggesting that the action of these peptides was largely due to a direct action on the smooth muscle. Complete dose-response curves were determined for the effect of these peptides on the force and frequency of contraction for muscle strips and for the effect on amplitude of the plateau and frequency of the action potential for single cells. CCK39 and CCK-OP had similar potencies and both forms were more potent than CCK33.

Application of Drug Receptor Theories to the Analysis of the Myotropic Effects of Bradykinin

1975 ◽  
Vol 53 (3) ◽  
pp. 345-353 ◽  
Author(s):  
J. Barabé ◽  
W. K. Park ◽  
D. Regoli
Keyword(s):  
Dose Response ◽  
Terminal Ileum ◽  
Maximal Response ◽  
Rat Stomach ◽  
Response Curves ◽  
Rat Uterus ◽  
Drug Concentrations ◽  
General Pharmacology ◽  
Dose Response Curves ◽  
Drug Receptor

Cat jejunum and terminal ileum, and rat stomach strip and rat uterus contract to bradykinin, while rat duodenum relaxes. Dose–response curves of classical hyperbolic shape are obtained in the first three preparations, but not in the others.The negative logs of the drug concentrations which give 50% of the maximal response. (pD2) values were, respectively, 7.68 and 7.77 in the cat jejunum and terminal ileum, 6.78 in the rat stomach strip and 8.64 in the rat uterus in estrus.Theoretical dose–response curves, constructed by using experimental pD2 values in the equation of Clark, (General pharmacology. Verlag Van J. Springer, Berlin, 1937), are superimposed to experimental curves, obtained in the cat jejunum and terminal ileum, but not in the rat stomach strip. This comparison was not made in the rat uterus and duodenum.The myotropic effect of bradykinin appears to be a direct one in the cat jejunum, the terminal ileum and the rat stomach strip, because it is not affected by anticholinergics, antiadrenergics, antihistaminics and indomethacin. pD2 values and the slope of the dose–response curves of the rat uterus were reduced by indomethacin.The results indicate that cat jejunum and terminal ileum are sensitive and specific for bradykinin and appear to be the most reliable preparations for studies on the structure–activity relationships of this peptide.

Calcium and angiotensin tachyphylaxis in rat uterine smooth muscle

1975 ◽  
Vol 228 (5) ◽  
pp. 1423-1430 ◽  
Author(s):  
RJ Freer
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscles ◽  
Rabbit Aorta ◽  
Rat Uterus ◽  
Uterine Smooth Muscle ◽  
Normal Tissues ◽  
High Concentrations ◽  
The Relationship ◽  
Very High ◽  
Stimulation Of

Studies were carried out to investigate the relationship between extracellular Ca++ and the ability of a particular smooth muscle to develop tachyphylaxis to angiotensin II (AII). Stimulation of rat uterus by AII was found to be dependent on extracellular Ca++. Placing the tissue in 0 Ca++ completely blocked AII-induced contractions as did the presence of the "Ca++ antagonists" verapamil (10- minus 5M), SKF 525-A (10- MINUS 5M), tetracaine (10- minus 4M), Mn++ (8 times 10- minus 3M), or La-3+ (10- minus 3M). In addition, it is no longer possible to produce tachyphylaxis to AII in deplorazed rat uterus under conditions of pH and Ca++ concentration in which a normally polarized preparation would be unresponsive. Verapamil, on the other hand, was an even more effective antagonist of AII in depolarized preparations (ID50 of 10- minus 8M) than in normal tissues (ID50 of 2.0 times 10- minus 7M). Like the rat uterus, the smooth muscle of the guinea pig ileum also develops tachyphylaxis to AII, and the effect of this peptide was also blocked by 10- minus 5 M verapamil. Rabbit aorta, however, was found to be relatively resistant to both development of tachyphylaxis under conditions of low Ca++ and low pH and also to inhibition by even very high concentrations of verapamil (10- minus 4M). The results of these studies suggest that the Ca++ site involved in the tachyphylactic response to AII may be a physiologically important one in those smooth muscles in which movement of extracellular Ca++ contributes to the inward ion currents during excitation. Verapamil, however, appears to act at a common step in the excitation-contraction sequence in rat uterus. A working model of the interaction of AII with rat uterine smooth muscle is presented.

Application of Drug–Receptor Theories to Angiotensin

1973 ◽  
Vol 51 (9) ◽  
pp. 665-672 ◽  
Author(s):  
F. Rioux ◽  
W. K. Park ◽  
D. Regoli
Keyword(s):  
New York ◽  
Smooth Muscle ◽  
Rabbit Aorta ◽  
Biologically Active ◽  
Mass Action ◽  
Intrinsic Activity ◽  
Rat Stomach ◽  
Response Curves ◽  
Threshold Phenomenon ◽  
Specific Receptors

The myotropic action of angiotensin II has been studied on two smooth muscle preparations: the strip of rat stomach and of rabbit thoracic aorta. Contractions evoked by angiotensin are not modified by atropine, methysergide, and diphenhydramine on the rat stomach or by phentolamine, methysergide, and diphenhydramine on the rabbit aorta. It appears that angiotensin acts directly on specific receptors and not through release of acetylcholine on the stomach or of noradrenaline on the aorta. Interference by intramural prostaglandins is excluded because angiotensin is equally active on tissues pretreated or not with indomethacin.Dose–response curves obtained with angiotensin on the two tissues are close to the theoretical curves predicted by the mass–action law. The relations stimulus effect is linear, indicating that the extent of the contraction is proportional to the number of receptors occupied by the agonist. No threshold phenomenon or spare receptor capacity could be demonstrated in either tissue. It is therefore concluded that the interaction of angiotensin with its specific receptors in the two smooth muscle preparations can be analyzed quantitatively with the occupation theory by applying the concepts of affinity and intrinsic activity as defined by Ariens in 1964. (Molecular pharmacology. Vol. 1. The mode of action of biologically active compounds. Academic Press, New York.)

The Cellular Origin in Atheromatous Lesion

1970 ◽  
Vol 28 ◽  
pp. 202-203
Author(s):  
T. M. Murad ◽  
H. A. I. Newman ◽  
K. F. Kern
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Rabbit Aorta ◽  
Mixed Population ◽  
The Other ◽  
Cellular Origin ◽  
Ultrastructural Studies ◽  
Atherosclerotic Lesions ◽  
Show Evidence ◽  
Early Lesion

The origin of lipid containing cells in atheromatous lesion has been disputed. Geer in his study on atheromatous lesions of rabbit aorta, suggested that the early lesion is composed mainly of lipid-laden macrophages and the later lesion has a mixed population of macrophages and smooth muscle cells. Parker on the other hand, was able to show evidence that the rabbit lesion is primarily composed of lipid-laden cells of smooth muscle origin. The above studies and many others were done on an intact lesion without any attempt of cellular isolation previous to their ultrastructural studies. Cell isolation procedures have been established for atherosclerotic lesions through collagenase and elastase digestion Therefore this procedure can be utilized to identify the cells involved in rabbit atheroma.

Medial Smooth Muscle Cell Proliferation in the Balloon Injured Rabbit Aorta: Effect of a Thiazole Compound with Platelet Inhibitory Activity

1984 ◽  
Vol 51 (01) ◽  
pp. 075-078 ◽  
Author(s):  
R G Schaub ◽  
C A Simmons
Keyword(s):  
Smooth Muscle ◽  
Platelet Aggregation ◽  
Balloon Catheter ◽  
Rabbit Aorta ◽  
Surface Characteristics ◽  
Inhibitory Effect ◽  
Lesion Size ◽  
Blue Staining ◽  
Morphologic Characteristics ◽  
Time Period

SummaryTwenty-seven adult male New Zealand rabbits (3–4 kgs) were used in this study. Six rabbits received vehicle, 3 groups of 6 each received doses of 4,5-bis(p-methoxyphenyl)-2-(trifluoromethyl)- thiazole, (U-53,059), at 0.3 mg/kg, 3.0 mg/kg and 30.0 mg/kg/day respectively. Drug and vehicle doses were given orally each day starting 3 days before balloon injury and continuing for the entire 2 week time period. Three rabbits were used as nontreated sham controls. In the vehicle and U-53,059 treated groups aortae were denuded of endothelial cells by balloon catheter injury. Two weeks after injury platelet aggregation to collagen was measured and the aortae removed for analysis of surface characteristics by scanning electron microscopy and lesion size by morphometry. All doses of U-53,059 inhibited platelet aggregation. The 3.0 and 30.0 mg/kg groups had the greatest inhibitory effect. All balloon injured aortae had the same morphologic characteristics. All vessels had similar extent and intensity of Evan’s blue staining, similar areas of leukocyte/platelet adhesion, and a myointimal cell cover of transformed smooth muscle cells. The myointimal proliferative response was not inhibited at any of the drug doses studied.

Characterization of a continuous smooth muscle cell line derived from rabbit aorta

1989 ◽  
Vol 25 (10) ◽  
pp. 892-898 ◽  
Author(s):  
Maurice Nachtigal ◽  
Madan L. Nagpal ◽  
Phillip Greenspan ◽  
Sidonia A. Nachtigal ◽  
Alain Legrand
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Cell Line ◽  
Muscle Cell ◽  
Rabbit Aorta ◽  
Muscle Cell Line
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