Cardiovascular and Gastrointestinal Effects of Bradykinin and Its Potentiation by Thiols in Rats

Sherman, William T.; Gautieri, Ronald F.

doi:10.1002/jps.2600580814

Cited by 6 publications

(4 citation statements)

References 12 publications

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“…Accordingly, the groups essential for potentiating activity are the amino and the sulfhydryl. This observation agrees with the work of S h e r m a n and G a u t ie r i [12] who reported that 2-propanethiol was inactive as a potentiator of the bradykinin response in the guinea pig ileum preparation. The fact that cysteine contains 3 functional groups whereas 2-propanethiol contains only a sulfhydryl, would lend support to the hypothesis of a second functional being necessary for potentiating activity.…”

Section: Discussionsupporting

confidence: 83%

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Modification of Polypeptide Activity by Cysteine Analogs: Structure-Activity Relationship

Potter¹,

Walaszek²

1971

Pharmacology

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The pharmacodynamic activity of the cysteine molecule was altered by structural modification of functional moieties. Increasing the basicity of the amino group by esterification of the carboxyl group increased potentiating activity. Substitution on either the amino or sulfhydryl moieties adversely affected potentiating activity. Several sulfhydryl-substituted analogs demonstrated noncompetitive antagonism toward bradykinin and acetylcholine responses. An apparent competitive inhibition of eledoisin responses by lower concentrations of several sulfhydryl-substituted analogs can perhaps be attributed to their structural similarity with methioninamide, the C-terminal amino acid in the eledoisin molecule, or to the involvement of spare receptors. The evidence presented by this work suggests that the amino and sulfhydryl groups are essential for the potentiating activity of cysteine.

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Section: Discussionsupporting

confidence: 83%

“…Several mechanisms have been suggested in explana tion of cysteine-induced augmentation of bradykinin responses [2,3,4,9,12,13]. Previous studies in this laboratory have indicated that the mechanism for this effect may be the release of acetylcholine since agents preventing this release block potentiation [10].…”

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confidence: 99%

Modification of Polypeptide Activity by Cysteine Analogs: Structure-Activity Relationship

Potter¹,

Walaszek²

1971

Pharmacology

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“…The effects of bradykinin on several isolated preparations are potentiated either by bradykinin potentiating factor (BPF) extracted from the venom of the Bothrops jararaca (Ferreira, 1965;Ferreira & Rocha e Silva, 1965) or by thiol compounds (Picarelli, Henriques & Oliveira, 1962;Ferreira & Rocha e Silva, 1962;Sherman & Gautieri, 1969). The potentiation was thought to be due to inhibition of kinin destruction by the tissue, for bradykinin potentiators are strong inhibitors of kininase activity in plasma or tissue homogenates.…”

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confidence: 99%

Action of bradykinin potentiating factor (BPF) and dimercaprol (BAL) on the responses to bradykinin of isolated preparations of rat intestines

Amargo

Ferreira

1971

British J Pharmacology

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BPF and BAL inhibited kininase activity of homogenates of rat intestine. However, BFP potentiated and BAL inhibited the contractions induced by bradykinin on rat isolated duodenum (low calcium solution) and terminal ileum (normal calcium solution). Neither BPF nor BAL affects the relaxation induced by bradykinin of rat duodenum bathed in normal Tyrode. These results suggest that two different types of pharmacological receptor are involved in the action of bradykinin on rat intestine, and that other factors besides the inhibition of agonist destruction participate in the mechanism of potentiation of kinin action by BPF.

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“…Compound 4, obtained fortuitously in one of the synthesis schemes, can be viewed as a conformationally biased analog of 2 and is therefore an interesting additional analog of deshydroxymuscarine. The cyclopentane ring was selected because it is isosteric with the tetrahydrofuran ring of muscarine (1), but the cyclopentane methylene cannot have the same electronic contribution toward receptor interaction postulated for oxygen in the tetrahydrofuran ring of muscarine.…”

Section: Discussionmentioning

confidence: 99%

cis- and trans-2-Mercaptocyclobutylamines, their benzylmercapto analogs, and aminomethyl homologs. Influence on bradykinin-induced contraction of the guinea pig ileum

Witiak¹,

Sinha²,

Ruffolo³

et al. 1973

J. Med. Chem.

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Many thio compounds, including 2-mercaptoethylamine ( l ) , have been shown to potentiate the effect of bradykinin on smooth muscle. In this paper we describe the synthesis of cyclic analogs, cis-and trans-2-mercaptocyclobutylmethylamine (3), and the action of these stereoisomers as well as cisand trans-2-mercaptocyclobutylamine (2) and cis-and trans-2-benzylmercaptocyclobutylamine (4) on bradykinin-induced contraction of the guinea pig ileum. Biological results are discussed in light of current proposals concerning the mechanism of action of thio analog influence on bradykinin contraction of the guinea pig ileum.The action of bradykinin on smooth muscle is of considerable importance; this polypeptide is a potent stimulator of many smooth muscles including guinea pig ileum, rabbit intestine, and rat uterus, exhibits a relaxant action on the rat duodenum and colon, and produces a fall in blood pressure in a number of small animals.' In addition, a number of SH compounds, such as 2-mercaptoethylamine (l), glutathione, cysteine, 2,3-dimercaptopropanol, and 2-mercaptoethanol, are known to potentiate bradykinin-induced contraction of the guinea pig i l e~m .~-~ Since Potter and Walaszek6j7 concluded that the NH2 and SH groups of cysteine are essential for the potentiating action of this amino acid, it seemed desirable to us to study the stereoselective effects of some recently synthesized' cyclobutane analogs of 1 in this system. Appropriately constructed compounds ultimately may serve as probes useful in elucidating structural requirements and mechanisms involved in bradykinin-induced responses of smooth muscle.The comparative effects of cis-and trans-2-mercaptocyclobutylamine (2), the aminomethyl homologs (cis-and trans-3), and the benzyl thioethers (cis-and trans-4) on bradykinininduced contraction of the guinea pig ileum are described in this article. / "2 d R +R --SR' U I S H SR' 1 cis-2, R = NH,; R' = H cis-3, R = CH,NH,; R' = H cis-4, R = NH,; R = CH,Ph trans-2, R = NH, ; R' = H trans-3, R = CH,NH,; R' = H trans-4, R = NH,; R' = CH,PhSynthetic Aspects. The synthesis for cis-and trans-2 and the isomerically pure benzyl thioethers 4 previously have been described.8 The isomeric homologs of 2, namely 3, were prepared from starting cis-or trans-2-benzylmercapto-1 -carbethoxycyclobutane (5).' LiAlH4 reduction of pure cis-or trans-5 afforded the respective cis-or trans-2-benzylmercaptocyclobutylcarbinols (6) in 85-90% yield. The cistosylate 7 was obtained from carbinol 6 as a crystalline solid; the trans-tosylate 7 could not be crystallized. The latter isomer was purified by dissolving in a minimum amount of HCC13 followed by precipitation with a large ?The authors gratefully acknowledge support of this work through Contract N o . $This work as well as ref 8 was abstracted in part from a dissertation presented b y B. K. S., March 1972, t o the Graduate School o f The Ohio State University.volume of petroleum ether. Treatment of cis-or trans-7 with a 10 M excess of NaN3 in dry DMF afforded the respective cis-azide (N3...

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Cardiovascular and Gastrointestinal Effects of Bradykinin and Its Potentiation by Thiols in Rats

Cited by 6 publications

References 12 publications

Modification of Polypeptide Activity by Cysteine Analogs: Structure-Activity Relationship

Modification of Polypeptide Activity by Cysteine Analogs: Structure-Activity Relationship

Action of bradykinin potentiating factor (BPF) and dimercaprol (BAL) on the responses to bradykinin of isolated preparations of rat intestines

cis- and trans-2-Mercaptocyclobutylamines, their benzylmercapto analogs, and aminomethyl homologs. Influence on bradykinin-induced contraction of the guinea pig ileum

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