icatibant and dazoxiben

Bradykinin receptors have been divided into B1 and B2 subtypes. The aim of this study on human umbilical arteries was: i) to compare the recognition properties of the mediating contractions of bradykinin receptors; and ii) to assess the possible role of thromboxane A2 in a bradykinin-induced contraction of smooth muscle. Umbilical arteries were dissected and mounted in organ baths for isometric measurement of force. Our results showed that the B1 agonist [Sar1dPhe8desArg9]-bradykinin had no effect on the concentration-response 10(-9)-3 x 10(-5) mM. Cumulative additions of bradykinin (10(-9)-3 x 10(-5) mM) and of the B2 agonist [Hyp3TyrMe8]-bradykinin (10(-9)-3 x 10(-5) mM) produced dose-dependent contractions. Dose response curves to bradykinin (10(-9)-3 x 10(-5) mM) were not significantly altered by the presence of B1 selective antagonist [des-Arg9, Leu8]-bradykinin (10(-5) mM), or by the selective B2 antagonist [Thi(5,8), D-Phe7]-bradykinin (10(-5) mM). However, Hoe 140 D-Arg-[Hyp3, Thi5,D-Tic7, Oic8]-bradykinin, an antagonist of B2 responses, significantly inhibited bradykinin-induced contraction. The responses to bradykinin were unaffected by indomethacin (10(-4) mM), dazoxiben (10(-5) mM) or even by nordihydroguaiaretic acid (10(-5) mM). However, bradykinin contractions were antagonized in a noncompetitive manner by quinacrine (10(-5) mM). These results showed that bradykinin contracts human umbilical arteries essentially through B2 receptors. Moreover, the responses to bradykinin are unlikely to be mediated by the cyclooxygenase/lipooxygenase pathway. The inhibitory effects of quinacrine may be due to a specific or nonspecific effect at a cellular level on smooth muscle contractility, or due to a direct action to block Ca2+ influx at membrane level.

Topics: Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Dose-Response Relationship, Drug; Endothelium; Humans; Imidazoles; Indomethacin; Masoprocol; Muscle Contraction; Muscle, Smooth, Vascular; Quinacrine; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Thromboxane A2; Umbilical Arteries

This study was designed to investigate the mechanisms by which bradykinin induces contraction of the pig iris sphincter muscle in vitro. Addition of bradykinin, Lys-bradykinin and Met-Lys-bradykinin to the pig iris sphincter resulted in a graded contraction with a mean EC(50s) of 21, 11 and 5 nM, respectively. The bradykinin B(1) receptor agonist des-Arg(9)-bradykinin only caused a slight contraction, measured 6 h after the tissue was set up. The B(2) receptor antagonists FR 173657 ((E)-3-(6-acetamido-3-pyridyl)-N [N-2-4-dichloro-3-[(2-methyl-8-quinolinyl) oxymethyl] phenyl]-N-methylamino-carbonyl-ethyl] acrylamide) and Hoe 140 (D-Arg(0)-[Hyp(3), Thi(5), D-Tic(7), Oic(8)]-bradykinin produced a graded shift to the right associated with marked inhibition of the bradykinin-induced contraction. Atropine, guanethidine or tetrodotoxin significantly reduced the bradykinin-induced contraction. Dazoxiben, an inhibitor of thromboxane A(2), and MK-571 (3-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl ((3-dimethyl amino-3oxo-propyl) thio) methyl) propanoic acid, a leukotriene D(4) receptor-selective antagonist, also caused inhibition of the bradykinin-mediated contraction. Cyclooxygenase-1 and -2 inhibitors, indomethacin, ibuprofen, valeryl salicylate and NS 398 (N-[2-(cyclohexyloxy)-4-nitrophenyl]methanosulfonamide) all significantly inhibited the bradykinin-mediated contraction without affecting the carbachol-induced contraction of the pig iris sphincter. Taken together, these results indicate that the bradykinin-mediated contraction of the pig iris sphincter muscle seems to be mediated primarily by the activation of the B(2) receptor release of acetylcholine, noradrenaline and both cyclooxygenase-1 and -2 metabolites besides the release of leukotriene D(4) and tromboxane A(2) from the arachidonic acid pathway.

Topics: Animals; Atropine; Bradykinin; Bradykinin Receptor Antagonists; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors; Guanethidine; Ibuprofen; Imidazoles; In Vitro Techniques; Indomethacin; Iris; Kallidin; Muscle Contraction; Muscle, Smooth; Nitrobenzenes; Propionates; Quinolines; Salicylates; Sulfonamides; Swine; Tetrodotoxin; Thromboxane-A Synthase

We previously demonstrated that the bradykinin-induced contraction of human isolated small bronchi is inhibited by indomethacin, capsaicin (N-methyl-N-6-nonenamide) and ruthenium red but not by tachykinin receptor antagonists. The thromboxane A2 receptor (TP receptor) antagonist GR32191 ((1R-(1 alpha(Z),2 beta,3 beta,5 alpha))-(+)-7-(5-(((1,1'-biphenyl)-4-yl)- methoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-heptenoic acid, hydrochloride) (10(-10) to 10(-8) M) dose dependently inhibited the effect of bradykinin, suggesting the mediation of the TP receptor in the action of bradykinin. With higher concentrations of GR32191 (10(-7) and 10(-6) M) bradykinin induced a relaxation which was inhibited by indomethacin and by the bradykinin B2 receptor antagonist Hoe 140 (D-Arg0[Hyp3,Thi-5,D-Tic7,Oic8]bradykinin). The thromboxane A2 synthase inhibitor dazoxiben (4-(-2-(1H-imidazol-1-yl)ethoxy) benzoic acid hydrochloride) 10(-6) M inhibited the bradykinin-induced contraction, suggesting that thromboxane A2 was involved in TP receptor stimulation. The thromboxane A2 mimetic U-46619 (9,11-dideoxy-11 alpha,9 alpha-epoxy-methano-prostaglandin F2 alpha)-induced contraction of human distal bronchi was not inhibited by capsaicin and ruthenium red. Our data suggest that bradykinin contracts human isolated small bronchi through thromboxane A2 release. The inhibitory effect of ruthenium red and capsaicin on the bradykinin response may be due to inhibition of thromboxane A2 release or arachidonic mobilisation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Aged; Biphenyl Compounds; Bradykinin; Bronchi; Capsaicin; Dose-Response Relationship, Drug; Heptanoic Acids; Humans; Imidazoles; Indomethacin; Male; Middle Aged; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Prostaglandin Endoperoxides, Synthetic; Receptors, Thromboxane; Ruthenium Red; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents

This study investigates the mechanisms involved in kinin-induced contractions in rings of rat portal vein (RPV). Bradykinin (BK), Lys-BK, Met-Lys-BK, Tyr8-BK (TBK) and des-Arg9-BK (DABK) all caused graded contractions in RPV, with the following order of potency (EC50, nanomolar): Met-Lys-BK (0.3) > Lys-BK (0.5) > BK (0.9) > TBK (2.3) >> DABK (46.0). The potency of DABK and maximal contractions for DABK and BK, but not for TBK or NE, increased as a function of in vitro incubation period, reaching the maximum at 4.5 hr. Cycloheximide (a protein synthesis inhibitor, 70 microM), incubated for 4.5 hr, inhibited almost completely the CRCs for DABK and blocked the latter phase of CRCs for BK, not altering contractions induced by U46619 (9,11-dideoxy-9 alpha, 11 alpha-methano-epoxy prostaglandin F2 alpha) (a thromboxane A2/prostaglandin H2-mimetic). Incubation of RPV with D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-BK (HOE 140, a selective B2 receptor antagonist, 0.01-100 nM), caused a parallel rightward displacement of the BK and TBK concentration-response curves (CRCs). Schild plots were linear, yielding pA2 values of 11.4 and 9.3, respectively. The slope for HOE 140 against TBK-induced contractions did not differ from unity (1.23 +/- 0.21), whereas against BK was significantly lesser than unity (0.72 +/- 0.20). The CRCs induced by DABK were not affected by HOE 140 (100 nM). In addition, the CRCs for DABK at 4.5 hr were shifted to the right in a parallel form in the presence of des-Arg9-[Leu8]-BK (a selective B1-receptor antagonist, 1 microM), yielding a pA2 value of 6.7.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bradykinin; Cycloheximide; Dose-Response Relationship, Drug; Imidazoles; In Vitro Techniques; Indoles; Male; Norepinephrine; Portal Vein; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Wistar; Receptors, Bradykinin; Thromboxane A2; Vasoconstriction