Actions of methoctramine, a muscarinic M2 receptor antagonist, on muscarinic and nicotinic cholinoceptors in guinea-pig airways in vivo and in vitro

L-670,596 ((−)6,8-difluoro-9-p-methylsulfonyl benzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid) has been shown to be a potent receptor antagonist as evidenced by the inhibition of the binding of 125I-labeled PTA-OH to human platelets (IC50, 5.5 × 10−9 M), inhibition of U-44069 induced aggregation of human platelet rich plasma (IC50, 1.1 × 10−7 M), and competitive inhibition of contractions of the guinea pig tracheal chain induced by U-44069 (pA2,9.0). The compound was also active in vivo as shown by inhibition of arachidonic acid and U-44069 induced bronchoconstriction in the guinea pig (ED50 values, 0.04 and 0.03 mg/kg i.v., respectively), U-44069 induced renal vasoconstriction in the pig (ED50, 0.02 mg/kg i.v.), and inhibition of ex vivo aggregation of rhesus monkey platelets to U-44069 (active 1–5 mg/kg p.o.). The selectivity of the compound was indicated by the failure to inhibit, first, ADP-induced human or primate platelet aggregation and, second, bronchoconstriction in the guinea pig in vivo and contraction of the guinea pig tracheal chain in vitro to a variety of agonists. It is concluded that L-670,596 is a potent, selective, orally active thromboxane A2/prostaglandin endoperoxide receptor antagonist.Key words: thromboxane A2, thromboxane antagonist, prostaglandin endoperoxides, platelet aggregation.

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Effects of the Peptide Leukotriene Receptor Antagonist ICI 198,615 on the In Vivo and In Vitro Changes in Guinea Pig Bladder Function Which Occur After Sensitization with Ovalbumin

The Journal of Urology ◽

10.1097/00005392-199509000-00101 ◽

1995 ◽

pp. 1217-1221 ◽

Cited By ~ 1

Author(s):

Jeong Gu Lee ◽

Robert M. Levin ◽

Lev Krasnopolsky ◽

Alan J. Wein ◽

Penelope A. Longhurst

Keyword(s):

Guinea Pig ◽

Receptor Antagonist ◽

Bladder Function ◽

Leukotriene Receptor Antagonist ◽

Leukotriene Receptor

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Effects of the Peptide Leukotriene Receptor Antagonist ICI 198,615 on the In Vivo and In Vitro Changes in Guinea Pig Bladder Function Which Occur After Sensitization with Ovalbumin

The Journal of Urology ◽

10.1016/s0022-5347(01)67034-4 ◽

1995 ◽

Vol 154 (3) ◽

pp. 1217-1221 ◽

Cited By ~ 8

Author(s):

Jeong Gu Lee ◽

Robert M. Levin ◽

Lev Krasnopolsky ◽

Alan J. Wein ◽

Penelope A. Longhurst

Keyword(s):

Guinea Pig ◽

Receptor Antagonist ◽

Bladder Function ◽

Leukotriene Receptor Antagonist ◽

Leukotriene Receptor

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The effect of ONO-3705, a novel TxA2 receptor antagonist, on U-46619-induced contraction of guinea pig and human tracheal strips in vitro and on bronchoconstriction in guinea pigs in vivo

Prostaglandins ◽

10.1016/0090-6980(91)90006-2 ◽

1991 ◽

Vol 41 (4) ◽

pp. 375-382 ◽

Cited By ~ 13

Author(s):

H. Nagi ◽

F. Tsuji ◽

N. Inagaki ◽

K. Kitagaki ◽

O. Fukutomi ◽

...

Keyword(s):

Guinea Pig ◽

Receptor Antagonist ◽

Guinea Pigs ◽

Txa2 Receptor ◽

Txa2 Receptor Antagonist

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Alteration of histamine response by H2-receptor antagonism in the guinea pig

Journal of Applied Physiology ◽

10.1152/jappl.1980.48.4.613 ◽

1980 ◽

Vol 48 (4) ◽

pp. 613-618 ◽

Cited By ~ 4

Author(s):

J. M. Drazen ◽

C. S. Venugopalan ◽

M. W. Schneider

Keyword(s):

Guinea Pig ◽

Receptor Antagonist ◽

Fold Increase ◽

H2 Receptor Antagonist ◽

Receptor Antagonism ◽

H2 Receptor ◽

H2 Receptors ◽

Histamine Response

Effects of H2-receptor antagonism on the response to histamine was studied in the guinea pig in vivo and in vitro. The H2-receptor antagonist, metiamide (100 micro M), resulted in an enhanced histamine response in eight of eight parenchymal strips and in four of eight tracheal spirals. On the average the parenchymal strips were 20-fold more sensitive to histamine (P less than 0.001), whereas the tracheal spirals demonstrated an insignificant, 20%, increase in sensitivity after metiamide treatment. These results are consistent with the hypothesis that there are inhibitory H2-receptors in guinea pig airways and they predominate in the periphery. When we determined the effects of H2-antagonism on the histamine response in vivo we found that the histamine response was enhanced only in animals that had been treated with the beta-receptor antagonist propranolol. In these animals there was a mean 2.2-fold increase in histamine sensitivity. These results suggest that although there are inhibitory H2-receptors in the guinea pig lung, their role in modulating the in vivo response is much less than beta-adrenergic mechanisms.

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In vitro and in vivo activity of analogues of the kinin B2 receptor antagonist MEN11270

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y02-022 ◽

2002 ◽

Vol 80 (4) ◽

pp. 293-302 ◽

Cited By ~ 2

Author(s):

S Meini ◽

A Lecci ◽

F Carini ◽

M Tramontana ◽

S Giuliani ◽

...

Keyword(s):

Guinea Pig ◽

Receptor Antagonist ◽

Cyclic Peptide ◽

Umbilical Vein ◽

Chinese Hamster Ovary Cells ◽

Parent Compound ◽

Chinese Hamster ◽

Topical Administration

In this study, we describe the in vitro and in vivo activities of a series of cyclic peptide analogues of the selective kinin B2 receptor antagonist MEN11270 on Chinese hamster ovary cells expressing the human B2 receptor (hB2R), the human isolated umbilical vein (hUV), the isolated guinea pig ileum (gpI), and bradykinin (BK) induced bronchoconstriction (BC) and hypotension in anaesthetized guinea pigs. Substitutions in the backbone of MEN11270 (H-DArg-Arg-Pro-Hyp-Gly-Thi-c(Dab-DTic-Oic-Arg)c(7γ-10α)) aimed to increase the potency in inhibiting bronchospasm versus hypotension following the topical (intratracheal (i.t.)) or systemic (intravenous (i.v.)) application of these antagonists. A series of analogues were left unprotected from N-terminal cleavage by aminopeptidases (MEN12739, MEN13052, MEN13346, and MEN13371): these compounds maintained sizeable affinities for the hB2R (pKi = 9.4, 9.6, 9.7, and 8.6, respectively) and antagonist activities toward BK in the hUV (pA2 = 7.9, 8.3, 8.2, and 7.5) and gpI assays (pKB = 7.4, 7.8, 7.9, and 7.9), but the inhibition of BK-induced BC and hypotension in vivo was negligible following either i.v. or i.t. administration. Two analogues (MEN12388 and MEN13405) could be potential substrates of angiotensin-converting enzyme: these have good activity in the hB2R (pKi = 9.5 and 8.9, respectively), hUV (pA2 = 8.2 for MEN12388), and gpI assays (pKB = 8.4 and 8.0) but an in vivo activity 10- to 30-fold lower than the parent compound MEN11270 (pKi = 9.4, pA2 = 8.1, pKB = 8.3) when given by either the i.v. or the i.t. route. Other analogues were functionalized with a quaternary ammonium Lys derivative (MEN13031, MEN12374, and the previously mentioned MEN13052) or with an ethyl group on Arg (MEN13655 and the previously mentioned MEN13346 and MEN13405) in order to hinder or facilitate local absorption. MEN13346 and MEN13031 (pKi = 9.7and 9.5, pA2 = 8.2 and 7.9, pKB = 7.9 and 8.5, respectively) were 10- to 30-fold less active in vivo than MEN11270, without improving the discrimination between BK-induced BC and hypotension after either systemic or topical administration. It is concluded that the decreased in vivo activities of cyclic analogues of MEN11270 on BK-induced BC and hypotension following either their intratracheal or their intravenous routes of administration might be due in large part to metabolic degradation.Key words: bradykinin, asthma, blood pressure, guinea pig, metabolism.

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Inhibition of Human and Animal Platelet Adhesiveness to Glass Bead Columns by Adenosine, Dipyridamole, Chlorpromazine and Acetylsalicylic Acid

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648055 ◽

1976 ◽

Vol 36 (02) ◽

pp. 401-410 ◽

Cited By ~ 6

Author(s):

Buichi Fujttani ◽

Toshimichi Tsuboi ◽

Kazuko Takeno ◽

Kouichi Yoshida ◽

Masanao Shimizu

Keyword(s):

Guinea Pig ◽

Acetylsalicylic Acid ◽

Guinea Pigs ◽

Glass Bead ◽

Animal Species ◽

Inhibitory Effect ◽

Rabbit Platelet ◽

Platelet Adhesiveness

SummaryThe differences among human, rabbit and guinea-pig platelet adhesiveness as for inhibitions by adenosine, dipyridamole, chlorpromazine and acetylsalicylic acid are described, and the influence of measurement conditions on platelet adhesiveness is also reported. Platelet adhesiveness of human and animal species decreased with an increase of heparin concentrations and an increase of flow rate of blood passing through a glass bead column. Human and rabbit platelet adhesiveness was inhibited in vitro by adenosine, dipyridamole and chlorpromazine, but not by acetylsalicylic acid. On the other hand, guinea-pig platelet adhesiveness was inhibited by the four drugs including acetylsalicylic acid. In in vivo study, adenosine, dipyridamole and chlorpromazine inhibited platelet adhesiveness in rabbits and guinea-pigs. Acetylsalicylic acid showed the inhibitory effect in guinea-pigs, but not in rabbits.

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