[Ureter drugs]. / Les médicaments de l'uretère.

Many improvements have been made recently in the field of the ureteral smooth muscle pharmacology. After a brief summary on physiological basis, we review what is known about effects on ureter of different drugs class. In a second part, we review clinical applications for renal colic analgesia, calculi expulsive medical therapy, ESWL adjuvant treatment and preoperative treatment before retrograde access. There are now sufficient data on NSAID and alpha-blockers. beta-agonists, especially for beta3 selective ones, and topical drugs before retrograde access are interesting and should be further evaluated.

Mixing rules for multicomponent mixture mass diffusion coefficients and thermal diffusion factors.

Mixing rules are derived for mass diffusion coefficient and thermal diffusion factor matrices by developing compatibility conditions between the fluid mixture equations obtained from nonequilibrium thermodynamics and Grad's 13-moment kinetic theory. The mixing rules are shown to be in terms of the species mole fractions and binary processes. In particular, the thermal diffusion factors for binary mixtures obtained by the Chapman-Enskog expansion procedure are suitably generalized for many-component mixtures. Some practical aspects of the results are discussed including the utilization of these mixing rules for high pressure situations.

[Synthesis of functionalized cyanines. Fluorescence properties following complexation of cations]. / Synthèse de cyanines fonctionnalisées. Etude de leurs propriétés de fluorescence en fonction de la complexation de cations.

The ionophoric properties of podands containing dioxazaphosphocane moieties linked by inactive spacers were studied. To increase the detection sensibility of these compounds we introduced a cyanine as spacer. Fluorescence analysis demonstrated the interest of cyanines as active spacers since the complexation by cations as Ca2+ and Mg2+ gives an enhancement of the emission intensity.

Inhibition of the Rac1 GTPase protects against nonlethal ischemia/reperfusion-induced necrosis and apoptosis in vivo.

Reperfusion of ischemic tissue results in the generation of reactive oxygen species that contribute to tissue injury. The sources of reactive oxygen species in reperfused tissue are not fully characterized. We hypothesized that the small GTPase Rac1 mediates the oxidative burst in reperfused tissue and thereby contributes to reperfusion injury. In an in vivo model of mouse hepatic ischemia/reperfusion injury, recombinant adenoviral expression of a dominant negative Rac1 (Rac1N17) completely suppressed the ischemia/reperfusion-induced production of reactive oxygen species and lipid peroxides, activation of nuclear factor-kappa B, and resulted in a significant reduction of acute liver necrosis. Expression of Rac1N17 also suppressed ischemia/reperfusion-induced acute apoptosis. The protection offered by Rac1N17 was also evident in knockout mice deficient for the gp91phox component of the phagocyte NADPH oxidase. This work demonstrates the crucial role of a Rac1-regulated oxidase in mediating the production of injurious reactive oxygen species, which contribute to acute necrotic and apoptotic cell death induced by ischemia/reperfusion in vivo. Targeted inhibition of this oxidase, which is distinct from the phagocyte NADPH oxidase, should provide a new avenue for in vivo therapy aimed at protecting organs at risk from ischemia/reperfusion injury.-Ozaki, M., Deshpande, S. S., Angkeow, P., Bellan, J., Lowenstein, C. J., Dinauer, M. C., Goldschmidt-Clermont, P. J., Irani, K. Inhibition of the Rac1 GTPase protects against nonlethal ischemia/reperfusion-induced necrosis and apoptosis in vivo.

Structure-activity analysis of the effects of lysophosphatidic acid on platelet aggregation.

Lysophosphatidic acid (1-acyl-sn-glycero-3-phosphate or LPA) is a phospholipid mediator displaying numerous and widespread biological activities and thought to act via G-protein-coupled receptors. Here we have studied the effects on human platelets of a number of LPA analogues, including two enantiomers of both N-palmitoyl-(L)-serine-3-phosphate ((L) and (D)NAPS for N-acyl-phosphoserine) and 2-(R)-N-palmitoyl-norleucinol-1-phosphate ((R) and (S)PNPA), cyclic analogues of 1-acyl-sn-glycero-3-phosphate (cPA) and of 1-O-hexadecyl-sn-glycero-3-phosphate (cAGP), sphingosine-1-phosphate (SPP), as well as two palmitoyl derivatives of dioxazaphosphocanes bearing either a P-H or a P-OH bond (DOXP-H and DOXP-OH, respectively). Nine of these compounds induced platelet aggregation with the following order of potency: SPP < cAGP < DOXP-OH < (L)NAPS = (D)NAPS < (R)PNPA = (S)PNPA < LPA < AGP, EC50 varying between 9.8 nM and 8.3 microM. Two of these compounds (SPP and cAGP) appeared as weak agonists inducing platelet aggregation to only 33% and 41%, respectively, of the maximal response attained with LPA and other analogues. In cross-desensitization experiments, all of these compounds specifically inhibited LPA-induced aggregation, suggesting that they were all acting on the same receptor(s). In contrast, cPA and DOXP-H did not trigger platelet aggregation but instead specifically inhibited the effects of LPA in a concentration-dependent manner. The inhibitory action of cPA did not vary with the acyl chain length or the presence of a double bond and did not involve an increase in cAMP. These data thus confirm the lack of stereospecificity of platelet LPA receptor(s). In addition, since the order of potency of some analogues is different from that described in other cells, our results suggest that platelets contain (a) pharmacologically distinct receptor(s) whose molecular identity still remains to be established. Finally, this unique series of compounds might be used for further characterization of other endogenous or recombinant LPA receptors.

Vasodilator responses to desmopressin and its diluent, chlorobutanol, in the hindquarters vascular bed of the cat.

Desmopressin is a synthetic analog of vasopressin used to promote hemostasis and reduce postoperative blood loss. Recent studies have shown that desmopressin decreases arterial blood pressure in the anesthetized rat and relaxes isolated segments of aorta and pulmonary artery. Responses to a clinical preparation of desmopressin were investigated in the hindquarters vascular bed of the cat under constant flow conditions so that changes in perfusion pressure directly reflect changes in vascular resistance. Responses to desmopressin and its vehicle, and the effect of receptor antagonists, inhibitors of prostaglandin, and nitric oxide synthesis inhibitors, were investigated.

Heparin treatment enhances the recovery of neoendothelial acetylcholine-induced vascular relaxation after balloon catheter injury in the rabbit aorta.

BACKGROUND: After catheter injury, the neoendothelium that grows is abnormal in morphology and in acetylcholine-induced generation of endothelium-derived relaxing factor (EDRF). Heparin has been shown to have stimulatory effects on vascular endothelial growth in vitro. Its effect in vivo on neoendothelial cell morphology and metabolism after injury has not been described. We investigated the effect of heparin treatment on the neoendothelium formed after injury. METHODS AND RESULTS: Four groups of New Zealand White rabbits were studied. Group 1 rabbits underwent catheter denudation and were killed 4 weeks after injury without receiving treatment (NO Tx, n = 8). Groups 2 and 3 underwent similar aortic injury, received 2 weeks of treatment with either heparin (n = 7) or low molecular weight heparin (LMWH, n = 5), and were killed at 4 weeks. Group 4 underwent sham operation (SHAM, n = 8). EDRF generation was determined by the relaxation of precontracted aortic rings in an organ bath in response to acetylcholine. The heparin-treated group exhibited a significant improvement in acetylcholine-induced relaxation (27%) versus both LMWH-treated (14%, P = .035) and untreated groups (11%, P = .004), although relaxation was only 50% of that observed in the uninjured control vessels (52%, P = .001). The neoendothelium formed in the heparin-treated group exhibited a more normal histological appearance and was aligned with the direction of blood flow as compared with that observed in the untreated or LMWH-treated groups. CONCLUSIONS: These results demonstrate that in vivo heparin administration enhanced the recovery of EDRF generation and augmented normalization of the morphologic appearance of the neoendothelium.

Angiopeptin enhances acetylcholine-induced relaxation and inhibits intimal hyperplasia after vascular injury.

The effects of the somatostatin analogue, angiopeptin (BIM-23014), on neoendothelial function, as evidenced by formation of prostaglandin (PG) I2 and by acetylcholine-induced relaxation (formation of endothelial-derived relaxing factor), were investigated in the rabbit aorta. A balloon catheter injury of the thoracic and abdominal aorta was induced in New Zealand White rabbits. Animals treated with angiopeptin for 2 or 4 wk were compared with untreated rabbits at 2 or 4 wk after the induction of injury, as well as to sham-operated controls. When the rabbits were killed, vascular rings were assessed for arachidonic acid-stimulated PGI2 formation, acetylcholine-induced relaxation, and the degree of intimal hyperplasia. Vascular rings from animals treated with angiopeptin exhibited enhanced acetylcholine-induced relaxation; however, angiopeptin treatment had no effect on arachidonic acid-stimulated PGI2 formation. Intimal hyperplasia in treated animals was reduced by 36%. Treatment with another somatostatin analogue, BIM-23030, did not enhance relaxation or inhibit intimal hyperplasia. These data suggest that treatment with angiopeptin may inhibit intimal hyperplasia in part by its beneficial effect on neoendothelial function.

Selective and complete blockade of acetylcholine-induced relaxation in rabbit aortic rings by N omega-nitro-L-arginine but not by glybenclamide.

This study addressed the possibility that acetylcholine-induced relaxation in the rabbit aorta is mediated by dual mechanisms: one N omega-nitro-L-arginine (NLA)-sensitive, the other glybenclamide-sensitive. Acetylcholine, nitroglycerin and BRL38227 (lemakalim), an activator of glybenclamide-sensitive potassium channels, were added to an organ bath containing rabbit aortic rings in a cumulative manner in the absence or presence of NLA and/or glybenclamide. NLA inhibited acetylcholine-induced relaxation and potentiated the relaxant response to nitroglycerin. BRL38227 caused a dose-dependent relaxation in rabbit aortic rings, and 30 microM glybenclamide produced essentially complete inhibition of this relaxation. Glybenclamide alone produced no inhibition of acetylcholine-induced relaxation. These results indicate that glybenclamide-sensitive potassium channels in the rabbit aorta play no role in mediating the relaxant response to acetylcholine, while NLA can produce a selective and essentially complete blockade of the relaxant response to acetylcholine in the rabbit aorta.

Analysis of the inhibitory effects of DuP 753 and EXP 3174 on responses to angiotensin II in the feline hindquarters vascular bed.

The effects of DuP 753 and EXP 3174, nonpeptide angiotensin II type 1 antagonists, on responses to angiotensin II were investigated in the hindquarters vascular bed of the cat. Under constant flow conditions, injections of angiotensin II into the hindquarters perfusion circuit elicited dose-dependent increases in perfusion pressure. Responses to the peptide were stable with respect to time, did not exhibit tachyphylaxis, and 2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)biph eny l-4-yl]methyl]methyl]imidazole (DuP 753) in doses of 1 and 2.5 mg/kg decreased vasoconstrictor responses to angiotensin II in a competitive manner, with a longer duration of action at the higher dose. DuP 753 had no significant effect on vasoconstrictor responses to vasopressin, norepinephrine, neuropeptide Y or 11 alpha,6 alpha-epoxymethano-9 alpha,11 alpha-dideoxy-prostaglandin F2 alpha, on biphasic responses to endothelin-1, or on vasodilator responses to acetylcholine. 2-n-Butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]im idazole-5-carboxylic acid (EXP 3174) also decreased responses to angiotensin II without altering responses to norepinephrine, vasopressin, U46619 or endothelin-1. The inhibitory effect of EXP 3174 was surmountable; however, large doses of angiotensin II were required, and the blockade was long in duration. The effects of DuP 753 and EXP 3174 on responses to angiotensin II and angiotensin III were similar, and when EXP 3174 was administered in doses of 0.1 and 0.05 mg/kg i.v., the blockade was overcome and the dose-response curves for angiotensin II were shifted to the right in a parallel manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effects of nitric oxide synthesis inhibitors on vascular resistance and responses to acetylcholine in cats.

The effects of dose and the duration of treatment with N omega-nitro-L-arginine (L-NNA) and N omega-nitro-L-arginine methyl ester (L-NAME) on vascular resistance and the vasodilator response to acetylcholine (ACh) were investigated in the hindquarters vascular bed of the cat under constant flow conditions. L-NNA and L-NAME increase perfusion pressure and reduce vasodilator responses to ACh in the hindquarters vascular bed; however, the dose and time of exposure required to produce these effects are different. When L-NNA (2.5-5 mg/min) was infused into the hindquarters vascular bed, the increase in perfusion pressure was observed 10 min after onset of the infusion, at which time responses to ACh were not changed. The time of exposure for 50% of the maximal change in hindquarters perfusion pressure was significantly less than the time of exposure for 50% of the maximal decrease in the vasodilator response to ACh during infusion of L-NNA. A similar pattern was observed after the intravenous administration of 3-300 mg/kg L-NAME, while 1 mg/kg L-NAME produced a large but submaximal pressor response and lesser decreases in responses to ACh. The arginine analogues did not completely inhibit the vasodilator response to ACh in the hindquarters vascular bed, with a 30-fold increase in dose producing no additional blockade; however, L-NNA completely inhibited the relaxant response to ACh in the isolated aorta of the cat.(ABSTRACT TRUNCATED AT 250 WORDS)

Penile erections induced by vasoactive intestinal peptide and sodium nitroprusside.

The use of vasoactive intestinal peptide (VIP), sodium nitroprusside (SNP), and the reference combination of papaverine, prostaglandin E1, and phentolamine was studied in 22 adult cats. The maximal erectile response (intracavernous pressure, penile length, and rigidity) was produced by intracavernous injection of a combination of 1.65 mg papaverine, 0.5 micrograms PGE1, and 25 micrograms phentolamine. This combination was considered as "control" in order to compare the effect of other agents. VIP and SNP increased the intracavernous pressure and caused erection in a dose-dependent manner with a maximal response obtained with 5 micrograms VIP or 10 micrograms SNP. The duration of peak erection and the total duration of drug effect were significantly shorter with VIP and SNP than with the reference combination (P < 0.01). Epinephrine (30 micrograms) reversed the effects of SNP and significantly shortened the duration of peak action and total effect (P < 0.05). This study supports the use of an in vivo feline model for the evaluation of vasoactive agents and demonstrates that the intracavernous injection of either VIP or SNP can induce penile erection in the adult cat.

Analysis of responses to big endothelin in the hindquarters vascular bed of the cat.

OBJECTIVE: To investigate vascular responses to the endothelin-1 (ET-1) precursor, human big endothelin 1-38 (big ET), in the peripheral vascular bed of the cat. DESIGN: These studies were designed to investigate the hypothesis that bit ET is converted to an active peptide with properties similar to ET-1. SETTING: Hindquarters vascular bed of the cat under conditions of controlled bloodflow; changes in perfusion pressure reflect changes in vascular resistance. ANIMALS: Fifty-four adult mongrel cats. INTERVENTIONS: Big ET, ET-1, the peptidases chymotrypsin, pepsin and cathepsin-D, and the metalloprotease inhibitor phosphoramidon. MAIN RESULTS: Intra-arterial injections of big ET induced a slow-developing and sustained increase in hindquarters perfusion pressure which could be blocked by phosphoramidon. ET-1 (0.3 nmol), administered as a slow infusion over a 10-min period, produced a slowly developing increase in hindquarters perfusion pressure in a manner similar to that observed in response to injection of big ET. A bolus injection of ET-1 produced a biphasic response characterized by a transient decrease in pressure followed by an increase which was significantly greater in magnitude and more rapid in onset than the pressor response to big ET (0.3 nmol). After incubation of big ET with chymotrypsin, pepsin and cathepsin-D (each 5% weight/weight) for 30 mins at 37 degrees C, injection of activated big ET produced a biphasic response characteristic of the response to ET-1 with an initial transient decrease in pressure followed by a secondary increase in hindquarters perfusion pressure. CONCLUSIONS: Big ET produces a phosphoramidon-sensitive pressor response which is similar to that produced by an infusion of ET-1. These data suggest that chymotrypsin, pepsin and cathepsin-D can convert big ET to an active peptide which elicits a biphasic response similar to that produced by ET-1.

Analysis of pulmonary and systemic vascular responses to platelet-activating factor in the cat.

Pulmonary and systemic vascular responses to platelet-activating factor (PAF) were investigated in the anesthetized cat. Intravenous injections of PAF decreased arterial pressure, increased pulmonary arterial pressure, and caused small but significant decreases in right and left atrial pressures. A transient increase in cardiac output was followed by a secondary decrease, and heart rate was increased. Pulmonary vascular resistance (PVR) was increased, systemic vascular resistance (SVR) was reduced, and changes in PVR and SVR in response to PAF were blocked by the novel PAF receptor antagonist, BN 50730. Under constant-flow conditions PAF dilated the hindlimb vascular bed in a dose-related manner, whereas in the pulmonary lobar vascular bed, PAF caused dose-related increases in perfusion pressure. Hindlimb and lobar vascular responses to PAF were blocked by BN 50730 in a selective manner, whereas cyclooxygenase inhibitors had no effect on responses to the phospholipid mediator. Hindlimb vasodilator responses to PAF were reduced by N omega-nitro-L-arginine in a dose that blocked the response to acetylcholine but did not decrease responses to prostaglandin E1 or nitroprusside. Increases in lobar arterial pressure in response to PAF were not altered by treatment with a thromboxane receptor antagonist, when the lung was perfused with a low-molecular-weight dextran solution, or when ventilation to the lobe was interrupted. These data suggest that the release of cyclooxygenase products, activation of thromboxane A2 receptors, cellular aggregation, release of leukocyte or platelet mediators, or changes in bronchomotor tone do not contribute to the pulmonary vasoconstrictor response to PAF and that the hindlimb vasodilator response to the phospholipid mediator is dependent in part on the release of endothelium-derived relaxing factor.

Comparison of responses to sarafotoxins 6a and 6c in pulmonary and systemic vascular beds.

Cardiovascular and pulmonary responses to sarafotoxin (S) 6a and S6c were investigated in the anesthetized cat. Intravenous injections of the peptides in doses of 0.1-1.0 nmol/kg caused decreases or biphasic changes in arterial pressure (AP) and increases in central venous pressure, pulmonary arterial pressure (PAP), and cardiac output (CO). Secondary decreases in CO were observed in response to higher doses, and biphasic changes in systemic (SVR) and pulmonary (PVR) vascular resistances were observed. Under constant-flow conditions, the peptides only increased pulmonary lobar arterial perfusion pressure and lobar vascular resistance. AP responses to S6a, S6c, endothelin (ET)-1, ET-2, vasoactive intestinal contractor (VIC), and Lys7-ET-1 were similar, whereas AP responses to S6b and ET-3 were similar. S6a, S6b, S6c, ET-1, ET-2, ET-3, VIC, Lys7-ET-1, and big ET-1 increased PAP. S6a and S6c increased distal aortic and superior mesenteric arterial (SMA) blood flow and caused biphasic changes at the highest doses. Under constant-flow conditions, S6a and S6c produced dose-dependent biphasic changes in hindquarters perfusion pressure. Changes in SVR and PVR in response to the peptide were not affected by hexamethonium, glyburide, or meclofenamate, indicating that responses are independent of autonomic reflexes, activation of ATP-regulated K+ channels, or release of cyclooxygenase products. In contrast, N-nitro-L-arginine methyl ester decreased hindquarters vasodilator response to S6a and S6c. The present data show that S6a and S6c produce both vasodilation and vasoconstriction in the systemic vascular bed and increase lobar vascular resistance and that hindquarters vasodilator responses are mediated, in part, by the release of endothelium-derived relaxing factor.

N omega-nitro-L-arginine methyl ester selectively inhibits pulmonary vasodilator responses to acetylcholine and bradykinin.

The effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelium-derived relaxing factor (EDRF) production, on vascular tone and responses were investigated in the pulmonary vascular bed of the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. When pulmonary vascular tone was elevated with U-46619, intralobar injections of acetylcholine, bradykinin, sodium nitroprusside, isoproterenol, prostaglandin E1 (PGE1), lemakalim, and 8-bromo-guanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intravenous administration of L-NAME elevated lobar arterial and systemic arterial pressures without altering left atrial pressure. When U-46619 was infused after L-NAME to raise lobar arterial pressure to levels similar to those attained during the control period, vasodilator responses to acetylcholine and bradykinin were reduced significantly, whereas responses to PGE1, lemakalim, and 8-bromo-cGMP were not altered, and responses to nitroprusside were increased. There was a small effect on the response to the highest dose of isoproterenol, and pressor responses to BAY K 8644 and angiotensin II were not altered. These results are consistent with the hypothesis that EDRF production may involve the formation of nitric oxide or a nitroso compound from L-arginine and that EDRF production may have a role in the regulation of tone and in the mediation of responses to acetylcholine and bradykinin in the pulmonary vascular bed of the cat.

Influence of SQ 29,548 on vasoconstrictor responses in the hindquarters vascular bed of the cat.

The effects of SQ 29,548, a thromboxane (TX) receptor blocking agent, on vasoconstrictor responses were investigated under conditions of controlled blood flow in the hindquarters vascular bed of the cat. Intravenous injection of SQ 29,548 at a dose of 0.1 mg/kg had no significant effect on systemic arterial pressure but caused a significant reduction in hindquarters perfusion pressure. Injection of the TXA2 mimics, U44069 and U46619, into the perfusion circuit caused dose-dependent increases in hindquarters perfusion pressure with U46619 being approximately 3 times more potent than U44069. Following the administration of SQ 29,548, pressor responses to both U44069 and U46619 were reduced significantly, and the dose-response curves for both TXA2 mimics were shifted to the right in a parallel fashion. SQ 29,548 had no significant effect on the dose-dependent increases in hindquarters perfusion pressure in response to angiotensin II or BAY K8644, a nifedipine analog which promotes calcium entry. The TXA2 receptor blocking agent had no significant effect on increases in hindquarters perfusion pressure in response to angiotensin II or BAY K8644, a nifedipine analog which promotes calcium entry. The TXA2 receptor blocking agent had no significant effect on increases in hindquarters perfusion pressure in response to sympathetic nerve stimulation or injections of norepinephrine and tyramine. These findings suggest that SQ 29,548 blocks responses to the TXA2 mimics in a competitive manner, and that this inhibitory effect is selective.(ABSTRACT TRUNCATED AT 250 WORDS)

N omega-nitro-L-arginine selectively inhibits vasodilator responses to acetylcholine and bradykinin in cats.

The effects of N omega-nitro-L-arginine (nitroarginine), an inhibitor of endothelium-dependent relaxing factor (EDRF) production, on vascular tone and responses to vasodilator and vasoconstrictor agents were investigated in the hindquarters vascular bed of the cat. Under constant flow conditions, infusion of nitroarginine into the hindquarters vascular bed caused a significant increase in systemic arterial and hindquarters perfusion pressures. During infusion of nitroarginine, hindquarters vasodilator responses to acetylcholine and bradykinin were reduced significantly whereas vasodilator responses to isoproterenol, PGE1, nitroprusside, and 8-bromoguanosine 3',5'-cyclic monophosphate were not altered. Infusion of nitroarginine significantly enhanced vasoconstrictor responses to the thromboxane receptor agonist U 46619 and to phenylephrine. The results of these studies are consistent with the hypotheses that EDRF production may involve the formation of nitric oxide or a nitroso compound from L-arginine, and that EDRF production may play a role in the regulation of vascular tone and in the mediation of responses to the endothelium-dependent vasodilators, acetylcholine and bradykinin, in resistance vessels in the hindquarters. These data support the concept that EDRF is very likely an endogenous nitrovasodilator derived from L-arginine in the hindquarters vascular bed of the cat.

Influence of SK&F 95587 and BN 50730 on bronchoconstrictor responses in the cat.

The effects of SK&F 95587 (4[2-(benzenesulfonamido)-ethyl] phenoxyacetic acid), a thromboxane (TX) receptor blocking agent, on bronchoconstrictor responses were investigated in paralyzed, anesthetized, mechanically ventilated cats. Intravenous injections of the TXA2 receptor mimics, U-46619 [(15S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta5Z,13E-dienoic acid] and U-44069 (9,11-dideoxy-11 alpha,9 alpha-epoxymethano PGF2 alpha), produced dose-related increases in transpulmonary pressure and lung resistance and decreases in dynamic compliance. After administration of SK&F 95587, 5 mg/kg i.v., bronchoconstrictor responses to U-46619 and U-44069 were reduced markedly, whereas airway responses to prostaglandin (PG)F2 alpha, serotonin, PGD2 or the PGD2 metabolite, 11 beta-PGF2 alpha, were not altered. The duration of action of SK&F 95587 was greater than 3 hr, and the blockade was overcome when 10-fold larger doses of the TXA2 mimics were administered. Bronchoconstrictor responses to platelet-activating factor (PAF) were blocked by SK&F 95587 and by the novel PAF receptor antagonist, BN 50730. BN 50730 also blocked the fall in systemic arterial pressure in response to PAF. However, BN 50730 did not influence airway responses to U-46619, PGF2 alpha, PGD2 or serotonin and had no effect on baseline bronchomotor tone or arterial pressure. The PAF receptor antagonism with BN 50730 was overcome when 10-fold larger doses of PAF were administered and the dose-response curves for changes in lung resistance and dynamic compliance were shifted to the right in a parallel manner. The present data suggest that SK&F 95587 has selective TX receptor blocking activity, and that BN 50730 has selective PAF receptor blocking properties in the airways of the cat. The present data also provide support for the hypothesis that bronchoconstrictor responses to PAF are mediated by specific receptors, which are coupled to a phospholipase and, when activated, result in the release of TXA2 and contraction of airway smooth muscle.