Measurements of relativistic self-phase-modulation in plasma.

We report the first systematic observations of relativistic self-phase-modulation (RSPM) due to the interaction of a high intensity laser pulse with plasma. The plasma was produced in front of a solid target by the prepulse of a 100 TW laser beam. RSPM was observed by monitoring the spectrum of the harmonics generated by the intense laser pulse during the interaction. The multipeaked broadened spectral structure produced by RSPM was studied in plasmas with different density scale lengths for laser interactions at intensities up to 3.0 x 10(19) W cm(-2) (a=p(osc)/m(e)c=4.7). The results are compared with calculated spectra and agreement is obtained.

Dynamics of the critical surface in high-intensity laser-solid interactions: modulation of the XUV harmonic spectra.

The generation of harmonics from the interaction of an intense (I>or=10(18) W cm(-2)) laser with a solid surface is investigated. Modulation of the harmonic emission spectrum with a periodicity of 2 to 4 harmonics is observed at higher laser intensities. A similar modulation is predicted by a particle-in-cell simulation. The modulation is shown to be caused by the higher modes of oscillation of the critical surface during the interaction. As a result, the dynamics of the critical surface can be inferred from the shape of the harmonic spectrum.

Measuring huge magnetic fields.

Huge magnetic fields are predicted to exist in the high-density region of plasmas produced during intense laser-matter interaction, near the critical-density surface where most laser absorption occurs, but until now these fields have never been measured. By using pulses focused to extreme intensities to investigate laser-plasma interactions, we have been able to record the highest magnetic fields ever produced in a laboratory--over 340 megagauss--by polarimetry measurements of self-generated laser harmonics.

Measurements of energetic proton transport through magnetized plasma from intense laser interactions with solids

Protons with energies up to 18 MeV have been measured from high density laser-plasma interactions at incident laser intensities of 5x10(19) W/cm(2). Up to 10(12) protons with energies greater than 2 MeV were observed to propagate through a 125 &mgr;m thick aluminum target and measurements of their angular deflection were made. It is likely that the protons originate from the front surface of the target and are bent by large magnetic fields which exist in the target interior. To agree with our measurements these fields would be in excess of 30 MG and would be generated by the beam of fast electrons which is also observed.

Photonuclear physics when a multiterawatt laser pulse interacts with solid targets

When a laser pulse of intensity 10(19) W cm(-2) interacts with solid targets, electrons of energies of some tens of MeV are produced. In a tantalum target, the electrons generate an intense highly directional gamma-ray beam that can be used to carry out photonuclear reactions. The isotopes 11C, 38K, (62,64)Cu, 63Zn, 106Ag, 140Pr, and 180Ta have been produced by (gamma,n) reactions using the VULCAN laser beam. In addition, laser-induced nuclear fission in 238U has been demonstrated, a process which was theoretically predicted at such laser intensities more than ten years ago. The ratio of the 11C and the 62Cu beta(+) activities yields shot-by-shot temperatures of the suprathermal electrons at laser intensities of approximately 10(19) W cm(-2).

Effect of the plasma density scale length on the direction of fast electrons in relativistic laser-solid interactions

The angular distribution of bremsstrahlung gamma rays produced by fast electrons accelerated in relativistic laser-solid interaction has been studied by photoneutron activation in copper. We show that the gamma-ray beam moves from the target normal to the direction of the k(laser) vector as the scale length is increased. Similar behavior is found also in 2D particle-in-cell simulations.

Energetic heavy-Ion and proton generation from ultraintense laser-plasma interactions with solids

Heavy ions with energies up to 430+/-40 MeV have been measured from laser-solid interactions at focused intensities of up to 5x10(19) W/cm(2). Observations of proton emission indicate significant structure in the energy spectrum as well as an angular emission profile which varies with energy. Two qualitatively different components of ion emission are observed: (i) a high-energy component which is likely generated by a combination of "Coulomb explosion" and acceleration by the space charge force from hot electrons which escape the plasma, and (ii) a lower-energy component which forms a ring likely created by magnetic fields in the ablated plasma.

Characterisation of the endothelin receptor mediating contraction of human pulmonary artery using BQ123 and Ro 46-2005.

We have characterised the endothelin receptor mediating contraction of human isolated pulmonary artery. Endothelin-1 induced a concentration-dependent contraction of human endothelium-denuded pulmonary artery (EC50 5.6 nM). In contrast, endothelin-3 produced only a small contraction (approximately 12% of maximum endothelin-1 response) at the highest concentration tested (1 microM). The ETB receptor-selective agonist, sarafotoxin S6c (0.1 nM to 1 microM) did not cause contraction of human pulmonary artery. Pretreatment of human pulmonary artery with BQ123 (1-10 microM), an ETA receptor-selective blocking drug, resulted in a concentration-dependent, surmountable antagonism of endothelin-1-induced contractions (apparent pKB 6.6-7.0). Schild analyses yielded a shallow slope (0.58), which was significantly less than unity and, consequently, the calculated pA2 (8.1) was greater than the individual pKB values. Pretreatment of human pulmonary artery with Ro 46-2005 (30 microM), a non-peptide. non-selective endothelin receptor-blocking drug, resulted in a surmountable antagonism of endothelin-1-induced contractions (apparent pKB 5.5). In conclusion, endothelin-1-induced contraction of human pulmonary artery appears to be mediated predominantly via ETA receptors, although the shallow Schild slope observed with BQ123 indicates possible receptor heterogeneity.

Characterization of three non-peptide endothelin receptor ligands using human cloned ETA and ETB receptors.

1. A number of putative endothelin (ET) receptor ligands were synthesized with a view to assessing their relative affinity for human recombinant ET receptors. 2. Human (h) and endothelin ETA and ETB receptor open reading frames were cloned by reverse transcription-polymerase chain reaction into the mammalian expression vector pcDNA1 and stable cell lines were created by transfection of Chinese hamster ovary cells. 3. Scatchard analyses of saturation isotherms for the specific binding of [125I]-endothelin-1 ([125I]-ET-1) to membranes, prepared from Chinese hamster ovary cells transfected with hETA or hETB receptors, yielded values for equilibrium dissociation constants (Kd) of 20.5 +/- 1.8 pM and 25.5 +/- 5.5 pM, respectively. Hill coefficients did not differ significantly from unity, suggesting binding to homogeneous, non-interacting receptor populations. 4. Pharmacological characterization of the transfected hETA and hETB receptors was undertaken by measuring the relative abilities of ETA and ETB receptor-selective peptide ligands to inhibit binding of [125I]ET-1. For interaction with hETA receptors, the relative order of potency was ET-1 > ET-3 = FR139317 = BQ123 >[Ala1,3,11,15]-ET-1 = sarafotoxin S6c (S6c). In contrast, the relative order of potency, at hETB receptors, was ET-1 = ET-3 = [Ala1,3,11,15]-ET-1 = S6c >> FR139317 = BQ123. 5. The novel non-peptide ligands, Ro 46-2005, SB 209670 and BMS 182874, were found to inhibit [125I]-ET-1 binding to human recombinant ETA and ETB receptors. At hETA receptors, the calculated pIC50 values were 6.7 (Ro 46-2005), 8.7 (SB 209670) and 5.8 (BMS 182874), while at hETB receptors, the corresponding pIC50 values were 6.8, 7.5 and <5, respectively.6. In conclusion, we have characterized the pharmacology of human cloned ETA and ETB receptors and used these in membrane binding assays to determine the affinity and selectivity of three structurally diverse non-peptide ET receptor ligands. SB 209670 is, to date, the highest affinity non-peptide ligand to be described for ET receptors. As such, it may prove to be a valuable tool in further examination of the physiological and pathophysiological roles of endothelins.

Human saphenous vein contains both endothelin ETA and ETB contractile receptors.

We have investigated the endothelin receptor subtypes mediating contraction in isolated preparations of human saphenous vein. Endothelin-1 (EC50: 17.8 nM), endothelin-3 (EC50: 82.3 nM) and the endothelin ETB receptor-selective agonists, [Ala1,3,11,15]endothelin-1 (EC50: 63 nM) and sarafotoxin S6c (EC50: 0.75 nM) all produced concentration-dependent contractions of human saphenous vein, although [Ala1,3,11,15]endothelin-1 and sarafotoxin S6c only produced a contraction in approximately 50% of the preparations tested. The endothelin ETA receptor antagonist, BQ123 (D-Val,Leu,D-Trp,D-Asp,Pro; 10 microM), antagonized endothelin-1-induced contractions with an estimated potency (pKB approximately 6.0) which was an order of magnitude lower than reported previously for non-human isolated vascular tissues from other species (pA2 values approximately 7.0). These data suggest that both endothelin ETA and endothelin ETB receptors can mediate vascular smooth muscle contraction in human saphenous vein.

Endothelin receptors mediating functional responses in human small arteries and veins.

1. In the present study, responses of human omental small arteries and veins to endothelin-1 and endothelin-3 were characterized by use of the ETB receptor selective agonist, sarafotoxin S6c, the ETA receptor antagonist, BQ123, the ETB receptor antagonist, IRL1038, the NO-synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 300 microM) and indomethacin (10 microM). 2. Small arteries (internal diameter 413 +/- 22 microns) and parallel running veins (646 +/- 35 microns) were mounted in a myograph under a normalized tension equivalent to 90% of a transmural pressure of 100 mmHg and 19 mmHg in vivo, respectively. 3. In small arteries and veins, endothelin-1 caused a concentration-dependent increase in wall tension (Emax = 3.90 +/- 0.56 mN mm-1 and 1.90 m +/- 0.32 mN mm-1 respectively, P < 0.05) and was equipotent (arteries: pD2 = 8.91 +/- 0.11; veins: pD2 = 8.63 +/- 0.08, NS). In endothelium intact arteries, L-NMMA significantly enhanced the sensitivity to endothelin-1 (pD2 control: 8.92 +/- 0.16; pD2 L-NMMA: 9.37 +/- 0.11; P < 0.05). L-NMMA did not affect the sensitivity of veins to endothelin-1. Indomethacin was without effect in arteries and veins. In veins, endothelin-3 was about a hundred times less potent than endothelin-1 and showed a biphasic response curve. Small arteries did not contract to endothelin-3. Neither small arteries nor veins contracted to sarafotoxin S6c. Furthermore, no relaxation to endothelin-1 or sarafotoxin S6c was seen in any precontracted vessels. 4. BQ123 (0.03-3 MicroM) produced a concentration-dependent rightward parallel displacement of the endothelin-l concentration-response curve in small arteries and veins yielding pA2 values of 7.09 and 7.48 respectively. The slope of the Schild plot in arteries and veins was 1.26 +/- 0.24 (NS from unity) and 0.61 +/- 0.13 (P <0.05 compared to unity) respectively. IRL1038 (3 MicroM) did not affect the potency of endothelin-1 in arteries and veins. In veins, the low sensitivity component (pD2 = 7.16 +/- 0.08) of the biphasic response curve to endothelin-3 was completely blocked by BQ123 (3 MicroM), whereas the high sensitivity component (pD2 = 8.66 +/- 0.08) was resistant to BQ123 (3 MicroM) and IRL1038 (3 MicroM).5. These results indicate that contractions of human small vessels to endothelin-l are predominantly mediated by ETA receptors and that nitric oxide modulates the response to endothelin-l in small arteries but not in veins. The different antagonistic potency of BQ123 against endothelin-l and the differential endothelin-1/endothelin-3 potency ratios in arteries and veins provide evidence for the hypothesis that ETA receptors in human small arteries are different from ETA receptors in human small veins. There is no evidence of contractions mediated by 'classical' ETB receptors in these vessels, but small veins appear to contain a functional non ETA/non ETB receptor with a high affinity for endothelin-3.

Cromakalim does not protect against skeletal muscle fatigue in an anaesthetized rat model of acute hindlimb ischaemia.

The effects of the potassium (K+) channel opener, cromakalim, on skeletal muscle performance were studied in a model of acute hindlimb ischaemia in the anaesthetized rat. Twitch contractions to direct electrical stimulation of the extensor digitorum and tibialis anterior skeletal muscles were recorded following administration of cromakalim (10-100 micrograms kg-1 i.v.) under normal and reduced whole limb blood flow. With normal blood flow, twitch responses (0.5 and 1 Hz) of the hindlimb skeletal muscles were sustained for > 30 min. Controlled adjustment of the perfusion pressure in the contralateral hindlimb to 45, 30 or 0 mm Hg by partial or total occlusion of the abdominal aorta produced a pressure-related fall in flow to the working hindlimb, and a corresponding increase in the rate of muscle fatigue. Cromakalim (10-100 micrograms kg-1 i.v.) produced a dose-dependent reduction in mean carotid arterial blood pressure, femoral arterial pressure and hindlimb vascular resistance together with an increase in iliac artery blood flow and heart rate, but did not attenuate skeletal muscle fatigue under the different conditions of muscle work and ischaemia employed. A similar profile was observed with levcromakalim (15 micrograms kg-1 i.v.), the active enantiomer of cromakalim. These results demonstrate that in the direct muscle-stimulated hindlimb of the anaesthetized rat, the K+ channel opener cromakalim does not prevent acute ischaemia-induced skeletal muscle fatigue. The previous observation that K+ channel openers improve nutritive blood flow in a chronic model of rat hindlimb ischaemia is not reflected by an improvement in muscle function in the present study.

The effect of endothelins on nitric oxide and prostacyclin production from human umbilical vein, porcine aorta and bovine carotid artery endothelial cells in culture.

1. This study has investigated the effects of the endothelin isopeptides, endothelin-1 (ET-1), ET-2 and ET-3 on the production of the endothelium-derived relaxing factors, nitric oxide (NO) and prostacyclin (PGI2) from primary cultures of endothelial cells obtained from human umbilical vein (HUVECS), porcine aorta (PAECS) and bovine carotid artery (BCAECS). 2. NO generation was assessed indirectly by measuring production of cyclic GMP and PGI2 formation was measured by radioimmunoassay of 6-keto PGF1 alpha. 3. In HUVECS, histamine (1 microM) increased cyclic GMP and 6-keto PGF1 alpha production by 12.6 +/- 2.0 and 4.9 +/- 0.7 fold respectively over the corresponding basal values. Haemoglobin (10 microM) and the NO synthase inhibitor NG-monomethyl-L-arginine (10 microM) significantly inhibited the increase in cyclic GMP formation in response to histamine but had no effect on 6-keto PGF1 alpha production. In contrast to histamine, the endothelin isopeptides (ET-1, ET-2 and ET-3; 0.01-1000 nM) produced no significant change in either cyclic GMP or 6-keto PGF1 alpha production in HUVECS. 4. In a separate series of experiments, ET-3 (0.01-1000 nM) also failed to produce any significant change in cyclic GMP or 6-keto PGF1 alpha production from primary cultures of PAECS and BCAECS. In contrast, bradykinin (0.1 microM) and sodium nitroprusside (1 mM) were used as positive control agents and increased cyclic GMP production in these cells. 5. In conclusion, the endothelin isopeptides do not release NO and PGI2 from primary cultures of HUVECS, PAECS and BCAECS. This suggests that endothelin receptors are either absent from these cells or are not coupled to NO or PGI2 production.

The effect of NG-nitro-L-arginine methyl ester upon basal blood flow and endothelium-dependent vasodilatation in the dog hindlimb.

1. The role played by the endothelium-derived relaxing factor (EDRF), nitric oxide (NO) in the regulation of blood flow to the skeletal muscle vasculature of the dog skinned hindlimb has been determined by examining the effects of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) upon (i) basal iliac artery blood flow, (ii) vasodilator responses to endothelium-dependent and -independent agonists and (iii) reactive hyperaemic responses to arterial occlusion. 2. L-NAME (0.1-3 mg min-1) infused directly into the iliac artery dose-dependently reduced basal iliac artery blood flow by a maximum of 48.6 +/- 6.9% (n = 4) and also increased mean systemic arterial blood pressure by 25.6 +/- 5.0 mmHg (n = 4) (at 3 mg min-1 L-NAME). 3. Over the same dose range, L-NAME also inhibited the peak vasodilator responses to intra-arterially administered, submaximal bolus doses of the endothelium-dependent agonists, bradykinin (3-300 ng) and acetylcholine (30-300 ng) by approximately 40%. In contrast, peak vasodilator responses to the endothelium-independent agonists, sodium azide (3-30 micrograms) and adenosine (0.3-1 mg), and peak reactive hyperaemic responses to arterial occlusion (60 s) were largely unaffected by L-NAME. 4. The dose-related effects of L-NAME on basal iliac artery blood flow, mean systemic arterial blood pressure and endothelium-dependent vasodilator responses were significantly attenuated by pretreatment with L-arginine (100 mg min-1) followed by co-infusion of L-arginine (100 mg min-1) with L-NAME. 5. In conclusion, these data suggest that NO plays some role in regulating basal blood flow and in mediating the vasodilator responses to the endothelium-dependent agonists bradykinin and acetylcholine in the skeletal muscle vasculature of the dog hindlimb. The substantial component (~60%) of the peak vasodilator responses to bradykinin and acetylcholine, unaffected by L-NAME, may be independent of NO, or be mediated by an alternative EDRF-dependent but L-NAME-insensitive mechanism.

Human placental membranes contain predominantly ETB receptors.

The endothelin (ET) receptors on human placental membranes (HPMs), coupled to fluomicrospheres, have been characterized by examining the binding of 125I-ET-1 in a scintillation proximity assay (SPA). Specific binding of 125I-ET-1 was potently inhibited by ET-1 (IC50: 80 pM), ET-3 (IC50: 170 pM), and the ETB receptor-selective agonists sarafotoxin S6c (S6c; IC50: 210 pM) and alanine1,3,11,15-ET-1 (4-Ala-ET-1; IC50: 3.56 nM). In contrast, the ETA receptor-selective antagonist BQ123 (D-Val-Leu-D-Trp-D-Asp-Pro) only weakly (28% at 10 microM) inhibited 125I-ET-1 binding. In addition, the inhibition curves for ET-3 and 4-Ala-ET-1 were shallow, with slopes less than unity, indicating binding-site heterogeneity. In keeping with this finding, the presence of a small population of ETA receptors was confirmed by the ability of BQ123 (1 microM) to reduce the maximum binding capacity of the HPMs for 125I-ET-1 by approximately 17%, without affecting the affinity for the radioligand. In conclusion, these results suggest that the HPM-SPA system contains predominantly (approximately 80%) ETB receptors, with a small ETA receptor population. These findings should be taken into account when this assay system is used to identify novel endothelin receptor ligands.

Endothelin ETA and ETB receptors mediate vascular smooth-muscle contraction.

Endothelin (ET) ETA receptors on vascular smooth muscle are believed to mediate the vasoconstrictor effects of ET isopeptides, and ETB receptors on the endothelium are thought to mediate the vasodilator effects. This study has investigated the receptors mediating endothelin-induced contraction of isolated ring preparations of rat thoracic aorta (RTA) and rabbit carotid artery (RCA), pulmonary artery (RPA), and jugular vein (RJV). In RTA and RCA, ET-1 (EC50 4.5 and 5.2 nM, respectively) was 82- and 108-fold, respectively, more potent than ET-3, whereas the ETB receptor-selective agonists sarafotoxin S6c (S6c) and Ala1,3,11,15-ET-1 (4-Ala-ET-1) were without effect up to > or = 1 microM. In contrast, in RPA and RJV, ET-1 (EC50 3.1 and 0.7 nM, respectively) and ET-3 (EC50 4.4 and 0.9 nM, respectively) were equipotent, and 4-Ala-ET-1 (EC50 10.7 and 2.1, respectively) and S6c (EC50 0.4 and 0.1 nM, respectively) were potent contractile agonists. The ETA receptor antagonist BQ123 (D-Val-Leu-D-Trp-D-Asp-Pro) competitively antagonized the effects of ET-1 in RTA and RCA (pA2 values 6.9 +/- 0.1 and 6.8 +/- 0.2, respectively) but did not antagonize (at 10 microM) contractions to ET-1, ET-3, or 4-Ala-ET-1 in RPA and RJV. In conclusion, contraction of vascular smooth muscle by endothelins can be mediated by both ETA and ETB receptors.

Endothelin ETA and ETB receptors mediate vascular smooth muscle contraction.

1. We have investigated the receptors mediating endothelin-induced contraction of rabbit isolated jugular vein (RJV) and rat isolated thoracic aorta (RTA). 2. Endothelin-1 (ET-1) and endothelin-3 (ET-3) contracted RJV preparations with similar potency (EC50 values approximately 1 nM), whereas, ET-1 (EC50:4.5 nM) was approximately 80 fold more potent than ET-3 in contracting RTA. In addition, the ETB receptor-selective agonist [Ala1,3,11,15]ET-1 contracted RJV (EC50:2.1 nM) but not RTA. 3. The ETA receptor antagonist, BQ123, competitively antagonized (pA2 6.93) the contraction of RTA produced by ET-1, but had no effect (at 10 microM) on the contractile effects of either ET-1, ET-3 or [Ala1,3,11,15]ET-1 in RJV. 4. These data suggest that both ETA and ETB receptors can mediate vascular smooth muscle contraction.

Fasting in the rat does not induce hyperfibrinogenaemia.

The effects of fasting in the rat on the plasma fibrinogen concentration have been investigated. Fasting for 24-48 hr produced the expected sustained increase (4-5-fold) in the concentrations in the plasma of non-esterified fatty acids, but no accompanying increase in that of fibrinogen was detected.

Thromboxane (Tx) A2 receptor blockade and TxA2 synthase inhibition alone and in combination: comparison of anti-aggregatory efficacy in human platelets.

1. The present study has compared the relative anti-aggregatory effect of various compounds which interfere with thromboxane (Tx) A2-dependent aggregation of human platelets in whole blood in vitro. These included the cyclo-oxygenase inhibitor aspirin, the TxA2 synthase inhibitor dazoxiben, the TxA2 (TP-) receptor blocking drug GR32191 and two compounds, R.68070 ((E)-5-[[[(3-pyridinyl) [3-(trifluoromethyl)phenyl]-methylen] amino]oxy] pentanoic acid) and CV-4151 [E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid), which possess both TP-receptor blocking and TxA2 synthase inhibitory activities in the same molecule. 2. GR32191, R.68070 and CV-4151 all antagonized aggregation to the TxA2 mimetic U-46619, with pA2 values of approximately 8.2, 5.4 and 4.8 respectively. This effect was specific, platelet aggregation induced by adenosine 5'-diphosphate (ADP) being unaffected by concentrations up to 10, 1000 and 300 microM respectively. In contrast, neither aspirin nor dazoxiben exhibited any measurable TP-receptor blocking activity. 3. The rank order of potency (pIC50) for inhibition of TxA2 formation in serum was R.68070 (7.4) greater than CV-4151 (6.9) greater than dazoxiben (5.7) greater than aspirin (5.3). In addition, all four drugs abolished collagen-induced platelet TxA2 formation. In contrast, GR32191 produced no consistent inhibition of TxA2 formation in either system up to concentrations of 10-30 microM. 4. The specificity of R.68070, CV-4151 and dazoxiben for TxA2 synthase was indicated by their ability to increase serum levels of prostaglandin E2 (PGE2) and PGD2 in parallel with decreases in TxA2 formation. This profile was not observed with aspirin or GR32191. However, high concentrations of R.68070 (100,microM) and CV-4151 (1000 microM) necessary for maximum TP-receptor blocking activity, produced substantially smaller increases in PGE2 and PGD2, consistent with an aspirin-like effect of these compounds upon cyclo-oxygenase. With dazoxiben (1000 microM), PGE2 and PGD2 levels remained elevated. 5. Aspirin inhibited collagen-induced platelet aggregation, the effect correlating with inhibition of TxA2 formation. Dazoxiben, whilst also achieving maximal inhibition of TxA2 formation, produced significantly less inhibition of aggregation than aspirin. In contrast, GR32191 (0.1-1O microM), at concentrations specific for TP-receptor blockade, produced a significantly greater antagonism of collagen-induced platelet aggregation than aspirin. This additional effect of GR32191 was absent in platelets pretreated with aspirin, indicating the probable involvement of an endogenous anti-aggregatory cyclo-oxygenase product in response to collagen stimulation. 6. R.68070 and CV-4151 also inhibited collagen-induced aggregation, with very high concentrations of R.68070 (100 microM) producing an effect equivalent to that of GR32191. 7. In contrast, the combination of GR32191 with either dazoxiben, R.68070 or CV-4151, at concentrations specific for TxA2 synthase, produced a synergistic inhibitory effect upon collagen-induced platelet aggregation which was greater than that achieved with either aspirin or any of the compounds used alone. Pretreatment of platelets with aspirin reversed this synergistic effect, consistent with it being dependent upon the formation and action of anti-aggregatory prostaglandins. 8. In conclusion, the present study has confirmed the superior platelet inhibitory profile of a combination of a TP-receptor blocking drug and a TxA2 synthase inhibitor to that of either activity alone. However, the maximum inhibitory effect of the currently available compounds, R.68070 and CV4151, which possess both activities in the same molecule, appears to be no greater in vitro than that obtained with the potent TP-receptor blocking drug, GR32191. This most probably reflects the inhibition by R.68070 and CV-4151 of platelet cyclo-oxygenase at the concentrations required for effective TP-receptor blockade which results in a reduction in the formation of anti-aggregatory prostanoids.