sq-29548 and Hypertension--Pulmonary

We sought to determine whether the intrinsic pulmonary hypertensive activity of the purported thromboxane A2/prostanoid (TP) receptor antagonist, daltroban, was mediated by TP receptors, using the high efficacy TP receptor agonist, U-46619, and the silent TP receptor antagonist, SQ 29,548. In pentobarbitone-anesthetized, open-chest rats (n = 4-10 per group), non-cumulative injections of U-46619, dose-dependently increased mean pulmonary arterial pressure (MPAP) with an ED50 (geometric mean with 95% confidence limits in parentheses) of 1.4 (1.1-2.3) microg/kg i.v.. Daltroban increased MPAP in a bell-shaped manner, with an apparent ED50 [29 (21-35) microg/kg i.v.] being 21 fold less potent than that of U-46619. The maximal pulmonary hypertensive responses evoked by daltroban represented about half those induced by U-46619 (25.4+/-1.0 vs. 12.7+/-2 mmHg; P < 0.05 between groups). The TP receptor antagonist SQ 29,548 fully antagonized increases in MPAP evoked by equihypertensive doses of U-46619 (1.25 microg/kg) or daltroban (80 microg/kg). Further experiments were carried out to determine whether daltroban antagonized the pulmonary hypertensive responses evoked by the high efficacy agonist, U-46619, or by itself as receptor theory would predict for a partial agonist. Daltroban (10-2500 microg/kg) antagonized, although not fully, U-46619 (20 microg/kg)-evoked pulmonary hypertensive responses, since prominent intrinsic pulmonary hypertensive effects of daltroban were observed in the same range of doses. Furthermore, in contrast to U-46619 (1.25 microg/kg), daltroban (80 microg/kg) failed to evoke a second pulmonary hypertensive response following a previous injection, as would be expected for a partial agonist. Collectively, the results strongly suggest that daltroban behaves as a partial agonist at TP receptors in the pulmonary vascular bed of the rat in vivo.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypertension, Pulmonary; Male; Phenylacetates; Rats; Receptors, Thromboxane; Sulfonamides; Thromboxane A2

1. We analysed the pulmonary hypertensive effects of the F2-isoprostane derivative, 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), in comparison with those of the high efficacy thromboxane A2/prostanoid (TP) receptor agonist, U-46619, in pentobarbitone-anaesthetized, open-chest rats (n=4-15 per group). 2. 8-iso-PGF2alpha produced dose-dependent increases in mean pulmonary arterial pressure, with an ED50 of 39.0 (31.4-50.6) microg kg(-1), i.v. (geometric mean with 95% confidence limits in parentheses) compared to 1.4 (1.1-2.3) microg kg(-1), i.v., for U-46619. The maximum responses evoked by U-46619 and 8-iso-PGF2alpha were not statistically significantly different (21.0+/-1.0 and 25.8+/-1.9 mmHg at 10 microg kg(-1) of U-46619 and 630 microg kg(-1) of 8-iso-PGF2alpha, respectively). 3. The TP receptor antagonist, SQ 29,548 (0.63 mg kg(-1), i.v. + 0.63 mg kg(-1) h(-1)) fully antagonised both U-46619 and 8-iso-PGF2alpha-induced pulmonary hypertensive responses. 4. Further experiments were carried out to determine whether 8-iso-PGF2alpha antagonized the pulmonary hypertensive responses evoked by U-46619, or those induced by itself, as would be predicted for a partial agonist. However, ED10 or ED25 doses of 8-iso-PGF2alpha (10 or 20 microg kg(-1), i.v.) failed to reduce the pulmonary hypertensive responses induced either by U-46619 or by itself. 5. The data suggest that in the pulmonary vascular bed of the rat, 8-iso-PGF2alpha acts as an agonist of high intrinsic activity at SQ 29,548-sensitive (probably TP) receptors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Dinoprost; Dose-Response Relationship, Drug; F2-Isoprostanes; Fatty Acids, Unsaturated; Hydrazines; Hypertension, Pulmonary; Infusions, Intravenous; Male; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Vasoconstrictor Agents

We investigated whether the physiological effects of prostaglandin B2 (PGB2) in the pulmonary circulation might be due to stimulation of thromboxane A2-prostaglandin H2 (TxA2/PGH2) receptors. In seven anesthetized rabbits, intravenous infusion of PGB2 (5.0 micrograms/kg) caused pulmonary hypertension as evidenced by increases in right ventricular systolic blood pressure. The magnitude of the pulmonary hypertension was comparable to that observed after infusion of the TxA2 mimetic U-46619 at a significantly lower dose (0.5 micrograms/kg), indicating that the effects of PGB2 in the intact animal are similar to TxA2 but less potent. Additionally, the TxA2/PGH2-receptor antagonist SQ-29548 blocked the pulmonary blood pressure responses elicited by PGB2. Receptor-binding studies using the TxA2 receptor ligand [3H]SQ-29548 indicated that PGB2 was a potent competitor for TxA2/PGH2 receptor binding. In agreement with the results from the intact animal, however, the efficacy of inhibition with PGB2 was significantly less than that measured for the TxA2 agonist U-46619. All of these results are consistent with the hypothesis that the physiological effects of PGB2 are mediated by stimulation of TxA2/PGH2 receptors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypertension, Pulmonary; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins B; Prostaglandins H; Pulmonary Circulation; Rabbits; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2

Losartan is a potent, nonpeptide, angiotensin II type 1 receptor antagonist. We investigated the possibility that losartan may interact with thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptors. We measured changes in mean systemic (MS) and pulmonary (MP) arterial pressures (AP) as well as in hematocrit induced by the TxA2 analog, U-46619 (9, 11-dideoxy-9 alpha, 11 alpha-methanoepoxy PGF2 alpha, during pharmacological blockade of either TxA2/PGH2 receptors or the renin-angiotensin system. In anesthetized, open chest rats, U-46619 dose dependently increased MPAP whereas MSAP presented a biphasic evolution. The U-446619 (1.25 micrograms/kg)-increased MPAP (52.4 +/- 12.1%; P < .005) was dose dependently inhibited by the TxA2/PGH2 receptor antagonist, SQ 29,548 ([1S-[1 alpha,2 alpha (5z),3 alpha, 4 alpha]]-7- [3-[[2-[(phenylamino)-carbonyl)hydrazino]methyl]-7-oxabiacyclo [2.2.1]hept-2-yl]-5-heptenoic acid) (10.6 +/- 2 and 2.1 +/- 1.4% at 0.63 and 2.5 mg/kg, respectively; both P < .05 vs. U-46619 in control rats). Losartan dose dependently reduced this increase (45.5 +/- 5.8 and 11.9 +/- 1.8% at 2.5 and 10 mg/kg, respectively; P = N.S. and P < .05 vs. U-46619 in control rats) whereas chronic suppression of angiotensin II generation by the converting-enzyme inhibitor enalapril (10 mg/kg/day per os for 4-5 days) did not affect this response. None of these treatments significantly reduced the U-46619-associated increase in MSAP. Moreover, the angiotensin II-evoked increases in MSAP and MPAP were suppressed by pretreatment with losartan but not with SQ 29,548.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Enalapril; Fatty Acids, Unsaturated; Hematocrit; Hydrazines; Hypertension, Pulmonary; Imidazoles; Losartan; Male; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Tetrazoles; Thromboxane A2

Exposure of isolated perfused rabbit lungs (IPL) to ischemia-reperfusion causes a transient increase in pulmonary arterial (PA) pressure at the onset of reperfusion. Because thromboxane A2 (TxA2) is a potent vasoconstrictor, we hypothesized that it may contribute to the ischemia-reperfusion-induced pressor response. To evaluate this hypothesis, we exposed IPL perfused with a cell-free solution to 40 min of warm ischemia followed by reperfusion and measured perfusate immunoreactive thromboxane B2 (iTxB2) and 6-ketoprostaglandin F1 alpha (i6-keto-PGF1 alpha). We observed that ischemia-reperfusion IPL compared with controls had an increase in PA pressure (40.2 +/- 4.8 vs. 9.3 +/- 0.3 mmHg, P < 0.05), lung edema (29.3 +/- 6.3 vs. -0.2 +/- 0.2 g, P < 0.05), iTxB2 perfusate levels (155 +/- 22 vs. < 50 pg/ml, P < 0.05), and i6-keto-PGF1 alpha (436 +/- 33 vs. 61 +/- 16 pg/ml, P < 0.05). In ischemia-reperfusion IPL, infusion of SQ 29548 (10(-6) M), a specific TxA2/prostaglandin H2 receptor antagonist, attenuated the PA pressor response and the degree of edema. We conclude that pulmonary hypertension associated with ischemia-reperfusion results in part from pulmonary release of TxA2. Furthermore, TxA2 directly through membrane effects or indirectly through hydrostatic mechanisms increases the severity of ischemia-reperfusion-induced lung edema.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypertension, Pulmonary; In Vitro Techniques; Ischemia; Lung; Organ Size; Pulmonary Circulation; Pulmonary Edema; Rabbits; Radioimmunoassay; Receptors, Thromboxane; Reperfusion Injury; Thromboxane A2; Thromboxane B2; Thromboxanes; Vasoconstriction

Lipid infusions can interfere with oxygenation and cause pulmonary hypertension. We studied the effects of iv lipid infusions on pulmonary hemodynamics and oxygen transport to investigate whether the vasoconstrictor, thromboxane (Tx), mediates resulting changes. Newborn piglets were instrumented to observe cardiopulmonary hemodynamics, blood gases, and oxygen contents. Oxygen delivery (DO2), oxygen consumption, and extraction ratios were calculated. All piglets received continuous 1-g/kg.h iv lipid infusions. After one hour, and as the lipid infusion continued, six piglets were given placebo (PL) and six others were given the Tx antagonist SQ 29548 (SQ). Pulmonary vasoconstriction occurred in both groups after one hour of lipid infusion (pulmonary artery pressure [PAP] 28 +/- 6 mm Hg in the PL piglets and to 31 +/- 13 mm Hg in the SQ piglets. After intervention, PAP remained elevated only in the PL group (32 +/- 2 vs. 23 +/- 8 mm Hg) (p less than .02). PaO2 and DO2 fell significantly with iv lipid and improved after intervention in SQ animals only (p less than .02). TxB2 increased in all animals with iv lipid (276 +/- 295 to 1481 +/- 716 in PL; 228 +/- 110 to 1402 +/- 580 in SQ), and fell with intervention in the SQ animals only (2632 +/- 1236 vs. 964 +/- 305, respectively; p less than .02). In conclusion, interference with DO2 associated with pulmonary hypertension and increased TxB2 occurred with iv lipid infusion in piglets. Tx antagonism ameliorated these changes.

Topics: Animals; Animals, Newborn; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fat Emulsions, Intravenous; Fatty Acids, Unsaturated; Hemodynamics; Hydrazines; Hypertension, Pulmonary; Lung; Oxygen Consumption; Pulmonary Artery; Swine; Thromboxane B2; Thromboxanes; Vascular Resistance; Vasodilation

The effects of two selective thromboxane (Tx) A2 antagonists (SQ 29,548 and SQ 28,668) on endotoxin-induced pulmonary hypertension were determined in anesthetized pigs. SQ 29,548 (10 micrograms/kg/min, i.v., n = 6) or vehicle (n = 7) was infused from 15 min before until 60 min after an intravenous infusion of Salmonella enteritidis endotoxin (1.0 microgram/kg). Within 20 min, vehicle-treated animals developed an acute 350 +/- 25% increase in pulmonary vascular resistance (PVR) with a 43% survival rate. In the presence of SQ 29,548 this initial pulmonary vasoconstriction was absent and all animals survived. However, a delayed increase in PVR of 58 +/- 20% was detected. The primary manifestation of the increase in PVR was an increase in pulmonary arterial pressure. In a similar preparation, septicemia was produced by Escherichia coli endotoxin (0.5 microgram/kg, i.v.) and SQ 28,668 (3, 10, 30 or 100 micrograms/kg/min, i.v., n = 5-6 per dose level) and vehicle (n = 6) treatments were compared. SQ 28,668 doses of 30 and 100 micrograms/kg/min mitigated the early, but not late, increases in PVR. These data demonstrate that endotoxemia in pigs produces an initial TxA2-receptor-dependent vasoconstriction and also a more slowly developing pulmonary hypertension which is probably due to other mediators.

Topics: Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Endotoxins; Escherichia coli; Fatty Acids, Unsaturated; Female; Hydrazines; Hypertension, Pulmonary; Male; Receptors, Prostaglandin; Receptors, Thromboxane; Swine; Thromboxane A2

Thromboxane A2 has been implicated as a mediator of cardiorespiratory dysfunction in sepsis. This study evaluated whether or not thromboxane A2 was necessary or sufficient for these adverse effects to occur during bacteremia. Fourteen adult swine under barbiturate anesthesia and breathing room air were monitored with arterial and pulmonary artery catheters. Animals were studied for 4 hours in three groups: group I, graded infusion of 10(9)/ml Aeromonas hydrophila; group II, Aeromonas hydrophila infusion plus SQ 29,548 (thromboxane A2 antagonist); and group III, U46619 (thromboxane A2 agonist) infusion in normal swine to pulmonary artery pressures observed in group I. Hemodynamic parameters, arterial and mixed venous blood gases, and plasma thromboxane B2 and prostaglandin 6-keto-F1 were measured. At sacrifice after 4 hours, wet-to-dry lung weights were calculated. Results indicated that thromboxane A2 was necessary and sufficient for the development of pulmonary hypertension and impaired alveolar-capillary oxygen diffusion in graded bacteremia. It was necessary but not sufficient for increased lung water to occur and sufficient but not necessary for decreased cardiac index and stroke volume index. Thromboxane A2 was neither sufficient nor necessary to the pathophysiology of systemic hypotension during graded bacteremia. Plasma prostaglandin 6-keto-F1 levels were increased in hypotensive animals with sepsis, suggesting its involvement in hypotension during sepsis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aeromonas; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Capillary Permeability; Cardiac Output; Epoprostenol; Fatty Acids, Unsaturated; Hemodynamics; Hydrazines; Hypertension, Pulmonary; Hypoxia; Male; Prostaglandin Endoperoxides, Synthetic; Pulmonary Gas Exchange; Sepsis; Shock, Septic; Swine; Thromboxane A2; Thromboxane B2