2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid and dazmegrel

The effect of five thromboxane-synthase inhibitors (UK-37248, UK-38485, UK-34787, CGS-13080 and OKY-1581) on arachidonic acid-induced platelet aggregation has been studied in vitro on platelets from 30 different healthy volunteers. The sensitivity of their platelets to adenylate cyclase stimulators or to dibutyryl cyclic AMP has been evaluated contemporarily. In 4 of the 30 volunteers tested no inhibition of platelet aggregation was obtained with any of the five thromboxane synthase inhibitors: these subjects were defined nonresponders; in 13 volunteers inhibition was observed with all the five drugs (responders). Significantly higher amounts of prostaglandin (PG)D2, prostacyclin and adenosine were required to suppress arachidonic acid-induced aggregation of platelets from nonresponders in vitro. No differences were instead observed between responders and nonresponders concerning platelet sensitivity to forskolin or dibutyryl cyclic AMP. The cyclic AMP rise obtained with exogenous prostacyclin was lower in platelets from nonresponders than in those from responders. PGE2 added in vitro to platelets from nonresponders exerted always a proaggregatory effect whereas this PG was antiaggregatory in most of the nonresponders. PGE2 blunted the antiaggregatory activity of PGD2 and limited the cyclic AMP increase induced by PGD2 in all the subjects tested. These data indicate that the unequal functional response of platelets from different subjects to thromboxane synthase inhibition depends essentially on adenylate cyclase function: a relative insensitivity of this enzyme to activating stimuli and the accumulation of substances (PGE2, PG endoperoxides, etc.) reducing the activity of adenylate cyclase may lead to continued platelet activation in some subjects despite the suppression of the synthesis of thromboxane A2.

Topics: Adenylyl Cyclases; Adult; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Dinoprostone; Eicosanoic Acids; Enzyme Activation; Female; Humans; Imidazoles; Indoles; Male; Methacrylates; Middle Aged; Platelet Aggregation; Prostaglandins E; Pyridines; Thromboxane-A Synthase

In general the effects of thromboxane A2(TXA2) on renal function are opposite those produced by other prostanoids. TXA2 synthase inhibitors decrease the biosynthesis of TXA2 and may increase the production of other prostanoids by causing endoperoxide shunting. Therefore, in situations of increased kidney arachidonate mobilization, inhibition of renal TXA2 synthase might alter renal function by reducing TXA2 production and/or increasing prostaglandin (PG) biosynthesis. This hypothesis was tested by comparing the changes in renal function induced by suprarenal aortic constriction in anesthetized dogs pretreated with either a TXA2 synthase inhibitor (UK38,485; n = 7 or OKY1581; n = 7) or vehicle (0.1 M Na2CO3; n = 9). Several renal function parameters were compared in control versus treated animals by analysis of variance. Neither UK38,485 (1 mg/kg, i.v.) nor OKY1581 (10 mg/kg, i.v.) significantly altered renal artery hypotension-induced changes in mean arterial blood pressure, heart rate, renal blood flow, renal vascular resistance, glomerular filtration, filtration fraction, urine flow rate, sodium excretion rate, fractional sodium excretion, potassium excretion, or fractional potassium excretion. However, both UK38,485 and OKY1581 seemed to attenuate the increase in renal renin secretion rate induced by suprarenal aortic constriction. We conclude that acute administration of TXA2 synthase inhibitors does not modify acute renal artery hypotension-induced changes in either electrolyte excretion or renal hemodynamics. However, acute administration of TXA2 inhibitors attenuates suprarenal aortic constriction-induced increases in renin release in anesthetized dogs by unknown mechanisms.

Topics: Acrylates; Animals; Arachidonic Acids; Dogs; Electrolytes; Female; Hemodynamics; Hypotension; Imidazoles; Kidney; Male; Methacrylates; Renin; Thromboxane-A Synthase

We examined the possibility that glomerular prostaglandin E2 (PGE2) regulates the action of angiotensin II (ANG II) on mesangial contraction and filtration surface area. Using isolated rat glomeruli we indirectly assessed mesangial contraction and filtration surface area through measurements of glomerular planar surface area (GPSA) by image-analysis microscopy. ANG II reduced GPSA by approximately 20% in human and rat glomeruli, with threshold concentrations of 1 X 10(-13) M and maximum effect at 5 X 10(-11) M ANG II. Inhibition of glomerular PG synthesis with indomethacin or meclofenamate potentiated the threshold response of ANG II to reduce GPSA. Arachidonic acid (5 micrograms/ml) blunted both the threshold and the maximum responses of GPSA to ANG II. PGE2, 10(-8) and 10(-9) M, also decreased glomerular contraction to ANG II. Endoperoxide (EP) analogues decreased GPSA and EP 045, a thromboxane A2 (TXA2) receptor blocker, eliminated the contractile responses of glomeruli to the EP analogues. Authentic TXA2, synthesized from sheep platelet microsomes, also reduced GPSA. We conclude that glomerular products of arachidonate cyclooxygenation may either relax or contract the mesangium, thereby preserving or reducing filtration surface area. PGE2 exerts protective actions to reduce the mesangial contraction of ANG II, primarily through postreceptor effects. TXA2 may decrease glomerular filtration rate in certain diseases through direct actions on the mesangium.

Topics: Angiotensin II; Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Cyclooxygenase Inhibitors; Dinoprostone; Eicosanoic Acids; Humans; Imidazoles; Kidney Glomerulus; Methacrylates; Microsomes; Prostaglandins E; Rats; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxane B2

Twenty-four hours of complete unilateral ureteral obstruction (UUO) produces intense renal vasconstriction in the rat even after release of obstruction. In the ex vivo perfused hydronephrotic rabbit kidney, bradykinin stimulates increased production of the vasoconstrictor autocoid thromboxane. In the present study, we measured basal and bradykinin-stimulated thromboxane and prostaglandin E2 production by UUO and contralateral rat kidneys perfused ex vivo. Furthermore, we evaluated thromboxane synthetase inhibition by imidazole and by two of its substituted derivatives, UK 37248 and UK 38485, in vitro. We compared these in vitro findings with in vivo measurements of renal hemodynamics and excretory function before and after the intrarenal artery administration of thromboxane synthetase inhibitors. Both basal and bradykinin-stimulated thromboxane and prostaglandin E2 production were significantly increased in hydronephrotic kidneys. Imidazole and its substituted congeners were effective inhibitors of bradykinin-stimulated thromboxane B2 production in vitro. However, the substituted imidazoles were more potent, more efficacious, and more selective for thromboxane synthetase inhibition than the parent compound. In vivo, administration of imidazole into the renal artery of the UUO kidney improved function slightly, whereas administration of UK 37248 or UK 38485 doubled renal blood flow and excretory function but did not restore them to normal. We conclude that the hydronephrotic rat kidney produces increased amounts of the vasoconstrictor eicosanoid thromboxane and that thromboxane is an important mediator of vasoconstriction in this model of disease.

Topics: Animals; Dinoprostone; Dose-Response Relationship, Drug; Hydronephrosis; Imidazoles; Methacrylates; Prostaglandins E; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxane-A Synthase; Ureteral Obstruction

Eicosanoid metabolites may play a role in the pathophysiology of nephrotoxic serum nephritis (NSN), a model of immune renal disease. Our purpose was to determine the relative importance of vasoconstrictor [thromboxane A2 (TX)A2] and vasodilator [prostaglandin E2 (PG)E2] eicosanoids as mediators of hemodynamic and renal functional changes. Glomerular filtration rate (GFR; inulin clearance), and renal plasma flow (RPF; para-aminohippurate clearance/extraction) were measured in rats on day 1 and day 14 of NSN. Specific inhibitors of TXA2 synthesis and receptor binding, and cyclooxygenase inhibitors were used to determine the relative roles of TXA2 and PGE2. In vitro glomerular production of radioimmunoassayable PGE2 and TXB2 were measured after clearances. At 1 day GFR is decreased compared to control, 1.9 +/- 0.2 vs. 2.6 +/- 0.2 ml/min. RPF is numerically increased, 10.0 +/- 1.0 vs. 7.0 +/- 0.6 ml/min. By 14 days GFR is normal, 2.2 +/- 0.2 ml/min, as a consequence of significantly increased RPF, 11.7 +/- 1.0 ml/min. Glomerular production of PGE2 and TXB2 was increased 11- and 15-fold respectively at both 1 and 14 days. Pretreatment with OKY-1581, or acute treatment with UK-38,485, both inhibitors of TXA2 synthesis, had no effect on GFR or RPF in NSN rats. Addition of EP 092, a TXA2 receptor antagonist was similarly without effect. In contrast, acute treatment with the cyclooxygenase inhibitors meclofenamate or indomethacin resulted in a 50% decrease in both RPF and GFR; these inhibitors had no effect in control rats. We conclude that PGE2 (vasodilator) is of greater relative significance than TXA2 (vasoconstrictor) with respect to renal function in the NSN rat at 1 and 14 days.

Topics: Animals; Dinoprostone; Glomerular Filtration Rate; Glomerulonephritis; Hemodynamics; Imidazoles; Kidney; Male; Methacrylates; Prostaglandins E; Rabbits; Rats; Rats, Inbred Strains; Renal Circulation; Thromboxane A2; Thromboxanes

The effect of inhibiting endogenous brain thromboxane (TXB2) on pentylenetetrazole-induced seizures was studied using the thromboxane synthetase inhibitors OKY-1581 (20 mg/kg) and UK 38,485 (50 mg/kg). Both compounds selectively decreased (greater than 90%) TXB2 production in brain measured after 2 min of convulsive activity but had no effect on brain PGE2, PGF2 alpha, or 6-keto-PGF1 alpha. No effect of these agents on the tonic seizure threshold was observed, whereas 10 mg/kg ip indomethacin, an agent which inhibits both TXB2 and prostaglandin production, reduced the tonic seizure threshold from 78 +/- 2.6 mg/kg in controls to 62 +/- 3.7 mg/kg. Thus, this study concludes that the availability of TXB2 with convulsant activity is unlikely to be a factor in altering tonic seizure activity observed with indomethacin.

Topics: Animals; Brain; Brain Chemistry; Female; Imidazoles; Indomethacin; Methacrylates; Mice; Pentylenetetrazole; Prostaglandins; Seizures; Thromboxane B2; Thromboxanes

The purpose of this investigation was to determine the effects of thromboxane synthase inhibition on vascular responsiveness. To achieve this goal, the effects of thromboxane synthase inhibitors on mesenteric vascular responses to sympathetic nerve stimulation, norepinephrine, and angiotensin II were determined in vivo. In normotensive rats, chronic treatment with the thromboxane synthase inhibitor, UK38,485 (100 mg/kg X d X 7 d), attenuated vascular responses to nerve stimulation and angiotensin II, but not to norepinephrine. Indomethacin treatment (5 mg/kg X three doses) did not attenuate vascular responses, but did prevent chronic UK38,485 administration from attenuating vascular reactivity. A single dose of UK38,485 (100 mg/kg) did not modify vascular responses to nerve stimulation or angiotensin II, even though platelet thromboxane synthase was inhibited completely. In spontaneously hypertensive rats, chronic administration (100 mg/kg X d X 7 d) of either UK38,485, OKY1581, or U-63557A (three structurally distinct thromboxane synthase inhibitors) attenuated vascular responses to nerve stimulation and angiotensin II. Only U-63557A suppressed responses to norepinephrine. Chronic treatment with UK38,485 or U-63557A did not influence vascular reactivity in hypertensive rats treated with indomethacin. Also, chronic administration of lower doses of UK38,485 or U-63557A (30 mg/kg X d X 7 d) did not affect vascular responsiveness in hypertensive rats, despite complete blockade of platelet thromboxane synthase. These data indicate that chronic administration of high doses of thromboxane synthase inhibitors attenuates vascular responses to sympathetic nerve stimulation and angiotensin II, but not usually to norepinephrine. This action may be mediated by endoperoxide shunting within the blood vessel wall.

Topics: Acrylates; Angiotensin II; Animals; Aorta, Abdominal; Benzofurans; Blood Platelets; Blood Pressure; Electric Stimulation; Imidazoles; Methacrylates; Norepinephrine; Rats; Thromboxane B2; Thromboxane-A Synthase; Vascular Resistance