FR 139317

The effects of the endothelin ETA receptor antagonist, FR 139317, on infarct size in a rabbit model of acute myocardial ischaemia and reperfusion.[Pubmed:8032665]

Br J Pharmacol. 1994 May;112(1):75-80.

1. The effects were investigated of the ETA receptor antagonist, FR 139317, on endothelin-1 (ET-1)-induced coronary vasoconstriction in the isolated perfused heart of the rabbit. In addition, this study examined whether FR 139317 reduced infarct size in a rabbit model of coronary artery occlusion and reperfusion. 2. In the rabbit isolated perfused heart, ET-1 (1-100 pmol) elicited a dose-dependent increase in coronary perfusion pressure (CPP). For example, 30 pmol ET-1 caused CPP to rise by 22 +/- 8 mmHg and 100 pmol ET-1 by 47 +/- 10 mmHg (n = 8). Infusion of FR 139317 (1 microM) significantly attenuated the increase in CPP caused by ET-1 (30 pmol: 3 +/- 1 mmHg, 100 pmol: 8 +/- 2 mmHg; n = 8). 3. In the anaesthetized rabbit, infarct size (expressed as a percentage of the area at risk) after 45 or 60 min of coronary artery occlusion followed by 2 h of reperfusion was 47 +/- 6% (n = 6) and 55 +/- 7% (n = 5), respectively. A continuous infusion of FR 139317 (0.2 mg kg-1 min-1 preceded by a loading dose of 1.0 mg kg-1, i.v.; n = 5-6) had no effect on the extent of the myocardial infarct size (45 min: 47 +/- 6%; 60 min: 49 +/- 7%). Even a three-times higher dose (0.6 mg kg-1 min-1 preceded by a loading dose of 3 mg kg-1, i.v.; n = 4) of FR 139317 had no effect on myocardial infarct size (48 +/- 5%) after 45 min occlusion of the antero-lateral branch of the left coronary artery (LAL) and 2 h reperfusion.4. In a separate group of experiments, the LAL was occluded for 60 min and subsequently reperfused for 6 h. FR 139317 (0.6 mg kg-1 min-1 preceded by a loading dose of 3 mg kg-1, i.v.; n =4) had no significant effect on infarct size even in this long reperfusion model (control: 48 +/- 3%, FR 139317:61 +/- 6%).5. Thus, the vasoconstrictor effects elicited by ET-1 in the coronary vasculature of the rabbit are primarily mediated via the ETA receptor, for they were inhibited by the ETA receptor antagonist, FR 139317. However, an enhanced formation of endogenous ET-1 does not play a major role in ischaemia/reperfusion injury of the rabbit heart, for FR 139317 had no effect on infarct size.

The effect of the ETA receptor antagonist, FR 139317, on [125I]-ET-1 binding to the atherosclerotic human coronary artery.[Pubmed:7521255]

Br J Pharmacol. 1994 Jun;112(2):386-9.

1. The distribution of [125I]-endothelin (ET-1) binding sites on atherosclerotic human epicardial coronary arteries has been studied by in vitro receptor autoradiography. 2. [125I]-ET-1 binding was to the tunica media and regions of neovascularization. 3. Competition studies were carried out in the presence of ET-1 and the ETA receptor antagonist, FR 139317. The IC50 values for ET-1 at the tunica media and regions of neovascularization were similar (mean +/- s.e.mean of n = 4 patients, 2.5 +/- 0.9 nM and 2.9 +/- 0.9 nM, respectively) whereas IC50 values for FR 139317 at regions of neovascularization (607 +/- 34 nM) were significantly higher than those of the tunica media (12.6 +/- 2.4 nM) (P < 0.0001). 4. These results indicate that ETA receptors are present on the tunica media of the diseased human coronary artery whereas a different ET receptor subtype exists at regions of neovascularization.

Endothelin-receptor antagonist FR 139317 reduces infarct size in a rabbit model when given before, but not after, coronary artery occlusion.[Pubmed:9007676]

J Cardiovasc Pharmacol. 1997 Jan;29(1):87-92.

Endothelins are potent vasoactive peptides that exist as isoforms having different affinities for two main receptor subtypes, ETA and ETB. Based on their potential to produce adverse effects as a result of marked vasoconstrictor actions, these mediators have been widely studied to investigate their role in disease states involving the cardiovascular system. In this study, we examined the effect of a selective ETA-receptor antagonist, FR 139317, on myocardial infarct size by using a rabbit arterial-occlusion model. The main coronary artery of 32 New Zealand white rabbits was occluded for 60 min, followed by 3 h of reperfusion. Sixteen animals received FR 139317 (5.0 mg/kg as a bolus + 30 mg/kg given over a 90-min period), whereas the remaining 16 control rabbits received the drug vehicle. Treatment began at 15 min before coronary artery occlusion and ended at 15 min after the start of tissue reperfusion. Infarct size, expressed as a percentage of the area at risk of infarction, was 64 +/- 4% in the control group and 41 +/- 2% in the treated animals (p < 0.001). In a second set of rabbits, five animals received the same treatment regimen and were compared with five controls; however, unlike the initial protocol, treatment was initiated 45 min after coronary artery occlusion (15 min before reperfusion) and ended after 75 min of reperfusion. In this case, infarct size was 65 +/- 4% in the control group and 56 +/- 10% in the animals that received FR 139317 (NS). The results suggest that endothelin is involved in the extension of myocardial infarction in this rabbit model and that its primary action is manifest during occlusion of the coronary artery.

A novel ETA-receptor antagonist, FR 139317, inhibits endothelin-induced contractions of guinea-pig pulmonary arteries, but not trachea.[Pubmed:8448595]

Br J Pharmacol. 1993 Feb;108(2):448-52.

1. The effects of a proposed endothelin-receptor antagonist, FR 139317, on the contraction induced by endothelin-1, endothelin-2 and endothelin-3, were analysed on isolated circular segments of pulmonary arteries and rings of trachea from the guinea-pig. 2. The pharmacological profiles of endothelin-1 and endothelin-2 were almost identical in the guinea-pig pulmonary artery, whereas endothelin-3 demonstrated a weaker and less potent contractile effect. The contractions induced by endothelin-1 and endotheliln-2 were competitively antagonized by FR 139317. Schild plot analysis revealed a straight line with a slope that did not differ from unity. The pA2 value was 6.65. In contrast, the endothelin-3 induced contractile response was unaffected by FR 139317. 3. In tracheal segments endothelin-1, endothelin-2 and endothelin-3 evoked contractions of similar magnitude and sensitivity. FR 139317 had no effect on the endothelin-induced contractions in tracheal segments. 4. In ring segments of pulmonary artery and trachea, potassium, noradrenaline and histamine caused concentration-dependent contractile effects. These contractions were not modified by FR 139317 in the concentration range 10(-7) to 3 x 10(-6)M. 5. FR 139317 seems to be a selective ETA-receptor antagonist which competitively antagonizes the endothelin-1- and endothelin-2-induced contractions of guinea-pig isolated pulmonary arteries. Thus, the guinea-pig pulmonary artery appears to be endowed with one receptor type (ETA) which is antagonized by FR 139317 and with another endothelin-receptor subtype which responds to endothelin-3, but is not antagonized by FR 139317. In the trachea, all three peptides act on a homogeneous population of receptors which is unaffected by FR 139317. This suggests an ETA-receptor in the guinea-pig pulmonary artery and another receptor, probably of ETB-type, in the guinea-pig trachea.

Role of endothelin ET(A)- and ET(B)-receptors in haemodynamic compensation following haemorrhage in anaesthetized rats.[Pubmed:11861314]

Br J Pharmacol. 2002 Feb;135(4):876-82.

1. This study examined the role of endothelin ET(A) and ET(B) receptors on haemodynamic compensation following haemorrhage (-17.5 ml kg(-1)) in thiobutabarbitone-anaesthetized rats. Rats were divided into four groups (n=6 each): time-control, haemorrhage-control, haemorrhage after treatment with FR 139317 (ET(A)-receptor antagonist), and haemorrhage after treatment with BQ-788 (ET(B)-receptor antagonist). 2. In the time-control rats, there were no significant changes in any haemodynamics for the duration of the experiments. Relative to the time-control rats, rats given haemorrhage had reduced mean arterial pressure (MAP), cardiac output (CO) and mean circulatory filling pressure (MCFP), but increased systemic vascular resistance (R(SV)). Venous resistance (R(V)) was slightly (but insignificantly) reduced by haemorrhage. MAP, however, gradually returned towards baseline (-17+/-4 and -3+/-2 mmHg at 10 and 60 min after haemorrhage, respectively) as a result of a further increase in R(SV). 3. Pre-treatment with FR 139317 (i.v. 1 mg kg(-1), followed by 1 mg kg(-1) h(-1)) accentuated haemorrhage-induced hypotension through abolition of the increase in R(SV). FR 139317 did not modify haemorrhage-induced changes in CO, MCFP and R(V). 4. Pre-treatment of BQ-788 (3 mg kg(-1)) did not affect MAP or MCFP following haemorrhage; however, CO was lower, and R(SV) as well as R(V) were higher relative to the readings in the haemorrhaged-control rats. 5. These results show that following compensated haemorrhage, ET maintains arterial resistance and blood pressure via the activation of ET(A) but not ET(B) receptors.

Subtype selectivity of a novel endothelin antagonist, FR139317, for the two endothelin receptors in transfected Chinese hamster ovary cells.[Pubmed:8429819]

Mol Pharmacol. 1993 Feb;43(2):127-31.

We investigated the receptor-binding properties and the antagonist activities of FR139317, a novel endothelin (ET) antagonist, in transfected Chinese hamster ovary cells permanently expressing the two ET receptor subtypes (ETA and ETB). In displacement analysis using membrane preparations derived from the receptor-expressing cells, FR139317 showed a high affinity for ETA (Ki = 1 nM) and a lower affinity for ETB (Ki = 7.3 microM). FR139317 inhibited ETA-mediated phosphatidylinositol hydrolysis and arachidonic acid release and produced a parallel shift in the dose-response curve for ET-1, with respective pA2 values of 8.2 and 7.7. In contrast, FR139317 had no inhibitory effects on these ET-1-induced responses in ETB-expressing cells. FR139317 itself showed no stimulatory effects on phosphatidylinositol hydrolysis and arachidonic acid release in ETA- and ETB-expressing cells. Thus, FR139317 is a potent, competitive, and highly selective antagonist for ETA. This compound should be a powerful tool for investigation of the physiological properties of ETA and exploration of its role in diseases.

Pharmacological profile of FR139317, a novel, potent endothelin ETA receptor antagonist.[Pubmed:8450448]

J Pharmacol Exp Ther. 1993 Mar;264(3):1040-6.

The effects of FR139317 on the cardiovascular system were investigated in cultured cells, isolated organs and whole animals. FR139317 inhibited the specific binding of [125]endothelin(ET)-1 to porcine aortic microsomes in a concentration-dependent, monophasic fashion with an IC50 of 0.53 nM. In contrast, FR139317 showed low affinity for [125I]ET-1 specific binding sites in porcine kidney (IC50, 4.7 microM). In isolated rabbit aorta, FR139317 shifted the ET-1-induced concentration-contractile response curve to the right with a pA2 value of 7.2 and lacked agonist activity. A single (i.v.) bolus dose of FR139317 completely inhibited the pressor response to ET-1 in vivo, but had no effect on the initial depressor response in conscious normotensive rats. These data indicate that FR139317 is a potent, highly specific ETA receptor antagonist. In addition, FR139317 also inhibited ET-1 induced [3H]thymidine incorporation in cultured vascular smooth muscle cells from rat aorta (IC50, 4.1 nM), suggesting that ET-1-induced mitogenesis is mediated only by the ETA receptor. FR139317 could become a useful tool for investigating the physiological and pharmacological actions of ET.