Cardiovascular haemodynamics and ventriculo-arterial coupling in an acute pig model of coronary ischaemia-reperfusion

in Experimental Physiology (2007), 92(1), 127-137

Although reperfusion after coronary occlusion is mandatory for myocardial salvage, reperfusion may trigger a cascade of harmful events (reperfusion injury) adding to myocardial injury. We investigated ... [more ▼]

Although reperfusion after coronary occlusion is mandatory for myocardial salvage, reperfusion may trigger a cascade of harmful events (reperfusion injury) adding to myocardial injury. We investigated effects of reperfusion on left ventricular (LV) haemodynamics and ventriculo-arterial (VA) coupling in pigs following acute myocardial ischaemia induced by coronary artery occlusion. Experiments were performed in six animals, with measurements of cardiac and arterial function at baseline, after 60 min of ischaemia (T60) and after 2 (T180) and 4 h of reperfusion (T300). Ventriculo-arterial coupling was assessed using the ventriculo-arterial elastance ratio of paper, as well as using a 'stiffness coupling' and 'temporal coupling' index. Reperfusion following ischaemia (T180 versus T60) induced a progressive decline in cardiovascular function, evidenced by a decrease in mean arterial blood pressure, cardiac output and ejection fraction which was not restored at T300. Although reperfusion also induced an increase in slope of the end-systolic pressure-volume relationship (ESPVR), the ESPVR curve shifted to the right, associated with a depression of contractile function. Histology demonstrated irreversible myocardial damage at T300. The ventriculo-arterial elastance ratio and the 'stiffness coupling' index were unaffected throughout the protocol, but the 'temporal coupling' parameter indicated a relative shift between heart period and the time constant of the arterial system. It is unlikely that these alterations are attributable to ischaemic injury alone. The combination of both the stiffness and temporal coupling index may provide more information when studying ventriculo-arterial coupling than the more commonly used ventricular end-systolic stiffness/effection arterial elastance (E-es/E-a) ratio. [less ▲]

Design, synthesis, and SAR study of a series of N-alkyl-N'-[2-(aryloxy)-5-nitrobenzenesulfonyl]lureas and -cyanoguanidine as selective antagonists of the TPalpha and TPBeta isoforms of the human thromboxane A2 receptor

in Journal of Medicinal Chemistry (2007), 50

BM-520, an original TXA(2) modulator, inhibits the action of thromboxane A(2) and 8-iso-prostaglandin F-2 alpha in vitro and in vivo on human and rodent platelets, and aortic vascular smooth muscles from rodents

in Prostaglandins & Other Lipid Mediators (2007), 84(1-2), 14-23

Thromboxane A(2) (TXA(2)) and 8-iso-PGF(2 alpha). are two prostanoid agonists of the thromboxane A(2) receptor (TP), whose activation has been involved in platelet aggregation and atherosclerosis. Agents ... [more ▼]

Thromboxane A(2) (TXA(2)) and 8-iso-PGF(2 alpha). are two prostanoid agonists of the thromboxane A(2) receptor (TP), whose activation has been involved in platelet aggregation and atherosclerosis. Agents able to counteract the actions of these agonists are of great interest in the treatment and prevention of cardiovascular events. Here, we investigated in vitro and in vivo the pharmacological profile of BM-520, a new TP antagonist. In our experiments, this compound showed a great binding affinity for human washed platelets TP receptors, and prevented human platelet activation and aggregation induced by U-46619, arachidonic acid and 8-iso-PGF(2 alpha). The TP receptor antagonist property of BM-520 was confirmed by its relaxing effect on rat aorta smooth muscle preparations precontracted with U-46619 and 8-iso-PGF(2 alpha). Further, its TP antagonism was also demonstrated in vivo in guinea pig after a single intravenous injection (10 mg kg(-1)). We conclude that this novel TP antagonist could be a promising therapeutic tool in pathologies such as atherosclerosis where an increased production of TXA(2) and 8-iso-PGF2., as well as TP activation are well-established pathogenic events. (c) 2007 Elsevier Inc. All rights reserved. [less ▲]

Development of a fluorescent microplate cell based assay for the rapid evaluation of human thromboxane A2 receptor modulators acting on α and β isoforms

Poster (2006, August)

Synthesis and pharmacological evaluation of novel thromboxane modulators as antiplatelet agents acting on both the alpha and beta isoforms of the human thromboxane receptor

in Journal of Medicinal Chemistry (2006), 49(12), 3701-3709

Activité préférentielle de la 8-iso-prostaglandine F2A (8-iso-PGF2A) sur l’isoforme alpha du récepteur au thromboxane A2

Poster (2006, June)

The use of an apoE–deficient (apoE-/-) mice model to characterize the therapeutic benefits of original thromboxane modulators

Poster (2006, May 17)

The aim of our study was to use an apoE–deficient mouse model to test drugs acting as thromboxane A2 antagonist. Presented here is the “en face” method 6 which allows the evaluation of atherosclerosis ... [more ▼]

The aim of our study was to use an apoE–deficient mouse model to test drugs acting as thromboxane A2 antagonist. Presented here is the “en face” method 6 which allows the evaluation of atherosclerosis lesions development in wild type and APO E-/- mice. This method involves pinning out the aorta and quantifying lesion area as a percentage of total surface area. The use of this mice model offers a unique opportunity to characterize the therapeutic benefits of pharmacologicals agents designed in our laboratory of which antioxidants and thromboxane modulators. The pharmacological characterization of BM-573 as potential antiatherosclerotic agent will also be discussed [less ▲]

From the design to the clinical application of thromboxane modulators

in Current Pharmaceutical Design (2006), 12(8), 903-923

Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of ... [more ▼]

Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H-2 (PGH(2)) which results from the enzymatic transformation of AA by the cyclooxygenases. It is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction, and has been involved in a series of major pathophysiological conditions. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by different laboratories since the early 1980s. Several Compounds have been launched on the market and others are tinder clinical evaluation. In the first part of this review. we will describe the physiological properties of TXA(2), thromboxane synthase and thromboxane receptors. The second part is dedicated to a description of each class of thromboxane modulators with the advantages and disadvantages they offer. In the third part. we aim to describe recent studies performed with the most interesting thromboxane modulators in major pathologies: myocardial infarction and thrombosis, atherosclerosis, diabetes, pulmonary embolism, septic shock.. preeclampsia, and asthma. Each pathology will be systematically reviewed. Finally, in the last part we will highlight the latest perspectives in drug design of thromboxane modulators and in their future therapeutic applications such as cancer, metastasis and angiogenesis. [less ▲]

Characterisation of an original model of myocardial infarction provoked by coronary artery thrombosis induced by ferric chloride in pig

in European Heart Journal (2005, September), 26(Suppl. 1), 455-456

Effects of dobutamine on left ventriculoarterial coupling and mechanical efficiency in acutely ischemic pigs

in Journal of Cardiovascular Pharmacology (2005), 45(2), 144-152

This study investigated the effects of dobutamine on left ventriculoarterial (VA) coupling and mechanical efficiency in acutely ischemic pigs. Experiments were performed in 12 pigs in which vascular ... [more ▼]

This study investigated the effects of dobutamine on left ventriculoarterial (VA) coupling and mechanical efficiency in acutely ischemic pigs. Experiments were performed in 12 pigs in which vascular properties, including peripheral resistance (R-2), compliance (C), and arterial elastance (E-a), were estimated with a windkessel model, and left ventricular (LV) function by the slope (E-es) of the end-systolic pressure-volume relationship (ESPVR) and stroke work (SW). VA coupling was defined as E-es/E-a, and mechanical efficiency as SW/pressure-volume area (PVA). In all animals, the left anterior descending coronary artery was ligated after basal measures. The animals were then randomly divided into 2 groups: group CTRL (n = 6) was followed for 180 minutes without other intervention, whereas group DOBU (n = 6) was infused with dobutamine (5 mug(.)kg(-1.)min(-1)) starting after T60 measures. Coronary occlusion induced a rightward shift of ESPVR and a decrease in E-es from 3.67 +/- 0.33 to 1.92 +/- 0.20 mm Hg(.)mL(-1), while E-a changed from 3.33 +/- 0.56 to 4.65 +/- 0.29 mm Hg(.)mL(-1), R-2 from 1.72 +/- 0.30 to 2.38 +/- 0.16 mm Hg(.)s(.)mL(-1), and C from 0.78 +/- 0.16 to 0.46 +/- 0.08 mL(.)mm Hg-1. This altered VA coupling from 1.22 +/- 0.11 to 0.44 +/- 0.07. SW decreased from 4056 +/- 223 to 2372 +/- 122 mm Hg(.)mL, and PVA and SW/PVA decreased from 5575 +/- 514 to 4830 +/- 3.17 mm Hg(.)mL, and from 0.76 +/- 0.04 to 0.49 +/- 0.03, respectively. In group DOBU, dobutamine restored E-es and the position of ESPVR to baseline values, while E-a decreased to 3.39 +/- 0.34 mm Hg(.)mL(-1) because of an R-2 decrease to 1.60 +/- 0.24 mm Hg(.)s(.)mL(-1). VA coupling was restored. SW and PVA increased to 3833 +/- 180 mm Hg(.)mL and to 7498 +/- 442 mm Hg(.)mL, respectively, while SW/PVA was unchanged. In ischemic pigs, dobutamine restored VA coupling through an increase in LV contractility and decrease in arterial elastance as a result of peripheral vasodilatation. However, myocardial oxygen consumption was increased, and mechanical efficiency impaired. [less ▲]