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Br J Pharmacol. Feb 2009; 156(4): 563–574.
PMCID: PMC2697704

Endothelium-dependent contractions in SHR: a tale of prostanoid TP and IP receptors


In the aorta of spontaneously hypertensive rats (SHR), the endothelial dysfunction is due to the release of endothelium-derived contracting factors (EDCFs) that counteract the vasodilator effect of nitric oxide, with no or minor alteration of its production. The endothelium-dependent contractions elicited by acetylcholine (ACh) involve an increase in endothelial [Ca2+]i, the production of reactive oxygen species, the activation of endothelial cyclooxygenase-1, the diffusion of EDCF and the subsequent stimulation of smooth muscle cell TP receptors. The EDCFs released by ACh have been identified as PGH2 and paradoxically prostacyclin. Prostacyclin generally acts as an endothelium-derived vasodilator, which, by stimulating IP receptors, produces hyperpolarization and relaxation of the smooth muscle and inhibits platelet aggregation. In the aorta of SHR and Wistar-Kyoto rats, prostacyclin is the principal metabolite of arachidonic acid released by ACh. However, in SHR aorta, prostacyclin does not produce relaxations but activates the TP receptors on vascular smooth muscle cells and produces contraction. The IP receptor is not functional in the aortic smooth muscle cells of SHR as early as 12 weeks of age, but its activity is not reduced in platelets. Therefore, prostacyclin in the rule protects the vascular wall, but in the SHR aorta it can contribute to endothelial dysfunction. Whether or not prostacyclin plays a detrimental role as an EDCF in other animal models or in human remains to be demonstrated. Nevertheless, because EDCFs converge to activate TP receptors, selective antagonists of this receptor, by preventing endothelium-dependent contractions, curtail the endothelial dysfunction in diseases such as hypertension and diabetes.

Keywords: nitric oxide, prostaglandins, EDCF, oxidative stress, superoxide anion, hypertension, endothelium, smooth muscle, platelets, cyclooxygenase


Endothelial cells synthesize and release various factors that modulate vascular tone as well as angiogenesis, inflammatory responses, haemostasis and permeability. As a major regulator of local vascular homeostasis, the endothelium maintains the balance between vasodilatation and vasoconstriction, inhibition and promotion of the proliferation and migration of smooth muscle cells, prevention and stimulation of the adhesion and aggregation of platelets as well as thrombogenesis and fibrinolysis. Upsetting this tightly regulated balance leads to endothelial dysfunction. A reduced bioavailability of nitric oxide (NO), an alteration in the production of prostanoids (including prostacyclin, thromboxane A2 and/or isoprostanes), an impairment of endothelium-dependent hyperpolarization as well as an increased release of endothelin-1 can individually or in association contribute to endothelial dysfunction (Félétou and Vanhoutte, 2006a). The present review focuses on the endothelial function observed in spontaneously hypertensive rats (SHR).

Endothelium-dependent contractions in SHR aorta

The endothelium-dependent relaxations are impaired in the aorta of hypertensive rats (Lockette et al., 1986; Luscher and Vanhoutte, 1986). Thus, in contracted aortic rings of SHR, acetylcholine (ACh) induces endothelium-dependent relaxations, but the concentration–response curve to the muscarinic agonist is biphasic and at concentrations higher than 100 nmol·L−1the relaxations become smaller. In quiescent aortic rings of SHR, ACh produces endothelium-dependent contractions that are amplified in the presence of inhibitor of NO synthases (NOS; Luscher and Vanhoutte, 1986; Auch-Schwelk et al., 1992; Iwama et al., 1992; Yang et al., 2002) (Fig. 1). These endothelium-dependent contractions are larger in aortae from male than female SHR (Kauser and Rubanyi, 1995), are positively correlated with the severity of hypertension and the aging process and occur in aging normotensive Wistar-Kyoto rats (WKY) (Koga et al., 1988; 1989; Iwama et al., 1992; Ibarra et al., 1995).

Figure 1
Endothelial dysfunction and endothelium-dependent contractions in SHR aorta. (A) In contracted rings of WKY and SHR aorta, acetylcholine induces endothelium-dependent relaxations, which at higher concentrations are blunted in the arteries of the hypertensive ...

Inhibitors of cyclooxygenase (COX) inhibit the endothelium-dependent contractions and fully restore the impaired endothelium-dependent relaxations, indicating that there is no or little alteration in NO production (Luscher and Vanhoutte, 1986), a conclusion strengthened by perfusion-superfusion bioassay studies (Hoeffner and Vanhoutte, 1989). Further bioassay studies using layered ‘sandwich’ preparations demonstrated that endothelium-dependent contractions to ACh involve the endothelial release of diffusible contractile COX derivatives, which oppose the relaxing effect of NO (Yang et al., 2003a) (Fig. 2).

Figure 2
Bioassay of endothelium-derived contracting factor in SHR aortic rings: layered or ‘sandwich’ preparation. Acetylcholine (ACh) produces contraction of the bioassay strip (without endothelium) only if endothelial cells are present on the ...

The generation of endothelium-derived contracting factor (EDCF) is observed not only in response to endothelial muscarinic M3 receptor stimulation (Boulanger et al., 1994) but also in response to ATP (Koga et al., 1989; Mombouli and Vanhoutte, 1993;Yang et al., 2004), VEGF (Liu et al., 2001), as well as in response to receptor-independent stimuli, for instance the calcium ionophore, A 23187 (Yang et al., 2004; Tang et al., 2007). EDCF contributes to the contractile responses of endothelin (Taddei and Vanhoutte, 1993a,b) and in the presence of inhibitor of NOS, a tonic generation of EDCF is observed in SHR aorta and in that of aging WKY (Abeywardena et al., 2002).

Mechanisms underlying endothelium-dependent contractions

Endothelium-dependent contractions can be elicited by receptor-dependent mechanisms and by A 23187, which allows the free entry of extracellular calcium into endothelial cells, indicating that an increase in intracellular calcium is necessary for the production of endothelium-dependent contractions (Yang et al., 2004; Gluais et al., 2006; Tang et al., 2007). Indeed, ACh causes a rapid increase in cytosolic calcium concentration in endothelial cells of SHR and to a lesser extent in that of WKY. This rise of calcium was not affected by inhibiting COX or by the combination of tiron (a superoxide scavenger) plus diethyldithiocarbamate acid (DETCA; a superoxide dismutase inhibitor) (Tang et al., 2007). However, endothelium-dependent contractions are reduced by the acute exposure to the combination of tiron plus DETCA or by a chronic treatment with dimethylthiourea (an in vivo depletor of free radicals) (Yang et al., 2002). Furthermore, the production of superoxide anions selectively enhances endothelium-dependent contractions (Yang et al., 2003b) and under bioassay conditions, the transfer of EDCF from the donor tissue to the bioassay preparation is diminished by the combination of superoxide dismutase plus catalase (Yang et al., 2003a). Confocal microscopy shows that ACh causes a rapid increase in reactive oxygen species in endothelial cells of SHR aorta but not in that of WKY. This burst in reactive oxygen species generation is prevented by COX inhibition or by the combination of tiron plus DETCA (Tang et al., 2007). In contrast to ACh, the increase in endothelial intracellular calcium, the generation of reactive oxygen species and the amplitude of endothelium-dependent contractions elicited by A 23187 are of similar amplitude in WKY and SHR aorta (Gluais et al., 2006; Tang et al., 2007).

These results indicate that an abnormal accumulation of calcium in SHR endothelial cells is a prerequisite to initiate the release of EDCF, and this can be mimicked in that of WKY when stimulated by the calcium ionophore. The sequence of events occurring during endothelium-dependent contractions firstly requires the accumulation of calcium, which then most likely induces the phospholipase A2-dependent mobilization of arachidonic acid (Luscher and Vanhoutte, 1986), COX activation and the production of reactive oxygen species along with that of EDCF(s) (Tang et al., 2007). Reactive oxygen species can diffuse towards the vascular smooth muscle cells and produce contraction (Auch-Schwelk et al., 1989; Katusic and Vanhoutte, 1989; Suzuki and Ford, 1992; Yang et al., 2002) and be involved in a positive feedback loop on the endothelial cells by further activating COX (Harlan and Callahan, 1984).

Identification of EDCFs

Cyclooxygenases and prostaglandin synthases

COX are the first enzymes involved in the biosynthetic pathway leading to prostanoid formation. A constitutive (COX-1) and an inducible isoforms (COX-2) have been cloned and characterized (De Witt, 1988; Merlie et al., 1988; Hla and Neilson, 1992; O'Banion et al., 1992; Yokoyama et al., 2002). COX-2 can be induced by several stimuli associated with cell activation and inflammation. In endothelial cells, COX-1 is expressed constitutively but can also be over-expressed, for instance by shear stress (Vane et al., 1998; Doroudi et al., 2000; Davidge, 2001). Both endothelial and vascular smooth muscle cells contain COX, however endothelial cells contain 20 times more of the enzyme than smooth muscle cells (DeWitt et al., 1983). Endothelial cells express preferentially COX-1 versus COX-2 (Onodera et al., 2000; Kawka et al., 2007). In SHR endothelial cells the mRNA and protein expression of COX-1 are enhanced when compared with that of WKY, and in both strains they are augmented by aging (Ge et al., 1995; Tang and Vanhoutte, 2008). Endothelium-dependent contractions to ACh are blocked by specific inhibitors of COX-1 and minimally affected by specific inhibitors of COX-2 (Ge et al., 1995; Yang et al., 2002; 2003a,b; Gluais et al., 2006) (Fig. 1). In agreement with a preponderant role for COX-1 in endothelium-dependent contractions, these responses are abolished in aorta taken from COX-1 knockout mice while they are maintained in aortic rings of COX-2 knockout animals (Tang et al., 2005). However, in some instances, COX-2-derived contractile prostanoids are produced by WKY and SHR aortic endothelial cells (Camacho et al., 1998; Zerrouk et al., 1998; Garcia-Cohen et al., 2000; Alvarez et al., 2005; Blanco-Rivero et al., 2005).

Various biologically active eicosanoids are formed from the short lasting but biologically active endoperoxide (PGH2), through the action of a set of synthases namely PGD, PGE, PGF, PGI and thromboxane synthases (Tsuboi et al., 2002). The expression of prostacyclin synthase (PGIS) is by far the most abundant of these synthases expressed in the rat aortic endothelial cells (Tang and Vanhoutte, 2008), and a greater co-distribution of PGIS with COX-1 is observed when compared with COX-2 (Kawka et al., 2007) explaining why the majority of the endothelial COX-1-derived endoperoxides are transformed into prostacyclin (Gluais et al., 2005; 2006; Tang and Vanhoutte, 2008) (Fig. 3). The expression of PGIS and thromboxane synthase is higher in SHR aortic endothelial cells than in those of WKY (Tang and Vanhoutte, 2008).

Figure 3
Acetylcholine-induced prostaglandin release in WKY and SHR aorta. Acetylcholine produces the endothelium-dependent release of prostacyclin (A, as measured as its stable metabolite 6-keto-PGF), thromboxane A2 (B, as measured as its stable metabolite ...

Acetylcholine-induced endothelium-dependent contractions and thromboxane A2

Prostaglandins interact with specific seven transmembrane, G protein-coupled receptors, which are classified in five subtypes DP, EP, FP, IP and TP in function of their sensitivity to the five primary prostanoids, prostaglandins D2, E2, F, I2and thromboxane A2 respectively (Tsuboi et al., 2002; Alexander et al., 2008). These receptors are all expressed in WKY and SHR aortae, although at low levels (Tang and Vanhoutte, 2008). ACh-induced endothelium-dependent contractions are blocked by antagonists of the TP receptors. However, inhibitors of thromboxane synthase do not affect these endothelium-dependent contractions indicating that thromboxane A2is not the EDCF released following muscarinic receptor activation (Luscher and Vanhoutte, 1986; Koga et al., 1989; Auch-Schwelk et al., 1990; Kato et al., 1990; Ge et al., 1995; Tesfamariam and Ogletree, 1995; Yang et al., 2002; 2003a,b; 2004; Gluais et al., 2005; 2006) (Fig. 4).

Figure 4
Thromboxane A2 generation and acetylcholine-induced endothelium-dependent contractions. Dazoxiben, the thromboxane synthase inhibitor, does not affect acetylcholine-induced release of prostacyclin (A), PGE2 (C), PGF (data not shown), but abolishes ...

Acetylcholine-induced endothelium-dependent contractions and PGH2

Thromboxane A2is the most potent agonist at TP receptors but is not its exclusive ligand. In fact, in WKY and SHR aorta numerous prostanoids produce contraction by activating TP receptors, with the following order of potency 9,11-dideoxy-9α,11α-epoxymethano prostaglandin F (U 46619) >> 8-isoprostane = PGF = PGH2 > PGE2 = PGD2 > PGI2. Among those agonists, only PGH2 and prostacyclin evoke transient contractions, possibly because of their short half-life in aqueous solutions (3–4 min, Dickinson and Murphy, 2002), that mimic endothelium-dependent contractions (Gluais et al., 2005). PGH2is the second most potent agonist at TP receptors, and there is an augmented sensitivity of the SHR smooth muscle cells towards this endoperoxide when compared with that of WKY (Ge et al., 1995; 1999). Therefore, PGH2 has been considered as a suitable candidate for an EDCF (Auch-Schwelk et al., 1990; Kato et al., 1990; Ge et al., 1995; Gluais et al., 2005; 2006; 2007). However, in SHR aortic endothelial cells, the massive expression of PGIS (Tang and Vanhoutte, 2008) and its close association with COX-1 (Kawka et al., 2007) are not in favour of a large PGH2spillover. The levels of PGH2 are difficult to measure and still need to be better assessed in order to evaluate more precisely the contribution of this endoperoxide to endothelium-dependent contractions.

PGH2 is spontaneously or enzymatically transformed in the more stable isomer PGE2 and in presence of mild reducing agent or enzymatically into PGF. Although PGE2, via EP receptor activation, is an endothelium-derived contractile factor in a rat model of diabetes (Shi et al., 2007), in the SHR aorta the involvement of this prostaglandin either via EP or TP receptor activation has been ruled out (Tang et al., 2008). However, when PGIS is inhibited, a compensatory increase in the production of PGE2 and PGF is observed, and then these prostaglandins act as EDCF (Gluais et al., 2005).

Acetylcholine-induced endothelium-dependent contractions and 8-isoprostane

8-isoprostane (8-epiPGF) is generally produced from the oxidative modification of polyunsaturated fatty acids via a free radical-catalysed mechanism (Morrow et al., 1990). However, under some circumstances, 8-isoprostane could be a direct product of COX or an indirect consequence of superoxide anion production by COX-mediated metabolism (Watkins et al., 1999). In both WKY and SHR aortic rings, 8-isoprostane is a potent constrictor (Gluais et al., 2005), supporting the hypothesis that an isoprostane could contribute to EDCF-mediated responses (Janssen, 2002). However, proper measurement of 8-isoprostane generation failed to detect significant ACh-stimulated and endothelium-dependent release of this prostanoid (Gluais et al., 2005). Therefore, in the SHR aorta, 8-isoprostane is unlikely to be an EDCF released by ACh.

Acetylcholine-induced endothelium-dependent contractions and PGI2

ACh produces the endothelium-dependent release of prostacyclin, PGE2, PGF and thromboxane A2 in the aorta of both WKY and SHR. The release of prostacyclin is 10 to 100 times larger than that of the other prostaglandins, while the generation of thromboxane A2 is the smallest. Furthermore, the release of prostacyclin is much larger in the aorta of SHR than in that of WKY (Gluais et al., 2005). In the SHR aorta and that of aging WKY, prostacyclin paradoxically is not a relaxing but a contracting prostaglandin (Gluais et al., 2005; Gomez et al., 2008) (Figs 5 and and6).6). Whether or not, the reduction in the relaxing response to prostacyclin in SHR and the decrease of this response during aging is associated with parallel changes in the expression of the IP receptor gene remains controversial (Numaguchi et al., 1999; Tang and Vanhoutte, 2008). Nevertheless, the IP receptor dysfunction is specific of vascular smooth muscle cells because IP receptor-dependent inhibition of platelet activation is not altered in SHR or by aging (Gomez et al., 2008). Therefore, endothelium-dependent contractions elicited by ACh in the aorta of SHR and aging WKY are likely to involve at least in part the release of prostacyclin.

Figure 5
Prostacyclin induces relaxation in WKY aortic rings but not in those of SHR. (A) In aortic rings with endothelium of young 12-week-old WKY, prostacyclin induces relaxations that are inhibited by the specific IP receptor antagonist CAY 10441. The presence ...
Figure 6
Prostacyclin-induced contractions and acetylcholine-induced endothelium-dependent contractions. (A) Original trace showing acetylcholine-induced concentration and endothelium-dependent contractions in SHR aortic rings (presence of L-nitro-arginine, L-NA). ...

This conclusion is based on the following observations: (i) in WKY and SHR, prostacyclin is a contracting but not a relaxing factor (Figs 5 and and6);6); (ii) prostacyclin is a more potent contracting agent in SHR than in WKY (Fig. 6); (iii) the contractions evoked by prostacyclin mimic the endothelium-dependent contractions produced by ACh both in term of duration and amplitude (Fig. 5); (iv) prostacyclin- and the endothelium-dependent contractions both involve activation of TP receptors (Figs 1 and and5);5); (v) prostacyclin is the most abundant prostaglandin released by ACh and is of endothelial origin (Fig. 3); (vi) the release of prostacyclin is two times larger in SHR than in WKY (Fig. 3); (vii) the time course of the release of prostacyclin is compatible with the time course of the observed endothelium-dependent contractions; (viii) the release of prostacyclin correlates with the amplitude of the endothelium-dependent contractions over the full concentration range of ACh in both WKY and SHR (Fig. 7); (ix) the endothelium-dependent contractions and the release of prostacyclin are affected similarly by COX inhibitors; (x) The expression of PGIS is by far the most abundant of the prostaglandin synthases expressed in the rat aortic endothelial cells and PGIS and COX-1 co-segregate; and finally (xi) the inhibition of prostacyclin synthesis enhances the ACh-induced endothelium-dependent contractions. Paradoxically, this latter observation also supports the hypothesis that prostacyclin contribute to endothelium-dependent contractions because the inhibition of PGIS may enhance PGH2spillover, a more potent TP receptor agonist than prostacyclin itself (Rapoport and Williams, 1996; Gluais et al., 2005). The hypothesis that prostacyclin is an EDCF is in agreement with the conclusion that prostacyclin is the main factor accounting for endothelial dysfunction in the aorta of WKY and SHR treated with aldosterone (Blanco-Rivero et al., 2005).

Figure 7
Acetylcholine-induced concentration-dependent and endothelium-dependent prostacyclin release and contractions. (A) WKY aortic rings with and without endothelium. (B) SHR aortic rings with and without endothelium. Prostacyclin release is represented on ...

EDCFs released in response to other stimuli

In response to other stimuli, such as ATP or the calcium ionophore A 23187, thromboxane synthase inhibitors partially inhibit endothelium-dependent contractions indicating that thromboxane A2contributes to these responses, prostacyclin and/or PGH2 being the other contributors (Gluais et al., 2006; 2007) (Fig. 8). Similarly, in response to endothelin, the endothelial generation of thromboxane A2 contributes to the contractile response (Taddei and Vanhoutte, 1993a,b).

Figure 8
Thromboxane A2 and endothelium-dependent contractions in SHR aortic rings. (A) The calcium ionophore, A23187, produces a significantly larger endothelial release ...

Different stimuli, that is, ATP, ACh and A 23187, induce a very different pattern in prostaglandin release. Subsequently, the endothelium-dependent contractions do not involve the same COX derivatives, although the final effector remains the prostanoid TP receptor on the vascular smooth muscle cells (Yang et al., 2004). These differences are not linked to agonist stimulating G protein-coupled receptors versus receptor-independent mechanism because thromboxane A2 contributes to both ATP- and A 23187-induced endothelium-dependent contractions but not in those evoked by ACh. These differences are unexplained at present but could be linked to differences in the dynamic of the increase in endothelial intracellular calcium evoked by these different stimuli (Gordon and Martin, 1983; Carter et al., 1988). (Fig. 9)

Figure 9
Mechanisms of endothelium-dependent contractions in WKY and SHR aortic rings. The sequence of events occurring during endothelium-dependent contractions firstly requires the intracellular accumulation of calcium, which then most likely induces the phospholipase ...

Endothelial dysfunction in other SHR vascular beds

The endothelial dysfunction observed in the mesenteric (Lüscher et al., 1990; Fu-Xiang et al., 1992; Takase et al., 1994; Lang et al., 1995; Hutri-Kahonen et al., 1997; Dantas et al., 1999; Xavier et al., 2008), renal (Lüscher et al., 1988; Dai et al., 1992; Fu-Xiang et al., 1992; Ito and Carretero, 1992; Dohi et al., 1996; Kagota et al., 1999) and skeletal muscle (Huang et al., 1993; Lübbe et al., 1993; Huang and Koller, 1996; Mori et al., 2006) vascular beds is qualitatively similar to that reported for the aorta. The generation of EDCFs similar to those identified in the aorta contributes to the altered endothelium-dependent relaxations/vasodilatations.

In these resistance arteries, in contrast to the aorta, endothelium-dependent hyperpolarizations (EDHF-mediated responses) participate to endothelium-dependent relaxations (Félétou and Vanhoutte, 2006b). Most studies show a marked attenuation of the EDHF-mediated component in SHR arteries (Fujii et al., 1992; 1993; Hayakawa et al., 1993; 1995; Mantelli et al., 1995; Dohi et al., 1996; Hutri-Kahonen et al., 1997; Bussemaker et al., 2003). The decrease in EDHF-mediated response has been associated with, but not yet causally linked, to a change in the expression profile of gap junctions in endothelial cells (Busse et al., 2002; Félétou and Vanhoutte, 2004; Griffith, 2004). Indeed, the expression of connexins 37 and 40 is lower in arteries of the SHR than in that of the WKY (Kansui et al., 2004; Rummery and Hill, 2004). Additionally, alterations in the expression or function of endothelial calcium-activated potassium channels may lead to the preferential activation of calcium-activated chloride channels and endothelium-dependent depolarization instead of endothelium-dependent hyperpolarization (Corriu et al., 1996; Coleman et al., 2001; Goto et al., 2007). The production of NO is generally not altered, although in the mesenteric artery, a decrease in its bioavailibity due to the generation of oxidative stress may occur (Tschudi et al., 1996; DeLano et al., 2006; Macarthur et al., 2008). In renal arteries of the WKY, inhibitors of EDHF-mediated responses favour endothelium-dependent contractions (Michel et al., 2008b).

EDCF-mediated responses are not ubiquitous in SHR arteries. Thus, in the carotid and cerebral arteries of that strain, the endothelium-dependent relaxations to ACh are attenuated, but this involves an impairment of the NO component without generation of EDCF and without alteration of the EDHF-mediated responses (Hongo et al., 1988; Lüscher et al., 1988; Mayhan, 1990; Sobey et al., 1999; Dina et al., 2004; Iaccarino et al., 2004). Likewise, in SHR coronary arteries when compared with those of WKY, the endothelium-dependent relaxations are not or minimally affected and are not associated with the production of EDCF (Tschudi et al., 1994; 1995; Nava et al., 1995; Bund, 1998; Garcia and Bund, 1998).

Conclusions and perspectives

In the SHR, prostacyclin, PGH2, thromboxane A2and depending on the circumstances, PGE2 and PGF can act as EDCFs and all converge towards the TP receptor (Fig. 9). The generation of EDCFs has been demonstrated in human essential hypertension and also in various other animal models of cardiovascular diseases, in particular diabetes (Taddei et al., 2001; Vanhoutte et al., 2005; Verbeuren, 2006a,b; Xu et al., 2006; Cheng et al., 2007; Matsumoto et al., 2007; 2008; Shi et al., 2007; Michel et al., 2008a). In apo E-deficient mice blockade of TP receptors but not aspirin inhibits atherogenesis (Cayatte et al., 2000). In patients with coronary artery disease, a TP receptor blocker improves endothelial function beyond the simple inhibition of COX (Belhassen et al., 2003), indicating that eicosanoids other that the above-mentioned arachidonic acid metabolites, possibly isoprostanes, activate TP receptor and are involved in these pathologies. In the SHR, a functional impairment of IP receptors of the vascular smooth muscle is likely to contribute to the endothelial dysfunction. Mice knockout for the IP receptor (Xiao et al., 2001; Cheng et al., 2002) and human patients with a dysfunctional prostacyclin IP receptor mutation (Arehart et al., 2008) show accelerated atherothrombosis indicating that an imbalance between vasoconstrictor/relaxing and thrombogenic/anti-thrombogenic prostaglandins is of major importance in the generation of cardiovascular disease.



diethyldithiocarbamate acid
endothelium-derived contracting factor
nitric oxide synthase
prostacyclin synthase
spontaneously hypertensive rats
Wistar-Kyoto rats

Conflicts of interest

MF and TJV are employees of the Institut de Recherches Servier, a pharmaceutical company that is currently involved in the clinical development of a TP receptor antagonist (S 18886 or Terutroban, or Triplion®). PMV is a consultant for the group Servier and a former employee of this company.


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