Background and purpose: PGE 2 has been shown to induce relaxations in precontracted human pulmonary venous preparations, while in pulmonary arteries this response was not observed. We investigated and characterized the prostanoid receptors which are activated by PGE 2 in the human pulmonary veins. Experimental approach: Human pulmonary arteries and veins were cut as rings and set up in organ baths in presence of a TP antagonist. A pharmacological study was performed using selective EP 1À4 ligands. The cellular localization of the EP 4 receptors by immunohistochemistry and their corresponding transcripts were also investigated in these vessels. Key results: PGE 2 and the EP 4 agonists (L-902688, ONO-AE1-329) induced potent vasodilatation of the human pulmonary vein, pEC 50 values: o7.22 ± 0.20, 8.06 ± 0.12 and 7.80 ± 0.09, respectively. These relaxations were inhibited by the EP 4 antagonist GW627368X and not modified in presence of the DP antagonist L-877499. Higher concentrations (X1 mM) of the EP 2 agonist ONO-AE1-259 induced relaxations of the veins. The EP 4 agonists had no effect on the precontracted arteries. Finally, the EP 1 antagonists ONO-8713 and SC-51322 potentiated the relaxation of the veins induced by PGE 2 . EP 4 and EP 1 receptors were detected by immunohistochemistry in the veins but not in the arteries. EP 4 mRNA accumulation was also greater in the veins when compared with the arterial preparations. Conclusions and implications: Of the 4 EP receptor subtypes, smooth muscle cells in the human pulmonary vein express the EP 4 and EP 1 receptor subtypes. The relaxations induced by PGE 2 in this vessel result from the activation of the EP 4 receptor.
Objective-Because inhibition of the renin-angiotensin system (RAS) reduces the onset of type 2 diabetes (T2D) and prevents atherosclerosis, we investigated the expression of RAS in the arterial wall of T2D and nondiabetic (CTR) patients. Methods and Results-mRNA and protein levels of angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and AT1 receptor (AT1R) were determined in carotid atheroma plaque, nearby macroscopically intact tissue (MIT), and in vascular smooth muscle cells (VSMCs) before and after insulin stimulation from 21 T2D and 22 CTR patients. AGT and ACE mRNA and their protein levels were 2-to 3-fold higher in atheroma and in MIT of T2D patients. VSMCs from T2D patients had respectively 2.5-and 5-fold higher AGT and AT1R mRNA and protein contents. Insulin induced an increase in AGT and AT1R mRNA with similar ED50. These responses were blocked by PD98059, an inhibitor of MAP-kinase in the two groups whereas wortmannin, an inhibitor of PI3-kinase, partially prevented the response in CTR patients. Phosphorylated ERK1-2 was 4-fold higher in MIT from T2D than from CTR patients. Conclusions-The arterial RAS is upregulated in T2D patients, which can be partly explained by an hyperactivation of the ERK1-2 pathway by insulin. Key Words: renin Ⅲ carotid atheroma Ⅲ type 2 diabetes mellitus Ⅲ MAP-kinase Ⅲ P85-PI3-kinase T ype 2 diabetes mellitus (T2D) is an important risk factor of atherosclerosis, and nearly 80% of diabetic patients die of cardiovascular disease. 1 The inhibition of the renin-angiotensin system (RAS) may be achieved with angiotensin converting enzyme (ACE) inhibitors or angiotensin type 1 receptor (AT1R) antagonists. These drugs demonstrated a decrease in the mortality and frequency of cardiovascular events, in primary prevention of cardiovascular diseases in high risk patients (Heart Outcomes Prevention Evaluation study [HOPE], Losartan Investigation For Endpoints reduction in hypertension study [LIFE]) and in secondary prevention after myocardial infarction (Gruppo Italiano per lo Studio della Soppravvivenza nell'Infarto miocardico [GISSI3], International Study of Infarct Survival-4 [ISIS4]). [2][3][4] In atherosclerotic regions of arteries, the amounts of immunoreactive ACE and angiotensin II (Ang II) are significantly increased. [5][6][7][8] We previously showed that ACE and other enzymes such as cathepsin G and tissue kallikrein that are able to cleave Ang II from AGT mRNA were also increased in carotid atheroma with a concomitant decrease in AT1R mRNA. 9,10 This suggests that RAS is involved in the atherogenic process. Inhibition of RAS in T2D patients has been shown to be more beneficial than in nondiabetic subjects in terms of reduction of cardiovascular events. 1,2 Moreover, RAS blockers reduced the development of diabetes and insulin resistance in hypertensive patients. 2,11 Thus, RAS is likely to be involved in the development of both insulin resistance and atheroma.Insulin has been shown to activate, via the MAP kinase ERK1-2 pathway, the expression of AGT and AT1R in vascu...
BACKGROUND AND PURPOSE
Human internal mammary arteries (IMA) and saphenous veins (SV) are frequently used for coronary artery bypass graft surgery. Intra‐ and postoperatively, the bypass grafts are exposed to inflammatory conditions, under which there is a striking increase in the synthesis of prostaglandin E2 (PGE2). In this context, the physiological response of these vascular grafts to PGE2 is highly relevant. The aim of this study was thus to characterize the PGE2 receptor subtypes (EP1, EP2, EP3 or EP4) involved in modulation of the vascular tone in these two vessels.
EXPERIMENTAL APPROACH
Rings of IMA and SV were prepared from 48 patients. The rings were mounted in organ baths for isometric recording of tension, and a pharmacological study was performed, together with associated reverse transcriptase PCR and immunohistochemistry experiments.
KEY RESULTS
PGE2 induced contractions of IMA (Emax= 1.43 ± 0.20 g; pEC50= 7.50 ± 0.10); contractions were also observed with the EP3 receptor agonists, sulprostone, 17‐phenyl‐PGE2, misoprostol or ONO‐AE‐248. In contrast, PGE2 induced relaxation of the precontracted SV (Emax=–0.22 ± 0.02 g; pEC50= 7.14 ± 0.09), as did the EP4 receptor agonist, ONO‐AE1‐329. These results were confirmed by the use of selective EP receptor antagonists (GW627368X, L‐826266, ONO‐8713, SC‐51322) and by molecular biology and immunostaining.
CONCLUSIONS AND IMPLICATIONS
PGE2 induced potent and opposite effects on the human vascular segments used for grafting, namely vasoconstriction of the IMA and vasodilatation of the SV via EP3 and EP4 receptors respectively. These observations suggest that EP3 and EP4 receptors could constitute therapeutic targets to increase vascular graft patency.
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