Comparison of Endothelial Pleiotropic Actions of Angiotensin Converting Enzyme Inhibitors and Statins

Abstract

Two in vitro and one in vivo assay were performed to study the endothelial pleiotropic actions of “tissue type” angiotensin converting enzyme inhibitors (ACE‐Is) such as perindopril and quinapril, their active forms, that is, quinaprilat and peridoprilat, or of statins belonging to natural (lovastatin), semisynthetic (simvastatin), and synthetic enantiomeric (atorvastatin, cerivastatin) classes. Cytoplasmic [Ca2+]i levels in cultured bovine aortic endothelial cells and endothelium‐dependent nitric oxide‐mediated coronary vasodilatation in the Langendorff preparation of guinea pig heart constituted our in vitro assays. The in vivo assay consisted of study of PGI2‐mediated thrombolytic response in arterial blood of rats after intravenous administration of drugs. In this last assay, perindopril and quinapril proved to be, by two orders of magnitude, more potent PGI2‐dependent thrombolytics than the most potent statin (atorvastatin). However, in both in vitro assays we found a higher endothelial efficacy of statins as compared to ACE‐Is. In particular, those statins that contain the lactone ring in their molecules (lovastatin, simvastatin) were the most potent coronary vasodilators. In summary, the in vivo profile of action of ACE‐Is and statins contrasted with their reversed order of potency in vitro. We hypothesize that the endocrine‐like function of the pulmonary circulation [28‐31] may be responsible for the in vivo bradykinin‐triggered, PGI2‐mediated thrombolysis by ACE‐Is, whereas the pleiotropic action of statins, possibly involving inhibition of prenylation [14‐19], is diffused throughout many vascular beds.

No effects of atorvastatin (10mg/d or 80mg/d) on nitric oxide, prostacyclin, thromboxane and oxidative stress in type 2 diabetes mellitus patients of the DALI study

“…Nevertheless, the statistically insignificantly changed urinary excretion rates of 2,3-dinor-TxB 2 and 2,3-dinor-6-keto-PGF 1␣ , as well as their molar ratio suggest that the TxA 2 /PGI 2 homeostasis was not altered to a major extent by atorvastatin or placebo in the patients investigated. Literature reports on the effects of atorvastatin on TxA 2 [71][72][73][74][75][76][77][78][79] and PGI 2 [80][81][82][83] synthesis in diabetes are rare and contradictory, presumably because the TxA 2 and PGI 2 synthesis has not been assessed by measuring 2,3-dinor-TxB 2 and 2,3-dinor-6-keto-PGF 1␣ , respectively, as required [41] and has been performed in the present study. It is of particular interest that the urinary excretion of 8-iso-PGF 2␣ correlated considerably with that of 2,3-dinor-TxB 2 but not with the urinary excretion of 2,3-dinor-6-keto-PGF 1␣ , although 2,3-dinor-6-keto-PGF 1␣ correlated with 2,3-dinor-TxB 2 .…”

Statin therapy, alone or with rapamycin, does not reverse monocrotaline pulmonary arterial hypertension: the rapamcyin-atorvastatin-simvastatin study

“…Although atorvastatin is generally believed to be more potent than simvastatin in terms of LDL reduction and certain pleiotropic effects, including antiinflammatory and antioxidant properties, it is possible, although in our opinion unlikely, that simvastatin has more potent pleiotropic effects that are most relevant in MCT-PAH. For example, it has been suggested that simvastatin is a more potent coronary artery vasodilator than atorvastatin, perhaps due to the presence of a lactone ring (13). It might be that simvastatin behaves as a potent pulmonary vasodilator in MCT-PAH instead of an antiproliferative therapy.…”

Anti-thrombotic effects of nebivolol and carvedilol: Involvement of β2 receptors and COX-2/PGI2 pathways

“…28 Most cardiovascular disorders are associated with endothelial 29 dysfunction, which is characterized by diminished production or 30 bioavailability of endothelium-derived nitric oxide (NO), as well as 31 the alteration in prostacyclin (PGI 2 ) activity. In contrast to the 32 numerous reports on the effects of third generation beta- 33 adrenergic antagonists on NO-dependent function, including 34 reports documenting their ability to reverse the impairment of 35 NO-dependent endothelial function in humans [22][23][24][25][26][27], little is 36 known on the ability of carvedilol and nebivolol to modulate PGI 2 -37 dependent endothelium functions. Interestingly, antiplatelet 38 effects of nebivolol [28,29] and carvedilol [30] were demonstrated, 39 but the involvement of PGI 2 in these effects was not investigated.…”

“…Furthermore, the inhibition of platelet activation by low dose 263 aspirin or the stimulation of COX-2-derived PGI 2 by ACE inhibitors 264 or by other drugs afforded pronounced anti-thrombotic effects in 265 this model, while the NO-dependent pathway played a negligible 266 role [32,36]. Accordingly, our present findings that nebivolol and 267 carvedilol display an ability to limit platelet-dependent thrombo-268 sis by the COX-2/PGI 2 pathway seems fully consistent with the 269 nature of this experimental model.…”

“…were formed on the collagen strip superfused with blood 260 [36]. Importantly, in this model of arterial thrombosis, the platelets 261 made a major contribution to the development of thrombosis.…”