Comparison of endothelial pleiotropic actions of angiotensin converting enzyme inhibitors and statins.
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.
Gryglewski
R J
RJ
Jagiellonian University, Cracow, Poland. mfgrygle@kinga.cyf-kr.edu.pl
Uracz
W
W
Swies
J
J
Chlopicki
S
S
Marcinkiewicz
E
E
Lomnicka
M
M
Madej
J
J
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001011:Aorta; D002417:Cattle; D002478:Cells, Cultured; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D011464:Epoprostenol / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000502:physiology
D000806:Angiotensin-Converting Enzyme Inhibitors; D000924:Anticholesteremic Agents; D005343:Fibrinolytic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010975:Platelet Aggregation Inhibitors; D009569:Nitric Oxide; D011464:Epoprostenol