Wojciech Uracz

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.

Protective Role of Pulmonary Nitric Oxide in the Acute Phase of Endotoxemia in Rats

We present for the first time direct continuous assay of NO concentration (porphyrinic sensor) in the lung parenchyma of Sprague-Dawley rats in vivo during endotoxemia. Intravenous infusion of lipopolysaccharide (LPS, 2 mg x kg(-1) x min(-1) for 10 minutes) stimulated an acute burst of NO from constitutive NO synthase (NOS) that peaked 10 to 15 minutes after the start of LPS infusion, mirroring a coincident peak drop in arterial pressure. NO concentration declined over the next hour to twice above pre-LPS infusion NO levels, where it remained until the rats died, 5 to 6 hours after LPS infusion. The chronic drop in arterial pressure observed from 70 minutes to 6 hours after the start of LPS infusion was not convincingly mirrored by a chronic increase in NO concentration, even though indirect NO assay (Griess method, assaying NO decay products NO2-/NO3-) showed that NO production was increasing as a result of continuous NO release by inducible NOS. A NOS inhibitor, N(omega)-nitro-L-arginine (L-NNA, 10 mg/kg i.v.) injected 45 minutes before LPS infusion, resulted in sudden death accompanied by macroscopically/microscopically diagnosed symptoms similar to acute respiratory distress syndrome <25 minutes after the start of LPS infusion. Pharmacological analysis of this L-NNA+LPS model by replacing L-NNA with 1-amino-2-hydroxy-guanidine (selective inhibitor of inducible NOS) or by pretreatment with S-nitroso-N-acetyl-penicillamine (NO donor), camonagrel (thromboxane synthase inhibitor), or WEB2170 (platelet-activating factor receptor antagonist) indicated that in the early acute phase of endotoxemia, LPS stimulated the production of cytoprotective NO, cytotoxic thromboxane A2, and platelet-activating factor.

Unusual effects of aspirin on ticlopidine induced thrombolysis

For hundreds of years salicylates have been used to treat fever and pain. Following the discovery that aspirin inhibits the biosynthesis of prostanoids,1 particularly thromboxane A2 (TXA2) in blood platelets, aspirin gained a new clinical indication as an antiplatelet and antithrombotic drug. Aspirin acetylates the serine 529 residue of cyclo-oxygenase 1 (COX-1) in platelets and megakaryocytes2; however, tyrosyl residues in inducible COX-2 are also acetylated.3 The anti-inflammatory action of aspirin depends on its interaction with COX-2 and subsequent removal of proinflammatory prostanoids or, possibly, on the appearance of cytoprotective 15-epi-lipoxins.4 Only diclofenac induced COX-2 remains insensitive to aspirin.5 Inhibition of nuclear factor kappa B (NFκB) activation is another mechanism of anti-inflammatory action of salicylates.6 Many unusual actions of aspirin are associated with its acetylating power that extends beyond serine residues in COX-1 or tyrosine residues in COX-2. For instance, the anti-cataract effect of aspirin seems to be associated with acetylation of cysteinyl residues of lens γ-crystallins which prevents the formation of opaque disulphide bonding.7 Aspirin affects the rheological properties of erythrocytes,8 decreases erythrocyte mediated activation of platelets,9 and modifies the functioning of haemoglobin by acetylation of its lysyl residues.10 Even platelet membranes possess protein sites available for acetylation by aspirin.11 In humans thrombinogenesis is inhibited by aspirin, possibly as a consequence of acetylation of either platelet membranes or active sites of prothrombin.12 The relation between sodium salicylate and aspirin is complex. Protective effects of sodium salicylate against inhibition of COX by aspirin have been reported in many systems including patients with aspirin induced asthma.13 On the other hand, both drugs enhance the generation of nitric oxide by activated murine macrophages14 or by cultured rat smooth muscle cells.15 The antithrombotic activity of …