Ewa Marcinkiewicz

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.

Platelet aggregation and thromboxane A2 formation in cat platelet rich plasma.

Summary Platelet aggregation in cat platelet rich plasma (PRP) was induced by the threshold concentrations of adenosine diphosphate (ADP 0.5–2.0 μM), collagen (1.0–5.0 μg/ml), arachidonic acid (/AA/50–150 μM) and thrombin (0.2–0.6 units/ml). Aggregation induced by the first three agents was associated with the release of thromboxane A 2 (TXA 2 ). TXA 2 was bioassayed on a strip of rabbit mesenteric artery against 11,9-epoxymethano analog of PGH 2 (EMA). The maximal TXA 2 synthetizing capacity of cat PRP was 2000–3000 ngEq EMA/ml as measured during the AA-induced (600–800 μM) platelet aggregation. Collagen-induced (10–50μg/ml) platelet aggregation was accompanied by the release of TXA 2 in an amount of 490±40 ngEq EMA/ml PRP. When PRP was aggregated by the threshold concentrations of AA or collagen then the amounts of the detected TXA 2 ranged from 100–250 ngEq EMA/ml. The second phase of ADP-induced (1–5 μM) platelet aggregation produced a short-lasting peak of the TXA 2 release in PRP (maximal rise up to 250 ngEq EMA/ml). AA-induced, collagen-induced and the second phase of ADP-induced platelet aggregation as well as the generation of TXA 2 by PRP, all of them were suppressed by the TXA 2 synthetase inhibitor — nictindole (10 nM-3 μM). It is concluded that in platelet aggregation induced by AA, collagen and ADP TXA 2 plays an important role.

Mesoionic Oxatriazoles (MOTA): NO-Donating Characteristics and Pharmacology

Biological role of nitric oxide (NO), functioning of isoforms of NO synthetases (NOS) and pharmacology of principle NO-donors were reviewed. NO donating characteristics and pharmacology of 23 mesoionic oxatriazoles (MOTA) were compared with those of 5-morpholinosydnonimine (SIN-1), S-nitroso-N-acetylpenicillamine (SNAP), sodium nitroprusside (NaNP) and glyceryl trinitrate (GTN). It is concluded that in vitro NO donating profile of MOTA hardly can be used as a predicting measure for their pharmacological activities either in vitro or in vivo. If anything, fast NO releasers seem to be stronger vasorelaxants than MOTA with slow NO releasing properties. Still, among representatives of this last category of MOTA one may find efficient antithrombotic and thrombolytic agents. For instance, MOTA 5-oxides were more potent thrombolytics than SIN-1, SNAP or NaNP. Also MOTA with potent anti-platelet action in vitro seem to be potent relaxants of tracheal strips. In summary, by manipulating the chemical structures of MOTA one may obtain relative selectivity towards vasorelaxant, anti-platelet, thrombolytic or tracheorelaxant properties. Thus different categories of MOTA might be designed with a hope of achieving hypotensive, antithrombotic, thrombolytic or anti-asthmatic drugs.