title: Cardiovascular effects induced by polymeric 3-alkylpyridinium salts from the marine sponge Reniera sarai.
abstract: Water-soluble polymeric 3-alkylpyridinum salts (poly-APS), isolated from the marine sponge Reniera sarai, are natural products with promising biomedical applications. However, their ability to form non-specific cell membrane pores raises safety issues. Therefore, the aim of the present study was to investigate the direct toxic effects of poly-APS on the cardiovascular system. To study the impact of poly-APS toxicodynamics on vascular function, the relaxation and contraction responses of isolated rat thoracic aortas incubated in poly-APS solutions (0.01-10 μM) were tested. In addition, cardiac toxicity was studied by measuring coronary flow, lactate dehydrogenase release rate, left ventricular pressure, heart rate, and the duration of arrhythmias in isolated rat hearts perfused with poly-APS (0.001-1 μM). Poly-APS diminished endothelium-dependent relaxation and contraction in a concentration- and time-dependent manner. Endothelial function was affected earlier and to a greater extent than contractile responses. Likewise, in isolated hearts the most evident cardiotoxic effects were observed after perfusion with the highest concentration (1 μM) of poly-APS: compared to the control group the coronary flow and heart rate were diminished by 2.2- and 1.8-fold, while lactate dehydrogenase release rate and left ventricular pressure were increased by 7.8- and 2.2-fold (all P < 0.001). Further, poly-APS had evident proarrhythmogenic activity in a concentration-dependent manner. However, in the low concentration range (1-10 nM) poly-APS showed only minor toxicity. Our results confirmed the direct toxic effects of poly-APS on the rat cardiovascular system. Therefore, it seems reasonable to conclude that the use of poly-APS as therapeutic adjuvants has limited safety margins.
authors: Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia.
authors: Mojca
authors: M
authors: Lunder
authors: Gorazd
authors: G
authors: Drevenšek
authors: Simon
authors: S
authors: Hawlina
authors: Kristina
authors: K
authors: Sepčić
authors: Lovro
authors: L
authors: Ziberna
mesh_terms: D000818:Animals; D054715:Cardiotoxins / Q000633:toxicity; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000503:physiopathology*; D002319:Cardiovascular System / Q000187:drug effects* / Q000473:pathology; D002462:Cell Membrane / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D011108:Polymers / Q000633:toxicity*; D011161:Porifera / Q000737:chemistry*; D011726:Pyridinium Compounds / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D054715:Cardiotoxins; D011108:Polymers; D011726:Pyridinium Compounds; C115254:poly-APS; D007770:L-Lactate Dehydrogenase