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Ex-vivo effect of roxithromycin on human and rat arterial vasoactivity

¹ Departments of Cardiothoracic Surgery, Rabin Medical Center, Beilinson Campus, Petach Tikva, Affiliated to Tel Aviv University, Tel Aviv, 49100 Israel
² Departments of Cardiology, Rabin Medical Center. Affiliated to Tel Aviv University, Tel Aviv, Israel
³ Cardiac Research Laboratory, Felsenstein Center, Rabin Medical Center. Affiliated to Tel Aviv University, Tel Aviv, Israel

*Corresponding author. Tel.: +972-3-9376701; fax: +972-3-9240762.

E-mail address: mariusb{at}clalit.org.il (M. Berman), mariusby{at}yahoo.com (M. Berman).

Background: Prior studies have suggested that inflammation and possibly bacterial infections play a role in atherogenesis and in the clinical pathogenesis of cardiovascular diseases. Treatment with the macrolide antibiotics has been associated with improved outcome from cardiovascular disease, although the mechanism through which they exert their effects may be unrelated to their antibiotic properties. Drugs that exert a vasodilator effect on arteries have been associated with attenuated atherogenesis and improved outcome from cardiovascular disease. Aim: To determine the effect of the macrolide, roxithromycin (RX), on arterial vasoactivity. Methods: Human internal mammary artery (IMA) and rat thoracic aorta (TA) rings were placed in organ chambers and contracted with norepinephrine (NE). Endothelial and smooth muscle integrity were assessed using acetylcholine (ACh) and nitroprusside (SNP), respectively. After restabilization, the rings were exposed to 10^–6 M NE, followed by increasing concentrations of RX (10^–7–10^–4 M), then by 10^–5 M SNP. The mechanism of RX action was tested in rats using solutions containing 10^–6 M L-NAME, a nitric oxide synthase inhibitor; 10^–6 M calcium ionophore (Ca), a calcium channel agonist; 10^–6 M indomethacin (Indo), a prostaglandin inhibitor; 10^–6 M glibenclamide (Glib), a membrenal ATP-sensitive-K⁺-channel inhibitor; 10^–6 M 5-hydroxydecanoic acid (5-HD), a mitochondrial ATP-sensitive-K⁺-channel inhibitor. Results: Human IMAs and rat TAs exhibited similar contraction in response to NE and relaxation in response to RX, and ACh. RX-related relaxation was dose dependent (4.5±1 to 15±3%), similar to ACh, and lower than SNP. Relaxation was significantly reduced in the presence of Ca, L-NAME, and 5-HD (P<0.005). Glib and Indo had no effect on relaxation. Lower levels of relaxation in response to RX were observed in TAs without endothelium (P<0.005). Conclusions: RX exerts a mild endothelium-dependent vasodilatory effect mediated by calcium, mitochondrial K⁺-ATP channels and NO production, possibly explaining part of its mild salutary clinical effects.

Key Words: Atherosclerosis; Roxithromycin; Coronary disease; Macrolide; Endothelium

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