EFFECT OF MACROLIDES ON VASCULAR CELLS AND BLOOD PRESSURE CONTROL

Hypertension is a major risk factor for an estimated 17.9 million people who died from cardiovascular diseases in 2019, representing 32% of all global deaths. There are an estimated 1.13 billion people affected around the world (B. Zhou,2021). For decades there many pharmacological approaches to treat hypertension have been developed, and now are many classes of antihypertensive drugs acting on different levels targeting the main pathophysiological mechanisms involved in the development of hypertension (Tarun Saxena et al., 2018). The calcium channel blocker (CCB) class is one of the important classes of drugs for hypertension treatment, acting at the level of vascular smooth muscle cells by blocking L-type calcium channels and improving vasodilation (Jacek Rysz et al.,2020). The use of calcium channel blockers is a well well-established class of drugs and is widely used. (Thomas Unger et al., 2020). Concomitant use of calcium channel blockers (CCB) and macrolides antibiotics has been reported to induce low blood pressure. Macrolides are believed to prolong the metabolism of calcium channel blockers by interfering with cytochrome P450(CYP3A4) action, which metabolizes the calcium channel blockers in the liver. In the MAPA (Macrolides for KCNJ5-mutated aldosterone-producing adenoma) study (not published), that looked at the effect of Roxithromycin on blood pressure in patients with primary aldosterone vs. control of primary hypertension, when given a single dose of roxithromycin, there was a decline in systolic blood pressure in a group of patients with primary hypertension. Despite the well-explained drug interaction, in lowering blood pressure, between macrolides and calcium channel blockers through P450(CYP3A4) action, one may wonder what is the mechanism behind the drop of blood pressure when macrolides were used alone as it was found in the MAPA study. We hypothesized that: There is a direct effect of macrolides on vascular cells with ensuing blood vessel relaxation and blood pressure regulation. Therefore, this study aimed to investigate if macrolides acting locally on vessels can induce vasorelaxation and identify the underlying mechanisms. MATERIAL AND METHODS: to prove the hypothesis: the effects of 3 macrolides (roxithromycin, azithromycin, clarithromycin) were acutely investigated in isolated C57BL/6J mice aortas on wire myograph, following standard protocols. Longer-term effects of azithromycin (50 mg/Kg/d intraperitoneally for 14 days) were investigated in a mouse model of Ang II (AngII; 1.44 mg/kg/day, 14 days) induced hypertension. Blood pressure, functional, and structural/mechanical properties of the aorta and mesenteric arteries were evaluated as appropriate. RESULTS:1. In acute conditions using a concertation response curve and single doses, all 3 macrolides (roxithromycin, azithromycin, clarithromycin) induced vasorelaxation in phenylephrine pre-contracted aorta segments of C57BL/6J mice, this was not the case with vehicle drug (DMSO) which in contrary caused vasoconstriction. 2. In acute conditions, after the removal of the endothelium in phenylephrine pre-contracted, the Azithromycin-induced relaxation effect was abolished. Furthermore, the incubation with L-NAME abolished the vasorelaxation effect of Azithromycin.3. Preventive treatment with Azithromycin significantly reduced AngII-induced hypertension, vascular hypercontractility, and endothelial dysfunction and increased bioavailability of the Vaso protective factors NO. Moreover, Azithromycin partially modified AngII-induced vascular remodeling without affecting vascular stiffness. CONCLUSION: the current results of this Doctoral Thesis suggest that in acute conditions Macrolides can induce vasorelaxation. This effect is endothelial-dependent and driven by Nitric Oxide. In long-term treatment, Azithromycin reduced systolic blood pressure, provided endothelial protection, and modified Ang II-induced structure changes in mesenteric-resistant arteries.