Free chlorine reactions of angiotensin II receptor antagonists: Kinetics study, transformation products elucidation and in-silico ecotoxicity assessment.

Angiotensin II receptor antagonists (ARA II) are widely employed in the treatment of hypertension-related diseases. Because of their partial metabolization and limited biodegradability, these drugs have become ubiquitous pollutants in the aquatic environment, including surface water. This research evaluated the reactivity of the ARA II drugs: irbesartan (IRB), losartan (LOS) telmisartan (TEL) and valsartan (VAL) with free chlorine. Responses of parent compounds and their transformation products (TPs) were followed by liquid chromatography (LC) with quadrupole (Q) time-of-flight (TOF) mass spectrometry. Degradation experiments were carried out using ultrapure and river water samples, adjusted at different pHs and, in some cases, adding a small amount (ng mL-1 level) of bromide salts. Whilst TEL and VAL remained stable in presence of relatively high concentrations of free chlorine (10 mg L-1), IRB and LOS were removed according to a pseudo-first order kinetics model. Considering an initial chlorine concentration of 10 mg L-1, their half-lives varied between 6 and 734 min, depending mostly on the water pH. IRB reacted with free chlorine through hydroxylation processes, with and without molecular cleavage and re-arrangements in the imidazolone ring. Its TPs showed a lower in-silico predicted toxicity than the parent drug. In case of LOS, two major competitive degradation routes were identified. They involved replacement of the methanol group attached to the imidazole cycle by chlorine or bromine, and the cleavage of this cycle with removal of the chlorinated carbon and the nitrogen in alpha position. The TPs generated following the first route are predicted to be more toxic than LOS.

Long-term treatment of spontaneously hypertensive rats with PD123319 and electrophysiological remodeling of left ventricular myocardium.

To investigate the effects of PD123319, an antagonist of angiotensin II subtype-2 receptor (AT2R), on the electrophysiological characteristics of the left ventricular hypertrophic myocardium in spontaneously hypertensive rats (SHR). A total of twenty-four 10-week-old male SHR were divided into two groups: PD123319 and non-PD123319 groups (n = 12 in each). Twelve 10-week-old Wistar-Kyoto rats served as the control group. Systolic blood pressure, left ventricular mass index (LVMI), ventricular effective refractory period, and ventricular fibrillation threshold were also measured after 8 weeks. I Na, I CaL, I to, and membrane capacitance were measured in the left ventricular myocytes after 8 weeks by whole-cell patch clamp. PD123319 increased LVMI compared with the non-PD123319 group (PD123319 vs. non-PD123319, 3.83 ± 0.11 vs. 3.60 ± 0.19 mg/g; P < 0.01). PD123319 also decreased the ventricular fibrillation threshold compared with the non-PD123319 group (PD123319 vs. non-PD123319, 14.75 ± 0.65 vs. 16.0 ± 0.86 mA; P < 0.01). PD123319 enhanced membrane capacitance compared with the non-PD123319 group (PD123319 vs. non-PD123319, 283.63 ± 5.80 vs. 276.50 ± 4.28 pF; P < 0.05). PD123319 increased the density of I CaL compared with the non-PD123319 group (PD123319 vs. non-PD123319, -6.76 ± 0.48 vs. -6.13 ± 0.30 pA/pF; P < 0.05). PD123319 decreased the density of I to compared with the non-PD123319 group (PD123319 vs. non-PD123319, 11.49 ± 0.50 vs. 12.23 ± 0.36 pA/pF; P < 0.05). Long-term treatment with PD123319 worsened the development of myocyte hypertrophy and associated electrophysiological alterations in spontaneously hypertensive rat.