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Deficiencies in Cystathionine‐β‐synthase (CBS) lead to hyperhomocysteinemia (HHCy), which is considered a risk factor for cardiovascular, bone and neurological disease. Moreover, CBS is important for the production of cysteine, hydrogen sulfide (H2S) and glutathione. Studying the biological role of CBS in adult mice has been severely hampered by embryological disturbances and perinatal mortality. To overcome these issues and assess the effects of whole‐body CBS deficiency in adult mice, we engineered and characterized a Cre‐inducible Cbs knockout model during ageing. No perinatal mortality occurred before Cbs−/− induction at 10 weeks of age. Mice were followed until 90 weeks of age and ablation of Cbs was confirmed in liver and kidney but not in brain. Severe HHCy was observed in Cbs−/− (289 ± 58 µM) but not in Cbs+/− or control mice (<10 µM). Cbs−/− showed impaired growth, facial alopecia, endothelial dysfunction in absence of increased mortality, and signs of liver or kidney damage. CBS expression in skin localized to sebaceous glands and epidermis, suggesting local effects of Cbs−/− on alopecia. Cbs−/− showed increased markers of oxidative stress and senescence but expression of other H2S producing enzymes (CSE and 3‐MST) was not affected. CBS deficiency severely impaired H2S production capacity in liver, but not in brain or kidney. In summary, Cbs−/− mice presented a mild phenotype without mortality despite severe HHCy. The findings demonstrate that HHCy is not directly linked to development of end organ damage. [ABSTRACT FROM AUTHOR]

SUL-compounds are protectants from cold-induced ischemia and mitochondrial dysfunction. We discovered that adding SUL-121 to renal grafts during warm machine reperfusion elicits a rapid improvement in perfusion parameters. Therefore, we investigate the molecular mechanisms of action in porcine intrarenal arteries (PIRA). Porcine kidneys were stored on ice overnight and perfusion parameters were recorded during treatment with SUL-compounds. Agonist-induced vasoconstriction was measured in isolated PIRA after pre-incubation with SUL-compounds. Receptor binding and calcium transients were assessed in α1-adrenoceptor (α1-AR) transgenic CHO cells. Molecular docking simulation was performed using Schrödinger software. Renal pressure during warm reperfusion was reduced by SUL-121 (−11.9 ± 2.50 mmHg) and its (R)-enantiomer SUL-150 (−13.2 ± 2.77 mmHg), but not by the (S)-enantiomer SUL-151 (−1.33 ± 1.26 mmHg). Additionally, SUL-150 improved renal flow (16.21 ± 1.71 mL/min to 21.94 ± 1.38 mL/min). SUL-121 and SUL-150 competitively inhibited PIRA contraction responses to phenylephrine, while other 6-chromanols were without effect. SUL-150 similarly inhibited phenylephrine-induced calcium influx and effectively displaced [7-Methoxy-3H]-prazosin in CHO cells. Docking simulation to the α1-AR revealed shared binding characteristics between prazosin and SUL-150. SUL-150 is a novel α1-AR antagonist with the potential to improve renal graft perfusion after hypothermic storage. In combination with previously reported protective effects, SUL-150 emerges as a novel protectant in organ transplantation. [ABSTRACT FROM AUTHOR]