Hydrogen sulfide regulation of renal and mesenteric blood flow

Abstract

Hydrogen sulfide (H2S) dilates isolated arteries, and knockout of the H2S-synthesizing enzyme cystathionine γ-lyase (CSE) increases blood pressure. However, the contributions of endogenously produced H2S to blood flow regulation in specific vascular beds are unknown. Published studies in isolated arteries show that CSE production of H2S influences vascular tone more in small mesenteric arteries than in renal arteries or the aorta. Therefore, the goal of this study was to evaluate H2S regulation of blood pressure, vascular resistance, and regional blood flows using chronically instrumented rats. We hypothesized that during whole animal CSE inhibition, vascular resistance would increase more in the mesenteric than the renal circulation. Under anesthesia, CSE inhibition [β-cyanoalanine (BCA), 30 mg/kg bolus + 5 mg·kg−1·min−1 for 20 min iv) rapidly increased mean arterial pressure (MAP) more than saline administration (%Δ: saline −1.4 ± 0.75 vs. BCA 7.1 ± 1.69, P < 0.05) but did not change resistance (MAP/flow) in either the mesenteric or renal circulation. In conscious rats, BCA infusion similarly increased MAP (%Δ: saline −0.8 ± 1.18 vs. BCA 8.2 ± 2.6, P < 0.05, n = 7) and significantly increased mesenteric resistance (saline 0.9 ± 3.1 vs. BCA 15.6 ± 6.5, P < 0.05, n = 12). The H2S donor Na2S (50 mg/kg) decreased blood pressure and mesenteric resistance ,but the fall in resistance was not significant. Inhibiting CSE for multiple days with dl-proparglycine (PAG, 50 mg·kg−1·min−1 iv bolus for 5 days) significantly increased vascular resistance in both mesenteric (ratio of day 1: saline 0.86 ± 0.033 vs. PAG 1.79 ± 0.38) and renal circulations (ratio of day 1: saline 1.26 ± 0.22 vs. 1.98 ± 0.14 PAG). These results support our hypothesis that CSE-derived H2S is an important regulator of blood pressure and vascular resistance in both mesenteric and renal circulations. Furthermore, inhalation anesthesia diminishes the effect of CSE inhibition on vascular tone. NEW & NOTEWORTHY These results suggest that CSE-derived H2S has a prominent role in regulating blood pressure and blood flow under physiological conditions, which may have been underestimated in prior studies in anesthetized subjects. Therefore, enhancing substrate availability or enzyme activity or dosing with H2S donors could be a novel therapeutic approach to treat cardiovascular diseases.

Vasorelaxant Activity of AP39, a Mitochondria-Targeted H2S Donor, on Mouse Mesenteric Artery Rings In Vitro

“…In the present study, we showed that resistance mesenteric arteries express all three H 2 S-producing enzymes, CSE being the most abundant, with a minor expression of both CBS and 3MPST, in agreement with previous reports [ 38 ] and confirming the relevant physiological role of CSE in the control of mesenteric blood flow [ 37 , 39 ]. Although CSE and 3MPST play major roles in the cardiovascular system (they are also the main enzymes expressed in vessels such as the coronary artery [ 40 ] and aorta [ 41 ]), some studies performed on human endothelial cells from an umbilical vein (HUVEC) point out that CBS activity can be involved in endothelial function regulation [ 42 , 43 ].…”

“…Resistance arteries are the main vessels responsible for the control of blood flow, and consequently blood pressure, due to their small internal diameter and the thick muscular wall in relation to the narrow lumen [ 8 , 37 ]. In this way, investigations on the vascular effects of new compounds on resistance vessels are a mandatory step for the development of novel cardiovascular drugs.…”

Sulfur-Containing Amino Acids, Hydrogen Sulfide, and Sulfur Compounds on Kidney Health and Disease

“…Meanwhile, renal blood flow can be increased by intrarenal arterial infusion of NaHS [ 52 ]. Additionally, a CSE inhibitor decreased blood flow in the renal artery in rats, suggesting CSE-derived H 2 S has a prominent role in regulating renal blood flow and vascular resistance in renal circulation [ 53 ].…”

Roles of Hydrogen Sulfide Donors in Common Kidney Diseases

“…Treatment with a phosphorothioate-based synthetic H 2 S donor JK-1 suppresses the activation of RAAS, reduces BP, and improves renal functions (Li et al, 2018). It has also been shown that the treatment of anesthetized rat models with H 2 S donor Na 2 S can significantly decrease the BP and mesenteric resistance; meanwhile, the administration of CSE inhibitors (β-cyanoalanine) and PAG could increase BP and resistance in both mesenteric and renal circulations (Morales-Loredo et al, 2019). Another component involved in BP regulation is cyclic guanosine monophosphate (cGMP).…”

“…Although primary injuries can be well repaired, the defects in the repair mechanism can augment the condition, thus resulting in tissue and organ injury. For instance, HIF activation can prevent the degeneration of tissue by improving oxygen balance and promoting cell repair ( Bernhardt et al, 2006 ); however, its prolonged stimulation can result in the progression of tissue injury by increasing ECM accumulation and inflammatory responses ( Haase, 2012 ; Conde et al, 2017 ). The injuries are the result of high apoptosis, podocyte loss, accumulation of ECM, and inflammation.…”