Elif Alan Albayrak

Background/Objectives: Hydrogen sulfide (H₂S) is an important regulator of pulmonary vascular tone; however, the mechanisms underlying its biphasic contractile and relaxant effects, as well as the distinct contributions of endogenous and exogenous H₂S to nitric oxide (NO) signaling, remain incompletely understood. This study investigated the roles of endogenous and exogenous H₂S in regulating pulmonary vascular responses under physiological and oxidative stress conditions. Methods: Rat intrapulmonary arteries were studied using wire myography and simultaneous measurements of vascular force and intracellular Ca²⁺. Pharmacological inhibitors were used to examine the contribution of endogenous H₂S synthesis, NO synthase, soluble guanylate cyclase (sGC), K_ATP channels, and oxidative stress to vascular responses. Results: Sodium hydrogen sulfide (NaHS) produced biphasic concentration-dependent responses, with contraction at low concentrations followed by relaxation at higher concentrations. Simultaneous measurements of vascular force and intracellular Ca²⁺ showed that the initial contractile response to low concentrations of NaHS was not accompanied by a clear increase in intracellular Ca²⁺, whereas relaxation developed despite maintained or increasing intracellular Ca²⁺, indicating that NaHS-induced relaxation cannot be explained solely by reduced intracellular Ca²⁺ levels. Inhibition of endogenous H₂S synthesis reduced vascular responsiveness to the NO donor sodium nitroprusside, whereas relaxation induced by exogenous NaHS was largely preserved after inhibition of NO synthase or sGC, indicating distinct roles of endogenous and exogenous H₂S. Oxidative stress impaired acetylcholine- and riociguat-induced relaxation, while NaHS partially restored endothelial function. Conclusions: Endogenous and exogenous H₂S regulate pulmonary vascular tone through distinct mechanisms. Endogenous H₂S supports vascular responsiveness to NO, whereas exogenous H₂S induces relaxation largely independently of NO–sGC signaling. Furthermore, NaHS-induced relaxation occurs despite maintained intracellular Ca²⁺, suggesting an important contribution of Ca²⁺-independent mechanisms, and partially preserves endothelial function under oxidative stress.

Cyanide is widely recognized for its potent toxicity, yet evidence shows that concentrations below 1 μM may enhance cytochrome c oxidase activity and have a regulatory function. Recent findings also demonstrate that mammalian cells, including endothelial cells, produce cyanide endogenously, where it can modulate mitochondrial bioenergetics. However, the vascular implications of this endogenous production remain unexplored. The review addresses this gap and evaluates the vascular effects of glycine, a proposed substrate for endogenous cyanide synthesis. This systematic review was conducted in accordance with PRISMA 2020 guidelines. Seventy‐eight studies were included. Eligible studies with quantifiable vascular outcomes were screened and synthesized. Exogenous cyanide elicited vascular responses through mitochondrial inhibition, modulation of calcium signalling and interference with the soluble guanylyl cyclase/cyclic guanosine monophosphate pathway. Subchronic low‐dose in vivo cyanide exposure reduced contractions and enhanced relaxation in endothelium‐denuded aortic rings. Collectively, evidence indicates a biphasic pattern: high concentrations are cytotoxic, whereas low concentrations may exert protective/regulatory effects. Low‐dose cyanide may have therapeutic potential in managing vascular disorders associated with endothelial dysfunction. Determining an effective and safe dosage range is crucial, and further studies are needed to clarify the role of endogenous cyanide in regulating vascular function.

Background and Purpose: An estimated 40% of patients with erectile dysfunction have a poor prognosis for improvement with currently available treatments. The present study investigated whether a newly developed monoamine transport inhibitor, IP2015, improves erectile function.Experimental Approach: We investigated the effects of IP2015 on monoamine uptake and binding, erectile function in rats and diabetic mice and the effect on corpus cavernosum contractility.Key Results: IP2015 inhibited the uptake of 5‐HT, noradrenaline and dopamine by human monoamine transporters expressed in cells and in rat brain synaptosomes. Intracavernosal pressure measurement in anaesthetized rats revealed that IP2015 dose‐dependently increased the number and the duration of spontaneous erections. Whereas pretreatment with the dopamine D₂‐like receptor antagonists, clozapine and (−)‐sulpiride, or cutting the cavernosal nerve inhibited IP2015‐induced erectile responses, the phosphodiesterase type 5 inhibitor sildenafil further enhanced the IP2015‐mediated increase in intracavernosal pressure. IP2015 also increased the number of erections in type 2 diabetic db/db mice. Direct intracavernosal injection of IP2015 increased penile pressure, and in corpus cavernosum strips, IP2015 induced concentration‐dependent relaxations. These relaxations were enhanced by sildenafil and blunted by endothelial cell removal, a nitric oxide synthase inhibitor, N^G‐nitro‐l‐arginine and a D₁‐like receptor antagonist, SCH23390. Quantitative polymerase chain reaction (qPCR) showed the expression of the dopamine transporter in the rat corpus cavernosum.Conclusion and Implications: Our findings suggest that IP2015 stimulates erectile function by a central mechanism involving dopamine reuptake inhibition and direct NO‐mediated relaxation of the erectile tissue. This novel multi‐modal mechanism of action could offer a new treatment approach to erectile dysfunction.

High-calorie diet, alcohol, and multiple drug use increase reactive oxygen species (ROS) and cause liver damage. ROS are crucial in the initiation/progression of liver diseases. Antioxidants have beneficial effects but produce clinically complex results. The hydrogen sulfide (H₂S) pathway is considered a promising therapeutic target since it plays role in the pathogenesis/treatment of liver diseases. Sildenafil exerts antioxidant and hepatoprotective effects by increasing specific antioxidants such as superoxide dismutase, glutathione peroxidase, and regulating the Keap1/Nrf2 pathway which are common mechanisms underlying the effects of H₂S. We aimed to determine if H₂S has a role in the hepatoprotective and antioxidant effects of sildenafil. The effect of sildenafil on endogenous H₂S production was elucidated with an H₂S microsensor in the presence/absence of pyrogallol-induced oxidative stress and H₂S synthesis inhibitor aminoxyacetic acid (AOAA) in the liver. The relation between the antioxidant effect of sildenafil and H₂S was determined by luminol and lucigenin chemiluminescence. Sildenafil increased L-cysteine-induced H₂S synthesis in the healthy liver and prevented the pyrogallol-induced reduction in H₂S production. Sildenafil decreased the ROS production induced by pyrogallol and its protective effect was inhibited by AOAA. These results reveal that H₂S is a new pharmacological mechanism of action of sildenafil on the liver. Therefore, sildenafil can be a potential therapeutic agent in treating many liver diseases in which H₂S bioavailability is impaired. Additionally, the hepatoprotective effect of sildenafil by increasing endogenous H₂S synthesis advances our knowledge in terms of developing H₂S-targeting molecules.

Erectile dysfunction (ED) is the inability to achieve/maintain an erection. Because of the side effects, interactions, or ineffectiveness of currently used drugs, novel drug discovery studies are ongoing. The roots of Turkish endemic plants Prangos uechtritzii and Prangos heyniae are traditionally used as aphrodisiacs in Anatolia and contain coumarin-like relaxant compounds. This study aims to reveal the relaxant effect mechanisms of chloroform root extracts of P. heyniae (Ph-CE) and P. uechtritzii (Pu-CE). Isolated organ bath experiments were performed on Swiss albino mouse corpus cavernosum by DMT strip myograph. Relaxant responses to extract (10^-7 -10^-4 g/ml) were obtained in the presence/absence of NO and H₂ S synthesis inhibitors nitro-l-arginine methyl ester (l-NAME, 100 μM) and aminooxyacetic acid (AOAA, 10 mM) respectively. Sodium nitroprusside (SNP, 10^-9 to 10^-4 M) and Na₂ S (10^-6 to 3 × 10^-3 M)-induced relaxations and CaCl₂ (10^-6 to 10^-4 M), KCl (10^-2.1 to 10^-0.9 M) and phenylephrine (3 × 10^-8 to 3 × 10^-5 M)-induced contractions were taken in the presence/absence of the extracts (10^-4 g/ml). Relaxations induced by Ph-CE but not by Pu-CE were inhibited in the presence of l-NAME and AOAA. Ph-CE increased Na₂ S- and SNP-induced relaxations. Ph-CE and Pu-CE decreased the contractions of KCl, phenylephrine, and CaCl₂ . It was concluded that NO and H₂ S synthesis/downstream mechanisms play roles in relaxations of Ph-CE but not in Pu-CE-induced relaxations. Inhibition of calcium influx appears to be involved in the relaxant effect of Ph-CE and Pu-CE. Since the extracts act directly by relaxing smooth muscle or through H₂ S as well as NO, they may be a potential therapeutic agent in diseases such as ED where the bioavailability of NO is impaired.