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.

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.