EDN1 and peripheral arterial disease: Smoking can increase the levels of potent vasoconstricting peptides, such as endothelin-1, for approximately 15 minutes.22 Long-term increased endothelin-1 levels can reduce muscle blood flow and compromise vasodilation.23 Thus, smoking cessation is associated with a decreased risk of progression from PAD to CLI, improved walking ability, and decreased claudication symptoms.22, 23 However, a direct association between smoking cessation and ischemic pain exacerbation has not been established.22