The NO/ONOO？ cycle is a primarily local biochemical/physiological vicious cycle that appears to cause a series of chronic inflammatory diseases. This paper focuses on whether the cycle causes pulmonary arterial hypertension (PAH) when located in the pulmonary arteries. The cycle involves 12 elements, including superoxide, peroxynitrite (ONOO？), nitric oxide (NO), oxidative stress, NF-κB, inflammatory cytokines, iNOS, mitochondrial dysfunction, intracellular calcium, tetrahydrobiopterin depletion, NMDA activity, and TRP receptor activity. 10 of the 12 are elevated in PAH (NMDA?, NO?) and 11 have documented causal roles in PAH. Each stressor that initiates cases of PAH acts to raise cycle elements, and may, therefore, initiate the cycle in this way. PAH involves a primarily local mechanism as required by the cycle and the symptoms and signs of PAH are generated by elements of the cycle. Endothelin-1, which acts as a causal factor in PAH, acts as part of the cycle; its synthesis is stimulated by cycle elements, and it, in turn, increases each element of the cycle. This extraordinary fit to the principles of the NO/ONOO？ cycle allows one to conclude that PAH is a NO/ONOO？ cycle disease, and this fit supports the cycle as a major paradigm of chronic inflammatory disease. 1. Introduction Pulmonary arterial hypertension (PAH) is a progressive and often fatal disease characterized by several important properties including inflammation, oxidative/nitrosative stress, and mitochondrial dysfunction. Such hypertension leads to right ventricular dysfunction that leads in turn to subsequent right heart failure and death. A number of other chronic diseases that share properties described in the first sentence, above, are thought to be caused by a primarily local biochemical vicious cycle, known as the NO/ONOO？ cycle (pronounced no, oh no!) [1–11]. Thus the hypothesis being explored in this paper is whether pulmonary hypertension is caused by the local action of the NO/ONOO？ cycle in the pulmonary arteries. One of the testable properties of NO/ONOO？ cycle diseases is that for the cycle to be causal, the symptoms and signs of the disease must be generated by elements of the cycle. The classic properties of PAH are vasoconstriction and pulmonary fibrosis and arterial remodeling. Hypertension can be generated by excessive peroxynitrite (ONOO？), which is a vasoconstrictor [12–16], acting in part via oxidative stress and consequent elevated isoprostanes, because isoprostanes are potent vasoconstrictors [12, 13]. Elevated ONOO？ can lead to oxidation of tetrahydrobiopterin
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