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During global hypoxia, however,<jats:styled-content style=\"fixed-case\">HPV<\/jats:styled-content>induces general pulmonary vasoconstriction, which may lead to pulmonary hypertension (<jats:styled-content style=\"fixed-case\">PH<\/jats:styled-content>), impaired exercise capacity, right\u2010heart failure and pulmonary oedema at high altitude. In chronic hypoxia, generalized<jats:styled-content style=\"fixed-case\">HPV<\/jats:styled-content>together with hypoxic pulmonary arterial remodelling, contribute to the development of<jats:styled-content style=\"fixed-case\">PH<\/jats:styled-content>. The present article reviews the principal pathways in the<jats:italic>in\u00a0vivo<\/jats:italic>modulation of<jats:styled-content style=\"fixed-case\">HPV<\/jats:styled-content>, hypoxic pulmonary arterial remodelling and<jats:styled-content style=\"fixed-case\">PH<\/jats:styled-content>with primary focus on the endothelin\u20101, nitric oxide, cyclooxygenase and adenine nucleotide pathways. In summary, endothelin\u20101 and thromboxane A<jats:sub>2<\/jats:sub>may enhance, whereas nitric oxide and prostacyclin may moderate,<jats:styled-content style=\"fixed-case\">HPV<\/jats:styled-content>as well as hypoxic pulmonary arterial remodelling and<jats:styled-content style=\"fixed-case\">PH<\/jats:styled-content>. The production of prostacyclin seems to be coupled primarily to cyclooxygenase\u20101 in acute hypoxia, but to cyclooxygenase\u20102 in chronic hypoxia. The potential role of adenine nucleotides in modulating<jats:styled-content style=\"fixed-case\">HPV<\/jats:styled-content>is unclear, but warrants further study. Additional modulators of the pulmonary vascular responses to hypoxia may include angiotensin<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>, histamine, serotonin\/5\u2010hydroxytryptamine, leukotrienes and epoxyeicosatrienoic acids. Drugs targeting these pathways may reduce acute and\/or chronic hypoxic<jats:styled-content style=\"fixed-case\">PH<\/jats:styled-content>. Endothelin receptor antagonists and phosphodiesterase\u20105 inhibitors may additionally improve exercise capacity in hypoxia. Importantly, the modulation of the pulmonary vascular responses to hypoxia varies between species and individuals, with hypoxic duration and age. The review also define how drugs targeting the endothelin\u20101, nitric oxide, cyclooxygenase and adenine nucleotide pathways may improve pulmonary haemodynamics, but also impair pulmonary gas exchange by interference with<jats:styled-content style=\"fixed-case\">HPV<\/jats:styled-content>in chronic lung diseases.<\/jats:p>","DOI":"10.1111\/apha.12749","type":"journal-article","created":{"date-parts":[[2016,7,6]],"date-time":"2016-07-06T07:16:56Z","timestamp":1467789416000},"page":"728-756","source":"Crossref","is-referenced-by-count":77,"title":["The principal pathways involved in the<i>in\u00a0vivo<\/i>modulation of hypoxic pulmonary vasoconstriction, pulmonary arterial remodelling and pulmonary hypertension"],"prefix":"10.1111","volume":"219","author":[{"given":"D.","family":"Kylhammar","sequence":"first","affiliation":[{"name":"Department of Clinical Sciences Lund, Cardiology Faculty of Medicine Lund University Lund Sweden"},{"name":"The Section\u00a0for Heart Failure and Valvular 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