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In resistance arteries, aldosterone impairs the sensitivity of vascular smooth muscle cells to nitric oxide by promoting the local secretion of histamine which activates H<jats:sub>2<\/jats:sub> receptors. The present experiments tested <jats:italic>in vivo<\/jats:italic> and <jats:italic>ex vivo<\/jats:italic> the hypothesis that systemic H<jats:sub>2<\/jats:sub>-receptor antagonism reduces arterial blood pressure and improves vasodilatation in angiotensin II\u2013induced chronic hypertension. Hypertension was induced by intravenous infusion of angiotensin II (60 ng kg<jats:sup>\u22121<\/jats:sup> min<jats:sup>\u22121<\/jats:sup>) in conscious, unrestrained mice infused concomitantly with the H<jats:sub>2<\/jats:sub>-receptor antagonist ranitidine (27.8 \u00b5g kg<jats:sup>\u22121<\/jats:sup> min<jats:sup>\u22121<\/jats:sup>) or vehicle for 24 days. Heart rate and arterial blood pressure were recorded by indwelling arterial catheter. Resistance (mesenteric) and conductance (aortae) arteries were harvested for perfusion myography and isometric tension recordings by wire myography, respectively. Plasma was analyzed for aldosterone concentration. ANGII infusion resulted in elevated arterial blood pressure and while <jats:italic>in vivo<\/jats:italic> treatment with ranitidine reduced plasma aldosterone concentration, it did not reduce blood pressure. Ranitidine improved <jats:italic>ex vivo<\/jats:italic> endothelial function (acetylcholine 10<jats:sup>\u22129<\/jats:sup> to 10<jats:sup>\u22126<\/jats:sup> mol L<jats:sup>\u22121<\/jats:sup>) in mesenteric resistance arteries. This was abolished by <jats:italic>ex vivo<\/jats:italic> treatment with aldosterone (10<jats:sup>\u22129<\/jats:sup> mol L<jats:sup>\u22121<\/jats:sup>, 1 h). In aortic segments, <jats:italic>in vivo<\/jats:italic> ranitidine treatment impaired relaxation. Activation of histamine H<jats:sub>2<\/jats:sub> receptors promotes aldosterone secretion, does not affect arterial blood pressure, and protects endothelial function in conduit arteries but promotes endothelial dysfunction in resistance arteries during angiotensin II\u2013mediated hypertension. Aldosterone contributes little to angiotensin II\u2013induced hypertension in mice.<\/jats:p>","DOI":"10.1007\/s00424-024-02909-0","type":"journal-article","created":{"date-parts":[[2024,1,27]],"date-time":"2024-01-27T14:02:18Z","timestamp":1706364138000},"page":"307-321","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Histamine H2-receptor antagonism improves conduit artery endothelial function and reduces plasma aldosterone level without lowering arterial blood pressure in angiotensin II\u2013hypertensive mice"],"prefix":"10.1007","volume":"476","author":[{"given":"Kasper B.","family":"Assersen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7607-213X","authenticated-orcid":false,"given":"Boye L.","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Enggaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Vanhoutte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pernille B. 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