Although increased salt intake may stimulate the release of brain ouabain, activate the neuromodulatory pathway, and elevate the arterial pressure in salt-sensitive animals, our data suggest that the opposite is not true; the administration of ouabain does not cause salt sensitivity. The administration of ouabain at physiologically relevant doses never immediately increased arterial blood pressures. A delay of a minimum of one week, more often, 2–5 weeks, between the start of ouabain application and a significant arterial pressure elevation was invariably observed. The absence of an acute hypertensive effect and the delayed onset of an arterial blood pressure increase imply that either ouabain does not have a direct ABT-199 citations vasoconstrictory effect or that this effect is offset by some vasodilatory actions, e.g., enhanced endothelial function, or increased levels of regulator of G-protein signaling 2 protein. Ouabain also stimulated the release of acetylcholine and natriuretic peptides. It has been proposed that ouabain-induced endothelial dysfunction could represent a crucial step in the evolution of ouabain-induced hypertension. We confirmed the downregulation of nitric oxide synthase 1 and 3 gene expression in the aorta, which is a standard response to high salt intake; however, the unchanged expression of nitric oxide synthase genes in the mesenteric arteries and the normal plasma levels of cGMP suggest that there was no significant widespread damaging effect of ouabain on the endothelium. Inducible nitric oxide synthase mRNA was not detectable; this finding argues against the activation of vascular inflammation by ouabain proposed by Wenceslau and colleagues. Endothelial dysfunction in ouabain-treated hypertensive rats was associated with elevated expression of cyclooxygenase 2 and increased production of vasoconstrictory prostanoids. We did not find any significant changes in the mRNA expressions of cyclooxygenase 1 or 2 that were related to ouabain treatment. CGRP is a vasodilatory neuropeptide released from the capsaicin-sensitive sensory nerve endings that innervate the cardiovascular system. Both clinical studies and animal models of hypertension indicate that changes in the synthesis of, release of and/or vascular sensitivity to CGRP may have either a causative or a compensatory and protective role in the development of hypertension. However, to determine whether the documented association between the ouabain application and the elevation of CGRP in plasma is accidental or whether the relationship between CGRP and the resistance to the hypertensive effect of ouabain is indeed causative would require further experimental investigation; such studies might examine a combined application of ouabain and CGRP blocker or might test the arterial blood pressure response to ouabain in CGRP-knockout mice. In addition to being a strong vasodilator, CGRP also has the potential to induce changes in gene expression and autonomic nervous system activity. Thus, more information about the role of CGRP in arterial pressure regulation might shed new light on the pathogenesis of essential hypertension and the role of endogenous ouabain; this knowledge could help develop new treatment modalities.