In earlier studies, we provided statistical evidence that individual differences in the angiotensinogen gene, the precursor of the vasoactive hormone angiotensin II, constitute inherited predispositions to essential hypertension in humans (1). We have now identified a common variant in the proximal promoter, the presence of an adenine, instead of a guanine, 6 bp upstream from the initiation site of transcription, in significant association with the disorder. Tests of promoter activity and DNA binding studies with nuclear proteins suggest that this nucleotide substitution affects the basal transcription rate of the gene. These observations provide some biological insight about the possible mechanism of a genetic predisposition to essential hypertension; they may also have important evolutionary implications. ( J. Clin. Invest. 1997. 99:1786-1797.)
Abstract-To explore the role of oxytocin in the regulation of salt appetite and blood pressure, we conducted studies in oxytocin gene-knockout mice and determined (1) blood pressure and heart rate during day and night periods, (2) salt appetite after iso-osmotic volume depletion, and (3) salt appetite and blood pressure after central injection of angiotensin II. Long-term arterial catheters were inserted, and blood pressure and heart rate were recorded for 24 hours. There was a modest decrease in blood pressure and heart rate in knockout mice. Salt appetite was measured with a 2-bottle choice (water and 2% NaCl), with measurement of licking activity. Mice were injected subcutaneously with 30% polyethylene glycol (0.5 mL), and voluntary intakes were measured for 24 hours. Knockout mice consumed 3 times the amount of NaCl than did controls, 276Ϯ77 vs 90Ϯ38 licks/24 h (PϽ0.05). Water consumption was similar between groups. Angiotensin II (5, 50, and 200 ng/3 L) injected intracerebroventricularly produced dose-related increases in intake, with no differences between the groups. The 50-ng dose of angiotensin II elicited salt and water intakes of 151Ϯ43 vs 160Ϯ33 licks and 250Ϯ53 vs and 200Ϯ51 licks, respectively (control vs knockout). The pressor response to angiotensin II was not different between the groups. Results suggest that oxytocin plays a role in the regulation of blood pressure and salt appetite, specifically as mediated by volume receptors, and that the renin-angiotensin system is not involved in these changes. Key Words: mice Ⅲ blood pressure Ⅲ angiotensin Ⅲ renin-angiotensin system Ⅲ water-electrolyte balance Ⅲ sodium O xytocin (OT) is a posterior pituitary hormone that has a wide range of effects on target tissues from the brain to the vasculature. Although OT is well recognized for its role in reproduction, recent discoveries suggest that OT is also involved in regulation of fluid balance, blood pressure (BP), and cardiac function. [1][2][3][4] Oxytocinergic neurons innervate brain regions important in cardiovascular control, such as the nucleus tractus solitarius, locus ceruleus, dorsal motor nucleus of the vagus, and intermediolateral cell column in the spinal cord. 5-7 OT and OT receptors are present in the vasculature, heart, and kidney, 2 and OT has effects on BP, renal function, and salt intake. 1,3 Hypovolemia is a stimulus for cardiovascular and neuroendocrine reflexes, resulting in sympathetic, adrenal, and hypothalamic activation. 8 Experimentally, volume depletion is often induced by the injection of large-molecular-weight colloids, such as polyethylene glycol (PEG), which acts to draw iso-osmotic fluid from the tissues. Time-course and pharmacologic antagonist studies suggest that PEG-induced OT release inhibits salt intake. 9,10 There is also evidence for an OT-specific response to increased osmolality, rather than sodium. 11 A role for central angiotensin II (Ang II) in mediating the OT responses was suggested, because OT antagonists potentiated the salt intake induced by Ang II. 12,13 I...
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