title: Hepatic and renal mechanisms underlying the osmopressor response.
abstract: Increased blood pressure (BP) is observed in patients with impaired baroreflexes after water drinking. The stimulus for this effect is low blood osmolality, and it has been termed the osmopressor response (OPR). The BP increase is associated with activation of the sympathetic nervous system and a requirement for transient receptor potential vanilloid 4 (TRPV4) channels. However, the mechanisms underlying the OPR are poorly understood. We tested the hypothesis that hypotonicity is sensed in the portal area to initiate the OPR. Sino-aortic denervated mice were used and BP was monitored for 30min after fluid infusion while mice were under anesthesia. Infusion of hypotonic fluid (0.45% saline), but not of isotonic 0.9% saline, directly into the portal vein, produced an immediate OPR (increase in BP with saline 0.45%: 15±13 vs. 0.9%: -7±2mmHg, p=0.003; AUC: 0.45%: 150±99, n=7 vs. 0.9%: -74±60mmHg·min, n=5, p=0.003). However, 0.45% saline was not able to trigger a similar response in TRPV4-/-mice (ΔBPTRPV4: -2±5mmHg, n=8, p=0.009). Hypotonic saline did not raise BP when infused at the same speed and volume into the jugular vein (jugular: -5±6mmHg, p=0.002, compared to portal). Denervation of the splanchnic nerve by celiac ganglionectomy (CGX) did not abolish the OPR (CGX: 15±11 vs. Sham: 16±6mmHg, p=0.34). Renal denervation diminished the OPR elicited by duodenal water infusion (denervation: 9±4 vs. sham: 31±15mmHg, p=0.016). Therefore, hypotonicity in the portal circulation, probably sensed by TRPV4 channels, triggers the OPR and intact renal nerves are needed for the full response.
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN, United States; Department of Clinical Pharmacology, Vanderbilt University, Nashville, TN, United States.
authors.forename: Tu H
authors.initials: TH
authors.lastname: Mai
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, United States; Department of Clinical Pharmacology, Vanderbilt University, Nashville, TN, United States.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Garland
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, United States; Department of Biomedical Engineering, Vanderbilt University, United States; Department of Clinical Pharmacology, Vanderbilt University, Nashville, TN, United States.
authors.forename: André
authors.initials: A
authors.lastname: Diedrich
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN, United States; Department of Medicine, Vanderbilt University Medical Center, United States; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States; Department of Clinical Pharmacology, Vanderbilt University, Nashville, TN, United States. Electronic address: david.robertson@vanderbilt.edu.
authors.forename: David
authors.initials: D
authors.lastname: Robertson
mesh_terms: D000818:Animals; D017763:Autonomic Denervation; D017704:Baroreflex / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology*; D004326:Drinking / Q000502:physiology*; D060766:Drinking Water / Q000008:administration & dosage; D004386:Duodenum / Q000378:metabolism; D007038:Hypotonic Solutions / Q000008:administration & dosage; D007601:Jugular Veins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009994:Osmolar Concentration; D011169:Portal Vein / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013153:Splanchnic Nerves / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D060766:Drinking Water; D007038:Hypotonic Solutions; D017673:Sodium Chloride, Dietary; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse
keywords: Osmopressor response; Portal infusion; Renal denervation; Sino-aortic denervation