title: Impaired function of endothelial pressure-activated cation channel in salt-sensitive genetic hypertension.
abstract: Mechanosensitive ion channels have been suggested to act as endothelial mechanosensors for hemodynamic forces. The present study tested the hypothesis that the pressure-activated cation channel (PAC), a novel type of endothelial mechanosensitive ion channel, is involved in salt sensitivity in the Sabra rat model of hypertension. Groups of Sabra salt-sensitive (SBH/y) and salt-resistant (SBN/y) rats were loaded with deoxycorticosterone-acetate (DOCA)-salt for 8 wk or were fed a regular diet. Single channel function of PAC in SBH/y and SBN/y rats was investigated in intact endothelium of mesenteric artery using the patch-clamp technique. After DOCA-salt treatment, the SBH/y rats showed a full hypertensive response, whereas SBN/y rats were normotensive. Rats of both strains that received a regular diet were normotensive. In endothelium of both Sabra rats, Ca(2+) permeable PAC that was activated by positive pipette pressures was identified. Apparent PAC density (percentage of patches with PAC activity) was reduced in hypertensive SBH/y rats that were loaded with DOCA-salt compared with salt-loaded normotensive SBN/y rats (6 +/- 2% versus 24 +/- 8%, respectively; P < 0.05). In normotensive SBH/y and SBN/y rats that received a regular diet, PAC density was not altered. Mechanosensitivity and unitary conductance of endothelial PAC were similar in both strains under a regular diet as well as salt loading with DOCA-salt. In conclusion, the decreased density of PAC in mesenteric endothelium from hypertensive SBH/y rats indicates an impaired ion channel regulation. The defective PAC function presumably leads to an impaired mechanosensitive Ca(2+) entry and might contribute to endothelial dysfunction and high BP in this type of salt-sensitive genetic hypertension.
authors.affiliation: Department of Nephrology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhler
authors.affiliation: Department of Nephrology, Freie Universität Berlin, Berlin, Germany.|Department of Clinical Pharmacology and Toxicology, Benjamin Franklin Hospital, Freie Universität Berlin, Berlin, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kreutz
authors.affiliation: Department of Nephrology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Grundig
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Benjamin Franklin Hospital, Freie Universität Berlin, Berlin, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Rothermund
authors.affiliation: Laboratory for Molecular Medicine and Department of Nephrology and Hypertension, Faculty of Health Sciences, Ben-Gurion University, Barzilai Medical Center Campus, Ashkelon, Israel.
authors.forename: Chana
authors.initials: C
authors.lastname: Yagil
authors.affiliation: Laboratory for Molecular Medicine and Department of Nephrology and Hypertension, Faculty of Health Sciences, Ben-Gurion University, Barzilai Medical Center Campus, Ashkelon, Israel.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Yagil
authors.affiliation: Institute for Physiology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Axel R
authors.initials: AR
authors.lastname: Pries
authors.affiliation: Department of Nephrology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Hoyer
mesh_terms: D000818:Animals; D002412:Cations / Q000378:metabolism*; D003900:Desoxycorticosterone / Q000494:pharmacology; D004351:Drug Resistance; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D007473:Ion Channels / Q000502:physiology*; D008638:Mesenteric Arteries / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D011312:Pressure; D051381:Rats; D011919:Rats, Inbred Strains; D012965:Sodium Chloride / Q000494:pharmacology*
chemical_list: D002412:Cations; D007473:Ion Channels; D003900:Desoxycorticosterone; D012965:Sodium Chloride