title: Impaired relaxation of cerebral arteries in the absence of elevated salt intake in normotensive congenic rats carrying the Dahl salt-sensitive renin gene.
abstract: This study evaluated endothelium-dependent vascular relaxation in response to acetylcholine (ACh) in isolated middle cerebral arteries (MCA) from Dahl salt-sensitive (Dahl SS) rats and three different congenic strains that contain a portion of Brown Norway (BN) chromosome 13 introgressed onto the Dahl SS genetic background through marker-assisted breeding. Two of the congenic strains carry a 3.5-Mbp portion and a 2.6-Mbp portion of chromosome 13 that lie on opposite sides of the renin locus, while the third contains a 2.0-Mbp overlapping region that includes the BN renin allele. While maintained on a normal salt (0.4% NaCl) diet, MCAs from Dahl SS rats and the congenic strains retaining the Dahl SS renin allele failed to dilate in response to ACh, whereas MCAs from the congenic strain carrying the BN renin allele exhibited normal vascular relaxation. In congenic rats receiving the BN renin allele, vasodilator responses to ACh were eliminated by nitric oxide synthase inhibition with N(G)-nitro-l-arginine methyl ester, angiotensin-converting enzyme inhibition with captopril, and AT(1) receptor blockade with losartan. N(G)-nitro-l-arginine methyl ester-sensitive vasodilation in response to ACh was restored in MCAs of Dahl SS rats that received either a 3-day infusion of a subpressor dose of angiotensin II (3 ng·kg(-1)·min(-1) iv), or chronic treatment with the superoxide dismutase mimetic tempol (15 mg·kg(-1)·day(-1)). These findings indicate that the presence of the Dahl SS renin allele plays a crucial role in endothelial dysfunction present in the cerebral circulation of the Dahl SS rat, even in the absence of elevated dietary salt intake, and that introgression of the BN renin allele rescues endothelium-dependent vasodilator responses by restoring normal activation of the renin-angiotensin system.
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Durand
authors.forename: Carol
authors.initials: C
authors.lastname: Moreno
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Greene
authors.forename: Julian H
authors.initials: JH
authors.lastname: Lombard
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000008:administration & dosage; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D020296:Animals, Congenic; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000235:genetics; D002216:Captopril / Q000494:pharmacology; D003433:Crosses, Genetic; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007262:Infusions, Intravenous; D019808:Losartan / Q000494:pharmacology; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D020303:Rats, Inbred Dahl; D012083:Renin / Q000235:genetics* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics*; D017673:Sodium Chloride, Dietary / Q000378:metabolism; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000975:Antioxidants; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D017673:Sodium Chloride, Dietary; D013113:Spin Labels; D014665:Vasodilator Agents; D013481:Superoxides; D000804:Angiotensin II; D009569:Nitric Oxide; D002216:Captopril; D012083:Renin; D019808:Losartan; D000109:Acetylcholine; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester