title: Potassium channel openers increase aortic elastic fiber formation and reverse the genetically determined elastin deficit in the BN rat.
abstract: Hypertension is a cardiovascular disorder that appears in more than half of the patients with Williams-Beuren syndrome, hemizygous for the elastin gene among 26 to 28 other genes. It was shown that the antihypertensive drug minoxidil, an ATP-dependent potassium channel opener, enhances elastic fiber formation; however, no wide clinical application was developed because of its adverse side effects. The Brown Norway rat was used here as an arterial elastin-deficient model. We tested 3 different potassium channel openers, minoxidil, diazoxide, and pinacidil, and 1 potassium channel blocker, glibenclamide, on cultured smooth muscle cells from Brown Norway rat aorta. All tested potassium channel openers increased mRNAs encoding proteins and enzymes involved in elastic fiber formation, whereas glibenclamide had the opposite effect. The higher steady-state level of tropoelastin mRNA in minoxidil-treated cells was attributable to an increase in both transcription and mRNA stability. Treatment of Brown Norway rats for 10 weeks with minoxidil or diazoxide increased elastic fiber content and decreased cell number in the aortic media, without changing collagen content. The minoxidil-induced cardiac hypertrophy was reduced when animals simultaneously received irbesartan, an angiotensin II-receptor antagonist. This side effect of minoxidil was not observed in diazoxide-treated animals. In conclusion, diazoxide, causing less undesirable side effects than minoxidil, or coadministration of minoxidil and irbesartan, increases elastic fiber content, decreases cell number in the aorta and, thus, could be suitable for treating vascular pathologies characterized by diminished arterial elastin content and simultaneous hypertension.
authors.affiliation: CHU Xavier Bichat, 46 rue Henri Huchard, 75877 Paris Cedex 18, France. marie-paule.jacob-lenet@inserm.fr.
authors.forename: Séverin
authors.initials: S
authors.lastname: Slove
authors.forename: Morgane
authors.initials: M
authors.lastname: Lannoy
authors.forename: Jacques
authors.initials: J
authors.lastname: Behmoaras
authors.forename: Mylène
authors.initials: M
authors.lastname: Pezet
authors.forename: Natacha
authors.initials: N
authors.lastname: Sloboda
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacolley
authors.forename: Brigitte
authors.initials: B
authors.lastname: Escoubet
authors.forename: Julia
authors.initials: J
authors.lastname: Buján
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Jacob
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003981:Diazoxide / Q000494:pharmacology; D004547:Elastic Tissue / Q000187:drug effects* / Q000378:metabolism; D004549:Elastin / Q000235:genetics* / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D008297:Male; D008914:Minoxidil / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D020110:Pinacidil / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D011914:Rats, Inbred BN; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D015221:Potassium Channels; D014665:Vasodilator Agents; D008914:Minoxidil; D020110:Pinacidil; D004549:Elastin; D003981:Diazoxide; D005905:Glyburide
keywords: aorta; elastic tissue; elastin; potassium channels; rats