Amylin and hypertension: association of an amylin -G132A gene mutation and hypertension in humans and amylin-induced endothelium dysfunction in rats.
BACKGROUND
Amylin has been linked to the development of hypertension in several pathological states related to hypertension and insulin resistance, although there is scant data regarding its potential mechanisms of action. The -132 G/A mutation located within an activator domain of the amylin gene's promoter was first identified in a small cohort of Spanish patients with type 2 diabetes.


OBJECTIVE
The objective of the study was to test the interference of amylin peptide with endothelium-dependent responses as an added potential mechanism for amylin-induced hypertension.


METHODS
A total of 384 patients with type 2 diabetes and 207 healthy controls were subjected to clinical analysis and genetic screening for the -132 G/A mutation of the amylin gene. The effect of amylin on endothelium-dependent responses was analyzed in aortic rings and mesenteric microvessels from nondiabetic rats.


RESULTS
The prevalence of the mutation was 10.1 vs. 0.9% in the control population (P<0.001). Hypertension was higher in a diabetic population carrying the mutation than in diabetic noncarriers (74 vs. 57%; P<0.05). Diabetic carriers showed higher fasting amylin levels than diabetic noncarriers (11.4+/-7 vs. 8.2+/-3 pmol/liter; P<0.05). Preincubation with 20 pmol/liter amylin impaired the relaxant responses induced by acetylcholine in rat aorta and mesenteric microvessels. This effect was abolished in both vascular beds in the presence of 100 micromol/liter NG-nitro-L-arginine methyl ester.


CONCLUSIONS
We propose that amylin levels and hypertension may be linked by a novel mechanism involving the capacity of amylin to induce endothelial dysfunction by interfering with nitric oxide-mediated responses.
Novials
Anna
A
Institute of Diabetes, Sardà Farriol Foundation, Passeig Bonanova 69, 6th floor, 08017 Barcelona, Spain. anovials@fsf.es
Rodriguez-Mañas
Leocadio
L
Chico
Ana
A
El Assar
Mariam
M
Casas
Sílvia
S
Gomis
Ramon
R
D000368:Aged; D000682:Amyloid / Q000235:genetics* / Q000494:pharmacology*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D058228:Islet Amyloid Polypeptide; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
D000682:Amyloid; D058228:Islet Amyloid Polypeptide