Angiotensin receptor blockers improve insulin signaling and prevent microvascular rarefaction in the skeletal muscle of spontaneously hypertensive rats.
OBJECTIVE
Spontaneously hypertensive rats are an example of an animal model of genetic hypertension with insulin resistance. The aim of this study was to investigate insulin signaling in the heart and in the skeletal muscle of spontaneously hypertensive rats, as well as to evaluate the effects of renin-angiotensin system blockade.


METHODS
We investigated eight untreated spontaneously hypertensive rats of 12 weeks of age and eight age-matched normotensive Wistar-Kyoto controls. In addition, eight spontaneously hypertensive rats were treated for 8 weeks with the angiotensin receptor blocker olmesartan, and eight spontaneously hypertensive rats with the angiotensin-converting enzyme inhibitor enalapril. The heart and a skeletal muscle (quadriceps femoris) were promptly dissected and frozen. Insulin signaling was evaluated by Western blot analysis of involved proteins; in addition, microvessel density was indirectly evaluated by immunohistochemistry.


RESULTS
Blood pressure values were normalized by both olmesartan and enalapril. In the heart, no statistically significant difference in the expression of proteins involved in insulin signaling was observed between untreated spontaneously hypertensive rats and Wistar-Kyoto controls. On the contrary, in the skeletal muscle of untreated spontaneously hypertensive rats, we noted a significant reduction of insulin receptors, of insulin-receptor substrate-1, and of phosphorylated-mammalian target of rapamycin. The treatment with olmesartan normalized insulin signaling, including expression of glucose transporter-4, whereas the treatment with enalapril was ineffective for the insulin receptor and less effective than olmesartan on the insulin-receptor substrate-1, phosphorylated-mammalian target of rapamycin and glucose transporter-4. There was a significant reduction in microvessel density in the skeletal muscle of spontaneously hypertensive rats compared with Wistar-Kyoto controls, and this was completely prevented by both olmesartan and enalapril.


CONCLUSIONS
These results suggest that changes in insulin signaling occur in the skeletal muscle but not in the heart of untreated spontaneously hypertensive rats. In the skeletal muscle, insulin signaling was restored by olmesartan, whereas enalapril was less effective. Effective antihypertensive treatment with olmesartan or enalapril was associated with prevention of microvascular rarefaction.
Rizzoni
Damiano
D
Clinica Medica, Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy. rizzoni@med.unibs.it
Pasini
Evasio
E
Flati
Vincenzo
V
Rodella
Luigi F
LF
Paiardi
Silvia
S
Assanelli
Deodato
D
De Ciuceis
Carolina
C
Porteri
Enzo
E
Boari
Gianluca Em
GE
Rezzani
Rita
R
Speca
Silvia
S
Favero
Gaia
G
Martinotti
Stefano
S
Toniato
Elena
E
Platto
Caterina
C
Agabiti-Rosei
Enrico
E
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002196:Capillaries / Q000187:drug effects; D004656:Enalapril / Q000494:pharmacology*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008297:Male; D009206:Myocardium / Q000378:metabolism; D052097:Quadriceps Muscle / Q000098:blood supply* / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011972:Receptor, Insulin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; C519510:Crtc1 protein, rat; D051275:Glucose Transporter Type 4; D007093:Imidazoles; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; C495694:Slc2a4 protein, rat; D013777:Tetrazoles; D014157:Transcription Factors; D004656:Enalapril; C437965:olmesartan; D011972:Receptor, Insulin