A protein tyrosine kinase inhibitor, imatinib mesylate (Gleevec), improves erectile and vascular function secondary to a reduction of hyperglycemia in diabetic rats.
BACKGROUND
Erectile dysfunction (ED) afflicts 50% of diabetic men, many of whom experience poor results with phosphodiesterase type 5 inhibitors. The protein tyrosine kinase (PTK) inhibitor imatinib (Gleevec, Novartis Pharmaceuticals, Basel, Switzerland) has therapeutic potential in diabetic men by maintaining β-cell function.


OBJECTIVE
To determine if imatinib has a beneficial effect on erectile and vascular function in diabetic rats.


METHODS
Male Sprague-Dawley rats were divided into six groups: (i) control; (ii) imatinib (50mg/kg, daily gavage)-treated control; (iii) diabetic; (iv) preventive imatinib (8 weeks); (v) reversal imatinib (4 weeks untreated diabetes and 4 weeks of treatment); and (vi) insulin (8 weeks)-treated diabetic rats.


METHODS
After 8 weeks, all groups underwent cavernosal nerve stimulation and measurements of intracavernosal pressure (ICP) and mean arterial pressure (MAP). Contractile and relaxation responses were evaluated using isolated strips of corpus cavernosum smooth muscle (CCSM) and aorta.


RESULTS
Diabetic rats exhibited a 32% decrease in weight and fivefold increase in blood glucose levels. Imatinib-treated diabetic rats gained weight and partially improved blood glucose levels. Diabetic rats displayed a decrease in ICP/MAP. While maximum electrical field stimulation- and acetylcholine (ACh)-induced relaxations in CCSM strips from the diabetics were reduced, preventive imatinib or insulin treatment normalized ICP/MAP ratios and improved relaxation responses. ACh responses in diabetic aortas were diminished by 50.1% and restored by imatinib. While contractile responses to phenylephrine in diabetic CCSM were not altered, there was a significant enhancement (59.4 %) in the aortic contractile response in diabetic rats, which was restored by imatinib and insulin treatment.


CONCLUSIONS
In diabetic rats, prolonged therapy with imatinib improves diabetes-related ED and vascular function, which may involve normalization of high glucose levels and restoration of PTK activation. Future studies are needed to elaborate on the actions of imatinib on diabetic vascular complications.
Gur
Serap
S
Department of Urology, Tulane University Health Sciences Center, New Orleans, LA, USA.
Kadowitz
Philip J
PJ
Hellstrom
Wayne J G
WJ
D000818:Animals; D001549:Benzamides; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D004305:Dose-Response Relationship, Drug; D006943:Hyperglycemia / Q000150:complications; D000068877:Imatinib Mesylate; D018783:Impotence, Vasculogenic / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D010410:Penile Erection / Q000187:drug effects; D010879:Piperazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001549:Benzamides; D001786:Blood Glucose; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases