EFFECTS OF ENDOTHELIN RECEPTOR ANTAGONISM WITH BOSENTAN ON PERIPHERAL-NERVE FUNCTION IN EXPERIMENTAL DIABETES

1 The effects of the non-selective endothelin (ET) receptor (ET(A)/ET( B)) antagonist, bosentan, on sciatic nerve dysfunction in experimental diabetes were investigated. 2 Rats with 5-6 weeks untreated streptozo tocin-diabetes exhibited characteristic slowed motor nerve conduction velocity (mean +/- s.d., 36.6 +/- 3.4 m s(-1)) and nerve laser Doppler flux (197 +/- 64 arbitrary units) compared to age-matched control ani mals (42.7 +/- 2.4 m s(-1) and 398 +/- 77 arbitrary units, respectivel y). Preventative treatment of diabetic rats with bosentan at 100 mg kg (-1) day(-1) p.o. attenuated both these deficits (39.7 +/- 3.0 m s(-1) and 305 +/- 56 arbitrary units, respectively) without affecting mean arterial pressure. 3 In control and untreated diabetic rats, ET-1, 1 n mol kg(-1) i.v., caused an initial hypotension (duration, 30 +/- 13 an d 26 +/- 9s, respectively; change in mean arterial pressure, -27 +/- 1 3 and -25 +/- 7 mmHg, respectively) followed by prolonged hypertension (change in mean arterial pressure, 52 +/- 18 and 31 +/- 5 mmHg, respe ctively). Effectiveness of the chronic bosentan treatment was demonstr ated by inhibition of the hypotensive response to ET-1 in treated diab etic rats (duration, 5 +/- 2 s; change in mean arterial pressure, -4 /- 2 mmHg) although the hypertension was unaltered (change in mean art erial pressure, 32 +/- 9 mmHg). 4 Acute i.v. administration of 10 mg k g(-1) bosentan caused variable and transient rises in nerve laser Dopp ler flux in control (78 +/- 63 arbitrary units) and untreated diabetic rats (93 +/- 77 arbitrary units). Acute bosentan blocked the hypotens ive response to subsequent ET-1 administration and attenuated the late r hypertension (change in mean arterial pressure, 21 +/- 9 mmHg in con trol, 29 +/- 10 mmHg in diabetic). 5 Our results indicate that oral tr eatment of diabetic rats with an ET receptor antagonist can improve sc iatic nerve perfusion and conduction, suggesting that the vasoconstric tor action of endogenous ET may contribute to peripheral nerve dysfunc tion in experimental diabetes.