Substance P levels in peripheral nerve, skin, atrial myocardium and gastrointestinal tract of rats with long-term diabetes mellitus. Effects of aldose reductase inhibition.
This study measured the content of substance P-like immunoreactivity (SPLI) in peripheral nervous tissue (lumbar dorsal root ganglia, sciatic nerve), skin (snout, foot), gastrointestinal tract (stomach, terminal ileum) and in the atria of the heart. Animals studied were long-term (11 months) streptozotocin-diabetic rats compared with age-matched control rats. All diabetic rats were given a very long acting insulin preparation twice weekly to reduce morbidity. Half of the diabetic rats were given the aldose reductase inhibitor, sorbinil (mean dose 30 mg/kg/day body weight by dietary admixture) over the entire protocol. Diabetic rats (given insulin only) showed marked accumulation of sorbitol and fructose together with myo-inositol depletion in their sciatic nerves. The sciatic nerves of the sorbinil-treated diabetic rats contained amounts of sorbitol, fructose and myo-inositol which were similar to those of non-diabetic rats, in spite of large amounts of nerve glucose in the sorbinil-treated animals. Thus, the inhibition of aldose reductase was successful. The L4 and L5 dorsal root ganglia of the diabetic rats showed reduced SPLI (63% and 72% respectively of control ganglia; P less than 0.05). There was also numerical reduction in sciatic nerve SPLI (84% of control nerve). There were no effects of sorbinil treatment on the reduced SPLI levels in ganglia or sciatic nerve. In the gastrointestinal tract the levels of SPLI were reduced in diabetic rats even when data were adjusted to take account of tissue hypertrophy (diabetic SPLI/whole stomach was 60% controls, P less than 0.01 and SPLI/cm ileum was 78%, though the latter did not attain statistical significance). In skin SPLI/unit area was raised in the diabetic rats to 145% of controls for foot skin and 151% for snout skin. Changes in SPLI content of gastrointestinal tract were unaffected by sorbinil treatment; in the skin the elevations were enhanced to 188% and 270% of respective control values for foot and snout skin. The SPLI content of the atria was unaffected by diabetes or sorbinil. These data are not consistent with a generalised impairment of delivery of substance P by axonal transport in experimental diabetes; special factors appear to influence the levels in neurones innervating different tissues. Exaggerated flux through the polyol pathway appears to be uninvolved.
Willars
G B
GB
Department of Physiology and Pharmacology, Medical School, Queen's Medical Centre, Nottingham, U.K.
Calcutt
N A
NA
Compton
A M
AM
Tomlinson
D R
DR
Keen
P
P
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004064:Digestive System / Q000032:analysis*; D006325:Heart Atria / Q000032:analysis; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D007294:Inositol / Q000032:analysis; D008297:Male; D009206:Myocardium / Q000032:analysis*; D010525:Peripheral Nerves / Q000032:analysis*; D051381:Rats; D011919:Rats, Inbred Strains; D012867:Skin / Q000032:analysis*; D013311:Streptozocin; D013373:Substance P / Q000032:analysis*; D013997:Time Factors
D001786:Blood Glucose; D007093:Imidazoles; D048289:Imidazolidines; D013373:Substance P; D007294:Inositol; D013311:Streptozocin; D000449:Aldehyde Reductase; C026411:sorbinil