IMPAIRED INTRACELLULAR SIGNAL-TRANSDUCTION IN GASTRIC SMOOTH-MUSCLE OF DIABETIC BB W RATS/

The pathophysiological mechanisms responsible for diabetic gastropares is remain unclear. Diabetes mellitus occurs spontaneously in 90% of a partially inbred colony of BB/W rats. This animal model resembles huma n insulin-dependent diabetes and is suitable for investigating the mec hanism of diabetic gastroparesis. Diabetic BB/W rats were killed 6 mo after the onset of diabetes. Muscle contraction experiments and [H-3]a cetylcholine release studies were performed with muscle strips of the gastric body. Biochemical measurements of inositol trisphosphate (IP3) and protein kinase C (PKC) in gastric muscle were performed to charac terize abnormalities of the intracellular signal transduction system i n gastric myocytes. Circular muscle contractions in response to direct myogenic stimulants, carbachol (10(-7)-10(-3) M) or substance P (10(- 7)-10(-5) M), were significantly impaired in diabetic BB/W rats compar ed with controls. Similarly, muscle contractions in response to NaF (1 0 mM), a direct stimulant of G proteins, were also impaired in diabeti c BB/W rats. In contrast, muscle contractions in response to KCl (25-7 5 mM) were similar between control and diabetic BB/W rats, indicating normal voltage-dependent Ca2+ entry in muscle strips obtained from dia betic BB/W rats. [H-3]-acetylcholine release from gastric myenteric pl exus in response to electrical transmural stimulation remained intact in diabetic BB/W rats. In separate studies, we demonstrated that carba chol (10(-6)-10(-4) M)-induced IP3 responses were significantly reduce d in diabetic rats compared with control. In addition, there was also impairment of translocation of PKC in diabetic BB/W rats. These observ ations indicate that myogenic impairment occurred in diabetic BB/W rat s. This resulted from altered intracellular signal transduction involv ing abnormal IFS production and PKC translocation.