Augmented sympathetic response to bradykinin in the diabetic heart before autonomic denervation

We studied whether diabetes mellitus affects the bradykinin (BK)-induced re lease of norepinephrine (NE) from rat cardiac sympathetic endings in situ. Three groups were studied. Group A (n=12) was rendered diabetic with strept ozotocin (STZ), group B (n=13) received STZ and insulin, and group C (n=14) received citrate buffer only. NPH insulin was given to group B from day 7 after STZ. Atria were paced (3Hz) with rectangular voltage pulses at mechan ical threshold intensity (0.15 V/cm). The release of NE was assessed throug h its effects on contractile force in the presence of atropine (1 mu mol/L) . Intensifying the field stimulation above the neural threshold (approximat e to 0.4 V/cm) produced a graded positive inotropic effect that was due to the release of NE from sympathetic nerve endings. The additional effect of 0.1 mu mol/L BK on the force of contraction was determined at half-maximal neural stimulation (ie, at approximate to 0.65 V/cm). Then, after washing o ut BK and lowering the stimulation intensity to mechanical threshold, a cum ulative dose-response curve for added NE was generated, allowing the positi ve inotropic effects of neural stimulation (with or without BK) to be expre ssed in terms of an equivalent inotropic concentration of added NE ([NEeq]) . Neural stimulation, in the absence of BK, gave an [NEeq] of 32+/-3 nmol/L in group A, 44+/-6 nmol/L in group B, and 37+/-6 nmol/L in group C. BK inc reased [NEeq] by a factor of 6.2+/-0.9 in group A, 4.5+/-0.5 in group B, an d 3.7+/-0.3 in group C. This factor was greater in group A than in group C but indistinguishable in groups B and C, Atria from normal and diabetic rat s were incubated in (3)[H]NE for 60 minutes, Excess tracer was removed, and atria were stimulated during a series of 1-minute episodes at half-maximal neural stimulation to cause exocytotic (3)[H]NE release. BK augmented (3)[ H]NE release in normal (n=4) and in diabetic (n=4) atria. This BK-induced i ncrease of (3)[H]NE overflow (expressed as a fraction of tissue (3)[H]NE ra dioactivity) was 4 times greater in diabetic than in normal preparations. T he response to BK in releasing sympathetic neurotransmitter is augmented in diabetic rats, recovering in a manner dependent on insulin.