Impairment of Presynaptic ??2-Adrenoceptor-Regulated Norepinephrine Overflow in Failing Hearts from Zucker Diabetic Fatty Rats

Abstract

The aim of this study was to assess whether cardiac norepinephrine overflow is affected in Type 2 diabetes mellitus. Homozygous (fa/fa) Zucker diabetic fatty (ZDF) rats were used as a model of Type 2 diabetes; heterozygous (fa/+) ZDF rats served as non-diabetic controls. Cardiac performance was determined in isolated working hearts; release of endogenous norepinephrine was induced by electrical field stimulation in Langendorff-perfused hearts. At a mean age of 30 weeks, left ventricular contraction, relaxation, and developed pressure were reduced by 20% to 35% in ZDF-fa/fa rats compared with ZDF-fa/+ rats. Stepwise increase of stimulation frequency gradually increased norepinephrine overflow in isolated hearts from both rat strains. Compared to ZDF-fa/+ rats, cardiac norepinephrine overflow was suppressed by 25% to 45% in ZDF-fa/fa rats. During presynaptic alpha2-adrenoceptor blockade with rauwolscine, increase of norepinephrine overflow was significantly higher in ZDF-fa/fa rats than in ZDF-fa/+ rats whereas alpha2-adrenoceptor activation with UK 14,304 suppressed norepinephrine overflow solely in ZDF-fa/+ rats. Myocardial tissue content of norepinephrine did not differ markedly between the two groups. In conclusion, cardiac norepinephrine overflow is inhibited in failing hearts from ZDF-fa/fa rats. This inhibition may result from a hyperactive status of presynaptic alpha2-adrenoceptors.