Impairment of presynaptic alpha2-adrenoceptor-regulated norepinephrine overflow in failing hearts from Zucker diabetic fatty rats.
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.
Medizinische Klinik II, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. chbrg@compuserve.de
Christof
C
Burgdorf
Gert
G
Richardt
Frank
F
Schütte
Andreas
A
Dendorfer
Thomas
T
Kurz
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D000068438:Brimonidine Tartrate; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D004558:Electric Stimulation; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D009929:Organ Size / Q000187:drug effects; D010477:Perfusion; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism*; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000378:metabolism*; D015016:Yohimbine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D001786:Blood Glucose; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D017661:Receptors, Presynaptic; D015016:Yohimbine; D000068438:Brimonidine Tartrate; D009638:Norepinephrine