934 Experientia 38 (1982), Birkhauser Verlag, CH-4010 Basel/Switzerland Altered adrenergic responses of the coronary arterial bed in alloxan-diabetic dogs I. Palik, M. Zs. Koltai, M. Wagner, I. Kolonics and G. Pog~tsa Research Unit, National Institute of Cardiology, P.O. Box 9-88, H-1450 Budapest (Hungary), 30 November 1981 Summary. The conductivity of the coronary arterial bed increased in healthy and decreased in alloxan-diabetic dogs in response to intracoronary administration of norepinephrine or sympathetic stimulation. This suggests a modification of adrenergic receptor sensitivity in diabetes. Ischaemic heart diseases are more frequent and serious in patients with diabetes mellitus 1 than in nondiabetics. It is well known that metabolic alterations may influence both the structure 2 and the adrenergic receptor sensitivity 3 of the vascular wall. Therefore, the conductivity and morphology of the coronary arterial bed were studied in alloxan- diabetic dogs. Methods. Healthy mongrel dogs of both sexes, weighing 16-26 kg, 2-3 years of age were selected for the study. All animals received the same diet consisting of 25% protein, 60% carbohydrate and 15% fat. At the beginning of the experiment urine samples collected over 24 h were tested for glucose 4 and acetone 5. Fasting venous blood samples were also taken for glucose 4 and urea nitrogen 6. The plasma disappearance rate of glucose 7 was determined by i.v. challenge using 6 mmoles/kg glucose in the unanesthe- tized state, After determination of the basal values 12 dogs were made diabetic using alloxan tetrahydrate (Merck) 280 mmoles/kg i.v. 12 dogs served as controls. The haemo- dynamic investigation was performed 3 months after the induction of diabetes. Before pentobarbital (Nembutal, Serva, 133 mmoles/kg) anesthesia, all chemical variables were redetermined. The left anterior descending coronary artery was exposed and its blood flow was measured by an electromagnetic flowmeter (Godard-Statham, SP 2202). Ar- terial blood pressure was determined in the right carotid artery with a Statham gauge (p23Db). In 6 healthy and 6 alloxandiabetic dogs a polyethylene cannula was inserted through a collateral branch into the coronary artery. After recording of the basal values on a multiscriptor (9400 Hel- lige) 13-26-52-104 pmoles/kg/min norepinephrine (Nore- pinephrine bitartrate, Burroughs Wellcome) were infused till the steady state was reached. In the remaining 6 healthy and 6 alloxan-diabetic animals the cardiac plexus was exposed and electrically stimulated (Multistim 13G04, Disa) with 5 min long trains of square pulses of 1.0 msec duration, 8 V amplitude and increasing frequency (1-2-4-8-20 c/sec). In this way an overall effect of sympa- thetic intervention is described for the conductivitiy of the coronary arterial bed, characterized by the ratio of flow and pressure. Paraffin sections of the left coronary artery wall and myocardium were used for histological study, after fixation in formalin or Carnoy fixative. The sections were stained for PAS-reaction, with G6m0ri's silver stain, and partly exposed to digestion by diastase. Frozen sections were stained for lipids with Sudan III or Sudan black. The results were evaluated statistically using Student's paired and unpaired t-tests and regression analysis. , Results and discussion. The plasma disappearance rate of glucose and body weight decreased, while fasting plasma glucose level and urinary glucose excretion increased, after alloxan treatment. No acetone was excreted. Blood urea nitrogen, arterial blood pressure and coronary blood flow did not differ significantly from those of healthy animals (table). The conductivity of the coronary arterial bed increased in healthy and decreased in alloxan-diabetic dogs under intra- coronary infusion of norepinephrine and under the electri- cal stimulation of the cardiac plexus (fig.). An increase in cardiac work is not likely to be responsible for these observations, because there were no differences in the mean arterial blood pressure, heart rate and 'double prod- uct' characteristic of cardiac work calculated from heart rate and peak systolic pressure 8 between the 2 groups. A% -o 15C lOC 0 8 "6 56 A% 150 ~ 100 9 8 bfkb2 "5 50 t =3.11 IE p<O.O~ 13 ~6 ~2 lb4 ~ o Norepinephrine(pmoles kg -1 rain -1) b 1 :t: b 2 t=22.80 9<0.001 ~ ~ 2'0 8V Stimulation of cardiac plexus(c/s) Correlation between the percent change of conductivity in coronary arterial bed and the dosage of intracoronary administered nore- pinephrine or the increasing frequency of cardiac plexus stimulation. The open circles represent the mean values of 6 metabolically healthy dogs and the solid circles those of alloxan-diabetic animals. Metabolic and haemodynamic state of control and alloxan-diabetic dogs Plasma Plasma glucose Glucose Body weight Mean arterial Coronary blood disappearance (mmole/1) excretion (kg) blood pressure flow rate of glucose (mmole/day) (kPa) (ml/min) (~tmole/min) Control (n= 6) 12.5_+ 1.0 5.7 _+ 0.7 0 _+ 0 16.2 _+ 2.0 14.0 _+ 0.7 42.3 _+ 10.8 Before alloxan (n = 6) 13.2_+ 1.0 5.2 _+ 0.4 0 _+ 0 14.3 _+ 1.0 - After alloxan (n= 6) 7.0+0.5 a 14.2_+0.8 a 125-+ 10 a 12.8-t-_0.7 a 15.0-+ 1.4 50.0-+ 11.7 Data are expressed as mean_+ SEM. Significance, referred to values obtained before alloxan treatment is indicated by: ap < 0.001.
