Originals Basic Insulin Modulation of Chronotropic Response to Adrenaline in Diabetic Dogs N. Hiatt and J. R. Hiatt Department of Surgery and the Medical Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A.
In 8 unanesthetized dogs, 10-21 days post pancreatectomy, the cardiac chronotropic response to rapid infusion of a pharmacological dosage of Adrenaline was begun. During the subsequent month, the response was recorded electrocardiographically on 19 occasions. On 8 occasions, animals were treated with continuous intravenous administration of fluids and insulin up to the time of the test; on 11, insulin was omitted for 18 hours before Adrenaline injection. Insulin treated animals responded with the typical brief initial bradycardia, followed by some 2 minutes of ventricular tachycardia, and restoration of preinjection heart rate and electrocardiograph pattern within 5 minutes. On those occasions when insulin was omitted, the tachycardia was replaced by ventricular bradycardia. The altered chronotropic response of non-insulin treated dogs indicates impairment of their cardiac beta receptors. Key words Diabetes - Post Pancreatectomy - Beta Receptors - Cardiac - Insulin Treatment - Intravenous Adrenaline - Chronotropic Response
Introduction During an investigation of electrolyte metabolism in dogs Hiatt, Chapman, Davidson, Mack and Sheinkopf (1981) a pharmacological dosage of Adrenaline (Parke, Davis) was administered intravenously (IV) to an untreated post pancreatectomy (panx) diabetic animal while the electrocardiogram (ECG) was being recorded; the chronotropic response was atypical - ventricular bradycardia. That serendipitous finding prompted the present investigation. We found that in insulin treated post panx dogs IV Adrenaline produced the typical positive chronotropic responses, in those not treated with insulin, the typical ventricular tachycardia was replaced by ventricular bradycardia. Materials and Methods Data were gathered from 27 experiments carried out in 12 apparently healthy pound dogs of either sex that weighed between 10.6 and 15.2 kilograms; they were fasted for 18 hours before an Horm. metab. Res. 24 (1992) 501-503 © Georg Thieme Verlag Stuttgart • New York
experiment, 8 before panx and 4 before IV injection of hypertonic glucose. Preoperatively, the 8 were anesthetized with sodium pentobarbital (30 mg/kg IV) and panx by avulsion (Markowitz, Archibald and Downie 1965); a polyethylene catheter was fixed in an external jugular vein and kept open by continuous infusion of approximately 40 ml/hr of0.15 M NaCl. Cm the first postoperative morning, continuous IV treatment of post panx diabetes was begun, by replacing 0.15 M NaCl with a maintenance solution - 1000 ml of 5 % glucose in 0.45 M NaCl that contained, in addition, 2 ml of water soluble vitamins, 10 ml 10% Ca gluconate, 20 mEq KC1 and 25 U insulin (Iletin, Lilly); the solution was infused at rate of 50 ml/hr. The dogs had access to water ad lib and to 1000 ml whole milk daily. On 11 occasions, 18 hours before an experiment, the maintenance infusion was replaced, with one that was identical, but for the absence of insulin. The cardiac chronotropic response to Adrenaline was tested - immediately after discontinuing the maintenance infusion. At least once, each insulin treated animal (after a lapse of 8 or more days) was its own non-insulin treated control. The influence of hyperglycemia was investigated in 4 intact dogs. Adrenaline was rapidly infused 5 minutes after the animals were made hyperglycemic by rapid IV injection of a solution containing 0.6 g glucose/kg. One week later, the same four dogs served as their normoglycemic controls. Experimental procedures were identical in all instances. Twentyug/kg Adrenaline (Parke, Davis) were rapidly injected IV and Lead II of an ECG (Hewlett-Packard) was recorded for the next 5 minutes. Serum insulin (IRI) was determined by radioimmunoassay (Soeldner and Slone 1965) blood glucose by a rapid glucose oxidase procedure (Orzeck, Mooney and Owen 1971) urine glucose with Clinitest tablets and ketone bodies with Acetest tablets. Values are reported as mean + standard error of the mean (SEM). Data were analyzed by the unpaired Student's 2 tailed t-test; the null hypothesis was rejected at the 0.05 level. Results On the first post operative morning panx dogs seemed in excellent condition. Group 1: Post panx diabetes treated with insulin (Table 1, Fig. 1) Mean blood glucose concentration was 122 (90 -134) mg/dl and that of serum IRI 21 (9-34) uU/ml. Urine glucose varied between 0 and 1 + (1/4%), Acetest was negative. The chronotropic response was that anticipated. Six to 8 Received: 22 Nov. 1991
Accepted: 24 March 1992
Downloaded by: Georgetown University Medical Center. Copyrighted material.
Summary
Horm. metab. Res. 24 (1992) Table 1
T*
N. Hiatt and J. R. Hiatt
Heart rate following Adrenaline infusion in post panx dogs.
15
0
30
60
90
120
180
240
111+4
102±2
94 + 0
86±8
88±7
Treated with insulin (8)** 84 + 2***
59 + 1
201+8
219±8
118±2
Not treated with insulin (11)**
P
92 ±7
70±10
NS****
NS
57±3
65 + 5
70±4
78 + 5
< 0.001
< 0.001
< 0.001
< 0.001
In 8 unanesthetized dogs, 10-21 days post pancreatectomy, the cardiac chronotropic response to rapid infusion of a pharmacological dosage of Adrenaline was begun. During the subsequent month, the response was recorded electrocardiographically on 19 occasions. On 8 occasions, animals were treated with continuous intravenous administration of fluids and insulin up to the time of the test; on 11, insulin was omitted for 18 hours before Adrenaline injection. Insulin treated animals responded with the typical brief initial bradycardia, followed by some 2 minutes of ventricular tachycardia, and restoration of preinjection heart rate and electrocardiograph pattern within 5 minutes. On those occasions when insulin was omitted, the tachycardia was replaced by ventricular bradycardia. The altered chronotropic response of non-insulin treated dogs indicates impairment of their cardiac beta receptors. Key words Diabetes - Post Pancreatectomy - Beta Receptors - Cardiac - Insulin Treatment - Intravenous Adrenaline - Chronotropic Response
Introduction During an investigation of electrolyte metabolism in dogs Hiatt, Chapman, Davidson, Mack and Sheinkopf (1981) a pharmacological dosage of Adrenaline (Parke, Davis) was administered intravenously (IV) to an untreated post pancreatectomy (panx) diabetic animal while the electrocardiogram (ECG) was being recorded; the chronotropic response was atypical - ventricular bradycardia. That serendipitous finding prompted the present investigation. We found that in insulin treated post panx dogs IV Adrenaline produced the typical positive chronotropic responses, in those not treated with insulin, the typical ventricular tachycardia was replaced by ventricular bradycardia. Materials and Methods Data were gathered from 27 experiments carried out in 12 apparently healthy pound dogs of either sex that weighed between 10.6 and 15.2 kilograms; they were fasted for 18 hours before an Horm. metab. Res. 24 (1992) 501-503 © Georg Thieme Verlag Stuttgart • New York
experiment, 8 before panx and 4 before IV injection of hypertonic glucose. Preoperatively, the 8 were anesthetized with sodium pentobarbital (30 mg/kg IV) and panx by avulsion (Markowitz, Archibald and Downie 1965); a polyethylene catheter was fixed in an external jugular vein and kept open by continuous infusion of approximately 40 ml/hr of0.15 M NaCl. Cm the first postoperative morning, continuous IV treatment of post panx diabetes was begun, by replacing 0.15 M NaCl with a maintenance solution - 1000 ml of 5 % glucose in 0.45 M NaCl that contained, in addition, 2 ml of water soluble vitamins, 10 ml 10% Ca gluconate, 20 mEq KC1 and 25 U insulin (Iletin, Lilly); the solution was infused at rate of 50 ml/hr. The dogs had access to water ad lib and to 1000 ml whole milk daily. On 11 occasions, 18 hours before an experiment, the maintenance infusion was replaced, with one that was identical, but for the absence of insulin. The cardiac chronotropic response to Adrenaline was tested - immediately after discontinuing the maintenance infusion. At least once, each insulin treated animal (after a lapse of 8 or more days) was its own non-insulin treated control. The influence of hyperglycemia was investigated in 4 intact dogs. Adrenaline was rapidly infused 5 minutes after the animals were made hyperglycemic by rapid IV injection of a solution containing 0.6 g glucose/kg. One week later, the same four dogs served as their normoglycemic controls. Experimental procedures were identical in all instances. Twentyug/kg Adrenaline (Parke, Davis) were rapidly injected IV and Lead II of an ECG (Hewlett-Packard) was recorded for the next 5 minutes. Serum insulin (IRI) was determined by radioimmunoassay (Soeldner and Slone 1965) blood glucose by a rapid glucose oxidase procedure (Orzeck, Mooney and Owen 1971) urine glucose with Clinitest tablets and ketone bodies with Acetest tablets. Values are reported as mean + standard error of the mean (SEM). Data were analyzed by the unpaired Student's 2 tailed t-test; the null hypothesis was rejected at the 0.05 level. Results On the first post operative morning panx dogs seemed in excellent condition. Group 1: Post panx diabetes treated with insulin (Table 1, Fig. 1) Mean blood glucose concentration was 122 (90 -134) mg/dl and that of serum IRI 21 (9-34) uU/ml. Urine glucose varied between 0 and 1 + (1/4%), Acetest was negative. The chronotropic response was that anticipated. Six to 8 Received: 22 Nov. 1991
Accepted: 24 March 1992
Downloaded by: Georgetown University Medical Center. Copyrighted material.
Summary
Horm. metab. Res. 24 (1992) Table 1
T*
N. Hiatt and J. R. Hiatt
Heart rate following Adrenaline infusion in post panx dogs.
15
0
30
60
90
120
180
240
111+4
102±2
94 + 0
86±8
88±7
Treated with insulin (8)** 84 + 2***
59 + 1
201+8
219±8
118±2
Not treated with insulin (11)**
P
92 ±7
70±10
NS****
NS
57±3
65 + 5
70±4
78 + 5
< 0.001
< 0.001
< 0.001
< 0.001
