Volume 68, Issue 2, Pages 222-228 (August 1975) Direct and Vagally Mediated Chronotropic Effects of Morphine Studied by Selective Perfusion of the Sinus Node of Awake Dogs  Ferdinand Urthaler, M.D., James H. Isobe, M.D., Thomas N. James, M.D., F.C.C.P.  CHEST  Volume 68, Issue 2, Pages 222-228 (August 1975) DOI: 10.1378/chest.68.2.222 Copyright © 1975 The American College of Chest Physicians Terms and Conditions

FIGURE 1 Polygraph illustrating effect on heart rate by intravenous administration of thiopental (Pentothal) sodium to previously unanesthetized dog. With heart rate increase there is concomitant disappearance of regular irregularity characteristic of resting heart rate of unrestrained conscious dog. Heart rate (HR) is scaled in beats per minute. CHEST 1975 68, 222-228DOI: (10.1378/chest.68.2.222) Copyright © 1975 The American College of Chest Physicians Terms and Conditions

FIGURE 2 Time course of changes in heart rate (sinus rhythm) caused by anesthesia and intrathoracic surgery. Return to normal preoperative control resting heart rate did not occur until four days after surgery. There is no significant difference (P < 0.001) between the intraoperative and the immediate (six-hour) postoperative sinus rates (expressed in beats per minute). CHEST 1975 68, 222-228DOI: (10.1378/chest.68.2.222) Copyright © 1975 The American College of Chest Physicians Terms and Conditions

FIGURE 3 Remarkable similarity in time course of changes in heart rate between dogs undergoing sinus node artery cannulation (Fig 2) and ones which underwent sham operations (shown here) indicates that ligation and subsequent cannulation of sinus node artery did not significantly disturb pacemaking function of sinus node. CHEST 1975 68, 222-228DOI: (10.1378/chest.68.2.222) Copyright © 1975 The American College of Chest Physicians Terms and Conditions

FIGURE 4 Graph demonstrating that selective perfusion of sinus node with propranolol concentration sufficient to cause β-receptor blockade is not associated with significant change in normal resting sinus rate in awake dogs. It also illustrates that morphine sulfate solution (1 mg/ml) administered into sinus node artery after propranolol still caused immediate and significant (P < 0.001) sinus tachycardia followed by delayed and prolonged sinus bradycardia. CHEST 1975 68, 222-228DOI: (10.1378/chest.68.2.222) Copyright © 1975 The American College of Chest Physicians Terms and Conditions

FIGURE 5 Graph combining observations made in the same five dogs but on different days. Left panel shows early type of negative chronotropic effect of morphine sulfate solution (I mg/ml) injected into sinus node artery immediately after selective appropriate muscarinic blockade of sinus node.1 Right panel demonstrates that 29 minutes after selective sinus node perfusion with morphine sulfate solution (1 mg/ml), conscious dog shows sinus bradycardia which is immediately abolished by selectively perfused atropine sulfate solution (1 µg/ml). CHEST 1975 68, 222-228DOI: (10.1378/chest.68.2.222) Copyright © 1975 The American College of Chest Physicians Terms and Conditions

FIGURE 6 General increase in vagal tone centrally mediated by morphine (A, left) can be selectively eliminated in sinus node (B, right) by local perfusion with atropine. Morphine sulfate solution (1 mg/ml) had been perfused through sinus node 30 minutes before A, and atropine sulfate solution (1µg/ml) was then administered into sinus node artery 1 minute before B. During enhanced vagally-mediated sinus arrhythmia in A, vagal influence on AV junction was inapparent. With release of vagal effect on sinus node in B, negative dromotropic influence is unmasked. CHEST 1975 68, 222-228DOI: (10.1378/chest.68.2.222) Copyright © 1975 The American College of Chest Physicians Terms and Conditions