Yasuyuki Furukawa

Positive chronotropic and inotropic effects of angiotension II in the dog heart

The effects of angiotensin II on sinus rate and atrial contractility were investigated in 17 isolated canine atria and 5 isolated paced ventricular preparations perfused with arterial blood conducted from a heparinized donor dog. When angiotensin II was injected into the cannulated sinus node artery, positive chronotropic responses were dose-dependently produced starting from the 0.01 microgram dose although inotropic responses to angiotensin II were not consistently induced. Angiotensin II produced a similar inotropic response pattern in the paced ventricular preparation. Moreover, when angiotensin II was given into the jugular vein of the donor dog, similar positive chronotropic and inotropic responses were also shown in the isolated atrium. Angiotensin II-induced positive chronotropic and slight inotropic effects were not influenced by treatment with the beta-adrenoceptor blocking agents, propranolol and carteolol, but significantly suppressed by saralasin which has been reported to be a competitive antagonist of angiotensin II. From these results, it is suggested that angiotensin II induced a positive chronotropic and slight positive inotropic effect via angiotensin II receptors in the dog heart.

Effects of leukocyte and platelet depletion on ischemia--reperfusion injury to dog pancreas.

BACKGROUND/AIMS Ischemia-reperfusion injury has been studied in various organs. Effects of leukocyte and platelet depletion on ischemia-reperfusion injury were evaluated using the isolated, perfused dog pancreas in vivo. METHODS Pancreatic exocrine and endocrine functions were stimulated by an intra-arterial injection of cholecystokinin (10(-12) mol) and intravenous injection of glucose and arginine (1 g/kg body wt), respectively. The functions before and after 60 minutes of ischemia were evaluated in the no treatment and in the leukocyte and platelet depletion groups. RESULTS Cholecystokinin increased prostaglandin I2 and thromboxane A2 production and stimulated exocrine pancreatic secretion. Glucose and arginine stimulated insulin and glucagon release from the pancreas. Sixty minutes of ischemia followed by 60 minutes of reperfusion damaged the pancreatic acinar and ductular cells. Ischemia of 60 minutes followed by 90 minutes of reperfusion damaged beta cells. Removal of leukocytes (97.6%) and platelets (99.4%) by using a filter throughout the experiment prevented the ischemia-reperfusion injury, reduced plasma lipid peroxide and thromboxane A2, and increased prostaglandin I2 levels. CONCLUSIONS Leukocytes and platelets seem to damage the pancreas during ischemia-reperfusion by increasing the peroxidation of structurally important cell membrane lipids and reduced the thromboxane A2 prostaglandin I2 ratio, a predictor of cellular injury.

Autonomic control of the location and rate of the cardiac pacemaker in the sinoatrial fat pad of parasympathetically denervated dog hearts.

Autonomic Regulation of Pacemaker Sites. Introduction: Parasympathetic activity predominates over sympathetic activity not only with respect to heart rate but also with respect to the pacemaker location in the dog heart. After we removed the parasympathetic neural elements in the sinoatrial (SA) fat pad in the right atrium, we observed that cervical vagus stimulation did not decrease the atrial rate, but it did suppress the increase in rate evoked by sympathetic stimulation. We determined whether the pacemaker rate and location were affected by presynaptic or postsynaptic mechanisms.

Effects of zatebradine and propranolol on canine ischemia and reperfusion-induced arrhythmias

1,3,4,5-Tetrahydro-7,8-dimethoxy-3[3-[[2-(3, 4-dimethoxyphenyl)-ethyl]methylamino]propyl]-2H-3-benzazepin-2-one -hy drochloride (Zatebradine) is a specific bradycardiac agent, blocking the hyperpolarization-activated pacemaker current (I(f)), and thus has no negative inotropic effect. The purpose of this study was to examine whether zatebradine is effective against ischemia and reperfusion-induced arrhythmias in dogs compared to propranolol. Arrhythmia was induced by ligation of the left anterior descending coronary artery followed by reperfusion. Ischemia-induced biphasic arrhythmias were suppressed in both zatebradine and propranolol groups. During ischemia, fatal ventricular fibrillation occurred in four dogs in the control group, 0 in the zatebradine group, and two dogs in the propranolol group. Of the 31 dogs subjected to reperfusion, mortality rates in the zatebradine, propranolol, and control groups were 56%, 75%, and 86%, respectively, and there were no significant differences. In the heart beating 10 beats/min faster than the predrug heart rate by atrial pacing, both zatebradine and propranolol attenuated ischemia-induced arrhythmias but did not affect reperfusion arrhythmias. Our results suggest that I(f) and/or beta-adrenoceptors rather than the bradycardiac action might be related to the antiarrhythmic effects during ischemia, but that they do not play a role in the generation of the reperfusion-induced ventricular arrhythmias.

PACAP-38 activates parasympathetic nerves in isolated, blood-perfused dog atria

A pituitary adenylate cyclase-activating polypeptide (PACAP) activates PACAP and vasoactive intestinal peptide (VIP) receptors. We investigated the effects of PACAP-38 on the sinus rate and atrial contractile force in isolated, blood-perfused dog heart preparations and the stimulation by PACAP-38 of the parasympathetic nerve fibers. PACAP-38 (3-1000 pmol) caused positive and/or negative chronotropic responses and it dose dependently increased atrial and ventricular contractile force. The positive cardiac responses to PACAP-38 unlike those to VIP were much less than the positive responses to norepinephrine. Atropine inhibited the negative chronotropic responses to PACAP-38 and augmented the positive chronotropic and inotropic responses. Physostigmine potentiated the negative cardiac responses to PACAP-38 and acetylcholine. After physostigmine treatment, additionally, tetrodotoxin blocked the negative cardiac responses to PACAP-38 and intracardiac parasympathetic nerve stimulation. Propranolol did not inhibit the positive cardiac responses to PACAP-38 in atropine-treated atria. PACAP-(6-38) (1 and 3 nmol), an antagonist of PACAP-38, did not affect the cardiac responses to 100 pmol of PACAP-38. These results suggest that (1) PACAP-38 directly increases sinus rate and atrial contractile force and (2) PACAP-38 activates parasympathetic nerves and causes negative chronotropic and inotropic responses in the dog heart.

Pharmacologic analysis of ketamine-induced cardiac actions in isolated, blood-perfused canine atria.

Summary: Effects of ketamine were investigated on atrial rate and contractile force in the isolated, blood-perfused canine atrium. When a relatively small dose (3 μg) of ketamine was injected into the sinus node artery, positive chronotropic and inotropic responses were consistently observed. With doses of 10–300 μg i.a., biphasic (i.e., negative followed by positive) chronotropic and inotropic responses were induced. An extremely large dose of ketamine frequently produced biphasic chronotropic and only negative inotropic responses. The negative effects of ketamine were not affected by atropine pretreatment. After treatment with propranolol or imipramine, the positive effects were significantly suppressed. The effects were not influenced by tetrodotoxin. These results suggest that ketamine has (a) indirect cardioexcitatory properties mediated by a release of catecholamines which is due to a tyramine-like action, and (b) direct cardioinhibitory properties by which high doses depress the contractility rather than the pacemaker activity.

Effects of PACAP-38 on the SA nodal pacemaker activity in autonomically decentralized hearts of anesthetized dogs.

Pituitary adenylate cyclase-activating polypeptide (PACAP) receptors exist, but the physiologic role of PACAP is unclear in the heart in situ. We investigated effects of PACAP-38 on sinus rate and on the negative chronotropic response to acetylcholine (ACh) or stimulation of the intracardiac parasympathetic nerve fibers to the sinoatrial nodal region in the automatically decentralized heart of the open chest, anesthetized dog. PACAP-38 (0.1-1 nmol) injected directly into the sinus node artery caused transient positive followed by negative chronotropic responses. Both pretreatment with atropine and tetrodotoxin inhibited the negative chronotropic responses to PACAP-38. However, hexamethonium did not block the negative responses to PACAP-38. After treatment with PACAP-38 (0.1-1 nmol), ACh induced atrial fibrillation significantly (p < 0.01). On the other hand, the negative chronotropic responses to intracardiac parasympathetic stimulation were not changed. These results suggest that (a) PACAP-38 induces negative chronotropic responses and liberates ACh from intracardiac postganglionic parasympathetic nerves, and that (b) PACAP-38 reduces ACh-induced atrial fibrillation threshold in the dog heart in situ.

Inhibition by glibenclamide of negative chronotropic and inotropic responses to pinacidil, acetylcholine, and adenosine in the isolated dog heart

The blocking effects of glibenclamide on the chronotropic and inotropic responses to K+ channel openers pinacidil (ATP-sensitive) and acetylcholine (ACh) or adenosine (receptor-operated) were investigated in the isolated, blood-perfused canine atrium or ventricle. Glibenclamide (0.1–3 μmol) induced no significant cardiac effects. Cumulative administration of pinacidil (0.03–3 μmol) dose-dependently decreased sinus rate much less than the contractile force of the atrial and ventricular muscles. Glibenclamide similarly inhibited the negative chronotropic and inotropic responses to pinacidil in a dose-related manner. A high dose of glibenclamide (3 μmol) slightly but significantly attenuated the negative chronotropic and inotropic responses to ACh and adenosine but not to verapamil. These results demonstrate that glibenclamide inhibits the negative chronotropic and inotropic responses to the ATP-sensitive K+ channel opener pinacidil and the receptor-operated K+ channel openers ACh and adenosine but more selectively antagonizes the responses to pinacidil in the dog heart and suggest that in contrast to ACh and adenosine, an ATP-sensitive K+ channel opener has a greater effect on the ventricle than on the sinoatrial node.

Cardiac responses to VIP and VIP-ergic-cholinergic interaction in isolated dog heart preparations

Whereas i.v. administration of vasoactive intestinal peptide (VIP) to support dogs increased heart rate and decreased systemic blood pressure, sinus rate and contractile force increased in isolated right atria perfused with blood from the support dogs. VIP injected intraarterially into isolated atria induced dose-dependent positive chronotropic and inotropic effects. Intracardiac parasympathetic nerve stimulation attenuated the positive cardiac responses to VIP, but neither propranolol, imipramine, nor tetrodotoxin influenced the responses to VIP. VIP given to isolated left ventricles also increased the contractile force in a dose-dependent manner. However, VIP induced a greater maximum atrial contractility than ventricular contractility. This may indicate that VIP receptor density in the ventricle was lower than in the atrium, as it has recognized that VIP-ergic nerves innervate the right atrium more densely than the left ventricle. We therefore suggest that the positive cardiac responses to VIP, together with the VIP-ergic innervation in dog hearts and vagal activation, attenuate the VIP-mediated responses at site(s) in the cyclic AMP cascade.

Positive chronotropic and inotropic responses to BRL 37344, a β3-adrenoceptor agonist in isolated, blood-perfused dog atria

We investigated the chronotropic and inotropic responses to BRL 37344 (a beta 3-adrenoceptor agonist) and isoproterenol in isolated, blood-perfused dog atria. BRL 37344 (0.1-30 nmol) or isoproterenol (0.001-0.3 nmol) increased the sinus rate and contractile force dose dependently. BRL 37344 was 290 times less potent than isoproterenol to increase sinus rate and 140 times less potent to increase atrial force. Both propranolol and bisoprolol similarly inhibited the positive chronotropic and inotropic responses to BRL 37344 and isoproterenol dose dependently. ICI 118,551 (0.1 and 1 nmol) did not significantly affect the positive cardiac responses to BRL 37344 or isoproterenol. Neither imipramine nor tetrodotoxin significantly affected the positive cardiac responses to BRL 37344. These results suggest that the positive chronotropic and inotropic responses to BRL 37344 are mediated mainly by beta 1-adrenoceptors in the dog heart. It is unlikely that beta 3-adrenoceptors, as previously reported in adipose tissue or gastrointestinal smooth muscle, mediate chronotropic and inotropic responses in the normal dog heart.