A case of primary low grade mucosa associated lymphoid tissue (MALT) lymphoma of the oesophagus.

We report a very rare case of primary low grade mucosa associated lymphoid tissue (MALT) lymphoma of the oesophagus. An 83 year old woman was referred to our hospital in June 1999 for further examination and treatment of oesophageal tumour. Although a physical examination and laboratory data showed no significant abnormalities, endoscopic observation revealed two slightly elevated submucosal tumour-like lesions of the oesophagus. Tissue specimens were obtained by endoscopic mucosal resection of the oesophagus using a cap fitted panendoscope. The lesions were composed of diffuse small atypical lymphoid cells--that is, centrocyte-like cells--which were stained with CD20, L26, BCL-2, and kappa, but not with CD3, CD5, CD10, or cyclin D1. Monoclonality was detected by polymerase chain reaction analysis using the primer for CDR-3 of immunoglobulin H and diagnosed as low grade MALT lymphoma of the oesophagus. The tumours were considered to be completely resected and therefore additional treatment was not administered. The patient is alive and well 22 months after treatment and diagnosis.

[Supplementary motor area epilepsy associated with ADHD in an abused history].

A 6-year-old girl with attention-deficit hyperactivity disorder (ADHD) who had been abused by her mother in infancy developed supplementary motor area (SMA) epilepsy. The seizure was characterized by bilateral tonic seizure of the upper and lower extremities, speech arrest, preserved consciousness and a lack of postictal confusion. The duration of the seizure was usually 10-60 seconds. The seizures sometimes clustered. She was diagnosed as having SMA epilepsy based on the characteristic clinical symptoms, interictal EEG, ictal video-EEG and ictal SPECT. Though her seizure was initially improved by anti-epileptic drugs, the symptoms appeared again after discharge. Since her clinical course indicated that her seizure was aggravated by her mental state, treatment included both medication with anti-epileptic drugs and the adjustment of her living environment in cooperation with a child guidance clinic. Thereafter both her epileptic seizure and ADHD symptoms improved. These changes may be related to each other, because both conditions are associated with frontal lobe dysfunction. It was interesting that the adjustment of the environment improved frontal lobe epilepsy, which in turn ameliorated ADHD symptoms.

K+ channel blocking and anti-muscarinic effects of a novel piperazine derivative, INO 2628, on the isolated dog atrium.

The effects of a novel piperazine derivative, INO 2628, on the negative inotropic and chronotropic responses to intracardiac parasympathetic nerve stimulation and carbachol, to adenosine and to the K+ channel openers, pinacidil and nicorandil, were investigated in isolated, blood-perfused dog heart preparations. INO 2628 (0.1-10 mumol) injected into the sinus node artery of the isolated atrium induced negative chronotropic and small positive inotropic responses in a dose-dependent manner. INO 2628 antagonized the negative chronotropic and inotropic responses to intracardiac vagus stimulation and carbachol in a dose-dependent manner, whereas INO 2628 did not antagonize the negative cardiac responses to adenosine. Pinacidil and nicorandil caused dose-dependent negative inotropic and small negative chronotropic responses in isolated atria and ventricles, suggesting that pinacidil-related K+ channels are much sparser in SA nodal pacemaker cells than in cardiac muscle cells. INO 2628 dose dependently antagonized the negative inotropic responses to pinacidil and nicorandil, but it did not modify the nicardipine-, pentobarbital- or G-strophanthin-induced cardiac responses. These results suggest that INO 2628 inhibits the negative cardiac effects of acetylcholine at muscarinic receptors and directly inhibits K+ channels in the isolated dog heart.

Comparative study of cardiovascular effects of clonidine and alinidine in cross-perfused dog atrial preparations.

Cross-perfused canine atrial preparations were used to investigate the direct and indirect cardiac actions of clonidine and alinidine. Intravenous injections of clonidine (0.1-3 micrograms/kg) produced an initial brief pressor response and bradycardia followed by hypotension in the intact dog. Chronotropic and inotropic responses were absent in the isolated atrium perfused with the intact dog's blood. Intravenous clonidine (10-300 micrograms) also induced negative chronotropic and inotropic effects in isolated atria. On the other hand, alinidine, at doses which caused a depressor action and bradycardia in the intact dog, consistently produced negative chronotropic and inotropic effects in the isolated atrium. Therefore, it was confirmed that a relatively small dose of clonidine has a selective vascular action, while alinidine has direct cardiac depressant properties at all effective doses. Negative chronotropic and inotropic effects of peripheral vagal stimulation, carbachol and adenosine were not significantly modified by 100 or 300 micrograms doses of intraarterial clonidine. On the other hand, the effects of vagal stimulation and carbachol were significantly inhibited by 100 and 300 micrograms of alinidine, without affecting adenosine-induced cardiac actions. Therefore, it was demonstrated that alinidine has anti-muscarinic properties.

Beta-adrenoceptor blocking effects of a selective beta 2-agonist, mabuterol, on the isolated, blood-perfused right atrium of the dog.

1. Effects of (+/-)-1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.- butylamino-ethanol hydrochloride (mabuterol) on pacemaker activity and atrial contractility were investigated in the isolated and blood-perfused right atrium of the dog. 2. Mabuterol, injected into the sinus node artery of the isolated atrium, dose-dependently increased atrial rate and contractile force at doses of 0.01-10 nmol but the responses to over 10 nmol of mabuterol gradually decreased and mabuterol at higher doses induced biphasic cardiac responses, i.e., negative followed by positive cardiac responses. 3. The maximal increases in atrial rate and contractile force induced by mabuterol were 41.4% and 12.9%, respectively, of the maximal chronotropic and inotropic effects of isoprenaline. 4. Positive chronotropic and inotropic responses to mabuterol were dose-dependently inhibited by a selective beta 2-adrenoceptor antagonist, ICI 118,551. These responses were only slightly attenuated by atenolol. 5. Mabuterol (1-300 nmol) dose-dependently inhibited both dobutamine- and procaterol-induced positive chronotropic and inotropic responses. 6. These results indicate that mabuterol causes weak positive chronotropic and inotropic effects on the perfused canine right atrium by activating beta 2-adrenoceptors, and that higher concentrations non-selectively block both beta 1-and beta 2-adrenoceptors.

Positive chronotropic and inotropic effects of pimobendan (UD-CG 115 BS) in isolated, cross-circulated canine heart preparations.

The effects of pimobendan on the sinus node pacemaker activity and atrial contractility and on the left ventricular contractility were investigated in the isolated, cross-circulated right atrial and left ventricular preparations of the dog. Pimobendan, at a dose range of 1 to 1,000 nmol, injected into the sinus node artery of the isolated atrium, induced dose-dependent positive inotropic and chronotropic responses. At the same doses, it also induced dose-dependent increases in the left ventricular contractile force, similar to those in the atrial one, although the norepinephrine (NE)- and isoproterenol-induced positive inotropic effects in the ventricles were less than those in the atria. The positive cardiac effects were not inhibited by propranolol but they were depressed by intramural vagal nerve stimulation. These results suggest that pimobendan increases left ventricular contractility more effectively than atrial contractility in comparison with a beta-adrenoceptor agonist and that the positive cardiac effects of pimobendan were partially induced by a phosphodiesterase inhibition but not by a beta-adrenoceptor activation in the dog heart. When pimobendan, at a dose of 10 to 1,000 micrograms/kg, was cumulatively administered into the jugular vein of the support dog, a decrease in arterial blood pressure and an increase in heart rate were dose-dependently observed in the support dog. Half a minute after administration, the positive inotropic and chronotropic responses were induced in the isolated atrium in a dose-related manner. The pimobendan-induced positive cardiac effects were not inhibited by i.v. administration of propranolol, whereas the isosorbide dinitrate-induced positive chronotropic effects were significantly inhibited. These results indicate that pimobendan directly increases cardiac contractility and heart rate with vasodilatation in anesthetized dogs.

Beta-2 adrenoceptor-mediated effects on sinus rate and atrial and ventricular contractility on isolated, blood-perfused dog heart preparations.

Changes in the sinus rate, right atrial contractile force and left ventricular contractile force in response to isoproterenol, epinephrine, dobutamine, salbutamol and procaterol were studied in isolated, blood-perfused right atrial or left ventricular cardiac preparations of the dog. Each substance elicited dose-dependent increases in the three parameters and the ranking of the potency (ED50) for each effect was isoproterenol greater than epinephrine greater than dobutamine greater than or equal to salbutamol greater than or equal to procaterol. The ED50 of procaterol for changing sinus rate was lower than for altering atrial and ventricular contractile force, whereas the ED50 of dobutamine for changing sinus rate was higher. Ranking on the basis of the ratio of increase in sinus rate to increase in atrial tension induced by the agonists gave the following order: procaterol greater than or equal to salbutamol greater than epinephrine greater than or equal to isoproterenol greater than dobutamine. Procaterol-induced increases in sinus rate and atrial contractile force were dose-dependently inhibited by the beta-2 adrenoceptor antagonist, ICI 118,551, but only attenuated slightly by the beta-1 antagonist, atenolol. On the other hand, the positive chrono- and inotropic effects on the right atrium induced by dobutamine and isoproterenol were blocked completely by atenolol. The epinephrine- or salbutamol-induced positive chrono- and inotropic responses in the right atrium were inhibited moderately by both antagonists, but ICI 118,551 inhibited sinus rate increases more effectively than the atrial tension increases.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential vagal inhibition of the positive chronotropic and inotropic responses to cardiotonics in the isolated dog atrium.

The effects of vagal nerve stimulation on the chronotropic and inotropic responses to norepinephrine (NE), dobutamine, forskolin, 3-isobutyl-1-methylxanthine (IBMX) and Bay k 8644 were investigated in the isolated, blood-perfused right atrium of the dog. Electrical stimulation of intramural vagal nerves evoked decreases in the sinus rate and atrial contractile force, which were maintained at almost constant levels during stimulation. Vagal stimulation consistently attenuated both the positive chronotropic and inotropic responses to NE, dobutamine, forskolin and IBMX. The vagal inhibition of the chronotropic response to each substance was greater than that of the inotropic one except that to Bay k 8644. Vagal stimulation did not depress the positive chronotropic and inotropic responses to Bay k 8644. These results, therefore, suggest that, under parasympathetic tonic conditions, NE, dobutamine, forskolin and IBMX induce a positive chronotropic effect much less than a positive inotropic effect in the isolated dog atrium. Our results also suggest that the vagal inhibition of the chronotropic response to a beta-adrenoceptor agonist is induced at intracellular sites in the cyclic AMP cascade proximal to the Ca channel activation and also at a site proximal to the catalytic unit of adenylate cyclase.

Effects on atrio-ventricular conduction of alinidine and falipamil injected into the AV node artery of the anesthetized dog.

The effects of the bradycardic agents alinidine and falipamil, on atrio-ventricular (AV) conduction were compared with those of other negative chronotropic agents, acetylcholine (ACh), carbachol (CCh), adenosine and verapamil, in open-chest, anesthetized dogs. When each drug was selectively administered into the AV node artery, none of them changed the sinus rate and arterial blood pressure. Although alinidine did not significantly change the atrio-ventricular conduction time (AVCT), falipamil and others induced a dose-dependent prolongation of the AVCT. The order of the AVCT prolongation was CCh greater than ACh greater than verapamil much greater than adenosine greater than falipamil much greater than alinidine. ACh, CCh and verapamil frequently caused second or third degree AV block at higher doses. The His bundle electrocardiogram revealed that all AV blocks occurred between the atrium and the His bundle (A-H block). The CCh-induced prolongation of the AVCT, but not the adenosine-induced prolongation, was significantly suppressed by treatment with alinidine or falipamil. These results indicate that alinidine scarcely affects AV conduction in the in situ dog heart and that the muscarinic cholinergic receptor blocking effect of alinidine or falipamil modifies the AVCT secondarily when vagal activity is maintained.

Negative chronotropic and positive inotropic effects of a unique cardioactive agent, N,N'-dicyclopropyl methyl piperazine (bis) hydrochloride (INO 2628), in isolated, blood-perfused dog atria.

The effects of a novel piperazine derivative (INO 2628) on sinus node pacemaker activity and atrial contractile force were investigated in isolated, blood-perfused dog atrium. Injections of INO 2628 (0.03-100 mumol) into the sinus node artery of the isolated atrium induced a dose-dependent decrease in sinus rate and an increase in contractile force. The positive inotropic effects at more than 10 mumol were accompanied by a transient negative inotropism. Propranolol did not affect the positive inotropic response to INO 2628, but it significantly suppressed positive chronotropic and inotropic responses to norepinephrine. Atropine at a dose which completely blocked negative chronotropic and inotropic responses to carbachol, produced a slight but significant depression of INO 2628-induced negative chronotropic responses; inotropic responses were unaffected. These results suggest that INO 2628 induces noncholinergic negative chronotropic and nonadrenergic positive inotropic responses in isolated dog atria.

Bradycardic effects of AQ-A 39 (falipamil) in situ and in isolated, blood-perfused dog hearts. Comparison with alinidine and verapamil.

The cardiovascular effects of a specific bradycardic agent, AQ-A 39, were investigated in intact donor dogs and isolated and cross-perfused dog heart preparations. Intravenous administration of AQ-A 39 (10-1000 micrograms/kg) to the donor dog caused a dose-dependent heart rate decrease in the donor dog and a decreased atrial rate in the isolated atrium perfused by the donor's blood. The arterial blood pressure of the donor dog and contractile force of the atrial preparation were unchanged or slightly decreased. The direct injection of AQ-A (1-300 micrograms) into the sinus node artery of the isolated atrium caused dose-dependent negative chronotropic and slight, transient positive inotropic responses. Alinidine and verapamil caused marked negative chronotropic and inotropic responses. The negative chronotropic effect of AQ-A 39 was not modified by atropine. However, it was enhanced slightly but significantly by propranolol, indicating that AQ-A 39-induced bradycardia was antagonized partly by beta-adrenoceptor function. These results confirmed that AQ-A 39 selectively reduced sinus rate by a direct action on the sinus node. Furthermore, the potency of the bradycardiac action, compared with the decrease in contractility, was greater than for alinidine or verapamil. AQ-A 39 (300 micrograms) tended to depress norepinephrine (NE)-induced positive chronotropic but not inotropic effects in isolated atria. By contrast, verapamil (3-10 micrograms) significantly depressed the NE-induced positive inotropic but not the chronotropic effect, and propranolol (10 micrograms) suppressed both cardiac effects of NE. These data suggest that the AQ-A 39-induced, selective attenuation of the NE-induced chronotropic effect is not due to either calcium channel blockade or beta-adrenoceptor antagonism.

Different antagonism of the positive chronotropic and inotropic responses of the isolated, blood-perfused dog atrium to Bay k 8644 by nicardipine and verapamil.

The effects of Bay k 8644, a dihydropyridine calcium agonist, on sinoatrial (SA) node pacemaker activity and atrial contractility and its interaction with the calcium antagonists, nicardipine and verapamil, were investigated in the isolated, blood-perfused dog atrium. Bay k 8644 (0.03-30 micrograms) increased sinus rate and atrial contractility dose dependently. Norepinephrine (NE) and CaCl2 dose dependently increased the sinus rate and contractility but the positive chronotropic effect of CaCl2 was much less than that of the other drugs. The positive chronotropic effect of Bay K 8644 (0.3-1 microgram) was dose dependently depressed by nicardipine at doses of 1-10 micrograms but the inotropic effect was depressed only by a large dose of 10 micrograms. After sinus arrest induced by nicardipine (10-30 micrograms), SA node pacemaker activity was readily restored by Bay k 8644 or NE. Verapamil (1-3 micrograms) also depressed the positive chronotropic effect of Bay k 8644 more effectively than the inotropic effect although it did not attenuate the chronotropic effect of NE. The inotropic interaction could not be evaluated at higher doses of antagonists because of sinus arrest. Propranolol (3 micrograms) suppressed both positive chronotropic and inotropic effects of NE but did not depress the Bay k 8644-induced responses. These results show that the antagonism between Bay k 8644 and calcium antagonists is predominant on SA node pacemaker activity in cardiac tissues.

Cardiovascular effects of dibutyryl cyclic AMP in the intact dog heart and the isolated cross-perfused right atrium.

This study used an isolated right atrial preparation, cross-perfused with arterial blood from a support dog. We investigated the effects of dibutyryl cyclic AMP (DBcAMP) on heart rate and arterial blood pressure of the support dog and on the sinus rate and atrial contractile force of the isolated perfused atrium. DBcAMP was injected into the external jugular vein of the support dog or into the sinus node artery of the isolated atrium. DBcAMP to the support dog induced a small increase and/or decrease in arterial blood pressure at a dose of 3 or 10 mg/Kg i.v. It produced a decrease, with or without an increase in blood pressure, at a dose of 30 mg/Kg i.v., and a dose-dependent increase in heart rate in the support dog. In the isolated atrium, positive chronotropic and inotropic effects were observed. Direct injection of DBcAMP (3-30 mg) into the sinus node artery of the isolated atrium induced positive chronotropic and inotropic effects, after initial brief negative effects, in a dose-dependent manner. DBcAMP did not change norepinephrine-induced positive chronotropic and inotropic effects in the isolated atrium. These results demonstrate that DBcAMP induces a decrease in systemic arterial blood pressure with increases in sinus rate and atrial contractile force, and acts additively with the norepinephrine-induced positive cardiac effects in the dog heart.

Fade responses at neuroeffector junction to vagal stimulation in the isolated, blood-perfused dog atrium.

Effects of physostigmine and of beating rate on the negative chronotropic and inotropic responses to tonic intramural parasympathetic nerve stimulation at a frequency of 5 Hz for 2 min were investigated, using the isolated, blood-perfused dog atrium which was pretreated with propranolol. The responses to stimulation reached a maximum, and then "faded" back toward the control levels during stimulation. Before physostigmine, the fade of the inotropic response was consistently observed but the fade of the chronotropic response was minimal. Both the maximum effect and the fade of the chronotropic response were augmented dose-dependently by physostigmine in spontaneously beating atria. Physostigmine increased the maximum chronotropic response to infusion of acetylcholine (ACh) but did not potentiate the fade response. These results suggest that the potentiation of the fade of the chronotropic response to stimulation after physostigmine is due to decreases in the amount of ACh at the neuroeffector junction. The maximum negative inotropic responses were dose-dependently potentiated similarly by physostigmine in isolated spontaneously beating or paced atria. The fade of the inotropic response in spontaneously beating atria was decreased along with reduction of the rate by physostigmine, whereas the fades in paced atria at 2 and 3 Hz were not changed, showing that decreases in rate during stimulation influenced the reduction of the fade. Increases in contractile force induced by infusion of CaCl2 did not alter the maximum and fade responses to stimulation in 2 Hz paced atria. The blood flow into an isolated atrium was not changed detectably during stimulation. These results suggest that the fade of the inotropic response to parasympathetic nerve stimulation is related subsidiarily to acetylcholinesterase or washout of ACh at the neuroeffector junction in isolated perfused atria.

Bradycardic effect of alinidine on in situ and on isolated, blood-perfused heart preparations of dogs.

The cardiovascular effects of alinidine were studied on the donor dog and on the isolated dog right atrial or left ventricular preparation which was cross-perfused with arterial blood from the donor dog. When heart rate and systemic arterial blood pressure of the donor dog were decreased dose-dependently by i.v. administration of alinidine (10-300 micrograms/kg), decreases in atrial rate and atrial developed tension of the isolated preparation were induced in a dose-dependent manner, confirming that i.v. administration of alinidine directly induced negative chronotropic and inotropic effects in situ dog heart. The negative chronotropic effects at lower doses of alinidine were more prominent than the decrease in blood pressure of the anesthetized dog and the negative inotropic effect of the isolated atrium, respectively. Direct injection of alinidine (1-300 micrograms) into the sinus node artery of the isolated atrium induced predominant negative chronotropic responses at lower doses. In paced left ventricular muscle preparations, alinidine reduced the developed tension at higher doses. Ratios (decreases in atrial developed tension per decreases in atrial rate) for alinidine ranged from 1.2 to 2.1, which were smaller than those of acetylcholine, adenosine and verapamil, suggesting that alinidine has a predominant bradycardic property and induces bradycardia due to a different mechanism from those of other bradycardic agents in the isolated and blood-perfused dog heart. The responses to isoproterenol and norepinephrine were suppressed significantly by treatment with alinidine (300 micrograms) predominantly on chronotropism. The alinidine-induced decreases in atrial rate were relatively greater when the rate had been augmented by dibutyryl cyclic AMP and norepinephrine infusion, but the relative depression of contractility was slight. From these results, it is suggested that alinidine attenuates the positive chronotropic effects induced by increases in cyclic AMP without decreasing the positive inotropic ones in the blood-perfused dog atrium.

Blocking effects of alinidine on negative chronotropic and inotropic responses to vagal stimulation and injected acetylcholine and carbachol in dogs.

The effects of alinidine on negative chrono- and inotropic responses to cholinergic interventions, i.e., intramural vagal nerve stimulation and an injection of acetylcholine (ACh) or carbachol, were investigated in isolated, blood-perfused canine atrial preparations perfused by arterial blood from donor dogs. Vagal nerve stimulation (5, 10 or 30 Hz) and an injection of ACh (0.17-1.65 nmol) or carbachol (0.05-0.55 nmol) induced frequency-dependent and dose-dependent negative chrono- and inotropic responses, respectively. These responses were reproducible in the same preparation. During the negative chrono- and inotropic responses to alinidine (85-854 nmol), cardiac responses to cholinergic interventions were depressed dose-dependently. The depressive effects of alinidine on the negative chronotropic responses were significantly (P less than .05) greater than those on the negative inotropic ones. However, alinidine did not affect adenosine-induced negative cardiac responses. Atropine (0.43-4.32 nmol) uniformly blocked responses to cholinergic intervention dose-dependently. The potency of the antimuscarinic effect of alinidine was approximately 1/200 to 1/500 of the potency of atropine at the 50% inhibition dose for responses to vagal stimulation, carbachol and ACh. Intravenous administration of alinidine (1 mg/kg) to the donor dog also suppressed cardiac responses to choline esters and vagal stimulation in the isolated atrium perfused by the donor's blood. These results suggest that alinidine has suppressive effects on the negative chrono- and inotropic responses to exogenous choline esters and endogenous ACh from parasympathetic nerve terminals at the post-junctional cholinergic muscarinic receptors in the dog heart.

Pharmacological analysis of chrono- and inotropic responses to diazepam in the isolated, blood-perfused canine atrium.

Effects of diazepam on the pacemaker activity and atrial contractility were investigated using the isolated and blood-perfused canine atrium. When diazepam in a dose range of 3-300 micrograms was injected directly into the sinus node artery, biphasic (negative followed by positive) chrono- and inotropic responses were dose-relatedly evoked. These responses were not affected by atropine in a dose which blocked ACh-induced negative ones. Propranolol inhibited positive chrono- and inotropic responses to diazepam, and prolonged the duration of the negative responses. Imipramine, in a dose which blocked tyramine-induced positive responses, significantly augmented the positive inotropic responses to diazepam. From these results, it is suggested that diazepam induces direct negative chrono- and inotropic effects, the mechanism of which remains to be defined, and indirect positive effects by catecholamine release from the sympathetic nerve terminals, though not mediated by a tyramine-like action. Diazepam tended to potentiate negative chrono- and inotropic effects of adenosine but not significantly, suggesting that diazepam plays a minor role as an adenosine potentiator in the dog right atrium.

Effects of DJ-7141, a new alpha-2 agonist, 2-(2-chloro-6-fluorophenyl)-2,3,5,6-tetra-hydro-1H-imidazo[1,2-a] imidazole hydrochloride, on the isolated atrium, cross-perfused with blood from a support dog.

The effects of DJ-7141, a new alpha-2 agonist, on an isolated atrial preparation cross-perfused with arterial blood from a support dog were investigated. In the isolated atrium, a selective injection of DJ-7141 (1-100 micrograms) into the sinus node artery induced dose-dependent positive chronotropic and inotropic effects. The positive cardiac effects of DJ-7141 were not only inhibited by propranolol and by imipramine, but reversed to negative effects, whereas the positive cardiac effects of norepinephrine were blocked by propranolol and potentiated by imipramine. Tetrodotoxin (TTX) did not modify the cardiac responses to DJ-7141. After propranolol treatment, the negative chronotropic and inotropic responses to DJ-7141 were not influenced by atropine, which completely blocked acetylcholine-induced cardiac responses. When DJ-7141 was injected into the support dog at a dose of 10-300 micrograms/Kg i.v., it induced a brief increase in femoral arterial blood pressure and a long-lasting decrease in heart rate in the support dog and increases in atrial rate and contractile force in the isolated atrium. These results suggest that the new alpha-2 agonist, DJ-7141, induces indirect positive chronotropic and inotropic effects due to a tyramine-like action and direct negative cardiac effects in the isolated dog heart, and that the tyramine-like effect may be partially responsible for the increase in blood pressure seen with DJ-7141 in in situ dogs.