Effect of pindolol on neurosympathetic responsiveness, blood flow variability, and conduction in acutely ischaemic myocardium: the importance of heart rate

The effects of a beta-adrenoceptor antagonist with partial agonist activity (pindolol) were assessed in the open-chest anaesthetised dog during 12-minute periods of left anterior descending coronary artery (LAD) occlusion and reperfusion before and after sympathetic stimulation. Regional myocardial catecholamine efflux, blood flow, and epicardial activation abnormalities were assessed in three groups. In a control group (n = 8), two periods of ischaemia resulted in reproducible intraexperimental changes in catecholamine responses, blood flow, conduction abnormalities, and arrhythmias. Intravenous (i.v.) pindolol (0.45 mg/kg before the second occlusion) reduced nerve-stimulated norepinephrine (NE) overflow from nonischaemic (NI) myocardium but did not modify overflow from ischaemic (I) myocardium either during ischaemia or reperfusion. At constant heart rate (atrial pacing, n = 8), pindolol reduced absolute blood flow to I and NI but had no effect on the ratio of endocardial/epicardial blood flow, arrhythmias, or activation abnormalities during occlusion. Following a reduction in heart rate of 32 +/- 6 beats/min (no pacing, n = 8), pindolol resulted in similar reduction in blood flow to I and NI but also increased the ratio of endocardial/epicardial flow and reduced both spontaneous arrhythmias and activation delay during occlusion. The acute effects of pindolol on conduction abnormalities, arrhythmias, and blood flow distribution in I are thus dependent on reduction in heart rate.     

The effects of dipyridamole on blood flow and oxygen handling in the acutely ischaemic and normal canine myocardium

1. The effects of the intravenous administration of dipyridamole (0.25 mg/kg) were examined in a canine preparation that enabled simultaneous measurements to be made of blood flow in ischaemic and in essentially normal areas of the myocardium and also of oxygen handling (availability, consumption and extraction) in both these regions.2. When administered to dogs anaesthetized with trichlorethylene 2-3 h after acute ligation of the descending branch of the left coronary artery, dipyridamole markedly increased blood flow in essentially normal regions (left circumflex flow) but failed to increase flow in the area supplied by the ligated vessel (measured by (133)xenon clearance and by retrograde flow). In five of the six animals definite decreases in flow (; stealing ') were observed in the ischaemic region. These flow changes were related to the decreased trans-ventricular perfusion pressure (diastolic peripheral coronary pressure minus left ventricular end-diastolic pressure) and were accompanied by electrocardiographic evidence of increasingly severe myocardial ischaemia. The results support the suggestion that only increasing the perfusion gradient will usefully improve blood flow (and hence oxygen availability) to the acutely ischaemic myocardium.3. Despite these effects on ischaemic muscle blood flow, the oxygen tension of the blood draining the infarcting muscle was markedly elevated. The conclusion is drawn that dipyridamole decreases the efficiency of the myocardial circulation by opening up vessels that do not take part in tissue exchange.     

Effects of bepridil and lidocaine on the intravenctricular conduction in acutely ischaemic and infarcted canine myocardium

Summary Effects of bepridil, an antiarrhythmic and antianginal drug, on intraventricular conduction in acutely ischaemic and infarcted myocardium were examined in anaesthetized dogs, and compared with those of lidocaine. Bepridil at doses of 2 and 5 mg/kg markedly prolonged the conduction time of a premature excitation induced by a ventricular stimulation in the infarcted zone. The effect of bepridil was dependent on a coupling time of the stimulation. Bepridil showed a marked effect at a coupling time of 150 ms, while it showed no significant effect at a prolonged coupling time of 1 s. In other words, the effect of bepridil was interval-dependent. Lidocaine showed a similar interval-dependent effect, but the effect of lidocaine at a longer coupling time was less than that of bepridil. The premature stimulation produced severely delayed conduction which resulted in reentrant beats. Bepridil blocked these conductions, thereby preventing reentrant beats. In contrast to the depressant effect of bepridil in the infarcted myocardium, bepridil prevented the prolongation of conduction time during acute ischaemia. The alternation of the ST-T complex during acute ischaemia which is also an important arrhythmogenic factor was also attenuated by bepridil. Contrary to bepridil, lidocaine significantly enhanced the conduction delay and the alternation in the ST-T complex. In conclusion, bepridil as well as lidocaine showed an interval-dependent depression of the conduction in the infarcted zone of the heart, whereas during acute ischaemia bepridil in contrast to lidocaine attenuated the conduction delay and ST-T alternans. Send offprint requests to H. Hashimoto at the above address     

Drug-induced changes in blood flow in the acutely ischaemic canine myocardium; relationship to subendocardial driving pressure

SUMMARY 1. The effects of various drugs have been studied on blood flow and oxygen handling (availability, extraction and consumption) in both normal and acutely ischaemic regions of the canine myocardium. Ischaemia was produced by the acute ligation of the anterior descending branch of the left coronary artery.
2. Lidoflazine, like other coronary vasodilator drugs, increases blood flow in the normal myocardium, but does not increase flow through the ischaemic region. Drugs of this type may, in addition, open up 'shunt' vessels within the ischaemic region.
3. Of three cardiac stimulants studied, only oxyfedrine consistently increases blood flow through the ischaemic region; isoprenaline and glucagon do not.
4. Noradrenaline causes marked increases in flow through the ischaemic region: its effect is associated with an increase in coronary pressure in the artery distal to the ligature.
5. Evidence is put forward that the critical factor determining flow through ischaemic regions of the myocardium is the transventricular driving pressure. When the effects of various drugs on flow and driving pressure are analysed and compared, the only drugs that increase flow in an ischaemic region are those that increase the pressure gradient across the wall of the left ventricle.     

Effects of molsidomine and nitroglycerin on the regional blood flow in the normal and acutely ischemic myocardium (author's transl)]

In anaesthetized dogs regional myocardial blood flow (radioactive particle distribution technique) and several haemodynamic parameters were measured before and after acute ligation of left descending coronary artery. By injection of N-carboxy-3-morpholino-sydnonimine ethylester (molsidomine, Corvaton) or infusion of nitroglycerin it was tried to influence blood flow of the infarcted areas of the myocardium. 1. Ligation of the coronary artery induces myocardial infarction of anterior wall, predominantly restricted to the endocardial portions of the heart muscle. 2. Molsidomine and also nitroglycerin do not change overall blood flow of the heart in the sense of vasodilation. 3. In the infarcted area the ratio: blood flow of endocardial layers to blood flow of epicardial layers, is improved by molsidomine. 4. The positive effect of molsidomine becomes clearer in the border zone of infarction. Nitroglycerin remains without effect. 5. The effects of the compound molsidomine are explained by stronger action on extravascular factors of colonary vascular resistance (decrease in enddiastolic pressure).     

Effect of repeated regional myocardial ischemia in the rat heart on reperfusion arrhythmias and release of norepinephrine.

We tested the hypothesis that repetitive regional myocardial ischemia in the rat could decrease reperfusion ventricular arrhythmias, possibly acting by diminished release of norepinephrine. Isolated perfused working rat hearts were pre-labeled with tritiated norepinephrine (NE3H). The efflux of 3H-labeled compounds was measured in the effluent coronary flow. Each heart was subjected to two consecutive periods of regional myocardial ischemia induced by ligature of the left coronary artery. The duration of the first ischemic period was 5 or 10 min and that of the second was 10 min. Serious rhythm disturbances did not occur during the first period of ischemia but did after reperfusion. The amount of NE3H liberated during the reperfusion period was more marked after an initial ischemic period of 10 min than after 5 min of ischemia. Reperfusion arrhythmias were of little importance after 5 min of ischemia but developed in a sustained pattern when reperfusion followed 10 min of ischemia. After 5 min of ischemia, the mean duration of reperfusion arrhythmias was 12.8 +/- 10.4 s during the first 3 min of reperfusion, but after 10 min of ischemia the mean duration of serious rhythm disturbances was 149.7 +/- 16.7 s. Reperfusion after the second 10-min occlusion increased the release of NE3H. In series 5-10, the percentage of NE3H compared with the total radioactivity was a mean of 71.4 +/- 3.3% during the 5 min of ligature, 79.0 +/- 5.3% during the first 3 min of reperfusion. During the 10-10 series in which the ligature was maintained for 10 min, the percentage of NE3H compared with the total radioactivity was 70.6 +/- 5.1%, 81.1 +/- 8.7% during the first 3 min of reperfusion. These results show no reduction of any catecholamine release or of reperfusion arrhythmias by repetitive regional ischemia and provide no evidence for any preconditioning effect after short periods of regional ischemia. The antiarrhythmic effects of repetitive myocardial ischemia such as preconditioning previously reported may depend on the exact protocols used.     

Ischemia-induced conduction delay and ventricular arrhythmias: comparative electropharmacology of bethanidine sulfate and bretylium tosylate

Bretylium tosylate and bethanidine sulfate were studied in two models of experimental myocardial ischemia. In anesthetized dogs, left anterior descending coronary artery occlusion during rapid atrial pacing (180-200 min-1) produced ventricular tachycardia and fibrillation within 5 min in 9 of 11 dogs studied. In all cases, arrhythmias were preceded by and appeared to be temporally related to progressive fractionation and delay of electrograms recorded from the ischemic zone. In four dogs, bretylium (10 mg/kg) did not alter the time course of electrogram changes nor the time to onset of arrhythmia. However, in five dogs bethanidine (10 mg/kg) markedly exacerbated conduction changes in the ischemic zone and decreased the time to onset of ventricular arrhythmias (173 +/- 35 vs. 262 +/- 34 s control, mean +/- SEM, p less than 0.05). Bethanidine administration also facilitated ischemia-induced ventricular tachycardia and fibrillation in two dogs that did not exhibit ischemia-induced arrhythmias before receiving the drug. In isolated perfused rabbit hearts, global ischemia produced conduction slowing, depolarization of resting membrane potential, and decreases in amplitude and Vmax that were reproducible in serial 10 min ischemic episodes. Bretylium (10 mg/L) did not affect these parameters under either perfused or ischemic conditions. Although bethanidine (10 mg/L) also did not affect these parameters during perfusion, conduction slowing and depression of Vmax during ischemia were accelerated without affecting the time course of change in resting membrane potential. Both bretylium and bethanidine prolonged action potential duration under perfused conditions, but after 10 min of ischemia this effect was no longer evident. The results demonstrate that differences in the electrophysiologic effects of bretylium and bethanidine are markedly accentuated in the setting of acute ischemia. Although both these agents have been demonstrated to have antifibrillatory effects in other experimental settings, under the conditions of this study, bretylium failed to protect against ischemia-induced arrhythmias and acute bethanidine administration produced a proarrhythmic effect in association with an exacerbation of ischemia-induced conduction changes.     

Actions of the opioid antagonist, nalmefene, and congeners on reperfusion cardiac arrhythmias and regional left coronary blood flow

Opioid antagonists have been shown to prevent the occurrence of lethal arrhythmias following coronary reperfusion. In this study, we have examined the effect of a new, long-lasting, potent opioid antagonist, nalmefene, and congeners in the prevention of reperfusion arrhythmias in dogs. Nalmefene given at a dose of 1 mg/kg i.v. reduced the incidence of reperfusion arrhythmias significantly when compared to the saline control. Neither N-methyl nalmefene, a quaternary analog that does not cross the blood brain barrier, nor (+) nalmefene, an isomer with no anti-opioid actions, provided any protection against reperfusion arrhythmias. Regional myocardial blood flow profiles, during and after coronary occlusion, were not different between the nalmefene- and saline-treated groups. We conclude that nalmefene prevents the occurrence of reperfusion-induced arrhythmias by blocking opioid receptors in the brain.     

The effects of soman on norepinephrine uptake, release, and metabolism

The effects of 7-day administration of 5 micrograms/kg/day of soman sc on norepinephrine (NE) content, and catechol-O-methyl-transferase (COMT) and monoamine oxidase (MAO) activities of three rabbit tissues were examined. Effects on NE uptake by, and electrically stimulated release from, rabbit aorta were also determined, both in the 7-day study and with acutely applied soman. Tissues examined were the thoracic aorta, mesenteric artery, and brain stem. Significant (p less than 0.05) increases following 7 days of soman were observed in NE content: thoracic aorta, 20%; mesenteric artery, 48%; and brain stem, 121%. MAO activity decreased by 29% in the thoracic aorta, 20% in the mesenteric artery, and 48% in the brain stem. COMT activity also significantly decreased in two tissues, the thoracic aorta by 18% and brain stem by 23%. Acutely applied soman reduced electrically released NE from the thoracic aorta, but 7-day soman administration increased it. Seven-day soman administration, but not acutely applied soman increased NE uptake by the thoracic aorta. Thus, 7-day soman administration increased sympathetic capability by increasing NE content, nerve stimulation evoked NE release, and NE uptake, and by decreasing MAO and COMT activity. Therefore, repeated low-dose exposure to soman might exaggerate the response to any given level of sympathetic nerve stimulation and to NE-releasing agents.     

The effects of torbafylline on blood flow, pO2 and function of rat ischaemic skeletal muscle

Blood flow at rest and during contractions (measured with labelled microspheres), red cell flux (assessed by laser-Doppler flowmetry), surface pO2, lactate accumulation and release, the development of fatigue during acute muscle contractions, and performance in chronic experiments (running wheel) were estimated in rat hind limb muscles during unilateral acute occlusion or chronic ligation of the femoral artery. The effects of torbafylline (7-ethoxymethyl-1-(5-hydroxy-5-methylhexyl)3-methylxanthine) on the above-mentioned parameters were studied after acute i.v. infusion or chronic oral gavage. Torbafylline significantly ameliorated the decreased skeletal muscle blood flow, red cell flux and surface pO2 after acute occlusion of the femoral artery, with more pronounced effects on the microcirculatory parameters, the laser-Doppler flux and pO2. Chronic ligation of the femoral artery and consequent stimulation for 45 min induced increased fatigue (fatigue index in control muscles: 70%, in ligated muscles: 78%). Three weeks oral treatment with torbafylline (25 mg/kg per day) decreased fatigue to 68%. The blood flow in ligated muscles increased to a much smaller extent than in control muscles, and this smaller increase was attenuated by torbafylline. A chronic decrease in the blood supply resulted in a significant shortening of the running time. This decrease in running time was reversed by chronic treatment with torbafylline (25 mg/kg p.o. 2 times-day for 2 weeks). This improved performance may be explained by a decreased accumulation of lactate in muscles with a limited blood supply due to an effect of torbafylline to increase the release of lactate from ischaemic muscles.     

alpha- and beta-receptor blockade of isoproterenol- and norepinephrine-induced effects on regional blood flow and blood flow acceleration.

The effects of the beta-receptor blocking agent propranolol (100 microgram/kg i.v.) and of the alpha-receptor blocking agent dihydroergotamine (50 microgram/kg i.v.) on hemodynamic responses to isoproterenol and norepinephrine (both 1--1024 ng/kg) were investigated in anesthetized dogs. The effects studied were: (1) flow in the ascending aorta and the coronary, common hepatic, gastroduodenal, splenic, cranial mesenteric, renal and femoral arteries: (2) maximal flow acceleration in the splenic, cranial mesenteric and femoral arteries; (3) maximal rate of change of left ventricular pressure (LV dP/dt max). Propranolol shifted the dose-response curves for the isoproterenol-induced flow increases in the common hepatic, gastro-duodenal, and cranial mesenteric arteries to the right. It did not influence the flow responses to isoproterenol in the ascending aorta or the coronary, splenic, renal and femoral arteries. Propranolol prevented the decrease of arterial pressure evoked by isoproterenol. Propranolol shifted the isoproterenol-induced increase of LV dP/dt max and maximal blood flow to the same extent. Propranolol blocked the flow to the liver and gastrointestinal tract to a greater extent than the LV dP/dt max and maximal flow acceleration. Propranolol had no effect on the norepinephrine-induced increases in flow in the splenic, femoral and coronary arteries, but blocked the norepinephrine-evoked increases of flow accelerations and LV dP/dt max to the same extent. Dihydroergotamine inhibited the norepinephrine-induced increase in flow in the femoral artery and the decreases in flow in the hepatic, splenic, cranial mesenteric and renal arteries, and reversed the reduction of flow in the gastroduodenal artery. It is argued that dihydroergotamine may inhibit the increase in femoral flow through two mechanisms: (1) blocking the flow reduction to norepinephrine in the abdomen, and thereby passively shunting blood from the abdomen in preference to the femoral bed; (2) attenuating the norepinephrine-evoked reflexogenic femoral vasodilatation. It is concluded that: (1) propranolol is a beta-receptor blocking agent with a preference for blockade of isoproterenol-induced vascular effects; (2) norepinephrine-induced flow increases are not direct actions on vascular beta-receptors; (3) the increase of maximal blood flow accelerations after isoproterenol and norepinephrine is mediated by stimulation of cardiac beta-receptors; (4) dihydroergotamine is an alpha-receptor blocking agent particularly in the splanchnic vascular region.     

Left regional cardiac perfusion in vitro with platelet-activating factor, norepinephrine and K+ reveals that ischaemic arrhythmias are caused by independent effects of endogenous "mediators" facilitated by interactions, and moderated by paradoxical antagonism

Various putative drug targets for suppression of ischaemia-induced ventricular fibrillation (VF) have been proposed, but therapeutic success in the suppression of sudden cardiac death (SCD) has been disappointing. Platelet-activating factor (PAF) is a known component of the ischaemic milieu. We examined its arrhythmogenic activity, and its interaction with two other putative mediators, norepinephrine and K(+), using an ischaemia-free in vitro heart bioassay, and a specific PAF antagonist (BN-50739). PAF (0.1-100 nmol) was administered selectively to the left coronary bed of rat isolated hearts using a specially designed catheter. In some hearts, PAF was administered to the left coronary bed during concomitant regional perfusion with norepinephrine and/or K(+). In separate studies, PAF accumulation in the perfused cardiac tissue was evaluated using (3)H-PAF. PAF evoked ventricular arrhythmias concentration-dependently (P<0.05). It also widened QT interval and reduced coronary flow selectively in the PAF-exposed left coronary bed (both P<0.05). Two exposures of hearts to PAF were necessary to evoke the QT and rhythm effects. The PAF-induced arrhythmias and coronary vasoconstriction were partially suppressed by the PAF antagonist BN-50739 (10 microm), although BN-50739 itself widened QT interval. K(+) (8 and 15 mm) unexpectedly antagonised the arrhythmogenic effects of PAF without itself eliciting arrhythmias (P<0.05). Norepinephrine (0.1 microm) had little or no effect on the actions of PAF, while failing to evoke arrhythmias itself. Nevertheless, the combination of 15 mm K(+) and 0.1 microm norepinephrine evoked arrhythmias of a severity similar to arrhythmias evoked by PAF alone, without adding to or diminishing the arrhythmogenic effects of PAF. (3)H-PAF accumulated in the cardiac tissue, with 43+/-5% still present 5 min after bolus administration, accounting for the need for two exposures of the heart to PAF for evocation of arrhythmias. Thus, PAF, by activating specific receptors in the ventricle, can be expected to contribute to arrhythmogenesis during ischaemia. However, its interaction with other components of the ischaemic milieu is complex, and selective block of its actions (or its accumulation) in the ischaemic milieu is alone unlikely to reduce VF/SCD.     

Effects of sotalol, (-)-propranolol and prazosin on reperfusion-induced arrhythmias and increased cardiac norepinephrine release

The pharmacological actions of sotalol, (-)-propranolol and prazosin on norepinephrine (NE) concentration and creatine kinase (CK) activity in the coronary sinus blood of the ischemic heart were studied in open-chest dogs. A 60 min occlusion of the left anterior descending coronary artery was followed by a reperfusion period of 30 min. In saline-treated dogs, a significant increase in coronary sinus NE concentration occurring 30 s after the onset of reperfusion was followed by a rapid decrease to the initial value within 15 min. CK activity increased gradually and continuously starting 5 min after the beginning of reperfusion. A good correlation (r = 0.9, n = 8, P less than 0.05) was obtained in saline-treated dogs when the calculated slope of the time-activity curves for CK release was plotted against the corresponding peak concentration of NE. The increase in coronary sinus NE concentration upon reperfusion was accompanied by an increased arrhythmic ratio. Sotalol (5 mg/kg i.v.) diminished the increase in coronary sinus NE concentration along with a significant decrease in the arrhythmic ratio. The administration of either (-)-propranolol (0.1 mg/kg i.v.) or prazosin (1 mg/kg i.v.) did not significantly affect the increase in coronary sinus NE concentration. The arrhythmic ratio was significantly reduced by prazosin but not by (-)-propranolol. The rise in coronary sinus CK activity was significantly diminished in the presence of either sotalol, (-)-propranolol or prazosin. These results suggest that the occurrence of severe ventricular arrhythmias upon reperfusion may be related to the action of the increased myocardial NE on the cardiac alpha-adrenoceptors. The increased coronary sinus CK activity suggests that increased cardiac sympathetic activation may accelerate or aggravate the myocardial damage. We conclude that the antiarrythmic effect of sotalol may be due at least in part to its inhibitory action on the release of cardiac NE upon reperfusion.     

Beneficial effects of amiodarone pretreatment on early ischemic ventricular arrhythmias relative to infarct size and regional myocardial blood flow in the conscious dog

The effects of chronic pretreatment with amiodarone on ischemic ventricular arrhythmias were evaluated in fully conscious instrumented dogs. In control dogs (n = 14) with large myocardial infarcts, early (first 30 min) ventricular arrhythmias occurred in a bimodal distribution with peaks at 3-5 min and at 12-25 min, with only the former associated with epicardial conduction delay. Ventricular fibrillation occurred equally frequently during each peak of early ventricular arrhythmias. Amiodarone (30 mg/kg daily) for 3-4 weeks had no significant effect (n = 11) on anatomic infarct size (28 +/- 6 vs. 30 +/- 5% of left ventricular weight) nor on collateral blood flow in the center of the infarct (19 +/- 11 vs. 15 +/- 7 ml/min/100 g of tissue) or on the ratio of endocardial/epicardial perfusion (0.23 +/- 0.19 vs. 0.28 +/- 19). Despite significant lengthening of peak epicardial conduction delay (191 +/- 20 to 239 +/- 81 ms, p less than 0.05), the frequency of early ventricular arrhythmias, especially during the second peak of ectopic activity, were markedly attenuated by amiodarone pretreatment, with the extrasystole-free intervals often being as long as 6 h. The incidence of ventricular fibrillation was 9% in the treated animals compared with 29% in the controls. In the control animals, arrhythmias always supervened when epicardial fractionation was significant, and no ectopy-free interval was present in the first 6 h following coronary occlusion. The data indicate that chronic amiodarone pretreatment exerts a beneficial effect on the frequency and severity of such ventricular tachyarrhythmias, with reduction in the incidence of ventricular fibrillation and ectopic activity in the early phases following coronary occlusion.     

Comparison of the effects of Bay K 8644 and aortic constriction on regional myocardial blood flow and function in canine nonischemic and ischemic myocardium

The effects of Bay K 8644, aortic constriction, and a placebo on regional myocardial blood flows (RMBFs) and contractile function (RCF) were compared in three groups of open-chest anesthetized dogs during coronary stenosis. Bay K 8644 was investigated in two doses: 0.1 micrograms/kg, which exhibited no systemic hemodynamic effect, and 1 microgram/kg, which significantly increased arterial pressure. Aortic constriction was performed to raise afterload to the same extent as Bay K 8644 1 microgram/kg. As compared with placebo, Bay K 8644 0.1 microgram/kg, significantly increased coronary resistance, decreased RMBFs without changing RCF in nonischemic myocardial zones, and affected neither RMBFs nor RCF in ischemic zones. In nonischemic myocardium, Bay K 8644 1 microgram/kg increased RMBFs without affecting RCF, whereas aortic constriction did not modify RMBFs but decreased RCF. In ischemic myocardium, both Bay K 8644 1 microgram/kg and aortic constriction increased RMBFs but did not affect RCF. Thus, the low dose of Bay K 8644 exerts a direct and selective coronary vasoconstrictor effect that has no deleterious consequences on nonischemic RCF. Despite this intrinsic coronary vasoconstrictor effect, the high dose of Bay K 8644 increases RMBFs and maintains RCF in both ischemic and nonischemic zones in relation with the drug-induced increases in coronary perfusion pressure (both zones) and in contractility (nonischemic zones).     

Immediate vs. long-term desmethylimipramine or chlorimipramine: effects on regional cerebral blood flow

The immediate vs. long-term effects of desmethylimipramine (DMI) or chlorimipramine (CMI) on cerebral blood flow (CBF) were determined in 17 rabbit brain regions using radioactively tagged microspheres (15 +/- 3 micron in diameter). A single administration of either drug did not alter average CBF or its regional distribution 1 h later. Desmethylimipramine, an agent which primarily blocks re-uptake in presynaptic noradrenergic neurons, significantly increased CBF when administered daily for 21 consecutive days. The regional effects of DMI were not restricted to those areas dense in noradrenergic receptors. Flow was significantly increased in the hypothalamus, olfactory cortex, globus pallidus-putamen and midbrain. These flow increases probably reflect integrated cerebral metabolic, synthetic and/or functional activity which were associated with altered receptor sensitivity and/or number, rather than a direct cerebral vasodilatory effect. In contrast, CMI, a tricyclic antidepressant which primarily blocks presynaptic re-uptake in serotonergic neurons, and produced sedation, had little effect on CBF when administered daily for 21 consecutive days. The immediate effects of these agents on presynaptic re-uptake was not associated with altered CBF. The long-term antidepressant activity of these two agents on receptor sensitivity was probably not correlated with CBF, as evidenced by the lack of effect which CMI had on this parameter. Rather, CBF response appears to be correlated with the therapeutic spectrum of DMI which increases psychomotor activity in retarded depression.