Effects of propranolol on regional myocardial blood flow and function during severe coronary stenosis in dogs

The effects of propranolol alone or associated with atrial pacing were studied on regional myocardial blood flows (RMBF) and regional contractility (sonocardiometry) in non-ischemic, moderately and severely ischemic areas of the canine myocardium. In non-ischemic areas, propranolol reduced both epicardial and endocardial flows, increased the endo/epi ratio and decreased regional contractility. The reductions in subendocardial flow and function were correlated. In moderately and severely ischemic areas, propranolol increased subendocardial flow, reduced subepicardial flow, increased the endo/epi ratio and preserved or even slightly improved regional contractility. There was a good correlation between the propranolol-induced protective effects on regional contractility and the drug-induced increase in subendocardial flow since under atrial pacing subendocardial flow no longer increased and regional function dropped dramatically.     

The role of beta-adrenoceptors in coronary blood flow distribution in normal and ischemic canine myocardium.

beta-Adrenoceptor agonists increase myocardial ischemic injury, mainly by elevating myocardial oxygen consumption. Moreover, it has been shown that isoprenaline may "steal" regional myocardial blood flow (RMBF) from ischemic to non ischemic areas and from epicardium to endocardium. The mechanisms of these two isoprenaline-induced redistributions of RMBF have been investigated by the use of radioactive microspheres in an experimental model of canine myocardial ischemia with simultaneous measurement of ST-segment elevation. Isoprenaline increased RMBF in both epi- and endocardial non ischemic areas and in epicardial ischemic areas, leading to a significant decrease in the endo/epi ratio. After atenolol, isoprenaline still increased RMBF but to a lesser extent and the endo/epi ratio was still decreased. Salbutamol, in doses inducing no significant changes in cardiac parameters or myocardial oxygen consumption, produced effects similar to those of isoprenaline. These results indicate a non-homogeneous beta2-stimulation-induced vasodilation in endo- and epicardium, which might be due either to the higher epicardial coronary vasocilatory reserve or to a heterogeneous distribution of transmural beta2-adrenoceptors. Isoprenaline also decreased the ischemic/non ischemic total blood flow ratio (I/NI) and caused further increases in ST-segment elevation. These effects were abolished by atenolol pretreatment, indicating the deleterious effects of isoprenaline-induced tachycardia in this I/NI decrease and in the ischemic injury.     

Comparative effects of nicorandil, a nicotinamide nitrate derivative, and nifedipine on myocardial reperfusion injury in dogs

The effects of the nicotinamide nitrate compound nicorandil (SG-75) and the slow channel calcium entry blocker nifedipine on the recovery of subendocardial segment shortening (% SS) were compared with a vehicle-treated group following 30 min of left anterior descending coronary artery (LAD) occlusion and 3 h of reperfusion. Sonomicrometry was used to determine % SS in ischemic and nonischemic myocardium, and radioactive microspheres were used to determine regional myocardial blood flow. Nicorandil (100-micrograms/kg bolus followed by 25 micrograms/kg/min i.v.), nifedipine (10-micrograms/kg bolus followed by 3 micrograms/kg/min i.v.), or vehicle (saline) was administered 15 min prior to and throughout the occlusion period. Both drugs produced equivalent decreases in the heart rate X systolic pressure product before and during LAD occlusion. In addition, total left ventricular weights, the area at risk, the percent of the left ventricle at risk, and collateral blood flow were similar in all three groups. During coronary occlusion, % SS in the ischemic region was equally depressed in each series and passive systolic lengthening resulted. However, following reperfusion, only the nicorandil-treated animals showed an improvement in myocardial segment function through 3 h of reperfusion as compared with the control group. Transmural myocardial blood flow within the ischemic region during reperfusion returned to control values in all three groups; however, the endocardial/epicardial blood flow ratio (endo/epi) was significantly decreased in the control and nicorandil-treated dogs. In contrast, the endo/epi was greater than the preocclusion control in the nifedipine series during reperfusion. Thus, although the mechanism of action of nicorandil in this model is unknown, the improvement in % SS in the nicorandil-treated group was not related to changes in peripheral hemodynamics or improved regional blood flow, since nifedipine produced similar changes in hemodynamics and resulted in a better recovery of perfusion.     

Measurement of oxygen tension in the ischemic myocardium using encased polargraphic oxygen electrodes

The ability to continuously monitor the delicate balance between blood flow and oxygen consumption would be a great asset in the study of myocardial ischemia. The present study was performed, in anesthetized dogs, to validate the use of encased polargraphic oxygen electrodes in the study of myocardial ischemia. Polargraphic oxygen electrodes were placed in the area to be rendered ischemic at fixed tissue depths of 3 mm (epicardium) and 9 mm (endocardium). Endocardial and epicardial oxygen tensions as well as the ratio of endocardial to epicardial oxygen tension and left circumflex coronary flow were monitored. Ischemia was induced by decreasing left circumflex coronary flow by 50%. Upon completion of a 20-min poststenotic period, endocardial pO₂, endocardial/epicardial ratio, and coronary flow were significantly decreased (59 ± 7, 52 ± 7, and 55 ± 4%, respectively) whereas epicardial pO₂ was slightly decreased. Nitroglycerin (10 μg/kg, i.v.) markedly increased endocardial pO₂ and endocardial/epicardial ratio above poststenotic control (13 ± 5 mmHg and 64 ± 10%, respectively) whereas epicardial pO₂ was not significantly decreased. The increases in endocardial pO₂ occurred at a point where coronary flow and mean arterial pressure were not significantly changed. Conversely, dipyridamole (125 μg/kg, i.v.) significantly increased coronary flow (26 ± 2 ml/min/100 g) although it did not appreciably alter endocardial or epicardial pO₂. It is concluded that encased polargraphic oxygen electrodes provide a quantitative method for determination of oxygen tension in the ischemic myocardium.     

Adrenoceptor blocking hemodynamic and coronary effects of YM-09538, a new combined alpha- and beta-adrenoceptor blocking drug, in anesthetized dogs

In anesthetized dogs. YM-09538, a new sulfonamide-substituted phenylethylamine, competitively antagonised the phenylephrine-induced vasopressor response with a DR10 of 0.50 mg/kg i.v. and the isoproterenol-induced positive chronotropic response with a DR10 of 0.66 mg/kg i.v., indicating that YM-09538 blocks both alpha 1- and beta 1-adrenoceptors and almost to the same extent. YM-09538 was 4 times more potent than phentolamine in blocking alpha 1-adrenoceptors and 3 times less potent than propranolol in blocking beta 1-adrenoceptors. YM-09538 non-selectively blocked cardiac beta 1- and vascular beta 2-receptors and was devoid of intrinsic beta-sympathomimetic and local anesthetic activities. In anesthetized closed-chest dogs, YM-09538 resembled propranolol in reducing heart rate, cardiac output, max. dLVP/dt and left ventricular cardiac work but differed from propranolol in decreasing total peripheral resistance, in increasing femoral blood flow, in causing larger falls in arterial blood pressure and in decreasing pulmonary arterial pressure. In anesthetized open-chest dogs, YM-09538 reduced heart rate, myocardial contractile force and arterial blood pressure. In non-ischemic myocardium, transmural flow and coronary vascular resistance were respectively strongly increased and decreased and the endo/epi flow ratio was slightly but not significantly reduced. In ischemic myocardium, YM-09538 also increased transmural flow and since endocardial and epicardial flows were augmented to the same extent, the endo/epi flow ratio remained unchanged. All these hemodynamic and coronary effects of YM-09538 can be accounted for the drug's combined alpha- and beta-adrenoceptors blocking properties.     

Pentaerythritol trinitrate and glyceryl trinitrate on intramyocardial oxygenation and perfusion in the dog. Krogh analysis of transmural metabolism

1. The effect of intravenous pentaerythritol trinitrate and glyceryl trinitrate on left ventricular subepicardial (epi) and subendocardial (endo) Po₂ and perfusion were compared in anaesthetized open-chest mongrel dogs. Tissue Po₂ was determined simultaneously at a depth of 3 mm (epicardial) and 9 mm (endocardial) with small platinum electrodes by polarography. In a separate series of dogs tissue perfusion of those regions was measured by hydrogen (H₂) clearance using similar electrodes. 2. Both nitrates increased endocardial Po₂ while epicardial Po₂ was not altered. Perfusion was determined at the point of the maximal rise in endocardial Po₂ (4–7 min after injection of either nitrate). At that period average coronary artery inflow and epicardial perfusion were decreased but endocardial perfusion was not significantly altered. 3. Using the data on Po₂, hydrogen clearance and intercapillary distance, the effect of the nitrates on transmural metabolism (oxygen consumption) was estimated by Krogh analysis. Basal endocardial metabolism was 20–30% higher than epicardial metabolism. The nitrates reduced metabolism in each region. The absolute decrease in oxygen consumption was greater in the endocardium. 4. The results show that both pentaerythritol trinitrate and glyceryl trinitrate improve endocardial oxygenation by producing a more favourable balance between perfusion and oxygen requirements in that region.     

Enhanced subendocardial perfusion distal to a flow-limiting coronary artery stenosis in dogs: comparative effects of nicorandil, a potential new antianginal agent, and nitroglycerin

The purpose of this study was to compare the effects of nicorandil [SG-75; 2-nicotinamidoethyl nitrate (ester)] and nitroglycerin on the distribution of blood flow between subendocardium and subepicardium [endocardial/epicardial blood flow ration (endo/epi)] distal to a proximal flow-limiting coronary artery stenosis in anesthetized dogs. Myocardial blood flow distribution was determined by use of 15-micron radioactive microspheres. Various indices of reactive hyperemia (peak flow, duration, volume) and poststenotic coronary pressures were used to assess the severity of ischemia in the area distal to the stenosis. Partial ischemia was produced by a 10-s total left circumflex coronary occlusion followed by 110 s of reflow to 50-60% of the control flow. Microspheres were injected during steady-state conditions during the partial reflow period. In the absence of drug, coronary artery stenosis produced marked underperfusion of the subendocardium (endo/epi, 0.55 +/- 0.05). Following administration of nicorandil (60 micrograms/kg i.v.) or nitroglycerin (15 micrograms/kg i.v.), the endo-epi during a subsequent partial reflow (stenosis present) period was significantly increased (0.67 +/- 0.06). The duration of reactive hyperemia and reactive hyperemic flow were also decreased by both compounds following release of the stenosis. These results suggest that nicorandil and nitroglycerin reduce subendocardial ischemia distal to a flow-limiting coronary artery stenosis. This beneficial effect may partially explain the efficacy of these two compounds in the therapy of angina pectoris.     

Effect of pinacidil on myocardial blood flow in the chronically pressure overloaded hypertrophied left ventricle.

This study examined the effect of pinacidil on the transmural distribution of myocardial blood flow in the chronically pressure overloaded hypertrophied left ventricle. Studies were performed in six dogs in which banding of the ascending aorta had resulted in an 88% increase in left ventricular mass, as well as in six normal control animals. Two doses of pinacidil were administered to decrease mean arterial pressure by approximately 10 mm Hg (low dose) and 20 mm Hg (high dose). Animals with hypertrophy required significantly smaller drug doses to achieve the desired reductions in arterial pressure. During control conditions mean myocardial blood flow was significantly higher in animals with hypertrophy (1.90 +/- 0.21 ml/min/g) than in normal animals (1.12 +/- 0.08 ml/min/g; p less than 0.05). Subendocardial flow (endo) exceeded subepicardial flow (epi) in normal dogs during control conditions (endo/epi = 1.41 +/- 0.13), but not in animals with hypertrophy (endo/epi = 1.06 +/- 0.06; p less than 0.05). Pinacidil caused coronary vasodilation with similar relative increases in blood flow in both normal and hypertrophied hearts, so that after pinacidil, absolute blood flow rates remained higher than normal in animals with hypertrophy. Pinacidil caused a redistribution of blood flow away from the subendocardium in normal hearts (endo/epi = 0.90 +/- 0.11 during high-dose pinacidil) and in hearts with hypertrophy (endo/epi = 0.81 +/- 0.13 during high-dose pinacidil). The endo/epi ratios during high-dose pinacidil were not significantly different between the two groups. This study demonstrates that pinacidil is a potent coronary vasodilator in both normal and hypertrophied hearts.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular actions of N-allyl-clonidine (ST 567), a substance with specific bradycardic action.

In anaesthetized cats and dogs the prominent action of St 567 (1 and 2.5 mg/kg i.v.) was a decrease in heart rate. This was paralleled by a decrease in cardiac output; the decrease in blood pressure was much smaller or insignificant. The increase in heart period was mainly due to a prolongation of the diastolic period, the increase in ejection time was much smaller and of shorter duration. In cats the “triple product” of heart rate × ejection time × blood pressure was decreased by St 567. Cumulative injection of the drug also decreased the contractility of the heart (dp/dt max); this effect was partly due to the decrease in spotaneous heart rate as shown by comparison with results in electrically paced hearts. No obvious changes of the ECG, limb leads, were recorded except a small increase in $\text{PQ}\text{and}\text{QT}$ which accompanied the much greater increase in $\text{PP′}$. In cats with acute occlusion of a coronary artery branch, St 567 diminished the elevation of the ST-segment of the epicardial electrogram, parallel with the bradycardic effect. St 567 decreased the heart rate of conscious dogs. The bradycardia achieved thereby was directly correlated with the heart rate before injection of St 567, independent of whether this “control value” was achieved from a spontaneous sinus rate or increased by pretreatment with atropine or hydralazine. The cardiovascular profile of St 567 indicates a decrease in myocardial oxygen demand, a desirable therapeutic measure in the treatment of ischemic heart disease.     

Effect of adenosine on transmural flow gradients in normal canine myocardium

Previous reports suggest that in comparison to epicardial flow the response of endocardial blood flow to systemic adenosine is limited. However, intravenous adenosine results in reflex tachycardia and hypotension, which we avoided in six anesthetized dogs by infusing adenosine into the left circumflex (LCx) artery to evaluate the endocardial/epicardial ratio during partial and full vasodilation. The mean (+/- SD) LCx endocardial/epicardial ratio was 1.37 +/- 0.18 with partial vasodilation and 0.81 +/- 0.06 with full vasodilation, which represents an initial increase followed by a decrease when compared with the normal left anterior descending values (p less than 0.05). This biphasic response in the endocardial/epicardial ratio with increasing vasodilation was a direct effect of adenosine, as no hemodynamic alterations occurred during the protocol. These data suggest that in an experimental model with a relative tachycardia the endocardial layer is more sensitive to adenosine but there is a greater capacity to increase flow in the epicardial layer.     

Metabolic rate of phenacetin and of paracetamol in dogs before and after treatment with phenobarbital or skf 525 A

In six male mongrel dogs the apparent biological half life ($\text{t}\text{2}$) in plasma of intravenously injected phenacetin decreased from 34·6 to 27·2 min after treatment with phenobarbital (25 mg/kg/day for 8 days) (P < 0·025). In the same dogs, the apparent $\text{t}\text{2}$ of intravenously injected phenazone decreased from 78·6 to 32·4 min (P < 0·05). Treatment with SKF 525 A (25 mg/kg) increased the $\text{t}\text{2}$ of phenazone in three other dogs from 70·6 to 246·7 min, whereas the $\text{t}\text{2}$ of phenacetin remained unaffected.The concentration of phenacetin at zero time of intravenous injection increased from 29·5 ± 5·9 S.E. to 43·5 ± 12·6 μg/ml plasma (P < 0·2) after phenobarbital treatment; pretreatment with phenobarbital, however, had no influence on the mean concentration of phenazone at 0 time. SKF 525 A did not influence the zero time concentration of either phenacetin or phenazone.Beagle liver microsomal protein and cytochrome P-450 concentrations increased from 3·2 to 4·2 mg/ml and from 1·0 to 4·1 n-mole/mg protein, respectively, after phenobarbital treatment. Treatment with phenobarbital had no influence on the rates of formation of paracetamol and p-phenetidin nor was the apparent K_m of phenacetin affected.The binding of phenacetin to blood constituents increased from 50 per cent at 5 μg/ml to 59 per cent at 1 μg phenacetin/ml. In the presence of 30 μg phenobarbital/ml blood, the binding of phenacetin at 1 μg/ml blood decreased by 22 per cent.It is concluded that the decrease of the apparent $\text{t}\text{2}$ of phenacetin in dog plasma after phenobarbital treatment may be due to a change in the apparent volume of distribution and/or to some stimulation of an NADPH-dependent enzyme system of the liver less affected by treatment with SKF 525 A than in other species.     

Electrophysiologic and blood-flow responses in the endocardium and epicardium to disopyramide and MS-551 during myocardial ischemia in the dog.

The aim of this study was to determine whether a quantitative relation exists between changes in regional myocardial blood flow (RMBF) and those in electrophysiologic determinants recorded via left ventricular endocardial and epicardial bipolar electrograms after administration of disopyramide (DP) and a class III antiarrhythmic drug, MS-551 (MS), during myocardial ischemia in the dog. Dogs were given DP (1 mg/kg, i.v., n = 14), MS (1 mg/kg, i.v., and 0.1 mg/kg/min, d.i.v., n = 13), or saline (n = 12). The effective refractory period (ERP) was determined by an S1-S2 extrastimulus method, and RMBF by a nonradioactive microsphere technique. The duration of regional electrograms (DRE) was measured as an indicator of conduction time in the myocardium. DP blunted ischemia-induced shortening of ERPs and lengthened DREs at the endocardial and epicardial sites, with a greater effect seen epicardially (p < 0.01 each). DP reduced RMBF, especially at the endocardial surfaces of the ischemic zone (p < 0.05). MS prolonged ERPs at the endocardial and epicardial sites in the ischemic and normal zones (p < 0.05-0.01), but there were no significant differences between the two sites. MS prolonged DREs (p < 0.05), but the magnitude of the prolongation of the DREs was similar to the values in the control group. MS had no effects on RMBF. DP treatment prolonged DREs at both sites in the ischemic zone more markedly than MS or saline treatment (p < 0.01 each). DP reduced RMBF at the endocardial site of the ischemic zone more markedly than MS or saline (p < 0.05 in each). Accordingly, MS prolonged ERPs, but did not increase disparities between endocardial and epicardial sites in the ischemic myocardium, whereas DP had a greater ERP-prolonging effect at the epicardial site than at the endocardial site. DP reduced endocardial RMBF more markedly than epicardial RMBF. These observations suggest that differences in ERPs between endocardial and epicardial ischemic myocardium caused by DP treatment are not due to the difference in RMBF reduction between the two tissue layers, and that DP and MS do not affect the same population of ion channel(s) when ERPs are prolonged.     

Effects of intracoronary nifedipine on blood flow and segment shortening in normal and ischemic myocardium: potentiation by ischemia of the negative inotropic effect

The effects of intracoronary nifedipine on myocardial blood flow (flow probe or microspheres) and regional function (ultrasonic crystals in subendocardium) were examined both in the normal myocardium and in myocardium made ischemic by a partial coronary occlusion in the open-chest anesthetized dog. In a first group of experiments (n = 7), without ischemia, nifedipine infused into the left anterior descending coronary artery (LAD) during a 1-min period (doses 0.75-8 nmol/kg body weight) decreased coronary vascular resistance with a maximal effect at 4 nmol/kg. Systolic segment shortening was decreased from 10.7 to 7.4% (p less than 0.05) by 6 nmol/kg, whereas lower doses had no effect. In a second experimental group (n = 7), a partial LAD occlusion was applied to decrease subendocardial segment shortening by about 50%. Nifedipine (2 nmol/kg) injected into the partially occluded LAD induced a marked segmental bulging during early systole and systolic segment shortening was eliminated (from 4.2 to -3.1%, p less than 0.02) in the LAD-dependent myocardium. Concomitant with the decreased regional function, nifedipine caused a transmural redistribution of myocardial blood flow in the ischemic area, the endocardial/epicardial blood flow ratio increasing from 0.49 to 0.61 (p less than 0.02). It is concluded that ischemia potentiates the direct depressant effect of nifedipine on myocardial regional function.     

Actions of two new bradycardic agents, AQ-AH 208 and UL-FS 49, on ischemic myocardial perfusion and function

The effects of continuous infusions (30 min) of two new bradycardic agents, AQ-AH 208 (3,4-dihydro-6,7-dimethoxy-2-(3-((2-(3,4 dimethoxyphenyl) ethyl)-amino methyl) propyl)-1(2H)-isochinolinon) (10 and 25 micrograms/kg/min) and UL-FS 49 (1,3,4,5-tetrahydro-7,8-dimethoxy-3(3((2-(3,4-dimethoxyphenyl) ethyl) methylimino) propyl)-2H-3-benzazepin-2 on) (1.0 and 2.5 micrograms/kg/min) on ischemic myocardial perfusion and function were studied in anesthetized open chest dogs. Coronary stenosis was induced by narrowing an extracorporeal shunt between the carotid and left anterior descending coronary artery. Regional perfusion was measured by use of radioactive microspheres and regional myocardial function (% segment shortening) was assessed by sonomicrometry. AQ-AH 208 and UL-FS 49 produced dose-dependent reductions in heart rate of 13 to 55 beats/min without prominent effects on left ventricular dP/dt, aortic blood pressure, and % segment shortening of the normally perfused area. In nonischemic myocardium, AQ-AH 208 did not change transmural blood flow in spite of the bradycardia, whereas UL-FS 49 decreased flow. At the high infusion rate, ischemic subendocardial perfusion increased from 0.43 to 0.58 ml/min/g following UL-FS 49 and from 0.57 to 0.84 ml/min/g after treatment with AQ-AH 208. Consequently, endo/epi rose from 0.52 to 0.80 and 0.62 to 0.96, respectively. Atrial pacing abolished the effects of UL-FS 49 on ischemic myocardium whereas the effects of AQ-AH 208 were only partially reduced. Ischemic myocardial function deteriorated less during treatment with UL-FS 49 and was significantly improved following AQ-AH 208 as compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Protective effect of diltiazem against ischemia-induced decreases in regional myocardial flow in rat heart

Diltiazem has cardioprotective properties following myocardial ischemic injury. However, there are controversial results regarding the beneficial effects of diltiazem on regional myocardial flow after ischemia. Therefore, we investigated the effect of diltiazem on changes in regional myocardial flow due to ischemia for different periods. Non-radioactive colored microspheres were used for this measurement in isolated rat heart. After 20 or 40 min of global ischemia and 40 min of reperfusion, regional myocardial flow was decreased, especially in the endocardial layer. The endocardial/epicardial ratio was also decreased. The decreases in endocardial flow and the endocardial/epicardial ratio were more remarkable after 40 min of ischemia than after 20 min of ischemia. Diltiazem (10(-6) M), which was administered 15 min before ischemia, prevented only the decrease in endocardial flow and endocardial/epicardial ratio after 20 min of ischemia, whereas it did not prevent that after 40 min of ischemia. Nifedipine (2x10(-6) M) did not exert a cardioprotective effect. These findings suggested that the effect of ischemia is marked in the endocardium and, also, that the protective effect of diltiazem is seen only during a decrease in endocardial flow following short-term and reversible ischemia.     

Effect of pinacidil on myocardial blood flow in the presence of a coronary artery stenosis.

This study examined the effect of pinacidil on transmural distribution of myocardial blood flow during normal conditions and in the presence of a coronary artery stenosis. Studies were performed in 11 awake dogs; blood flow was measured with radioactive microspheres. Two doses of pinacidil were administered to decrease mean arterial pressure (MAP) by approximately 10 mm Hg (low dose, 0.18 +/- 0.02 mg/kg) and 20 mm Hg (high dose, 0.32 +/- 0.03 mg/kg). Measurements were performed during unimpeded arterial inflow and with two levels of coronary stenosis that limited blood flow to approximately 60% above (moderate stenosis) and approximately 30% above basal flow (severe stenosis). With no stenosis, coronary flow increased 227 +/- 17% after low-dose and 321 +/- 31% after high-dose pinacidil (each p less than 0.01). During control conditions, subendocardial (endo) flow exceeded subepicardial (epi) flow (endo/epi ratio = 1.33). This ratio was not changed by low-dose pinacidil but decreased to 0.93 after high-dose pinacidil (p less than 0.05). During high-dose pinacidil, a coronary stenosis caused uniform reduction of blood flow across the left ventricular wall, with no further significant change in the ratio of endo/epi flow. With low-dose pinacidil, both moderate and severe degrees of stenosis caused redistribution of flow away from the subendocardium similar to that observed with high-dose pinacidil. Although a stenosis that limited the increase in mean coronary flow after pinacidil administration to 162% of the predrug control value had a 95% probability of not causing a decrease in absolute subendocardial flow, the data suggest that pinacidil could have potential for aggravating subendocardial ischemia in severe occlusive coronary artery disease.     

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.     

Effect of long-term oral nisoldipine on infarct size and collateral development in pigs undergoing gradual occlusion of the left circumflex artery.

We examined the effects of nisoldipine on infarct size and collateral development in pigs, whose coronary circulation is similar to that of humans, using an experimental protocol reproducing as closely as possible the usual clinical setting. Fifteen pigs undergoing left circumflex Ameroid-occlusion were randomized into a control group (n = 8) and a group (n = 7) treated with oral nisoldipine 0.03 mg/kg every 6 h for 1 month starting on the second postoperative day. Infarct size (tetrazolium red) was 37.2 +/- 9.2% of the circumflex distribution in the control group and 10 +/- 3.2% in the treated group (p less than 0.01). Endocardial and transmural blood flows (microspheres) in the circumflex distribution were significantly higher (p less than 0.05) in the treated group (control endocardial 1.25 +/- 0.1 mg/g/min, treated endocardial 1.77 +/- 0.26 ml/g/min; control transmural 1.39 +/- 0.08 ml/g/min; treated transmural 1.78 +/- 0.23 ml/g/min). Epicardial flow and the ratio of subendocardial to subepicardial blood flow (endo/epi) were nonsignificantly higher in treated pigs. No differences were observed in heart rate (HR) and aortic pressure (AP). We conclude that in pigs undergoing left circumflex Ameroid-occlusion, long-term oral nisoldipine reduces infarct size and enhances collateral circulation to the ischemic myocardium.     

Lack of protection of ischemic myocardium by verapamil in conscious dogs

To determine whether coronary dilation and decreased myocardial oxygen requirements resulting from administration of verapamil, a calcium and slow current antagonist, protect ischemic myocardium in conscious dogs, we studied 15 treated and 15 control animals after coronary occlusion. Verapamil (0.2–0.7 mg/kg/h) was given by continoous infusion for 17 h beginning 5 h after the initial plasma creatine kinase (CK) elevation after coronary occlusion. Observed infarct size and infarct size predicted before verapamil were estimated from hourly plasma CK values and infarct size was estimated also from myocardial CK depletion measured directly, 24 h after occlusion. Changes in heart rate, blood pressure, and frequency of premature ventricular complexes (recorded every 30 min) after occlusion were similar in treated and control dogs. Coronary flow after verapamil, measured with radioactively labeled microspheres, did not increase in ischemic zones but increased by 90% in normal myocardium (p < 0.05). The differences between observed and predicted infarct size estimated from plasma CK changes in treated and controls were similar (3.0±2.2 (S.E.) and 2.0±1.4 CK-g-eq), and myocardial CK depletion was also comparable in the two groups (25 ± 2% and 23 ±2%). Thus although verapamil, administered five hours after the initial plasma CK elevation, increased coronary flow in normal myocardium, it did not augment flow in ischemic tissue or limit the extent of infarction.