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.     

Effects of verapamil on regional myocardial blood flow and ST segment. Role of the induced bradycardia

The effects of verapamil on regional myocardial blood flow and on the $\text{ST}$ segment were studied in both normal and ischemic regions in dogs with and without cardiac pacing.In the absence of cardiac pacing, verapamil (0.05 mg/kg/min/10 min) induced marked bradycardia, a drop in blood pressure and an increase in epicardial and endocardial flows both in normal and ischemic regions of the heart. However, in ischemic regions, redistribution was favorable since the endo/epi ratio increased from 0.46 to 0.61 (p<0.01) whereas this ratio did not vary in normal regions (0.94 vs. 0.92). This increase is accompanied by less marked $\text{ST}$ segment elevation during coronary occlusion in dogs treated with verapamil.In dogs with cardiac pacing, administration of verapamil under the same conditions again induced a drop in blood pressure and, in normal regions only, a homogeneous but less marked increase in epicardial and endocardial flows, the endo/epi ratio varying from 0.94 to 0.98. In contrast, in ischemic regions, blood flow was not modified by verapamil, but the endo/epi ratio dropped from 0.46 to 0.31 (p<0.01), while the $\text{ST}$ segment elevation observed did not differ from that recorded during the control occlusion.These results demonstrate the major role of verapamil-induced bradycardia in the anti-anginal effects of this drug.     

Effect of dilazep on coronary and systemic circulations

In order to assess the effects of dilazep on central hemodynamics and regional flows, 0.2 mg/kg of the drug were administered intravenously to 6 open-chest anesthetized dogs. Hemodynamic and flow measurements were performed under control conditions, and approximately 5, 10 and 25 min after treatment. Dilazep caused a marked and sustained reduction of coronary resistance and increased coronary blood flow. Flow increased uniformly in the subendocardial and subepicardial layers of the left ventricle so that no significant change occurred in the endo/epi flow ratio. Dilazep caused a significant reduction of total systemic resistance and aortic pressure, however flow to the liver, kidney and spleen was not reduced. We conclude that dilazep exerts a dilating action on the coronary and systemic arterial beds and increases uniformly regional myocardial blood flow. Dilazep does not alter the transmural distribution of coronary blood flow and does not impair kidney, liver and spleen perfusion.     

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.     

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)     

Influence of heart rate on the effects of prenalterol on regional myocardial blood flow and function during coronary stenosis in dogs.

The effects of prenalterol, a selective beta 1-adrenoceptor agonist with potent cardiac positive inotropic properties have been investigated on regional myocardial blood flow (RMBF) (microspheres) and contractile function (ultrasonic crystals) during partial circumflex coronary artery stenosis in 8 open-chest anaesthetized dogs. Prenalterol was investigated at two intravenous doses: 5 micrograms kg-1, which increased myocardial contractility (dP/dt max: +29%) more than heart rate (+12%, up to 150 beats min-1) and 20 micrograms kg-1 which induced almost similar increases in contractility (+35%) and heart rate (+31% up to 175 beats min-1). The induced modifications of regional flow and function were then compared to those produced in another series of 6 dogs by atrial pacing at 150 and 175 beats min-1 respectively. Prenalterol significantly increased RMBF and segment length (SL)-shortening in a dose-dependent manner in the nonischaemic zone. In the ischaemic zone, RMBF was maintained and SL-shortening increased with prenalterol, 5 micrograms kg-1 whereas both RMBF and contractile function were severely decreased with prenalterol, 20 micrograms kg-1. Atrial pacing had almost no effect on RMBF and SL-shortening in the nonischaemic zone. In the ischaemic zone, atrial pacing rate-dependently decreased both RMBF and SL-shortening. Thus, a significant increase in contractility, associated with little tachycardia (prenalterol, 5 micrograms kg-1), induces beneficial effects on RMBF and function in both the nonischaemic and ischaemic myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardioprotection by the calcium antagonist PN 200-110 in the absence and presence of cardiodepression.

The globally-ischaemic Langendorff rabbit heart model has been used to study the cardioprotective effects of the dihydropyridine PN 200-110 (PN) at two doses, one having no negative inotropic effect and a higher dose causing a 62 +/- 5% reduction in contractility. Following 45 min no-flow global ischaemia, recovery was monitored for a period of 90 min reperfusion. Hearts were paced at a constant rate throughout experiments. Contractile force and coronary flow were recorded continuously. Tracer microspheres were injected at regular intervals to assess regional flow distributions, drill biopsies were taken to determine tissue high energy phosphate content, and enzyme leakage in the coronary effluent measured during the first 15 min of reperfusion. Untreated hearts recovered 21 +/- 2% of their initial contractile force and flow to all heart regions was reduced. In particular, endocardial flow fell to 20% of its pre-ischaemic level, with the ratio of flow to the endocardium (endo)/epicardium (epi) decreasing from ca. 1.0 to 0.4. Hearts treated with 2 X 10(-8)M PN (included in the perfusate from 30 min before ischaemia until 30 min after ischaemia) recovered 49 +/- 2% of their initial, pretreatment contractile force, and following the ischaemia the endo/epi ratio was not significantly changed from the pre-ischaemic value. The lower PN dose (3 X 10(-10)M) afforded a lesser degree of protection, contractility recovering to 29 +/- 4% of the initial level, with an endo/epi ratio of 0.7 after 90 min reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

The effect of diltiazem on ST-segment elevation and myocardial blood flow distribution during pacing-induced ischemia

The purpose of this study was to determine if diltiazem can reduce the severity of pacing-induced ischemia independently of increases in overall and microregional ischemic blood flow. Sixteen anesthetized dogs were subjected to atrial pacing and had their left anterior descending coronary arteries (LAD) occluded until significant ST-elevation occurred. Cessation of pacing resulted in abolition of ST-segment elevation. ST-elevation as well as hemodynamics were measured during 5 min periods of pacing + LAD stenosis before, and 10, 40 and 70 min after treatment with intracoronary (i.c., just distal to the stenosis) diltiazem (1.8 micrograms/kg), i.v. diltiazem (180 micrograms/kg) or saline. Myocardial blood flow was measured using radioactive microspheres under baseline conditions, pacing, pacing + stenosis, and pacing + stenosis + drug (70 min post-drug). Both i.c. and i.v. diltiazem significantly and similarly reduced pacing-induced ST-elevation at 40 and 70 min post-drug with the highest measured reductions occurring for both at 70 min (50-60% reduction). Overall ischemic regional myocardial blood flow was unaffected by i.c. and i.v. diltiazem. Diltiazem given i.v. resulted in reduced flow in the lightly ischemic region and increased flows in the subepicardial half of the severely ischemic region. Diltiazem given i.c. resulted in a reduced subepicardial flow in the lightly ischemic region with no other changes occurring in the other regions. Thus, both i.c. and i.v. diltiazem can reduce the severity of pacing-induced ischemia and, in the doses given, in an equivalent fashion. Diltiazem also seems to be able to reduce severity of ischemia in a manner independent of increases in ischemic region flow and in fact can reduce flow in marginally ischemic tissue.     

Effects of beta-receptor blockade on regional blood flows during acute left ventricular failure in dogs

This study describes the effects of beta-receptor blockade on systemic hemodynamics and regional blood flows during acute ischemic heart failure in dogs. Depression of left ventricular (LV) function was induced by embolization of the left main coronary artery and was evidenced by a significant increase in LV end-diastolic pressure (LVEDP) and decrease in LV dP/dtmax and in cardiac output. Measurements of femoral, renal, mesenteric, and carotid blood flows showed a redistribution of cardiac output during failure. Femoral blood flow decreased to a greater extent than did cardiac output, carotid blood flow decreased in proportion to cardiac output, whereas mesenteric and renal blood flows were moderately reduced in relation to the decrease in cardiac output. Administration of 0.125 mg of propranolol intravenously (i.v.) significantly decreased the performance of the failing left ventricle. Reductions in cardiac output were accompanied by reductions in the peripheral circulations. The decrease in flow was evenly distributed in the femoral, mesenteric, and carotid vascular beds, while there was a relative preservation of renal blood flow. When the dose of propranolol was increased to 0.5 mg/kg, there were no further significant hemodynamic alterations.     

Beta-adrenoceptor stimulation and blockade during myocardial ischemia in dogs: effect on cardiac O2 supply and consumption

The effect of beta-adrenoceptor blockade and activation on ischemic regional and microregional myocardial O2 supply/consumption parameters was assessed in 28 open chest, anesthetized dogs. Ten minutes after LAD occlusion, dogs were given i.v. saline, 2 mg/kg propranolol, 0.2 mg/kg pindolol, or 1 microgram/kg per min isoproterenol. Coronary blood flow was determined using radioactive microspheres before and 2 h after LAD occlusion while O2 supply/consumption parameters were determined using microspectrophotometry. Ischemia resulted in a 66% reduction in subendocardial flow in controls in the ischemic zone and no experimental treatment significantly altered this flow. Pindolol resulted in a significant improvement in the ischemic regional subendocardial/subepicardial flow ratio (from 0.69 in the control ischemic region to 0.88 during pindolol treatment). O2 extractions were significantly increased and O2 consumptions were significantly depressed in the ischemic regions of all groups. O2 extractions were increased to a lesser degree in the ischemic region with the use of pindolol and propranolol. Propranolol and pindolol both significantly decreased the proportion of veins with low (0-20%) O2 saturations in the ischemic region indicating an improved microregional distribution of blood flow and/or O2 consumption within the ischemic region.     

Influence of levosimendan, pimobendan, and milrinone on the regional distribution of cardiac output in anaesthetized dogs.

1. The distribution of cardiac output during administration of levosimendan, a new myofilament calcium sensitizer, is unknown. We examined and compared the effects of levosimendan, pimobendan, and milrinone on regional tissue perfusion by use of the radioactive microsphere technique in barbiturate-anaesthetized dogs. 2. Haemodynamics and regional blood flow were determined before and during infusions of levosimendan (0.75, 1.5, and 3.0 micrograms kg-1 min-1), pimobendan (10, 20, and 40 micrograms kg-1 min-1), or milrinone (1.0, 2.0, and 4.0 micrograms kg-1 min-1). 3. All three drugs caused similar increases in heart rate, cardiac output, and left ventricular +dP/dt and decreases in end-diastolic pressure and systemic vascular resistance. No changes in subendocardial, midmyocardial, and subepicardial blood flow occurred during administration of levosimendan. However, a redistribution of blood flow from subendocardium to subepicardium was observed. Pimobendan increased midmyocardial and subepicardial blood flow and reduced the endo/epi ratio to a greater degree than levosimendan. Milrinone did not affect myocardial perfusion. 4. Levosimendan increased blood flow to the renal medulla and decreased renal medullary and cortical vascular resistance. Levosimendan increased blood flow to the small intestine and liver and reduced vascular resistance in these organs. Pimobendan increased hepatic blood flow to a greater degree than levosimendan but did not alter small intestinal perfusion. All three drugs decreased splenic blood flow to similar degrees. Levosimendan and pimobendan reduced cerebral vascular resistance. Levosimendan and milrinone reduced skeletal muscle vascular resistance. 5. The results indicate that levosimendan, pimobendan, and milrinone cause subtlety different alterations in regional tissue perfusion while producing similar haemodynamic effects.     

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.     

Comparative effects of a new nicotinamide nitrate derivative, nicorandil (SG 75), with nifedipine and nitroglycerin on true collateral blood flow following an acute coronary occlusion in dogs

The effects of nicorandil (NC), nifedipine (NF), and nitroglycerin (GTN) on true collateral blood flow were studied following an acute occlusion of the left anterior descending (LAD) coronary artery in anesthetized dogs. Ischemic tissue samples contaminated with overlap blood flow from the normal region were eliminated by using a special balloon reservoir technique for administration of radioactive microspheres. The effects of each drug on true collateral blood flow were determined following 1 h of coronary occlusion with the radioactive microsphere technique and an indirect index of collateral perfusion, retrograde pressure. NC (25 micrograms/kg/min, i.v.), NF (1.0 micrograms/kg/min, i.v.), and GTN (1.5 micrograms/kg/min, i.v.) infusions reduced mean arterial and left ventricular systolic pressures similarly (10-20 mm Hg). None of the drugs had any effect on true collateral blood flow in the presence of a decrease in aortic blood pressure. However, when aortic pressure was maintained by use of a cuff around the descending thoracic aorta, NC and NF increased collateral flow as measured by the microsphere technique as well as retrograde pressure. In addition, NC produced a significant increase in subendocardial blood flow, which resulted in an increase in the endocardial-epicardial blood flow ratio (endo/epi). GTN had no significant effect on any index of collateral function. These results indicate the importance of aortic pressure in determining the effects of vasodilators on coronary collateral function. Furthermore, NC may have more desirable effects on collateral blood flow than NF or GTN when hypotension is minimized, since this was the only agent that selectively increased subendocardial blood flow.     

Nitroglycerin improves the distribution of regional oxygenation in partially ischemic canine myocardium

The effect of nitroglycerin administration on regional oxygen supply and consumption of partially ischemic areas of myocardium was investigated in 14 open-chest anesthetized dogs. Flow in the left anterior descending coronary artery (LAD) was reduced by 50% with the aid of a specially designed screw clamp placed below the first bifurcation. Seven animals received nitroglycerin (20 micrograms/kg i.v.) 5 min following partial occlusion. The remaining animals served as controls. Regional blood flow as measured with radioactive microspheres (15 +/- 3 micron in diameter) was determined before and 10 min following partial occlusion. Regional O2 saturations in small arteries and veins were determined using a microspectrophotometric technique. Oxygen supply, A-V O2 difference, and consumption were calculated in both subepicardial and subendocardial regions of ischemic and non-ischemic myocardium after occlusion. Tissue blood flow to the partially occluded regions was reduced by about 40% in both treated and untreated animals. Nitroglycerin prevented a significant reduction in arterial and venous O2 saturation of the partially occluded region. In the occluded subendocardium, nitroglycerin reduced the skewness of the venous O2 saturation distribution. The O2 supply/consumption ratio was significantly improved by nitroglycerin in the ischemic subendocardium, compared with the same region in the control group. It is suggested that nitroglycerin improves the microregional relationship between blood flow and metabolism even in the absence of a change in total regional blood supply.     

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.     

Cardiovascular effects of tiapamil (Ro 11-1781), a new calcium-entry blocker

We studied the hemodynamic effects of the new calcium antagonist tiapamil (Ro 11-1781) in anesthetized open-chest dogs and compared them with those of verapamil. Increasing doses of tiapamil injected intravenously caused the following hemodynamic effects: increase in coronary flow and decrease in coronary vascular resistance, followed by decreases in heart rate, blood pressure, and total peripheral resistance. Tiapamil did not depress myocardial contractility over a rather wide dose range, while verapamil did. Tiapamil was more effective in increasing coronary flow than verapamil. Cardiac autonomic denervation did not modify the tiapamil-induced decrease in coronary vascular resistance and did not cause tiapamil to display negative inotropism. Both tiapamil and verapamil reduced the extent of S-T segment elevation in the epicardial electrocardiogram produced by transient occlusion of the left anterior descending coronary artery. Neither drug had this effect when heart rate was kept constant by atrial pacing. In contrast to nitroglycerin, tiapamil dilated small but not large coronary arteries. Tiapamil raised PO2 relatively more in the subendocardial than in the subepicardial layers of the myocardium. The hemodynamic and electrocardiographic effects of tiapamil were not changed by diphenylhydantoin and disopyramide or by pindolol, a beta-adrenoceptor blocking agent with intrinsic sympathomimetic activity. However, the decreases in heart rate and blood pressure in response to propranolol were enhanced by tiapamil.     

Improvement in regional myocardial O2 supply and O2 consumption by nitroglycerin during ischemia

In eight open-chest anesthetized dogs, nitroglycerin (10 micrograms/kg per min) was infused intravenously for 2 h, beginning 10 min following ligation of the left anterior descending coronary artery. Oxygen supply, (radioactive microspheres), extraction (microspectrophotometry) and consumption were determined in subepicardial and subendocardial regions of both ischemic and non-ischemic myocardium, and compared to eight control hearts. In control, coronary occlusion reduced both subepicardial and subendocardial blood flow by 49.5% and 79.5% respectively. In the presence of nitroglycerin, depression of blood flow to the occluded regions was significantly less marked (-79.5% in control and -26.6% in the nitroglycerin group in the subendocardium). O2 extraction was significantly lowered by nitroglycerin in all areas. Regional O2 consumption was significantly lower in the control occluded than non-occluded regions; no regional O2 consumption differences were observed following nitroglycerin. In the occluded regions, nitroglycerin reduced the number of veins with very low O2 saturation. It is concluded that nitroglycerin improves the O2 supply/consumption balance in ischemia by redistribution of blood flow and possibly by alterations in local O2 consumption.     

Atenolol, its cardioselective property for adrenergic beta-receptor blocking action and effect on the cardiac function (author's transl)

Cardioselective property of the beta-adrenoceptor blocking action of atenolol and its effect on the AV conduction, the atrial muscle refractory period and the cardiac contractility were studied in comparison with these of propranolol. A ratio of pA2 values obtained in the isolated right-atrial preparations and the isolated tracheal preparations of guinea pigs demonstrated that atenolol was highly cardioselective, while propranolol was non-selective. This cardioselective property of atenolol was confirmed in in vivo experiments using guinea pigs. Atenolol increased the AV conduction time and decreased the cardiac contractility dose-dependently in anesthetized dogs of which the heart was electrically driven at fixed rates. At 140 beats/min, AV block was observed at 10 mg/kg, i.v. in 3 of 8 dogs, and further increase in a dose ti 30 mg/kg resulted in acute heart failure in one of remaining 5 dogs, while propranolol, though showing a tendency to be less potent in depressing AV conduction in a dose range less than 0.3 mg/kg, produced a state of heart failure in 2 of 5 dogs at 3 mg/kg, i.v. and AV block in all of the remainder at 10 mg/kg, i.v. Functional refractory period of AV node as well as functional and effective refractory period the the atrial muscle were increased dose-dependently by atenolol and propranolol. There were no significant differences between both drugs regarding these effects. Further increase in a pacing rate to 160 and 180 beats/min augmented the depressing effect of both drugs on the AV conduction.     

The effects of TMB-8, an intracellular Ca2+ antagonist, on impaired left ventricular relaxation by global ischemia in dog

The effects of TMB-8, an inhibitor of Ca2+ release from the intracellular store site, on impaired left ventricular relaxation caused by global ischemia were examined in 45 anesthetized dogs. In the non-ischemic group, the intracoronary infusion of 100 micrograms/min TMB-8 suppressed the decrease in T, an index of left ventricular relaxation, by increasing the atrial pacing rate. In the ischemic group, the intracoronary infusion of 30 and 100 micrograms/min TMB-8 suppressed the increases of T and left ventricular end-diastolic pressure caused by ischemia and increase of pacing rate. The results indicate that TMB-8 suppresses the ability of relaxation in non-ischemic myocardium and prevents the impairment of left ventricular relaxation induced by left ventricular global ischemia.