R Seitelberger

Intracoronary alpha 2-adrenergic receptor blockade attenuates ischemia in conscious dogs during exercise.

Studies on the role of α-adrenergic constrictor tone in the coronary vascular bed during ischemia were performed in dogs running on a treadmill. The animals were instrumented with a left ventricular pressure transducer, and regional systolic wall thickening (%WTh) was assessed by sonomicrometry in the anterior and posterior walls of the left ventricle. An intracoronary catheter was implanted chronically in the circumflex coronary artery, and a hydraulic cuff was placed proximally around the artery. After β-adrenergic blockade with propranolol (0.8 mg/kg i.v.), acute stenosis of the coronary artery was performed during running in five dogs to Induce severe regional myocardial dysfunction in the posterior wall. Intracoronary infusion of the selective α2-adrenergic blocking agent idazoxan (80 μmlg/kg) improved %WTh in the ischemic region from 5.1 ± 1.6 to 10.8±2.8% (p<0.05), without any significant effect on the anterior wall. Blood flow to the subendocardium of the posterior wall (radioactive microspheres) increased from 0.17±0.05 to 0.45±0.30 (ml/min)/g (p<0.05). It is concluded that in exercising dogs subjected to β-adrenergic blockade, significant postjunctional α2-adrenergic receptor-mediated coronary vasoconstriction exists, even during severe ischemia. Regional α2-adrenergic receptor blockade can reduce regional ischemia and improve contractile function by attenuating exercise-induced sympathetic vasoconstriction in this conscious animal model.

Mechanism of beneficial effect of beta-adrenergic blockade on exercise-induced myocardial ischemia in conscious dogs.

We examined the importance of decreased heart rate in the beneficial effect of β-adrenergic blockade on exercise-induced regional myocardial ischemia and contractile dysfunction in conscious dogs with single vessel coronary stenosis (ameroid constrictor). Studies were performed during control treadmill exercise, which produced regional myocardial ischemia (blood flow measured with microspheres) and wall dysfunction (measured using sonomicrometers). A second run was performed after the administration of atenolol (0.3–1.0 mg/kg i.v.), and the reduced heart rate caused by atenolol during early steady-state running was then prevented by atrial pacing during the latter portion of the run. Atenolol reduced the exercise heart rate from 217 ± 25 beats per minute (SD, n = 9) to 166 ± 15, and ischemic zone wall thickening during systole improved from 27 ± 22% of the resting value in the control run to 50 ± 25% of the resting value in the atenolol run (p <0.01). Atrial pacing then increased heart rate to 217 ± 23 beats per minute, and regional wall thickening deteriorated to 15 ± 25% of the resting value. Regional subendocardial blood flow in the ischemic zone during atrial pacing with atenolol was slightly less than that observed in the control run, in both ischemic and control zones, indicating no remaining beneficial effect of atenolol when heart rate reduction was eliminated. We conclude that the only significant mechanism for the improvement in exercise-induced ischemia and wall motion produced by atenolol is a reduction in the exercise heart rate. Furthermore, when the heart rate decrease was prevented, regional blood flow and function tended to be more depressed after atenolol than during the control run.

Elimination of exercise-induced regional myocardial dysfunction by a bradycardiac agent in dogs with chronic coronary stenosis.

We have previously demonstrated that the beneficial effect of cardioselective beta-blockade on exercise-induced ischemia is due entirely to negative chronotropism. Therefore we studied the effect of a new bradycardiac agent (UL-FS 49) in 10 dogs with chronic coronary artery stenosis produced by an ameroid constrictor. Regional myocardial function (sonomicrometers, wall thickness) and blood flow (microspheres) were measured during a control treadmill exercise bout and an identical run 3 hr later after the administration of UL-FS 49 (1.0 mg/kg iv). In the control run, heart rate increased from 114 +/- 20 to 230 +/- 19 beats/min and systolic wall thickening (%WT) in the poststenotic myocardium decreased from 23.3 +/- 5.2% at rest to 9.3 +/- 5.0%, a 60% reduction. Subendocardial blood flow in the ischemic area decreased from 1.04 +/- 0.30 to 0.55 +/- 0.40 ml/min/g, blood flow per beat decreased from 9.1 X 10(-3) to 2.5 X 10(-3) ml/g, and mean transmural flow failed to increase (1.06 +/- 0.30 vs 1.08 +/- 0.39 ml/min/g). During exercise with UL-FS 49, heart rate increased from 89 +/- 10 to only 139 +/- 10 beats/min. End-diastolic left ventricular pressure was increased compared with that during the control run (35.7 +/- 3.0 vs 28.9 +/- 5.5 mm Hg) but left ventricular peak systolic pressure and dP/dt were unchanged. %WT in the ischemic zone did not change significantly during exercise with UL-FS 49 (23.3 +/- 7.9% at rest, 21.5 +/- 8.4% during the run), and in the nonischemic zone it increased to the same extent as during the control run.(ABSTRACT TRUNCATED AT 250 WORDS)

Attenuation of exercise-induced myocardial ischemia in dogs with recruitment of coronary vasodilator reserve by nifedipine

There is now evidence that under resting conditions coronary vasodilator reserve exists even in the presence of myocardial ischemia. Therefore, we tested the hypothesis that a vasodilator reserve may exist during exercise so that during exercise-induced ischemia a reduction in coronary constrictor tone can be produced that attenuates the decreases in regional myocardial blood flow and function distal to a severe coronary stenosis without changing the determinants of myocardial oxygen demand. Nine dogs were instrumented with an ameroid constrictor on the left circumflex coronary artery and were studied 2 to 3 weeks later. During a control treadmill run, heart rate increased from 119 +/- 20 to 225 +/- 20 beats/min and peak left ventricular pressure increased from 144 +/- 17 to 163 +/- 28 mm Hg. Poststenotic subendocardial blood flow (measured by a microsphere technique) fell from 1.19 +/- 0.36 to 0.51 +/- 0.30 ml/min X g and systolic wall thickening (by sonomicrometry) decreased from 24.3 +/- 5.8% to 6.0 +/- 6.1%. During an identical run after nifedipine (10 micrograms/kg iv), systemic hemodynamics were not significantly altered. However, subendocardial blood flow was increased to 0.85 +/- 0.51 ml/min X g (p less than .05) and systolic wall thickening to 11.4 +/- 7.8% (p less than .01). We conclude that in this study the amelioration of exercise-induced myocardial ischemia was due to the recruitment by nifedipine of coronary vasodilator reserve.

Early diastolic filling dynamics during experimental mitral regurgitation in the conscious dog

Diastolic flow into the left ventricle during mitral regurgitation must increase as total stroke volume increases in response to the volume overload. The mechanisms that allow augmented diastolic filling are not fully defined. Accordingly, the left ventricle of five dogs was instrumented with a micromanometer and sonomicrometers and studied during the conscious state before (control) and after the creation of significant mitral regurgitation. Serial measurements were made at control and up to 4 weeks after the creation of the volume overload. Heart rate, peak systolic wall stress, and peak positive dP/dt showed no significant changes between control and subsequent observations. End-diastolic volume and total stroke volume progressively and significantly increased during the 4-week course. When compared with the control state (51 +/- 4, mean +/- SD), the filling fraction during the first 40% of diastolic time was increased at 4 days (67 +/- 10%, p less than 0.001), 2 weeks (72 +/- 6%, p less than 0.001), and 4 weeks (76 +/- 10%, p less than 0.001). During the period of adaptation to the volume overload, filling fraction correlated with end-diastolic volume (r = 0.52, p less than 0.02) and total stroke volume (r = 0.80, p less than 0.001). Compared with the control state (0.81 +/- 0.04), eccentricity of the left ventricle at end systole decreased at 4 weeks (0.79 +/- 0.06, p less than 0.05); the absolute change in this ratio during the first 40% of diastolic time was significantly augmented at 2 weeks (0.09 +/- 0.02, p less than 0.05) and 4 weeks (0.11 +/- 0.04, p less than 0.005) compared with control (0.05 +/- 0.02). Ventricular elastance (pressure/volume) at end systole (minimum volume) was 1.70 +/- 0.50 mm Hg/ml at control, 1.09 +/- 0.46 at 4 days (p less than 0.05), 0.96 +/- 0.42 at 2 weeks (p less than 0.01), and 0.99 +/- 0.22 at 4 weeks (p less than 0.01). Moreover, the elastance change during the rapid-filling phase was significantly diminished after creation of mitral regurgitation. Thus, during the volume overload of mitral regurgitation, the left ventricle accommodates a higher percentage of its total stroke volume during early diastole; this adaptation can be correlated with augmented systolic shortening, and thereby with increased restorative forces or elastic recoil, and with reduced chamber elastance and eccentricity during the early part of diastole. Other potential mechanisms include altered systolic and relaxation loading, augmented elastic recoil of the left atrium, left atrium and left ventricular pressure gradient, accelerated myocardial inactivation, and increased adrenergic stimulation.

Myocardial effects of selective alpha-adrenoceptor blockade during exercise in dogs.

To study the effect of selective alpha 1- or alpha 2-adrenergic blockade on the myocardial contractile and chronotropic response to exercise, 29 dogs were chronically instrumented with a sonomicrometer for measuring myocardial wall thickness and a micromanometer for measuring left ventricular pressure. During treadmill exercise, either the selective alpha 1-blocker prazosin (80 micrograms/kg, n = 12) or the alpha 2-blocker idazoxan (80 micrograms/kg, n = 8) was infused into the left atrium beginning 2-3 minutes after the onset of exercise. alpha 1-Adrenoceptor blockade, like alpha 2-adrenoceptor blockade, was found to cause significant increases in systolic wall thickening, thickening velocity, heart rate, and left ventricular contractility, indicating an increase in inotropic state that was comparable to that with alpha 2-adrenoceptor blockade. Preventing the decrease in aortic blood pressure after selective alpha 1-blockade by using either systemic angiotensin II infusion (n = 6) or inflation of an intra-aortic balloon (n = 6) did not prevent the observed increases in wall thickening, heart rate, and left ventricular contractility. In four of the dogs treated with prazosin, the norepinephrine concentration in the coronary sinus was found to more than double after alpha 1-blockade. beta-Adrenergic blockade (propranolol, 1.0 mg/kg) prevented the increased contractile and chronotropic state caused by alpha 1- or alpha 2-blockade. Selective alpha-adrenergic blockade during adrenergic activation by intravenous norepinephrine infusion, in contrast to exercise, had no effect on wall thickening, heart rate, or left ventricular contractility. These data indicate that selective alpha 1-adrenergic blockade, like selective alpha 2-adrenergic blockade, causes a significant augmentation of heart rate and left ventricular contractility in the dog during dynamic exercise. These data are consistent with the hypothesis that this occurs through a presynaptic disinhibition of neural norepinephrine release mediated by a prejunctional alpha 1-adrenoceptor.

Experimental exercise-induced ischemia: Drug therapy can eliminate regional dysfunction and oxygen supply-demand imbalance

The purpose of this study was to test the hypothesis that moderately severe exercise-induced regional myocardial ischemia can be prevented by combined pharmacologic intervention. Eight chronically instrumented dogs were studied using an ameroid constrictor to produce critical stenosis of the left circumflex coronary artery. The dogs were studied during steady state treadmill exercise that induced regional myocardial dysfunction (reduced systolic wall thickening; sonomicrometers) and ischemia (reduced subendocardial blood flow; microspheres). During a control exercise run, wall thickening in the ischemic posterior wall decreased from 21.4 to 13.3% whereas subendocardial blood flow failed to increase normally (36% of that in the normal zone). In the control anterior wall, both wall thickening and subendocardial blood flow increased significantly during the control run. Wall thickness-left ventricular pressure loop areas were calculated as an index of regional work; this index increased abruptly with the onset of exercise in both regions but became significantly depressed in the ischemic region during the steady state exercise. Therapy with a combination of atenolol (0.3 mg/kg body weight orally), diltiazem (0.3 mg/kg intravenously) and isosorbide dinitrate (2.0 mg/kg orally) effectively prevented regional myocardial ischemia and regional dysfunction. After drug therapy, wall thickening in the posterior wall increased from 17.3% at rest to 18.8% during exercise, and the regional transmural blood flow pattern was markedly improved. The initial overshoot of the regional work index during exercise was blunted by the drug therapy, and at steady state no differences between the ischemic and control regions were detected. Thus, combined drug therapy can eliminate exercise-induced regional myocardial ischemic dysfunction and appears to normalize the oxygen supply-demand imbalance.

Exercise-induced regional dysfunction with subcritical coronary stenosis.

The hypothesis was tested that regional myocardial contractile dysfunction can detect subtle regional coronary blood flow maldistribution induced by exercise. In seven dogs, left ventricular pressure (micromanometer), regional systolic wall thickening (WTh, sonomicrometry), and myocardial blood flow (MBF, microspheres) were measured when mild degrees of coronary artery stenosis were produced during treadmill exercise. During exercise without coronary stenosis, WTh increased by 21 +/- 12% (SD), and transmural MBF increased uniformly. In each dog, two levels of coronary stenosis were produced during exercise by adjusting the coronary hydraulic cuff: (1) St-Ex I, where WTh during exercise failed to increase significantly (average change 0 +/- 7%), and (2) St-Ex II, where WTh during exercise decreased moderately from the resting control value (average -20 +/- 8%). In the potentially ischemic zone coronary hyperemia occurred with each run: resting subendocardial MBF was 1.09 +/- 0.30 mg/g/min, and it was 3.04 +/- 0.83 during control exercise, 2.48 +/- 0.75 during St-Ex I, and 1.55 +/- 0.59 ml/g/min during St-Ex II (p less than .01 compared with control exercise and control area). The subendocardial-subepicardial blood flow ratio fell from 1.32 +/- 0.27 during control exercise to 1.07 +/- 0.20 (p less than .05) during St-Ex I, and to 0.64 +/- 0.15 (p less than .01) with St-Ex II. Changes in the subendocardial electrogram and reactive hyperemia occurred more consistently during St-Ex II than St-Ex I. Thus, failure of regional function to increase during exercise detected slight maldistribution of regional MBF, whereas reduction of regional function during exercise of 10% or more below the resting value was a reliable marker of a regional flow defect and was always associated with other evidence of ischemia. Therefore, regional dysfunction during exercise can detect subcritical but functionally significant coronary stenosis, which may allow regional wall motion to be used for detecting coronary artery disease at a relatively early stage.

α2-Adrenergic Coronary Constriction in Ischemic Myocardium during Exercise

The effect of either selective alpha 1- or alpha 2-adrenoceptor blockade on ischemic myocardial blood flow and function was examined in beta-blocked dogs trained to run on a motor-driven treadmill. The animals were instrumented with sonomicrometers for the assessment of regional systolic wall thickening (%WTh) of the left ventricle. For drug infusion, an intracoronary catheter was implanted in the circumflex coronary artery and a hydraulic cuff was placed proximally around the artery. Following systemic beta-blockade with 0.8 mg/kg propranolol, an acute stenosis of the circumflex coronary artery inflated during exercise induced severe dysfunction in the posterior wall. Intracoronary infusion of 80 micrograms/kg of the selective alpha 2-adrenoceptor blocking agent idazoxan improved posterior wall (PW)-%WTh from 5.1 +/- 1.6 to 10.8 +/- 2.8% (p less than 0.06) and regional myocardial blood flow (radiolabelled microspheres) in the subendocardium of the posterior wall from 0.17 +/- 0.05 to 0.45 +/- 0.30 (ml/min)/g (p less than 0.05). No increases in regional blood flow and regional myocardial function were observed after infusion of the selective alpha 1-adrenoceptor blocking agent prazosin (20 micrograms/kg) under the same experimental conditions. It is concluded that during severe ischemia, significant postjunctional alpha 2-adrenoceptor mediated coronary vasoconstriction exists. Regional alpha 2-adrenoceptor blockade, but not alpha 1-adrenoceptor blockade is effective in reducing regional ischemia and dysfunction by attenuating sympathetic vasoconstriction in the conscious dog.