Effects of Calcium Entry Blockade on Myocardial Blood Flow

The calcium entry-blocking drugs produce effects on the coronary vasculature that might be expected to exert anti-ischemia activity. Although these agents cause little vasodilation of the epicardial coronary arteries during basal conditions, they block vasoconstriction that can increase stenosis severity during isometric exercise and interrupt coronary artery spasm in patients with variant angina. Administration of the calcium blockers causes transient vasodilation of the coronary resistance vessels, followed by decreased responsiveness to a brief ischemic stimulus. This results in decreased coronary reactive hyperemia after transient coronary occlusion. By preventing excessive ischemic vasodilation of the resistance vessels, these agents can enhance perfusion of the subendocardium distal to a flow-limiting coronary stenosis. The calcium entry blockers have relatively little effect on the immature coronary collateral vessels that exist at the time of acute coronary occlusion. Diltiazem, however, has been demonstrated to increase collateral blood flow in animals in which chronic coronary occlusion has resulted in growth of moderately well-developed collateral vessels.

T he calcium entry blockers produce significant effects at several levels of the coronary vasculature that might be expected to exert anti-ischemia activity. Because different segments of the coronary circulation possess differing physiological characteristics and exhibit differing responses to pharmacological intervention, these segments are best considered individually.
Epicardial Coronary Arteries Several investigators have examined the effects of calcium entry-blocking drugs on vasomotor activity of the epicardial coronary arteries. In chronically instrumented awake dogs in which proximal coronary artery diameter was measured with ultrasonic crystals affixed to opposing sides of a proximal coronary artery, Vatner and associates' reported that intravenous nifedipine produced dose-related coronary artery dilation. Using a similar experimental preparation, Schwartz and Bache2 observed that nifedipine, diltiazem, and verapamil all produced modest but significant epicardial coronary artery vasodilation and that the addition of nitroglycerin invariably caused further vasodilation. The effects of the calcium blockers and nitroglycerin were not additive, so the vasodilation produced by nitroglycerin alone was similar to that achieved when nitroglycerin was added after treatment with one of the calcium blockers.
In patients undergoing quantitative coronary angiographic studies, Feldman et a13 reported that sublingual nifedipine failed to increase the diameter of angiographically normal coronary artery segments, whereas the subsequent addition of nitroglycerin produced highly significant coronary artery dilation. Hossack et a14 found that intravenous diltiazem did not dilate angiographically normal coronary artery segments although the subsequent addition of sublingual nitroglycerin produced a 20% increase in coronary artery diameter. Chew et a15 reported that intravenous verapamil produced a 15% increase in luminal cross-sectional area of angiographically normal coronary arteries. This was substantially less than the response to nitroglycerin. 5 Normal coronary arteries undergo vasoconstriction in response to adrenergic stimulation.6 Because atherosclerotic coronary artery narrowings are frequently eccentric in location, the relatively uninvolved portion of the arterial wall can also undergo vasoconstriction, thereby increasing the stenosis severity. Using quantitative angiographic techniques, Brown et a17 demonstrated that handgrip exercise produced vasoconstriction of both normal and diseased coronary artery segments. This vasoconstrictor response likely resulted from generalized reflex sympathetic nervous system activation originating from skeletal muscle stretch receptors during isometric exercise.8 Although handgrip exercise produced only a modest increase in myocardial oxygen demands, pulmonary wedge pressure increased 56%, suggesting ischemic impairment of left ventricular function. Handgrip produced a mean 35% decrease in luminal cross-sectional area at stenotic coronary artery segments, suggesting that ischemia was, at least in part, the result of decreased oxygen supply. Diltiazem did not cause coronary artery vasodilation during basal conditions but did prevent the decrease in coronary artery diameter during handgrip, both in angiographically normal areas as well as in areas of pathological narrowing. Receptor-activated adrenergic coronary vasoconstriction requires movement of extracellular calcium into the smooth muscle cell; the calcium blocker prevents vasoconstriction by inhibiting calcium influx.9 Nitroglycerin produced an increase in basal coronary artery diameter and also blocked coronary vasoconstriction during handgrip exercise. 7 These studies indicate that isometric exercise can produce myocardial ischemia by causing vasoconstriction of narrowed epicardial coronary artery segments as well as by causing increased myocardial oxygen requirements. Both diltiazem and nitroglycerin effectively antagonized this coronary artery vasoconstriction.
Gage et al10 observed a fundamentally different mechanism for increasing coronary stenosis severity during supine bicycle exercise in patients undergoing coronary angiography. Unlike handgrip exercise, bicycle exercise resulted in vasodilation of normal coronary arterial segments. This difference appears to have occurred because bicycle exercise produces less reflex vasoconstrictor activity although it also causes a greater increase in myocardial oxygen demands. The increased coronary diameter in the normal arterial segments likely occurred because flow-mediated endothelial-dependent relaxation overwhelmed the modest increase in sympathetic nervous system activity." Nevertheless, stenotic segments demonstrated increasing severity during exercise. Failure of stenotic segments to dilate could have resulted from impaired endothelial function in atherosclerotic areas.12,3 Increase of stenosis severity during exercise has also been observed in the animal laboratory. In chronically instrumented dogs with a proximal coronary artery stenosis, treadmill exercise results in vasodilation of the coronary resistance vessels, with a marked decrease in coronary pressure distal to the stenosis.14 The decreased intra-arterial distending pressure allows passive collapse of the stenosis, with a marked increase in stenosis resistance that can be sufficient to cause an actual decrease in coronary blood flow. It is likely that this mechanism accounts, at least in part, for the increase of stenosis severity observed by Gage et al10 during bicycle exercise.
These investigators found that both nitroglycerin and diltiazem prevented the exercise-induced decrease in stenotic cross-sectional area.10,'5 The calcium entry-blocking drugs are less potent than nitroglycerin in causing vasodilation of normal or diseased epicardial coronary arteries during basal conditions. The calcium blockers and nitroglycerin are similarly effective, however, in antagonizing coronary artery vasoconstriction, both during the physiological response to isometric exercise and during coronary vasospasm in patients with variant angina.
Coronary Resistance Vessels Myocardial blood flow is normally controlled by vasomotor activity of the coronary resistance vessels. These vessels regulate blood flow in response to changing myocardial metabolic needs to maintain a nearly constant, very high level of oxygen extraction by the myocardium. In addition to regulating the volume of coronary blood flow, the resistance vessels are responsible for maintaining a normal distribution of perfusion across the wall of the left ventricle. Because cardiac contraction selectively impedes subendocardial blood flow by compression of the intramural coronary vessels,'6 the resistance vessels must maintain a gradient ofvascular resistance favoring blood flow to the subendocardium in diastole.17 By means of active vasomotion of the coronary resistance vessels, adequate subendocardial blood flow is maintained over a wide range of heart rates, despite marked changes in the duration of diastole available for perfusion of the subendocardium.
Administration of calcium entry-blocking drugs causes vasodilation of the coronary resistance vessels and an increase in myocardial blood flow. [18][19][20][21][22][23][24] This vasodilation is generally brief in duration, with coronary flow returning to pretreatment control levels within 5-30 minutes.22-24 The transient increase in coronary blood flow produced by nifedipine or diltiazem is followed by a period of depressed responsiveness of the coronary resistance vessels to an ischemic stimulus. This results in a decrease in the reactive hyperemia that follows brief periods of coronary artery occlusion. Dymek and Bache24 observed that nifedipine and diltiazem caused 40-46% reductions of the excess blood flow during the reactive hyperemia after a 10-second coronary artery occlusion in chronically instrumented awake dogs. Reduction of the reactive hyperemia response persisted for 1 hour after nifedipine and for at least 2 hours after a single dose of diltiazem. Microsphere measurements demonstrated no change in coronary collateral flow, indicating that the calcium blockers did not blunt reactive hyperemia by causing increased oxygen delivery during coronary occlusion. 22 24 Reduction of the reactive hyperemia occurred after the acute decrease in blood pressure and increase in coronary flow had subsided, at a time when myocardial oxygen consumption was not different from the pretreatment level.22,23 Because measurements of myocardial oxy-gen consumption before coronary occlusion might produced not reflect changes of myocardial metabolic activity decreased i during occlusion, Homans et a125 examined effects The decr of nifedipine on systolic segment shortening during tance vess coronary occlusion and reperfusion. Nifedipine did stimulus pi not alter systolic segment shortening during basal might be ( conditions and did not alter the rate or degree of arterial stei systolic-function loss during coronary occlusion. from incre The finding of unaltered mechanical performance tion of the ( suggests that nifedipine did not produce substantial a flow-limi alterations in myocardial metabolic demands during blood flow the coronary occlusion. Recovery of systolic funcr tion during reperfusion was not retarded after nifed-res1stancen ipine, despite reduction of blood flow rates during 10 by nifedipine might account for the reactive hyperemic response. reased vasodilation of the coronary resis-,els in response to a transient ischemic roduced by the calcium entry blockers of therapeutic importance. A proximal nosis can prevent myocardial blood flow asing normally in response to vasodilacoronary resistance vessels. The effect of iting coronary stenosis on myocardial during ischemic dilation of the coronary vessels is shown in Figure 1.23 A control coronary occlusion was followed by reacemia, with excess flow equal to 431% of ficit incurred during the occlusion (panel the 10-second occlusion was followed by Id interval of coronary stenosis that prev from increasing above the preocclusion reactive hyperemia was augmented (panigmentation of the reactive hyperemia a greater ischemic stimulus. The stenoer, did not decrease blood flow below the rel that had been adequate to meet myods before the total occlusion. When flow d by the stenosis, radioactive micro--re injected to assess the distribution of to four layers across the left ventricular epicardium to endocardium ( Figure 2). rntrol conditions, subendocardial blood slightly greater than subepicardial flow. rial inflow was limited by a proximal ter the resistance vessels had been dilated ,cond occlusion, there was a transmural ion of blood flow, with increased flow to cardium, but subendocardial underperfumia continued, not because total blood educed, but because the maldistribution n resulted in continuing hypoperfusion of locardium. Ischemic vasodilation interthe normal ability of the resistance   Because diltiazem and nifedipine both decreased coronary reactive hyperemia, studies were performed to determine whether this reduction of ischemic vasodilation of the coronary resistance vessels would enhance subendocardial perfusion when flow was limited-by a proximal stenosis. Both diltazem and nifedipine prevented augmentation of the coronary reactive hyperemia when a total occlusion was followed by a period during which a stenosis prevented blood flow from increasing beyond the preocclusion value ( Figure 1C).22,23 When flow was limited by the stenosis, microsphere measurements demonstrated that both diltiazem and nifedipine blunted the hyperemia in the subepicardium ( Figure  2). By blunting excessive vasodilation of the resistance vessels in response to an ischemic stimulus, the calcium entry blockers enhanced delivery of blood to the subendocardium. Coronary Collateral Vessels Acute coronary occlusion results in myocardial infarction, but the area of infarct is generally smaller than the region normally perfused by the occluded artery.3' Preservation of myocardium in this area at risk is dependent on blood flow through the intrinsic collateral vasculature present in the normal heart.32 In response to chronic occlusive coronary artery disease, the collateral vessels can undergo substantial growth and eventually take on the appearance of small arteries containing a well-organized smooth muscle coat. Pharmacological agents capable of dilating collateral vessels could be of therapeutic importance. Increased collateral flow after acute coronary occlusion would enhance salvage of ischemic myocardium. Even if collateral flow is ade-quate to meet resting myocardial requirements in patients with chronic coronary occlusion, flow might not increase adequately during exercise or other stress. In this situation, pharmacological vasodilators might prevent or decrease exercise-induced myocardial ischemia. Agents such as dipyridamole that dilate coronary resistance vessels and increase flow in normally perfused areas, however, will cause a greater pressure drop across the proximal arterial segment, resulting in decreased pressure at the origin of the collateral vessels. This decrease in collateral vessel driving pressure can decrease flow into the collateral-dependent area, resulting in "coronary steal."33 Acute Coronary Artery Occlusion Studies examining the effects of calcium entryblocking drugs on collateral blood flow after acute coronary artery occlusion have yielded variable and conflicting results. Using radioactive microspheres for measurement of blood flow in open-chest dogs, Henry et a134 and Vater et a135 reported that nifedipine increased collateral flow after acute coronary occlusion. Using radioactive microspheres to measure collateral flow after acute coronary artery occlusion in chronically instrumented awake dogs, Henry et a136 found that nifedipine increased blood flow in areas where initial flow was greater than 10 ml/100 g/min but did not increase blood flow to central ischemic areas where initial collateral flow rates were 10 ml/min/100 g or less. In contrast, Jolly et a137 and Weintraub et al,38 also using radioactive microspheres in anesthetized open-chest dogs, found that nifedipine did not alter blood flow to collateraldependent myocardium. The differing study results were addressed by Weintraub et al,38 who demonstrated that when microspheres are used to measure The effect of diltiazem on collateral flow after acute coronary artery occlusion has been studied in open-chest and awake dogs. Using radioactive microspheres, both Bourassa et a143 and Nakamura et a144 reported that diltiazem increased blood flow to the borderline ischemic areas but not to the central ischemic zone. When border areas that might include peninsulas of normally perfused myocardium were carefully excluded, several other investigators23,24 found that diltiazem had no significant effect on collateral flow after acute coronary occlusion in chronically instrumented awake animals.
In summary, the calcium entry blockers appear to have little effect on the intrinsic rudimentary collateral vessels that exist at the time of acute coronary artery occlusion. The increased collateral blood flows sometimes reported when microspheres were used to evaluate the effects of the calcium blockers appear to have resulted from inclusion of peninsulas of normally perfused myocardium in the collateraldependent tissue specimens. Chronic Coronary Artery Occlusion Several investigators have used the ameroid constrictor technique to study the effects of calcium entry blockers on moderately well-developed collateral vessels in experimental animals. After surgical placement of the ameroid constrictor on a proximal coronary artery, progressive coronary narrowing occurs, resulting in total occlusion after 2-3 weeks. Because occlusion occurs gradually, collateral vessel development is generally sufficient to allow total arterial occlusion without myocardial infarction.
Using measurements of retrograde flow 6 weeks after ameroid occlusion of the anterior descending coronary artery of dogs, Nagao et a145 found that diltiazem significantly increased collateral flow. Franklin et a146 studied collateral blood flow with microspheres, 1 month after ameroid occlusion, in chronically instrumented dogs. Collateral vessels were sufficiently developed so that blood flow and systolic function were normal in the collateral-dependent area during basal conditions. During cardiac pacing, however, blood flow in the collateral-dependent area failed to increase normally, and regional systolic function decreased. Diltiazem increased blood flow but did not prevent deterioration of systolic function in the collateral-dependent region.
Bache et a147 used microspheres to study the effect of nifedipine on coronary collateral blood flow during treadmill exercise, 4 weeks after ameroid coronary artery occlusion, in chronically instrumented dogs. During control conditions, blood flow in the collateral-dependent region was normal at rest; exercise, however, caused a subnormal increase of flow with subendocardial hypoperfusion. Thirty minutes after nifedipine administration, when heart rate and arterial pressure had returned to control levels, the volume and transmural distribution of blood flow in the collateral-dependent area was not significantly different from control, either at rest or during exercise. This finding is in agreement with the report of Schultz et a148 that nifedipine failed to relieve exercise-induced ischemia in patients with occluded coronary arteries that were collateralized to varying degrees, whereas isosorbide dinitrate did improve exercise performance in these patients. This study supports the concept that, unlike the nitrates, which are known to be potent collateral vessel dilators, nifedipine does not improve blood flow to collateral-dependent myocardial areas.
These studies indicate that diltiazem, but not nifedipine, increases collateral flow in animals with moderately well-developed coronary collateral vessels. The finding, however, of Franklin et al,46 that the increased collateral flow did not prevent deterioration of systolic function during pacing, questions the efficacy of this increased flow in maintaining myocardial function during periods of cardiac stress.