Coronary Collateral Blood Flow Research Articles

The role of insulin-like and basic fibroblast growth factors on ischemic and infarcted myocardium: a mini review

Current therapeutic techniques in acute myocardial infarction (AMI) are inadequate since restoration of blood flow through the obstructed coronary artery does not always preserve the ischemic myocardium. Therefore, deterioration of cardiac function and detrimental left ventricular remodeling may follow. Alternative therapeutic modalities are now being actively sought. Insulin-like growth factor (IGF) and fibroblast growth factor (FGF) are two polypeptides found in wide distribution and high concentrations in the normal myocardium. They play a key role in vascular growth (FGF) and affect the differentiation of cardiac myocytes (IGF). IGF has been found to promote physiological forms of cardiac hypertrophy, and FGF induces neovascularization. During myocardial ischemia and infarction there is a marked elevation in the concentration of these growth promoting factors in the myocardium concomitant with increased coronary collateral blood flow, neovascularization and peri-infarct hypertrophy. In animal models of myocardial infarction, exogenous administration of FGF and IGF induced neovascularization and cardiac hypertrophy thus, preserving cardiac function. We assume that these growth factors may become an additional tool in the future treatment of patients with AMI.

Oral nitrates: more than symptomatic therapy in coronary artery disease?

The predominant venodilator properties of the nitrates and their augmentation of collateral coronary blood flow to the ischemic myocardium endows them with some ideal characteristics for treating myocardial ischemic syndromes. Additional efficacy stems from the ability of the nitrates to replenish the deficient endothelium-derived relaxing factor (EDRF), nitric oxide (NO), in patients with coronary heart disease and also to inhibit platelet aggregation. In stable angina pectoris, the antianginal and antiischemic effects of oral nitrates are well established. Continuous administration of nitrates may lead to tolerance of their clinical efficacy. Recent studies, however, have demonstrated that when used in recommended doses, tolerance can be avoided during long-term treatment with oral nitrates without provocation of anginal attacks during periods of low nitrate levels at night and early hours of the morning. Thus, prolonged treatment with an asymmetric twice-daily regimen of immediate-release isosorbide-5-mononitrate in patients with stable angina pectoris does not give rise to clinical tolerance, prolongs exercise duration, and delays the onset of myocardial ischemia. In unstable angina pectoris, nitrates rapidly relieve chest pain and ameliorate the electrocardiographic signs of myocardial ischemia. In patients with acute myocardial infarction, early treatment with nitrates prevents left ventricular dilatation, improves pumping function, and reduces the risk of ventricular arrhythmias. In patients with chronic heart failure, oral nitrates improve exercise tolerance and, when given in combination with the systemic arterial dilator hydralazine, extend survival. Meta-analysis of published studies has demonstrated that both intravenous and oral nitrates reduced infarct size and morbidity and mortality in patients with acute myocardial infarction. In the ISIS 4 post-infarction study, isosorbide-5-mononitrate 60 mg once daily was not superior to placebo in reducing mortality risk. However, in the GISSI 3 study, the combination of nitrates with an angiotensin-converting enzyme (ACE) inhibitor reduced mortality risks by 17% in patients with acute myocardial infarction. In both the ISIS 4 and GISSI 3 studies, 62% and 57% of the patients in the placebo and control groups, respectively, were treated with nitrates for control of rest angina, myocardial ischemia, and or left ventricular failure symptoms, and this widespread use of open-label nitrates in the control groups may have diluted the true beneficial effects of nitrates in both studies. Taken together, these many studies with oral nitrate treatment in coronary heart disease and heart failure clearly emphasize that these drugs are safe and play more than a symptomatic role in the management of patients with acute and chronic ischemic syndromes due to coronary artery disease.

Intracoronary administration of the 1-receptor agonist, methoxamine, does not reproduce the infarct-limiting effect of ischemic preconditioning in dogs

The cardioprotective effect of ischemic preconditioning has been hypothesized to occur through one or more signalling mechanisms which activate protein kinase C. Stimulation of alpha 1-adrenergic receptors by catecholamines released during the preconditioning episodes of ischemia is one of these putative signalling mechanisms. To determine whether stimulation of alpha 1-adrenergic receptors before an ischemic challenge can mimic preconditioning, anesthetized dogs were treated with 4 intracoronary infusions of methoxamine HCl (10 micrograms/kg/min; n = 8), each 5 min in duration and followed by 5 min of washout. Control dogs (n = 10) were given similar infusions of 0.9% NaCl. A third group of dogs was preconditioned with 4 cycles of 5 min ischemia, each followed by 5 min of reperfusion (n = 8). All dogs then underwent 60 min of ischemia (circumflex coronary occlusion) followed by 3 h of reperfusion. Infarct size (expressed as % of area-at-risk) was measured with TTC macrochemistery and analyzed (using analysis of covariance [ANCOVA]) with respect to coronary collateral blood flow (measured using radioactive microspheres). Methoxamine markedly increased systemic arterial and left atrial pressures prior to but not during the ischemic challenge. Baseline predictors of infarct size were not different among the groups. Mean infarct size (adjusted from ANCOVA) did not differ between control and methoxamine-treated groups, 28.3 +/- 2.8% vs. 29.7 +/- 3.2%, respectively (P = NS), but was only 12.7 +/- 3.2% in the preconditioned group (P < 0.01 vs. control and methoxamine). A series of methoxamine infusions before an ischemic challenge did not affect infarct size. Thus, stimulation of alpha 1-adrenergic receptors alone is insufficient to mimic the cardioprotective effect of ischemic preconditioning in this canine model.

Differential characterization of human coronary collateral blood flow velocity

The functional importance and protective nature of the coronary collateral circulation has been well established. There are few data, however, regarding the phasic nature and absolute velocities of collateral flow in patients. The aim of this study was to characterize and quantify ipsilateral coronary collateral blood flow velocity in patients during coronary angioplasty. Coronary collateral flow velocity was measured in 49 patients during coronary angioplasty. Angiographic collateral filling was categorized by the Rentrop grading scale (0 to 3) and by anatomic pathway (epicardial, intramyocardial, or unknown [acutely recruited]). Collateral blood flow velocity was measured with a Doppler-tipped guide wire placed distal to the balloon occlusion in the collateralized vessel. Collateral flow velocity was characterized as predominantly systolic or diastolic, and phasic flow patterns were defined as biphasic (both systolic and diastolic), monophasic (only systolic or diastolic), or bidirectional (antegrade and retrograde velocity). Twenty-three (47%) patients had biphasic flow; 17 (35%) patients had monophasic flow; and 9 (18%) patients had bidirectional flow. Thirty-six (73%) of 49 patients had predominantly systolic flow signals. Epicardial collateral pathways had the highest total flow velocity integral, at 15.0 ± 7.0 (vs intramyocardial [8.4 ± 5.7] and acutely recruitable [5.4 ± 2.1]; p < 0.05). There were no differences in flow velocity integrals among the Rentrop angiographic grades of collateral filling. These data establish three patterns of coronary collateral blood flow and demonstrate that the majority of collateral flow in the ipsilateral receiving vessel occurs during systole. The measurement of coronary collateral flow velocity provides a unique means to study the effects of pharmacologic or mechanical interventions on human collateral blood flow.

Vasomotor responses of newly developed coronary collateral vessels.

Well-developed coronary collateral vessels contain an abundant muscular media and can undergo active vasomotion. However, early after coronary occlusion, coronary collateral vessels are thin walled with little smooth muscle, suggesting that vasomotor capability might be limited. Consequently, this study determined whether newly developed coronary collateral vessels have active vasomotor activity and whether endothelial function in these newly developed vessels is impaired. Retrograde blood flow was measured as an index of coronary collateral blood flow approximately 2 wk after embolic occlusion of the anterior descending coronary artery of dogs. Agonists were administered into the left main coronary artery to reach collaterals originating from the left coronary system. Baseline retrograde blood flow was 25.1 +/- 2.7 ml/min and increased to 36.7 +/- 3.7 ml/min after nitroglycerin (6 micrograms.kg-1.min-1, P < 0.05). Cyclooxygenase blockade with indomethacin (5 mg/kg i.v.) decreased retrograde collateral blood flow to 16.8 +/- 2.3 ml/min (P < 0.05). Subsequent administration of acetylcholine increased retrograde flow to 29.4 +/- 3.7 ml/min (P < 0.05), indicating intact endothelium-mediated vasodilation. Inhibition of nitric oxide synthase with NG-nitro-L-arginine further decreased coronary collateral retrograde flow to 12.0 +/- 2.8 ml/min (P < 0.05) and markedly blunted the response to acetylcholine. These findings demonstrate substantial vasomotor capability even early during coronary collateral development and indicate that both nitric oxide and cyclooxygenase-dependent endothelial mechanisms are intact.

Volume Expansion Increases Right Ventricular Infarct Size in Dogs by Reducing Collateral Perfusion

Plasma volume expansion is frequently recommended to correct the low output state resulting from right ventricular (RV) infarction. However, any subsequent increase in pericardial and RV filling pressures from volume expansion could impair RV collateral blood flow. We examined whether volume expansion in dogs before right coronary ligation reduced collateral perfusion and worsened the extent of RV necrosis. Randomized experimental study. Animal research laboratory in university medical center. Forty anesthetized, closed-chest dogs were randomly assigned to normovolemic, pericardium opened (n = 10) or intact (n = 10) groups, and hypervolemic, pericardium opened (n = 10) or intact (n = 10) groups. Hypervolemic animals received 24 mL/kg of 6% hetastarch. All animals underwent 90 min right coronary ligation, followed by 120 min reperfusion. Collateral coronary blood flow (radioactive microspheres) and area of necrosis (An) were determined in the area at risk (Ar). Stroke volume decreased in all groups with ischemia but remained 25 to 40% greater in both hypervolemic groups than in normovolemic animals (p < 0.05). In hypervolemic animals with intact pericardium, RV end-diastolic pressure increased to 10.4 +/- 2.1 mm Hg (mean +/- SD), a value that significantly exceeded those of the other three groups. During RV ischemia, collateral perfusion in the Ar was similar in both normovolemic groups and in hypervolemic animals with opened pericardium (mean range, 12.9 +/- 8.8 to 13.8 +/- 7.6 mL/min/100 g; p = NS), and the An/Ar varied from 11.8 +/- 6.3 to 18.6 +/- 17.4% (p = NS). In contrast, in hypervolemic animals with intact pericardium, collateral perfusion decreased to 7.2 +/- 3.5 mL/min/100 g and the An/Ar was increased to 38.2 +/- 18.6% (p < 0.05 compared with other groups, respectively). Overall, An/Ar was inversely related to collateral blood flow in the Ar (r = -0.46; p < 0.05) and correlated positively with RV end-diastolic pressure (r = 0.61; p < 0.05). Volume expansion preserved stroke volume during RV ischemia, independent of pericardial integrity. However, volume expansion in animals with an intact pericardium increased RV infarct size by twofold to threefold secondary to reduced periischemic collateral perfusion. This detrimental effect of volume expansion on infarct size was prevented by opening the pericardium.

Inhaled anesthetics alter the determinants of coronary collateral blood flow in the dog.

Whether coronary steal is induced by inhaled anesthetic agents remains controversial in part because multiple factors determine collateral blood flow. We used an established model to determine how halothane, isoflurane, and desflurane affect the hemodynamic determinants of coronary collateral blood flow. Twelve dogs were studied 4-5 weeks after ameroid constrictor implantation. Retrograde flow draining from the occluded artery was measured as an index of collateral flow after antegrade embolization. Pressure in the supplying artery at the origin of the collaterals was estimated with a stop-flow technique. These techniques allow calculation of collateral segment resistance and the resistances of the supply artery upstream and downstream from the origin of the collaterals. None of the inhaled anesthetics affected collateral segment resistance. Downstream (arteriolar) resistance of the supplying artery was decreased by desflurane (-45%), isoflurane (-35%), and halothane (-15%), lowering pressure at the origin of the collaterals, an effect that was partially offset by a decrease in upstream resistance. Retrograde flow was unaffected by isoflurane and halothane but decreased by about 20% during desflurane administration. Inhaled anesthetics have many effects on segmental resistance and pressure in the coronary circulation. These findings help explain conflicting results from previous studies and provide a useful model for investigating the effects of inhaled agents on small coronary arteries.

Quantification of recruitable coronary collateral blood flow in conscious humans and its potential to predict future ischemic events

Objectives. The present study was designed to evaluate the applicability of a pressure-flow equation for quantitative calculation of recruitable collateral blood flow at coronary artery occlusion in conscious patients and to investigate the value of that index to predict future ischemic events.Background. Recent experimental studies have indicated that recruitable collateral blood flow at coronary artery occlusion can be expressed as a fraction of normal maximal myocardial blood flow by simultaneous recordings of mean arterial, coronary wedge and central venous pressures, respectively. This index is called the pressure-derived fractional collateral flow and is independent of hemodynamic loading conditions.Methods. In 120 patients undergoing elective coronary angioplasty, mean arterial, coronary wedge and central venous pressures were measured at balloon inflations of 2 min. All patients had a recent exercise electrocardiogram (ECG) with positive findings showing clearly distinguishable, reversible ECG abnormalities, enabling recognition of ischemia at balloon inflation. Fractional collateral blood flow at angioplasty was calculated by coronary wedge pressure minus central venous pressure divided by mean arterial pressure minus central venous pressure and correlated to the presence or absence of ischemia at balloon inflation. Ischemic events were monitored during a follow-up period of 6 to 22 months.Results. In 90 of the 120 patients, ischemia was present at balloon inflation, and in 82 of these patients, fractional collateral blood flow was ≤23%. By contrast, in 29 patients, no ischemia was present, and fractional collateral blood flow was >24% in all 29. During the follow-up period, 16 patients had an ischemic event. Fifteen of these 16 patients were in the group with insufficient collateral flow (p < 0.05).Conclusions. To our knowledge, this study presents the first method for quantitative assessment of recruitable collateral blood flow in humans in the catheterization laboratory. Sufficient and insufficient collateral circulation can be reliably distinguished by this method. Use of this method can also help to provide more insight into the extent and behavior of the collateral circulation for investigational purposes and may have potential clinical implications.

Therapeutic potential of potassium channel activators in coronary heart disease.

Potassium channel activators have the ability to open potassium channels in a variety of cells. Since most of their effects are antagonized by antidiabetic sulfonylureas, the ATP-sensitive potassium channel is their likely target. Opening of potassium channels leads to hyperpolarization of the surface membrane with consequent closure of voltage-dependent ion channels and reduction of free intracellular calcium ions. Currently available potassium channel activators, including aprikalim, bimakalim, cromakalim, emakalim, nicorandil, pinacidil etc., display a high affinity for potassium channels of vascular smooth muscle. Vasodilation and a reduction in systemic vascular resistance are their prominent pharmacological effects. Coronary and cerebral arteries are highly sensitive to potassium channel activator-induced dilation. Apart from treatment of hypertension, potassium channel activators appear to have therapeutic potential in coronary heart disease. They reduce cardiac afterload, increase native and collateral coronary blood flow and reduce the size of experimental myocardial infarcts. This last effort cannot be satisfactorily explained entirely by haemodynamic or coronary vascular actions of potassium channel activators and a cardioprotective effect is postulated. For these drugs ischaemia-induced and activator-induced opening of cardiac ATP-sensitive potassium channels appear to work in concert. Nicorandil combines the pharmacological properties of an organic nitrate with those of potassium channel activators. Experimental and clinical results characterize nicorandil as a unique and promising drug for the treatment of coronary heart disease.

Volatile Anesthetics and Coronary Collateral Circulation

In this chapter, a study demonstrates that isoflurane and a new volatile anesthetic, sevoflurane, do not abnormally redistribute collateral blood flow away from an area distal to a total coronary artery occlusion. Vasodilation in the region supplied by the stenotic artey causes a decrease in coronary artery pressure distal to the stenosis. Agents that produce coronary vasodilation can act at one or more regions in the coronary vasculature. Arterioles are the primary vessels controlling resistance in the coronary circulation, and, thus, arteriolar dilators such as adenosine, dipyridamole, and chromonar are capable of producing maximal increases in flow and a redistribution of flow away from collateraldependent zones. Volatile anesthetics, including isoflurane, enflurane, and halothane, have been shown to cause coronary vasodilation, primarily of small resistance vessels. This property makes these agents potential candidates for the production of coronary steal. Volatile anesthetics also depress sinoatrial (SA) node and cardiac conduction tissue function in vitro . Volatile anesthetic-induced reductions in myocardial contractility, left ventricular afterload, and heart rate contribute to a reduction in myocardial oxygen consumption and lead to a concomitant increase in coronary vascular resistance via metabolic autoregulation. Thus, the sum of indirect and direct effects in vivo determines the observed alterations in coronary blood flow and vascular resistance. In the present investigation, sevoflurane has been shown to increase coronary collateral blood flow during maintenance of heart rate and arterial pressure at levels observed in the conscious state. In contrast, coronary collateral blood flow remains constant with correction of heart rate and blood pressure during isoflurane or desflurane anesthesia.

Alterations of coronary collateral blood flow velocity during intraaortic balloon pumping

Controversy exists regarding the ability of intraaortic balloon pumping to increase coronary blood flow either directly or through collateral perfusion. 1–4 In patients, directly measured coronary flow velocity by intracoronary Doppler guidewire technique distal to severe coronary stenoses is minimal and unaffected by intraaortic balloon pumping. 5 After coronary angioplasty, intraaortic balloon pumping increases both proximal and, more importantly, distal coronary artery flow velocity. 5 Whether collateral flow is altered during intraaortic balloon pumping has not been adequately studied in humans because of a lack of quantitative means to assess collateral blood flow. 6 With the use of a Doppler-tipped angioplasty guidewire, retrograde collateral flow velocity can be directly measured, and thus quantitate the effects of interventions altering collateral blood flow responses. 7 While performing angioplasty with the Doppler guidewire, we quantitated intracoronary collateral blood flow alterations during intraaortic balloon pumping in 3 patients: 2 with acute myocardial infarction and 1 with unstable angina. These observations using flow velocity techniques to evaluate perturbations of collateral flow are the first physiologic demonstrations in patients of one of the unique hypothesized beneficial antiischemic mechanisms of intraaortic balloon pumping.

Effect of aspirin on coronary collateral blood flow.

Although aspirin exerts beneficial antiplatelet activity in patients with coronary artery disease, cyclooxygenase blockade produced by aspirin causes a potentially deleterious effect by interrupting endothelial production of prostacyclin. Collateral vessels that develop in response to coronary occlusion display prominent endothelial cell proliferation and undergo vasoconstriction in response to indomethacin. This study was performed to test the hypothesis that cyclooxygenase blockade with aspirin would cause constriction of coronary collateral vessels and that such vasoconstriction would be reversed with nitroglycerin. Collateral vessel growth was induced by embolic occlusion of the left anterior descending coronary artery in dogs. Four to 6 months later, coronary collateral flow was measured as retrograde flow from the cannulated collateral-dependent artery. Aspirin (1 mg/kg i.v.) caused 70 +/- 8% blockade of the increase in coronary blood flow produced by intra-arterial arachidonic acid and decreased retrograde flow from 37 +/- 7 to 28 +/- 7 ml/min (p < 0.03). Increasing the dose of aspirin to 15 mg/kg i.v. caused 91 +/- 3% blockade of the response to arachidonic acid and further decreased retrograde flow to 21 +/- 4 ml/min (p < 0.01). After aspirin administration, nitroglycerin (150 micrograms/min i.c.) reversed the collateral constriction and increased retrograde flow to 37 +/- 10 ml/min (p < 0.01). These data suggest that products of cyclooxygenase metabolism cause tonic vasodilation of well-developed coronary collateral vessels. Blockade of cyclooxygenase with even low-dose aspirin caused collateral vessel constriction with a decrease in collateral blood flow. However, nitroglycerin was able to fully reverse aspirin-induced collateral vasoconstriction and restore flow to the control level.

Local beta-adrenergic blockade does not reduce infarct size after coronary occlusion and reperfusion: A study of coronary venous retroinfusion of metoprolol

Previous studies have demonstrated pronounced ischemic zone myocardial concentrations of metoprolol following coronary venous retroinfusion in pigs with coronary artery ligation. The effect of coronary venous retroinfusion of metroprolol on myocardial infarct size was studied in 16 pentobarbital-anesthetized open-chest pigs undergoing 60-minute occlusion of the left anterior descending coronary artery followed by 3 hours of reperfusion. Pigs in the experimental group (n = 8) were given 0.4 mg/kg (1.0 mg/ml) of metroprolol via the anterior interventricular vein over a period of 5 minutes, beginning immediately after coronary occlusion followed by 0.2 mg/kg/hr intravenously. Control pigs (n = 8) received the same volume of saline as the treated group. The risk area and the necrotic area were assessed by monastral blue dye and triphenyl tetrazolium chloride staining, respectively. Metoprolol did not influence hemodynamics. Plasma concentrations of metoprolol were within therapeutic levels. The administration of the beta-blocker resulted in a trend toward reduced norepinephrine concentrations, both in the aorta and coronary vein after coronary occlusion, but it did not prevent norepinephrine overflow following reperfusion. Infarct size expressed as a percentage of the risk area was 77 +/- 11% in the control group and 75 +/- 12% (mean +/- SD; NS) in the treated group. Thus, metoprolol retroinfusion did not reduce infarct size and did not prevent catecholamine overflow after reperfusion. It is concluded that the beneficial effects of metroprolol in acute infarction are probably unrelated to local beta-adrenergic blockade, at least in the pig, an animal with a paucity of coronary collateral blood flow.

Endothelial function in well-developed canine coronary collateral vessels.

This study examined responses of coronary collateral blood flow to endothelial-dependent vasodilators. Studies were performed in 13 dogs 4-6 mo after embolic occlusion of the left anterior descending coronary artery (LAD). Collateral flow was determined as the sum of retrograde flow from the cannulated LAD, and continuing tissue flow was measured with microspheres administered during the retrograde flow collection. Agonists were introduced into the left main coronary artery to reach collaterals arising from the left coronary arterial system. The endothelial-dependent vasodilators acetylcholine and bradykinin caused 21 +/- 7 and 25 +/- 8% increases of collateral flow, respectively (each P < 0.05). This was not different from the 28 +/- 8% increase in collateral flow produced by nitroglycerin. To determine whether vasodilator prostaglandins contributed to the increased collateral flow, studies were performed after cyclooxygenase blockade with indomethacin (5 mg/kg iv). Indomethacin caused a 30 +/- 9% decrease of retrograde flow during basal conditions but did not blunt the maximum collateral flow rates produced by acetylcholine, bradykinin, or nitroglycerin. These data demonstrate intact endothelial-dependent vasodilator mechanisms in the well-developed coronary collateral circulation.

Collateral blood flow from skeletal muscle to normal myocardium

Collateral blood vessels from skeletal muscle to myocardium might supplement intramyocardial collaterals during periods of acute myocardial ischemia. This study was conducted to verify the existence of such collaterals and to measure their contribution to collateral flow. In 12 male goats, the innate coronary collateral system to a moderate size myocardial risk area was defined with colored microspheres, and a latissimus dorsi pedicle flap was then apposed to the heart. After 3 weeks, skeletal muscle to myocardial collaterals were characterized by (a) creation of vascular casts (three animals); (b) estimation of skeletal muscle to myocardial collateral blood flow (three animals); and, (c) measurement of total collateral blood flow to the risk area (innate plus skeletal muscle to myocardial collateral flow). Under a dissecting microscope the vascular casts revealed direct communications from the skeletal muscle which penetrated deeply into the myocardium. With the coronary artery to the risk area open, the estimated myocardial collateral blood flow derived from the muscle flap was 0.01, 0.02, and 0.04 ml/min. With the coronary artery to the risk area closed, there was no significant increase in total coronary collateral blood flow. Although the quantity of blood flow delivered by skeletal muscle collaterals was small, this study demonstrates that clearly identified collateral blood vessels form between skeletal muscle and myocardium in a cardiomyoplasty model. This raises the possibility that, under conditions more favorable to their development, extramyocardial collaterals from skeletal muscle might be exploited to augment the intramyocardial collateral system.

Nitrous oxide impairs functional recovery of stunned myocardium in barbiturate-anesthetized, acutely instrumented dogs.

The purpose of this investigation was to characterize the effects of nitrous oxide or nitrogen (70%) on systemic and regional hemodynamics and myocardial tissue perfusion after a brief coronary artery occlusion (15 min) and reperfusion (3 h). Two groups of experiments (14 experiments total) were completed with 24 open-chest, barbiturate-anesthetized dogs. Coronary collateral blood flow was diverted from the ischemic zone during coronary artery occlusion to eliminate a source of variability in degree of ischemia produced by differences in degrees of collateral blood flow among animals. Seven of 16 dogs treated with nitrous oxide and 7 of 8 dogs treated with nitrogen survived coronary occlusion and reperfusion (P less than 0.05). Coronary artery occlusion produced paradoxical systolic bulging in the ischemic zone in both groups of experiments. After reperfusion, segment shortening gradually returned toward control levels but remained depressed from the preocclusion state after 3 h in the nitrogen-treated control group. Similar results were observed after reperfusion in the nitrous oxide group; however, segment function in the ischemic region was significantly (P less than 0.05) depressed throughout the 3-h reperfusion period compared with the control group. Transmural coronary collateral blood flow during occlusion was not significantly different (P greater than 0.05) between groups, indicating that differences in recovery of contractile function observed between groups could not be attributed to differences in myocardial oxygen supply. In addition, the similarity in systemic hemodynamics between the nitrous oxide and control groups indirectly suggests that differences in recovery of function could not be attributed to differences in myocardial oxygen demand. The results indicate that 70% nitrous oxide produces greater mortality after coronary artery occlusion and reperfusion and reduces functional recovery of post-ischemic, reperfused myocardium compared with 70% nitrogen in open-chest, acutely instrumented dogs.

Distribution of coronary collateral blood flow at different levels of collateral growth in conscious ponies.

Coronary collateral growth was stimulated in chronically instrumented conscious ponies by a previously validated intermittent coronary occlusion method. Changes in regional myocardial function (sonomicrometry) and reactive hyperemia (Doppler method) were used to monitor collateral growth and to program measurements of regional myocardial blood flow (microsphere method). A serial analysis of the transmural and lateral distributions of collateral blood flow was performed at the native and three superimposed levels of collateral growth. Results in nine animals undergoing an average of 553 +/- 188 brief coronary occlusions over 68 +/- 18 days demonstrated that as collateral conductance increased, the perfusion field within the ischemic region increased from the epicardium to the endocardium but not from the lateral edges to the center of the ischemic region. The findings are consistent with an analog model consisting of interarterial collaterals whose collective resistance is in series with arteriolar resistance of the recipient artery. No special protection of deeper myocardial layers by a subendocardial plexus or intramural collaterals was noted. Instead, the findings suggest that coronary extravascular compressive forces play a more important role than the transmural location of collaterals in determining the volume and spatial distribution of collateral blood flow during collateral growth in the pony.

Angiographic demonstration of spontaneous variation in coronary artery collateral blood flow: A mechanism for post-infarction angina

Angiographic demonstration of spontaneous variation in coronary artery collateral blood flow: A mechanism for post-infarction angina

KT-362 related effects on intracellular calcium release and associated clinical potential: Arrhythmias, myocardial ischemia, and hypertension

The following discourse addresses the pharmacologic profile of KT-362, its clinical potential as an anti-arrhythmic agent with associated hypotensive effects, as well as its additional related potential in myocardial ischemia and related sequellae, and the specific cellular actions that may be responsible for these potential therapeutic effects. Although these include specific actions on both sodium and calcium entry, the focus is on the relevance of independent effects on calcium release. KT-362 relaxes arterial smooth muscle, concomitantly reducing the total peripheral resistance and mean arterial blood pressure. Vascular relaxing actions are attributed primarily to inhibitory effects on calcium release and secondarily to inhibitory effects on calcium entry via both potential-gated and receptor-linked channels. The "intracellular calcium antagonist" properties are correlated with a decrease in the production of the major second messenger, inositol 1,4,5-trisphosphate, which is responsible for calcium release and a concurrent ryanodine-like action that further decreases the amount of calcium released. Ventricular arrhythmias associated with coronary occlusion, cardiac glycosides, catecholamines, and chloroform are prevented by KT-362. General antiarrhythmic properties are associated with a use-dependent block of the "fast" sodium channel, primarily in the activated state, with ancillary effects on the "slow" calcium current. More selective effects on arrhythmias specifically associated with delayed after-depolarizations are attributed to effects on calcium release. In myocardial ischemia, KT-362 primarily reduces myocardial oxygen consumption rather than increases oxygen supply. The former is accomplished by depressing myocardial contractility and reducing afterload, while the latter is associated with a limited effect on coronary collateral blood flow. The negative inotropic effect is fundamentally related to its effects on calcium release, with additional contributions from its effects on calcium entry. Thus, the one intrinsic property of KT-362 that consistently emerges as significant and relevant in cardiovascular disease is the capacity to diminish calcium release.

Effect of atrial natriuretic peptide on coronary collateral blood flow.

This study was carried out to examine the effects of atrial natriuretic peptide on coronary collateral blood flow. Studies were performed in nine adult mongrel dogs 3.4 months after embolic occlusion of the left anterior descending coronary artery had been performed to stimulate collateral vessel growth. At the time of study the anterior descending coronary artery was cannulated to allow estimation of interarterial collateral flow from measurements of retrograde blood flow. Injection of radioactive microspheres during retrograde flow collection allowed simultaneous determination of continuing tissue flow for evaluation of microvascular collateral communications. Atrial natriuretic peptide in doses of 20 and 200 micrograms administered into the left atrium resulted in 17 +/- 3.0% and 34 +/- 4.5% increases in retrograde flow, respectively (each p less than 0.01). Tissue flow in the collateral dependent myocardial region did not change in response to atrial natriuretic peptide. After the larger dose of atrial natriuretic peptide, the administration of nitroglycerin (10 micrograms/kg into the left atrium) caused no further increase of retrograde blood flow, and no further decrease of collateral vascular resistance. These data indicate that atrial natriuretic peptide causes vasodilation of moderately well-developed interarterial coronary collateral vessels.