Increase In Collateral Blood Flow Research Articles

Stimulating the Facial Nerve to Treat Ischemic Stroke: A Systematic Review

Acute ischemic stroke (AIS) is a common devastating disease that has increased yearly in absolute number of cases since 1990. While mechanical thrombectomy and tissue plasminogen activator (tPA) have proven to be effective treatments, their window-of-efficacy time is very short, leaving many patients with no viable treatment option. Over recent years there has been a growing interest in stimulating the facial nerves or ganglions to treat AIS. Pre-clinical studies have consistently demonstrated an increase in collateral blood flow (CBF) following ganglion stimulation, with positive indications in infarct size and neurological scores. Extensive human trials have focused on trans-oral electrical stimulation of the sphenopalatine ganglion, but have suffered from operational limitations and non-significant clinical findings. Regardless, the potential of ganglion stimulation to treat AIS or elongate the window-of-efficacy for current stroke treatments remains extremely promising. This review aims to summarize results from recent trial publications, highlight current innovations, and discuss future directions for the field. Importantly, this review comes after the release of four important clinical trials that were published in mid 2019.

Abstract 5516: Cardioprotective Effects of Hydrogen Peroxide and Erythropoietin During Acute Coronary Occlusion in Canine Coronary Native Collateral Microvessels in vivo

Background: We have previously demonstrated that endothelium-derived hydrogen peroxide (H 2 O 2 ) is an endothelium-derived hyperpolarizing factor (EDHF) in canine coronary autoregulation in vivo. The aim of this study was to examine the role of H 2 O 2 during acute coronary occlusion with recombinant human erythropoietin (EPO) in the collateral vasodilatation of coronary microcirculation in vivo. Methods and Results: Canine subepicardial native collateral coronary small arteries (CSA, ≥100 μ m) and arterioles (CA, <100 μ m) were observed by an intravital microscope under cyclooxygenase blockade. Experiments were performed after LAD occlusion (90 min) under the following 8 conditions (n=5, each); control, low-dose EPO (100 IU/kg, L-EPO), high-dose EPO (1000 IU/kg, H-EPO), H-EPO+catalase (a H 2 O 2 decomposer), H-EPO+NO synthase inhibitor (L-NMMA), H-EPO+L-NMMA+catalase, H-EPO+L-NMMA+tetraethylammonium (TEA, a K Ca channels blocker) and H-EPO+ wortmannin (PI3K inhibitor). Ischemia caused a significant collateral arteriolar vasodilatation of control, which was significantly inhibited by catalase. After H-EPO, the vasodilatation was significantly increased in both-sized arteries (CSA 6±1%, CA 22±4%) compared with control (CSA 1±1%, CA 16±3%) or L-EPO (CSA 2±1%, CA 18±3%) associated with increase in collateral blood flow (microsphere technique). H-EPO+catalase significantly decreased the vasodilatation in CA (12±2%). The vasodilatation was markedly attenuated after H-EPO+L-NMMA+catalase (CSA −4±1%, CA 6±1%), H-EPO+L-NMMA+TEA (CSA −5±1%, CA 6±1%) and H-EPO+ wortmannin (CSA −5±1%, CA 6±1%). In the control group, expression of Akt phosphorylation in the ischemic LAD area was significantly decreased compared with the H-EPO group. In H-EPO+L-NMMA+catalase or H-EPO+wortmannin group, expression of Akt phosphorylation was further decreased compared with H-EPO or L-NMMA+H-EPO group. Plasma 8-hydroxydeoxyguanosine from coronary sinus as a myocardial oxidative stress marker (HPLC-ECD method) significantly decreased in H-EPO compared with control. Conclusions: H 2 O 2 and EPO play an important collaborative role in native collateral vasodilatation in response to acute coronary occlusion in canine coronary microcirculation in vivo.

The Y 2 receptor mediates increases in collateral-dependent blood flow in a model of peripheral arterial insufficiency

We have utilized a rat model of peripheral artery disease (PAD) to examine whether the known angiogenic activity of the Y 2 receptor would translate into a meaningful increase in collateral blood flow. The maximal increase in collateral blood flow capacity of ∼60% ( p < 0.001) was obtained with a 10 μg/kg day (IA infusion, 14 days) of either PYY or PYY 3–36 and did not differ from that obtained with a maximally angiogenic dose of VEGF 165. Pharmacodynamic modeling based upon single dose pharmacokinetic plasma profiles of both agonists suggests that E max is reached when the Y 2 receptor is occupied by ≥50%. Furthermore, for PYY 3–36, occupancy of the Y 2 receptor is sufficient to promote a significant benefit in collateral blood flow.

Time course of changes in collateral blood flow and isolated vessel size and gene expression after femoral artery occlusion in rats.

The objectives of this study were to assess the time course of enlargement and gene expression of a collateral vessel that enlarges following occlusion of the femoral artery and to relate these responses to the increases in collateral-dependent blood flow to the calf muscles in vivo. We employed exercise training to stimulate collateral vessel development. Rats were exercise trained or kept sedentary for various times of up to 25 days postbilateral occlusion (n=approximately 9/time point). Collateral blood flow to the calf muscles, determined with microspheres, increased modestly over the first few days to approximately 40 ml.min(-1).100 g(-1) in sedentary animals; the increase continued over time to approximately 80 ml.min(-1).100 g(-1) in the trained animals. Diameters of the isolated collateral vessels increased progressively over time, whereas an increased vessel compliance observed at low pressures was similar across time. These responses were greater in the trained animals. The time course of upregulation of vascular endothelial growth factor and placental growth factor, and particularly endothelial nitric oxide synthase and fms-like tyrosine kinase 1, mRNAs in the isolated collateral vessel implicates these factors as integral to the arteriogenic process. Collateral vessel enlargement and increased compliance at low pressures contribute to the enlarged circuit available for collateral blood flow. However, modulation of the functioning collateral vessel diameter, by smooth muscle tone, must occur to account for the observed increases in collateral blood flow measured in vivo.

A review of the effects of chronic exercise and physical fitness level on resting pharmacokinetics.

Pharmacological intervention in cooperation with physical activity is currently being used in the prevention and treatment of diseases like cardiovascular disease and obesity. Physical activity, both acute and chronic, can cause changes in physiology that can alter the observed pharmacokinetics of drugs. The purpose of this paper is to focus on how chronic exercise can change pharmacokinetics. Chronic exercise can affect drug absorption by the increase in collateral blood flow and absorption may also be affected by changes in gastrointestinal transit times. Chronic exercise may affect volume of distribution of drugs by the increases in lean body mass, decreased fat mass, increased plasma protein and increased plasma volume that occurs with physical conditioning. Changes in hepatic clearance of drugs may explain the differences in systemic clearance seen when comparing physically trained subjects to sedentary ones. Some studies have shown that hepatic enzymes are increased with training but other studies have found no change or lower activities. Finally, renal elimination of drugs may be altered by changes in protein binding but there is little evidence that renal elimination of drugs changes with long-term exercise. Therefore, changes in pharmacokinetics associated with chronic exercise can differ from those during acute exercise and in sedentary subjects. The differences between the physically active and sedentary individuals may require individualization of dosing regimens. It should be noted that there are no standardized protocols to evaluate the influence of exercise on drug disposition.

Reactive oxygen species are critical mediators of coronary collateral development in a canine model.

Recent evidence suggests that reactive oxygen species (ROS) promote proliferation and migration of vascular smooth muscle (VSMC) and endothelial cells (EC). We tested the hypothesis that ROS serve as crucial messengers during coronary collateral development. Dogs were subjected to brief (2 min), repetitive coronary artery occlusions (1/h, 8/day, 21 day duration) in the absence (occlusion, n = 8) or presence of N-acetylcysteine (NAC) (occlusion + NAC, n = 8). A sham group (n = 8) was instrumented identically but received no occlusions. In separate experiments, ROS generation after a single 2-min coronary artery occlusion was assessed with dihydroethidium fluorescence. Coronary collateral blood flow (expressed as a percentage of normal zone flow) was significantly increased (71 +/- 7%) in occlusion dogs after 21 days but remained unchanged (13 +/- 3%) in sham dogs. Treatment with NAC attenuated increases in collateral blood flow (28 +/- 8%). Brief coronary artery occlusion and reperfusion caused ROS production (256 +/- 33% of baseline values), which was abolished with NAC (104 +/- 12%). Myocardial interstitial fluid produced tube formation and proliferation of VSMC and EC in occlusion but not in NAC-treated or sham dogs. The results indicate that ROS are critical for the development of the coronary collateral circulation.

Octreotide ameliorates the increase in collateral blood flow during postprandial hyperemia in portal hypertensive rats

Background/Aims : The aims of this study were to examine, in a conscious rat model of portal hypertension, the effect of postprandial splanchnic hyperemia on collateral blood flow and to determine whether octreotide has an effect on postprandial collateral flow changes. Methods : In rats with portal vein ligation, pulsed-Doppler flowmeters were implanted chronically around the splenorenal venous shunt (SRS), which is the main spontaneous collateral vessel in the portal hypertensive rat and around the superior mesenteric artery (SMA). Changes in flow after a standard liquid meal gavage and after the administration of octreotide were examined in the rat under unanesthetized and unrestricted conditions. Results : SRS flow increased significantly after gavage with a standard liquid meal (10.6±2.9%) compared to orogastric intubation alone (−6.5±2.1%) ( P <0.01). Similar flow changes were observed in the SMA after liquid meal gavage. The subcutaneous administration of octreotide at a dose of 400 μg/kg reduces basal SRS flow (−19.5±2.3%) and significantly attenuated the change in SRS flow after liquid meal gavage (−8.1±2.9%) compared to animals that received placebo (3.6±4.1% and 27.8±7.6%, respectively) ( P <0.05). Conclusions : These results demonstrate that, in an experimental model of prehepatic portal hypertension, postprandial splanchnic hyperemia results in an increase in collateral flow that can be ameliorated with the use of octreotide.

Prior exercise training produces NO-dependent increases in collateral blood flow after acute arterial occlusion

We previously reported that prior training improves collateral blood flow (BF) to the calf muscles after acute-onset occlusion of the femoral artery (Yang HT et al. Am J Physiol Heart Circ Physiol 279: H1890-H1897, 2000). The purpose of this study was to test the hypothesis that increased release of nitric oxide (NO) by NO synthase (likely endothelial NOS) contributes to the increased BF to calf muscles of trained rats after acute femoral artery occlusion. Adult male Sprague-Dawley rats (~325 g) were limited to cage activity and were sedentary (SED; n = 28) or exercise trained (TR; n = 30) for 6 wk by treadmill running. On the day of the investigation, rats were anesthetized with ketamine-acepromazine and instrumented for determination of BF (using (141)Ce- and (85)Sr-labeled microspheres) and distal limb arterial pressure, and femoral arteries were occluded bilaterally. Four hours after surgery, collateral BF was determined twice during treadmill running: first at a demanding speed (20 m/min, 15% grade) and second, after a brief rest and at a faster running speed (25 m/min, 15% grade). The fact that BF did not increase further at the higher running speed indicated that maximal collateral BF was measured. Approximately half of the rats in each group received 20 mg/kg body wt N(G)-nitro-L-arginine methyl ester (L-NAME) intra-arterially 30 min before treadmill exercise and BF measurement to block production of NO by NOS. Results indicate that prior training improved collateral-dependent BF to the skeletal muscle of rats after acute femoral artery occlusion due primarily to an increase in the conductance of the upstream collateral circuit. Blockade of NOS with L-NAME produced decreased vascular conductance, both in the upstream collateral circuit and in the distal skeletal muscle microcirculation, and the difference between collateral vascular conductance in TR and SED rats was abolished. Our results indicate that the primary determinant of the increased collateral BF with prior training is the resistance of the upstream collateral circuit and imply that enhanced endothelium-mediated dilation induced by training serves to increase collateral BF following acute arterial occlusion.

VEGF(121)- and bFGF-induced increase in collateral blood flow requires normal nitric oxide production.

The angiogenic proteins basic fibroblast growth factor (bFGF; FGF-2) and vascular endothelial growth factor 121 (VEGF(121)) are each able to enhance the collateral-dependent blood flow after bilateral femoral artery ligation in rats. To study the effect of nitric oxide (NO) synthase (NOS) inhibition on bFGF- or VEGF(121)-induced blood flow expansion, the femoral arteries of male Sprague-Dawley rats were ligated bilaterally, and the animals were given tap water [non-N(G)-nitro-L-arginine methyl ester (L-NAME) group; n = 36] or water that contained L-NAME (L-NAME group; 2 mg/ml, n = 36). Animals from each group were further divided into three subgroups: vehicle (n = 12), bFGF (5 microg x kg(-1) x day(-1), n = 12), or VEGF(121) (10 microg x kg(-1) x day(-1), n = 12). Growth factors were delivered via intra-arterial infusion with osmotic pumps over days 1-14. On day 16, after a 2-day delay to permit clearance of bFGF and VEGF from the circulation, maximal collateral blood flow was determined by (85)Sr- and (141)Ce-labeled microspheres during treadmill running. L-NAME (approximately 137 mg x kg(-1) x day(-1)) for 18 days increased systemic blood pressure (approximately 26%, P<0.001). In the absence of L-NAME, collateral-dependent blood flows to the calf muscles were greater in the VEGF(121)- and bFGF-treated subgroups (85 +/- 4.5 and 80 +/- 2.9 ml x min(-1) x 100 g(-1), respectively) than in the vehicle subgroup (49 +/- 3.0 ml x min(-1) x 100 g(-1), P<0.001). In the presence of NOS inhibition by L-NAME, blood flows to the calf muscles were essentially equivalent among the three subgroups (54 +/- 3.0, 56 +/- 5.1, and 47 +/- 2.0 ml x min(-1) x 100 g(-1) in the bFGF-, VEGF(121)-, and vehicle-treated subgroups, respectively) and were not different from the blood flow in the non-L-NAME vehicle subgroup. Our results therefore indicate that normal NO production is essential for the enhanced vascular remodeling induced by exogenous bFGF or VEGF(121) in this rat model of experimental peripheral arterial insufficiency. These results imply that a blunted endothelial NO production could temper vascular remodeling in response to these angiogenic growth factors.

Influence of the angiotensin II AT1 receptor antagonist irbesartan on ischemia/reperfusion injury in the dog heart.

The aim of the present study was to investigate whether the non-peptide angiotensin II type 1 (AT1) receptor antagonist irbesartan (SR 47436, BMS 186295, 2-n-butyl-3 [2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-1,3-diaza-spiro [4,4]non-1-en-4-one) has myocardial protective effects during regional myocardial ischemia/reperfusion in vivo. Eighteen anesthetized open-chest dogs were instrumented for measurement of left ventricular and aortic pressure (tip manometer and pressure transducer, respectively), and coronary flow (ultrasonic flowprobes). Regional myocardial function was assessed by Doppler displacement transducers as systolic wall thickening (sWT) in the antero-apical and the postero-basal wall. The animals underwent 1 h of left anterior descending coronary artery (LAD) occlusion and subsequent reperfusion for 3 hours. Irbesartan (10 mg kg(-1), n = 9) or the vehicle (KOH, control, n = 9) was injected intravenously 30 min before LAD occlusion. Regional myocardial blood flow (RMBF) was measured after irbesartan injection and at 30 min LAD occlusion using colored microspheres. Infarct size was determined by triphenyltetrazolium chloride staining after 3 h of reperfusion. There was no recovery of sWT in the LAD perfused area in both groups at the end of the experiments (systolic bulging, -15.1+/-6.1% of baseline (irbesartan) vs. -12.3+/-3.0% (control), mean+/-SEM). Irbesartan led to an increase in RMBF in normal myocardium (2.47+/-0.40 vs. 1.35+/-0.28 ml min(-1) g(-1), p<0.05), and also to an increase in collateral blood flow to the ischemic area (0.27+/-0.04 vs. 0.17+/-0.02 ml min(-1) g(-1), P = <0.05). Infarct size (percent of area at risk) was 24.8+/-3.2 % in the treatment group compared with 26.9+/-4.8% in the control group (P = 0.72). These results indicate that a blockade of angiotensin II AT1 receptors with irbesartan before coronary artery occlusion led to an increase in RMBF, but did not result in a significant reduction of myocardial infarct size.

Efficacy and specificity of bFGF increased collateral flow in experimental peripheral arterial insufficiency.

Angiogenic growth factors could prove to be useful in managing peripheral arterial insufficiency. The present study was designed to evaluate the dose response of basic fibroblast growth factor (bFGF), the efficacy of critical routes and dosing regimens, and the specificity of action in rats with peripheral arterial insufficiency. Bilateral ligation of femoral arteries greatly reduces blood flow capacity to the calf muscles but does not impair resting flow needs. Collateral blood flow to calf muscles was determined 16 days postocclusion, during treadmill running, with (85)Sr and (141)Ce microspheres, in blinded-randomized trials that included intra-arterial and intravenous infusions and subcutaneous injections of recombinant human bFGF. Peak blood flow of 75-80 ml. min(-1). 100 g(-1) for calf muscle was observed at a bFGF dose of 5 microg. kg(-1). day(-1) (ia for 14 days) compared with 50 ml. min(-1). 100 g(-1) for vehicle groups. Similar increases in collateral blood flow were observed with short-term or prolonged and continuous or intermittent delivery of bFGF by any route. Collateral blood flows were similar in corresponding muscles across both limbs. Vascular remodeling induced by bFGF required attendant vascular occlusion, inasmuch as vessels in the normal nonoccluded vascular tree were unresponsive to circulating bFGF. Improvement in collateral blood flow with exogenous bFGF is robust, amenable to short-term administration, and requires vascular occlusion to be effective.

Protective effect of TA-993, a novel therapeutic agent for peripheral circulatory insufficiency, on skeletal muscle fatigue in a rat model of hindlimb ischemia.

TA-993 (cis-(-)-2-(4-methylphenyl)-3-acetoxy-2,3-dihydro-5-(2-dimethylaminoethy l)-8-methyl1,5-benzothiazepine-4(5H)-one maleate), a new 1,5-benzothiazepine derivative, has a selective increasing action on limb blood flow in addition to an antiplatelet action. In this report we studied the effect of TA-993 on a time dependent decrease in developed tension of electrically-induced contraction of tibialis anterior muscle in a rat model of peripheral circulatory insufficiency induced by occlusion of abdominal aorta. In our preparation, the developed tension decreased by 20-30% in a sham-operated group and 30-40% in an abdominal aorta-occluded group at the end of the experimental period of 60 min. Intraduodenal administration (i.d.) of TA-993 (10 mg/kg) to the abdominal aorta-occluded rats ameliorated the decrease in developed tension to the level of the sham-operated group. Moreover, TA-993 at 10 mg/kg, i.d. significantly increased femoral arterial blood flow supplied through collateral circulation and decreased the whole blood viscosity in this model. These results suggest that TA-993 improves dysfunction of skeletal muscle contraction due to peripheral circulating insufficiency through an increase in collateral blood flow and an improvement of red blood cell deformability.

Protective Effect of TA-993, a Novel Therapeutic Agent for Peripheral Circulatory Insufficiency, on Skeletal Muscle Fatigue in a Rat Model of Hindlimb Ischemia

TA-993 (cis-(–)-2-(4-methylphenyl)-3-acetoxy-2,3-dihydro-5-(2-dimethylaminoethyl)-8-methyll,5-benzothiazepine-4(5H)-one maleate), a new 1,5-benzothiazepine derivative, has a selective increasing action on limb blood flow in addition to an antiplatelet action. In this report we studied the effect of TA-993 on a time dependent decrease in developed tension of electrically-induced contraction of tibialis anterior muscle in a rat model of peripheral circulatory insufficiency induced by occlusion of abdominal aorta. In our preparation, the developed tension decreased by 20–30% in a sham-operated group and 30–40% in an abdominal aorta-occluded group at the end of the experimental period of 60 min. Intraduodenal administration (i.d.) of TA-993 (10 mg/kg) to the abdominal aorta-occluded rats ameliorated the decrease in developed tension to the level of the sham-operated group. Moreover, TA-993 at 10 mg/kg, i.d. significantly increased femoral arterial blood flow supplied through collateral circulation and decreased the whole blood viscosity in this model. These results suggest that TA-993 improves dysfunction of skeletal muscle contraction due to peripheral circulating insufficiency through an increase in collateral blood flow and an improvement of red blood cell deformability.

Transient MRI-detected water apparent diffusion coefficient reduction correlates with c- fos mRNA but not hsp70 mRNA induction during focal cerebral ischemia in rats

Cerebral ischemia induces immediate early genes such as c- fos and stress genes such as hsp70. In this study, the spatial relationships between c- fos and hsp70 mRNA expression and changes detectable with diffusion and perfusion magnetic resonance (MR) imaging were examined. The middle cerebral artery (MCA) of young adult rats was occluded for 30 or 60 min. Diffusion MR (D-MR) images were acquired continuously during the ischemic period and dysprosium-contrast perfusion (P-MR) images were acquired at the end of the ischemic period. C- fos and hsp70 mRNA expression were examined with in situ hybridization. The most significant finding of this work was that for both durations of ischemia, c- fos induction was observed in cortical and sub-cortical regions exhibiting a transient reduction in the apparent diffusion coefficient of water (ADC). Transients which occurred on a time scale of 3 min may have been caused by spreading depression. Those occurring on a 10-min time scale may have been caused by an initial reduction in blood flow with occlusion that was followed by an ischemia-induced increase in collateral blood flow. P-MR imaging showed that perfusion in c- fos positive regions was higher than in regions with persistently reduced ADC. Hsp70 induction did not correlate with transient ADC reduction. It was induced in the MCA territory in regions showing persistent ADC changes, with induction being greatest at the periphery of these regions. It was also induced in regions that exhibited both spontaneous reversal of the diffusion changes and decreased perfusion.

Exercise training enhances basic fibroblast growth factor-induced collateral blood flow.

This study evaluated whether daily exercise would enhance the peripheral collateral vessel development found in response to exogenous basic fibroblast growth factor (bFGF) infusion. After bilateral femoral occlusion, male Sprague-Dawley rats (approximately 325 g) received intra-arterial infusions of either bFGF (1 microg/day; n = 15) or carrier solution (n = 13) via osmotic pumps for 2 wk. Subgroups of each treatment were kept sedentary (cage activity) or trained by walking at 20 m/min at 15% grade, two times a day, 5 days/wk for 4 wk. Training markedly increased citrate synthase activity in the active muscle (P < 0.001). Muscle function and blood flows (85Sr microsphere) were evaluated using an isolated hindquarter perfused at 100 mmHg via the abdominal aorta. The significant increase in blood flow to the entire hindlimb in the sedentary animals, caused by bFGF infusion (P < 0.05), was further increased (P < 0.01) in the bFGF-trained group. The quantitatively largest increases in blood flows were observed in the collateral-dependent tissues of the distal hindlimb. Blood flows to the entire calf muscle group increased approximately 140% in carrier-trained (P < 0.001), approximately 180% in bFGF sedentary (P < 0.001), and approximately 240% in the bFGF-trained (P < 0.001) groups compared with the carrier sedentary group. The increases in collateral blood flow were functionally important, as improvements in calf muscle performance correlated with measured blood flows. Our results demonstrate that exogenous bFGF administration in combination with a moderate-intensity exercise program greatly increases collateral-dependent blood flow and improves muscle performance. That physical activity enriched the bFGF response is consistent with the hypothesis that hemodynamic factors are important contributors to collateral vessel enlargement.

Effect of Poloxamer 188 on Collateral Blood Flow, Myocardial Infarct Size, and Left Ventricular Function in a Canine Model of Prolonged (3-Hour) Coronary Occlusion and Reperfusion.

Poloxamer 188 is a surfactant with hemorheological, antithrombotic, and neutrophil-inhibitory properties. This agent has been demonstrated to reduce infarct size and to improve left ventricular function in animal models of myocardial infarction and reperfusion, and recently in a randomized trial of patients receiving thrombolytic therapy for acute myocardial infarction. In addition to reducing reperfusion injury, poloxamer 188 might be beneficial by increasing collateral blood flow. The purpose of this study was to determine the effect of poloxamer 188 on collateral blood flow, myocardial infarct size, and left ventricular function in a canine model of prolonged (3 hours) coronary occlusion and reperfusion. Closed-chest dogs (n = 21) underwent a 3-hour coronary occlusion and 3 hours of reperfusion. At 1 hour of occlusion, dogs received poloxamer 188, 75 mg/kg IV bolus, followed by 150 mg/kg/h IV for the final 2 hours of coronary occlusion and throughout reperfusion, or a saline placebo. Regional myocardial blood flow was measured using colored microspheres. Myocardial infarct size and area at risk were determined by postmortem histochemical staining. Compared with controls, poloxamer 188-treated dogs showed no significant increase in collateral blood flow during the final 2 hours of a 3-hour coronary artery occlusion. In addition, poloxamer 188 treatment had no beneficial effect on infarct size or left ventricular function in this model. Increased collateral blood flow is unlikely to be a beneficial mechanism of poloxamer 188 in myocardial infarction. These data also question the benefit of this agent to reduce reperfusion injury in the setting of more prolonged (3-hour) coronary occlusion.

FACTORS IMPORTANT IN THE bFGF-INDUCED INCREASE IN COLLATERAL BLOOD FLOW IN CLAUDICANT RATS 802

Exogenous infusion of bFGF enhances collateral-dependent blood flow (BF) in rats with bilateral femoral artery ligation (Circ. Res. 79:62-69, 1996) by expansion of conduit vessels in the upper thigh. We evaluated the specificity in this response by controlling the time of vascular occlusion in the presence of bFGF infusion. Collateral-dependent calf muscle BF was determined during treadmill running at 20 and 25 m/min with 85Sr and 141Ce labeledμspheres. BF measured 16 d following ligation of the left femoral artery of male Sprague-Dawley rats (≈325 g) exhibited the expected increase induced by an effective dose of bFGF (5 μg/kg/d); however, bFGF did not induce an increase in collateral BF in the right limb of the same rats where the femoral artery was patent during bFGF infusion, but only occluded on day 16 (cf. Fig; No Ligation). Thus, ligation renders the upper thigh vasculature responsive to bFGF, possibly by altered fluid dynamics in the vessels that become functioning collaterals. Additionally, infusion of Heparinase (Type I; 10 U/d) coincident with an effective dose of bFGF renders bFGF incompetent (cf.Fig). This implies that the heparan sulfates of the extracellular matrix are important in the neovascular actions of bFGF. This could occur via the binding/storage of the infused bFGF and/or interactions with the endothelial cells. Figure

971–58 Does Regional Ischemic Preconditioning Affect Collateral Blood Flow to Remote Myocardium During Subsequent Occlusion?: Insights Using Myocardial Contrast Echocardiography

Although it has recently been shown that brief periods of ischemia in one vascular bed protect distant myocardium from subsequent sustained coronary occlusion (occ), its mechanisms are unclear. We hypothesized that “preconditioning” (PC) with repetitive transient ischemia in one coronary bed induces an acute increase in collateral blood flow to a distant bed undergoing subsequent prolonged ischemia, which manifests as a reduction in risk area (RA) size. Accordingly, 11 open-chested dogs were studied: 6 had PC with 4 episodes of 5 min left circumflex (LCX) branch occ plus 5 min reflow, followed by 1 hr left anterior descending artery (LAD) occ, while 5 received 1 hr LAD occ only. In-vivo LAD RA was serially depicted using myocardial contrast echocardiography (MCE). Regional flow was measured using radiolabeled microspheres. During the 1 hr LAD occ, MCE and microsphere measurements were made at 10 and 50 min into occ. To assess the original LAD RA size prior to PC, MCE and microsphere measurements were made during an initial 90 sec LAD occ before intermittent LCX occ. RA was planimetered from the MCE images and expressed as percent of the short-axis. In the PC dogs, the original LAD RA prior to PC was 30 ± 8%, and decreased after intermittent LCX occ to 23 ± 10% at 10 min, and 15 ± 11% at 50 min, into the 1 hr LAD occ (p &lt; 0.03), due to new contrast enhancement at the lateral and epicardial borders of the RA. This net 52% reduction paralleled progressive increases in normalized epicardial flow to the LAD bed at these 3 stages (0.45 ± 0.17 to 0.58 ± 0.14 to 0.66 ± 0.18, P &lt; 0.001). In comparison, in control dogs, there was no significant change from the original LAD RA (36 ± 7%) to that at 10 (38 ± 3%) nOr 50 (36 ± 3%) min into LAD occ. The slight increase noted in normalized epicardial flow during these 3 stages in the controls (0.31 ± 0.11 to 0.33 ± 0.010 to 0.38 ± 13, P &lt; 0.01) was significantly less than in PC dogs, and was not detected with MCE. In conclusion, in this canine model, collateral flow to an occluded vascular bed is enhanced by prior brief ischemia/reperfusion in a distantly located coronary bed. Furthermore, the resulting decrease in RA size appears ongoing during the sustained occ. “Remote” PC may facilitate the recruitment of preformed collaterals situated between the 2 beds, and this phenomenon may help explain the reductions in infarct size associated with this PC model.

Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs.

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that is angiogenic in vitro and in vivo. It has been hypothesized that VEGF plays a role in myocardial collateral formation; however, the effects of VEGF on collateral flow to ischemic myocardium are unknown. We studied the effect of VEGF on collateral blood flow in dogs subjected to gradual occlusion of the left circumflex coronary artery (LCx). Beginning 10 days after placement of an LCx-constricting device, VEGF 45 micrograms (n = 9) or saline (n = 12) was administered daily via an indwelling catheter in the distal LCx, at a point just beyond the occlusion. Treatment was maintained for 28 days. Collateral blood flow was determined with microspheres 7 days before treatment, immediately before treatment (day 0), and 7, 14, 21, and 28 days into the treatment period. Collateral blood flow was quantified during chromonar-induced maximal vasodilation and expressed as a collateral zone/normal zone (CZ/NZ) ratio. Treatment with VEGF was associated with a 40% increase in collateral blood flow (final CZ/NZ blood flow ratios of 0.49 +/- 0.06 and 0.35 +/- 0.02 in the VEGF-treated and control groups, respectively, P = .0037) as well as an 89% increase in the numerical density of intramyocardial distribution vessels (> 20 microns diameter) in the CZ (6.6 +/- 1.4 versus 3.5 +/- 0.7 vessels/mm2 in VEGF-treated and control dogs, respectively, P < .05). We conclude that intracoronary VEGF enhances the development of small coronary arteries supplying ischemic myocardium, resulting in marked augmentation of maximal collateral blood flow delivery. These results demonstrate the feasibility of pharmacological enhancement of collateral growth and suggest a new therapeutic approach for the treatment of myocardial ischemia.

Chronic stimulation enhances extramyocardial collateral blood flow after a cardiomyoplasty

We have previously demonstrated that collateral blood flow can be established between skeletal muscle and myocardium in animals that have undergone a latissimus dorsi cardiomyoplasty. We have also shown that 5 minutes after the thoracodorsal nerve is electrically stimulated at 1.25 Hz, there is a sixfold increase in the collateral blood flow between the latissimus dorsi and the heart. In this experiment, we hypothesized that chronic stimulation of a latissimus dorsi cardiomyoplasty would result in a sustained increase in the latissimus-derived collateral blood flow. In 24 adult male goats, an ameroid constrictor was placed around a branch of the circumflex coronary artery, and a latissimus dorsi cardiomyoplasty was performed. After a rest period of about 1 week, the latissimus dorsi cardiomyoplasties were stimulated continuously at a 2-Hz frequency for 6 weeks. Collateral blood flow between the muscle and the heart was then measured with colored microspheres. Sixteen animals survived to the final experiment, and collaterals developed in 10. In these 10 animals, the latissimus collaterals continuously delivered 0.17 ± 0.03 mL · g −1 · min −1 (mean ± the standard error) of blood to ischemic myocardium. This flow represents 24.0% ± 3.9% of the flow measured to normal myocardium. These results demonstrate that in an animal model of coronary artery disease, chronic electrical stimulation of a latissimus dorsi cardiomyoplasty maintains an elevated level of latissimus-derived collateral blood flow to the myocardium.