Ischemic Regional Blood Flow Research Articles

Therapeutic Angiogenesis Using Basic Fibroblast Growth Factor in Combination with a Collagen Matrix in Chronic Hindlimb Ischemia

Although therapeutic angiogenesis by angiogenic cytokines is a feasible strategy to improve regional blood flow in ischemic regions, the optimal delivery mode needs to be established. Here we designed a complex of collagen matrix (CM) and basic fibroblast growth factor (bFGF) and evaluated its proangiogenic effect in ischemic hindlimbs. The bFGF-CM was prepared using lyophilization. The morphology, porosity and toxicity of CM were examined. The bFGF releasing profile and bioactivity of released bFGF were assessed. bFGF-CM was intramuscularly implanted into the rabbit ischemic hindlimb model. Oxygen saturation parameters (OSP) of ischemic hindlimbs was measured to evaluate the extremity perfusion at intervals. Histological examination was performed to evaluate the level of angiogenesis. The CM and bFGF-CM were of identical multiporous structure lacking cytotoxicity. The releasing profile lasted 10 days and the released bFGF remained bioactive. OSP in bFGF-CM group was significantly higher than that in CM, bFGF and ischemic groups at 2 and 4 weeks. The number of capillaries and mature vessels in bFGF-CM group were significantly greater than that in untreated control, CM and bFGF groups. Therefore, bFGF-CM enables the safe and effective long-term release of bFGF with improved angiogenesis in ischemic hindlimbs compared with CM devoid of bFGF.

Identification of human placenta‐derived mesenchymal stem cells involved in re‐endothelialization

Human placenta is an attractive source of mesenchymal stem cells (MSC) for regenerative medicine. The cell surface markers expressed on MSC have been proposed as useful tools for the isolation of MSC from other cell populations. However, the correlation between the expression of MSC markers and the ability to support tissue regeneration in vivo has not been well examined. Here, we established several MSC lines from human placenta and examined the expression of their cell surface markers and their ability to differentiate toward mesenchymal cell lineages. We found that the expression of CD349/frizzled-9, a receptor for Wnt ligands, was positive in placenta-derived MSC. So, we isolated CD349-negative and -positive fractions from an MSC line and examined how successfully cell engraftment repaired fractured bone and recovered blood flow in ischemic regions using mouse models. CD349-negative and -positive cells displayed a similar expression pattern of cell surface markers and facilitated the repair of fractured bone in transplantation experiments in mice. Interestingly, CD349-negative, but not CD349-positive cells, showed significant effects on recovering blood flow following vascular occlusion. We found that induction of PDGFβ and bFGF mRNAs by hypoxia was greater in CD349-negative cells than in CD349-positive cells while the expression of VEGF was not significantly different in CD349-negative and CD349-positive cells. These findings suggest the possibility that CD349 could be utilized as a specialized marker for MSC isolation for re-endothelialization.

Ascending versus descending aortic balloon: Pumping: organ and myocardial perfusion during ischemia

Background. The ICS-Supracor (Abiomed, Danvers, MA) is a preshaped ascending aorta balloon pump. We compared the effects of this catheter with the classical descending intraaortic balloon pump (IABP). The study focused on hemodynamic effects, myocardial blood flow in normal and ischemic regions, cerebral perfusion, and peripheral organ perfusion. Methods. We placed a stenosis on the lateral branch of the coronary artery to reduce flow 50% (sheep). Measurements included hemodynamic changes, myocardial blood flow, and organ flow (colored microspheres) at baseline, after stenosis, during IABP support, and during ICS support. Results. Counterpulsation with the ICS led to a significantly higher peak diastolic aortic augmentation than with the IABP (IABP, 99 ± 14 mm Hg; ICS, 140 ± 29 mm Hg; p = 0.003). There was no significant change in cerebral perfusion or peripheral organ perfusion. Myocardial blood perfusion was significantly increased by the IABP as well as the ICS. This effect was seen in ischemic and nonischemic regions (subendocardial and subepicardial). The ICS improved myocardial blood flow significantly more than the IABP (IABP, 0.65 ± 0.1 mL/min/g; ICS, 0.94 ± 0.06 mL/min/g; p = 0.0005). Conclusions. The ICS increases myocardial blood flow in ischemic regions significantly more than the IABP, without impairment of cerebral flow. Assessment of vascular complications, peripherally and in the ascending aorta, has to await results of clinical trials.

Pharmacologic profile of the dihydropyrimidine calcium channel blockers SQ 32,547 and SQ 32,926 [correction of SQ 32,946

SQ 32,926 and SQ 32,547, two dihydropyrimidine calcium channel blockers, were characterized as potent inhibitors of depolarization-induced contractions of isolated smooth muscle preparations. In rat aorta, the IC50 values were 5.5 nM for SQ 32,547 and 8.1 nM for SQ 32,926, values which compare favorably with that of 2.9 nM for nifedipine. The dihydropyrimidines were also tested in a model of stable angina: pacing-induced ischemia in dogs. Both SQ 32,547 and SQ 32,926 reduced the ST-segment elevation observed in vehicle-treated animals. No significant changes in hemodynamic status were detected, suggesting that a reduction in cardiac work secondary to afterload reduction was probably not a major contributor to the protective effects. Neither was increased coronary blood flow important for the antiischemic outcome because no significant effects of the dihydropyrimidines were observed on ischemic regional blood flow. SQ 32,547 was also studied in globally ischemic, isolated rat hearts. In this model, SQ 32,547 was protective because it significantly reduced contracture formation and lactate dehydrogenase (LDH) release. Washing out the effect of SQ 32,547 in isolated hearts and smooth muscles was difficult, presumably due to its lipophilicity. In the smooth muscle preparations, the effects of both nifedipine and SQ 32,926 were much more easily washed out. As with other calcium channel blockers, increasing the antiischemic effects of SQ 32,547 was associated with a higher cost in terms of cardiac function. In summary, the two novel dihydropyrimidines, SQ 32,547 and SQ 32,926 showed antiischemic properties in animal models.

Protective effect of the serotonin receptor antagonist cinanserin in two canine models of pacing-induced myocardial ischemia.

Previous studies have indicated that structurally dissimilar serotonin2 (5HT2) antagonists can protect globally ischemic/reperfused reperfused rat hearts. We therefore determined if the 5HT2 antagonist cinanserin can protect the ischemic myocardium in two models of pacing-induced ischemia in anesthetized dogs. In one model, dogs were subjected to repeated 5-min episodes of pacing superimposed upon left anterior descending coronary artery stenosis such that an ST segment elevation of 10-11 mV was obtained and upon cessation of pacing, a return of ST segment elevation to baseline. In vehicle-treated animals, this ST segment elevation to baseline. In vehicle-treated animals, this ST segment elevation was constant for all pacing-induced ischemic episodes. After infusion of 20 micrograms/kg/min cinanserin (intracoronary, i.c.), ST segment elevation was significantly reduced during pacing-induced ischemia at all times measured postdrug. In the second model, animals were subjected to pacing-induced ischemia for 15 min such that segmental shortening was reduced to zero. Upon cessation of pacing-induced ischemia, recovery of shortening was assessed. In vehicle-treated dogs, function recovered to only 40% of baseline at 3 h into recovery. Pretreatment with 5 micrograms/kg/min cinanserin i.c. significantly improved recovery of postischemic function. In both protocols, cinanserin had no effect on ischemic regional blood flow or peripheral hemodynamics. Thus, cinanserin appears to exert profound protective effects in two models of effort-induced ischemia.

Anti-Ischemic Activity of the Novel Benzazepine Calcium Antagonist SQ 31,486

We tested the benzazepine, SQ 31,486 for its ability to selectively block the voltage-dependent calcium channel and to protect the ischemic myocardium. SQ 31,486 was found to be a selective calcium antagonist in vascular tissue with an IC50 value of 1.5 microM in KCl-contracted rabbit aorta. SQ 31,486 decreased contractile function and increased coronary flow in nonischemic isolated rat hearts in a concentration-dependent manner. SQ 31,486 also significantly reduced postischemic lactate dehydrogenase (LDH) release and end-diastolic pressure (EDP) compared to vehicle. Reperfusion double product [heart rate (HR) x left ventricular developed pressure (LVDP)] was also significantly improved by SQ 31,486. Diltiazem was a less potent anti-ischemic agent and was significantly more cardiodepressant relative to its anti-ischemic efficacy than was SQ 31,486. Thus, SQ 31,486 should have a larger therapeutic index. In a model of pacing-induced myocardial ischemia in anesthetized, open chest dogs, SQ 31,486 reduced pacing-induced ST-segment elevation approximately 50% at 10, 40, and 70 min after drug administration. This protective effect occurred despite a lack of effect of SQ 31,486 on ischemic regional blood flow and peripheral hemodynamic status.

Contrast echocardiographic estimation of regional myocardial blood flow after acute coronary occlusion.

Contrast echocardiography can predict pathologic area at risk during acute coronary occlusion. In this study we evaluated (1) whether the intensity and timing of contrast appearance in ischemic regions can provide a quantitative measure of residual myocardial perfusion, and (2) whether changes in these parameters observed after serial injections reflect changes in blood flow to acutely ischemic tissue. Supra-aortic hydrogen peroxide contrast echocardiography was performed in 12 consecutive dogs at 1, 20, and 120 min after acute circumflex coronary occlusion. Contrast enhancement was determined qualitatively with a segmental four-point scoring system based on the appearance time and peak perceived intensity of contrast enhancement and quantitatively with a computer algorithm designed to reflect these parameters. Comparison was made in each segment to concomitant radioactive microsphere blood flow. Qualitative scoring related systematically to normalized segmental blood flow (3+ = 93%; 2+ = 61%; 1+ = 32%; 0 = 18%; p less than .01 for each vs adjacent value), as did quantitative analysis including all segments (r = .78; p less than .01) and isolated to the ischemic region (flow = 1.13 intensity change +6.8%; r = .83, p less than .001). Changes in microsphere flow in ischemic regions between sequential observations were correlated with changes in qualitative score (r = .88, p less than .001) and results of quantitative analysis (r = 0.70, p less than .01). The amount of contrast enhancement can provide quantitative information about residual myocardial blood flow in ischemic regions and can also be used to track changing patterns of flow in vivo after acute coronary occlusion.

Effects of changes in carbon dioxide pressure and arterial pressure on blood flow in ischemic regions of the brain in dogs.

The effect of locally induced cerebral ischemia on regional cerebral blood flow before and during elevation of Paco2 was measured qualitatively in anesthetized dogs by a thermistor probe technique and a photographic method involving cerebral angiography. The flow response to changes in systemic arterial pressure was also noted in the ischemic zone. Increased Paco2 resulted in increased flow to the ischemic zone and shrinkage of the area of ischemia, by virtue of collateral circulation from other arterial trunks. In no instance was intracerebral steal, as previously reported, noted in response to increased Paco2, though there was no means of determining if the quantitative response in the ischemic area was similar to that in normal brain. Arteries and arterioles in the ischemic zone were seen to be constricted and irregular, rather than maximally dilated, as has been proposed. The percent decrease in pressure in the occluded arterial segment was much greater than in the patent cerebral arteries. Response...