Differential Expression Pattern of Exosome Long Non-Coding RNAs (lncRNAs) and MicroRNAs (miRNAs) in Vascular Endothelial Cells Under Heat Stroke.

BACKGROUND Heat stroke is a life-threatening disease which is characterized by a high body temperature and multiple organ dysfunction syndrome. Vascular endothelial cell injury is a main feature of heat stroke. Little is known about the long noncoding RNA (lncRNA) and microRNA (miRNA) expression alternation in endothelial cell exosomes related to heat stroke. The aim of this study was to explore the changes of lncRNAs and miRNAs expression pattern in exosomes derived from vascular endothelial cells under heat stroke temperature conditions. MATERIAL AND METHODS Cultured medium exosomes from HUVECs (human vascular endothelial cells) either under normal temperature or heat stroke temperature conditions were harvested; then RNA was extracted and the lncRNAs and miRNAs were analyzed by high throughput sequencing. RESULTS Ten significantly upregulated and 10 downregulated lncRNAs were identified in exosomes derived from heat stroke temperature treated cells. Furthermore, GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses were used to evaluate the signaling pathway of differential expressions in lncRNAs. Finally, the interaction network of lncRNAs-miRNAs-mRNA was uncovered using ceRNA (competing endogenous RNA) principle via prediction software. CONCLUSIONS These results indicate that the identified lncRNAs and miRNAs in endothelial cell exosomes might serve as non-invasive biomarkers for heat stroke.

[Evaluation of tumor angiogenesis using microbubbles conjugated with RGD peptides and contrast enhanced ultrasound].

OBJECTIVE: To assess the feasibility of usage of microbubbles conjugated with RGD peptides and contrast enhanced ultrasound (CEU) in detection of tumor angiogenesis. METHODS: Lipid microbubbles (MB) were prepared, and the RGD peptides were covalently conjugated to the lipid shell of MB (MB(RGD)). Six nude mice with tumor created by dorsal inoculation of HepG2 tumor cells were used as the test group. Six nude mice without tumor were served as the control group. 10 minutes after bolus injection of MB and MB(RGD) randomly (30 min interval) via a tail vein catheter, CEU was performed on the tumors of the test group and the thigh skeletal muscles of control group. The video intensity (VI) of tumors and the skeletal muscles were measured. The tumors and the skeletal muscles were harvested for immunohistochemical examination. RESULTS: Only a slight contrast enhancement of the tumor was seen with MB, and the VI was 5.33 ± 1.71. While a remarkable enhancement of the tumor was observed after injection of MB(RGD). The VI was up to 17.03 ± 3.58, 3.18 folds higher as compared with that obtained by injection of MB (P < 0.05). As expected, there were no obvious contrast enhancement of the skeletal muscles with both MB(RGD) and MB. There was a high expression of αvß3-integrin in tumor neovascular endothelium, however, no apparent expression of αvß3-integrin was observed in the skeletal muscle vascular endothelium. CONCLUSION: CEU with MB(RGD) can be used to effectively evaluate the angiogenesis of tumors, and it may greatly contribute to the early judgement of the nature of tumor.

[Evaluation of myocardial ischemia-reperfusion injury in mouse by molecular imaging of P-selectin with targeted contrast echocardiography].

OBJECTIVE: To assess the feasibility of evaluating myocardial ischemia-reperfusion injury in mouse with targeted myocardial contrast echocardiography (MCE). METHODS: Phospholipid microbubbles targeted to P-selectin (MBp) and control microbubbles (MBc) were created by conjugating monoclonal antibody against murine P-selectin or isotype control antibody with the lipid shell via "avidin-biotin" bridging. Ten mice with myocardial ischemia-reperfusion were injected intravenously of MBp and MBc in a random order with a 30 min interval. After 5 min of intravenous injection of microbubble, targeted MCE imaging was performed in all mice. And then the video intensity (VI) was determined. RESULTS: A significant ultrasonic enhancement was observed in ischemic region of MBp-group. Increment in VI value of ischemic region in MBp-group was great and it amounted to (26.0 +/- 6.2) U. However, increment in VI value of ischemic region in MBc-group was minor and it was merely (9.1 +/- 0.9) U. Difference was evident in ischemic region between of two groups (P < 0.05). In both MBp-group and MBc-group, the VI value of ischemic region was significantly greater than that of non-ischemic region (6.5 +/- 1.0) U vs (6.4 +/- 0.8) U (P < 0.05). There was no obvious difference in the VI of non-ischemic region between two groups. CONCLUSION: Molecular imaging of P-selectin with targeted contrast echocardiography can effectively evaluate myocardial ischemia-reperfusion injury.

Optimal use of fielder XT guidewire enhances the success rate of chronic total occlusion percutaneous coronary intervention.

BACKGROUND: Chronic total occlusion (CTO) is found in 18-31% of patients who undergo coronary angiography. Successful recanalization of CTOs is associated with reduced recurrent angina pectoris rates and increased long-term survival. Although the success rate of CTO percutaneous coronary intervention (CTO-PCI) has improved, CTO-PCI remains technically challenging. The Fielder XT guidewire was designed for CTO lesions. To validate whether the use of the guidewire increases the success rate, we compared the results of CTO-PCI with or without the guidewire. We hypothesized that the use of Fielder XT guidewire can increase the success rate of CTO-PCI. AIM: To investigate whether the use of Fielder XT guidewire increases the final procedural success of CTO-PCI via the anterograde approach. METHODS: Between January 2013 and December 2015, a retrospective study was conducted on 1230 consecutive patients with CTO who received PCI via the anterograde approach at the General Hospital of Northern Theater Command. The patients were divided into an XT Group (n = 686) and a no-XT Group (n = 544) depending on whether Fielder XT guidewire was used. Both groups were compared for clinical parameters, lesion-related characteristics, procedural outcomes and in-hospital complications. The data were statistically analyzed using Pearson's χ 2 test for categorical variables, and Students' t test was used to compare the quantitative data. Significant independent factors and a risk ratio with 95% confidence interval (CI) were assessed by multivariate logistic regression analysis. RESULTS: In total, 1230 patients were recruited; 75.4% of the patients were male, and 55.8% of the patients were in the XT group. The overall success rate was 83.9%, with 87.8% in the XT group. Based on multivariate logistic regression analysis, factors positively associated with procedural success were the use of Fielder XT guidewire (P = 0.005, 95%CI: 1.172-2.380) and systolic blood pressure (P = 0.011, 95%CI: 1.003-1.022), while factors negatively associated with procedural success were blunt stump (P = 0.013, 95%CI: 1.341-11.862), male sex (P = 0.016, 95%CI: 0.363-0.902), New York Heart Association (NYHA) class (P = 0.035, 95%CI: 0.553-0.979), contrast amount (P = 0.018, 95%CI: 0.983-0.998) and occlusion time (P = 0.009, 95%CI: 0.994-0.999). No significant differences were found between the XT group and the no-XT group with respect to clinical parameters, lesion-related characteristics, coronary artery rupture [3 (0.4%) vs 8 (1.5%), P = 0.056], in-hospital death [2 (0.3%) vs 6 (1.1%), P = 0.079] or in-hospital target lesion revascularization [3 (0.4%) vs 7 (1.3%), P < 0.099]. However, there were significant differences between the groups with respect to success rate [602 (87.8%) vs 430 (79.0%), P < 0.001], procedure time [(74 ± 23) vs (83 ± 21), P < 0.001], stent length [(32.0 ± 15.8) vs (37.3 ± 17.6), P < 0.001], contrast amount [(148 ± 46) vs (166 ± 43), P < 0.001], post-PCI myocardial infarction [43 (6.3%) vs 59 (10.8%), P = 0.004], major adverse cardiovascular event [44 (6.4%) vs 57 (10.7%), P = 0.007], side branch loss [31 (4.5%) vs 44 (8.1%), P = 0.009], contrast-induced nephropathy [29 (4.2%) vs 40 (7.4%), P = 0.018] and no reflow [8 (1.2%) vs 14 (2.9%), P = 0.034]. CONCLUSION: The use of Fielder XT guidewire shortens the Procedure and increases the success rate of CTO-PCI, and is also associated with reduced complication rates.

Effects of nitroglycerin on erythrocyte rheology and oxygen unloading: novel role of S-nitrosohemoglobin in relieving myocardial ischemia.

BACKGROUND: We hypothesized that nitroglycerin improves O2 delivery to ischemic tissue by altering erythrocyte rheology and O2 unloading through an increase in bioactive nitric oxide (NO) content. METHODS AND RESULTS: Twelve dogs with resting flow-reducing single-vessel stenosis were studied at rest and during intracoronary infusion of nitroglycerin (0.3 to 0.6 microg.kg(-1).min(-1)). Half the dogs also had occlusion of the remote coronary artery to remove any collateral effects. Systemic and coronary hemodynamics, myocardial blood flow (MBF), whole blood viscosity (WBeta), erythrocyte charge (EC) and mobility (EM), regional myocardial O2 delivery and consumption, and tissue O2 pressure (Po2) were measured. No changes in systemic hemodynamics were seen with nitroglycerin. Despite flow-limiting stenosis, MBF increased significantly in the central 25% of the ischemic bed, which was associated with an approximately 19% decrease in WBeta. There was a good correlation (r=0.87) between the two. The decrease in WBeta was associated with a decrease in EC and an increase in EM (r=0.83). The nitroglycerin-induced increase in tissue Po2 was disproportionate to the increase in MBF, indicating enhanced O2 unloading. Erythrocyte S-nitrosothiol content (reflecting mainly S-nitrosohemoglobin) was significantly higher for blood exposed in vitro to 0.1 micromol/L nitroglycerin or the NO donor SNAP, as compared with control (18.9+/-8.8 and 10.5+/-6.5 versus 2.6+/-0.5x10(-5), P<0.05). CONCLUSIONS: The augmented MBF in the ischemic microcirculation during nitroglycerin administration occurs in tandem with increased erythrocyte S-nitrosothiol content, EM, and O2 unloading. These additional microvascular mechanisms may contribute to the powerful antiischemic effects of nitroglycerin, especially during low-flow states.

Transmyocardial revascularization ameliorates ischemia by attenuating paradoxical catecholamine-induced vasoconstriction.

BACKGROUND: The mechanism by which transmyocardial revascularization (TMR) offers clinical benefit is controversial. We hypothesized that TMR ameliorates ischemia by reversing paradoxical catecholamine-induced vasoconstriction. METHODS AND RESULTS: Chronic ischemic cardiomyopathy was created in 11 dogs by placing ameroid constrictors on the proximal coronary arteries and their major branches. Six weeks later, 35 channels were created percutaneously in the left circumflex artery region, with the left anterior descending artery region serving as control. At rest, wall thickening and myocardial blood flow did not change in the treated region, whereas they deteriorated in the control bed. Contractile and myocardial blood flow reserve increased in the treated region but deteriorated in the control region. There was diminished iodine 123 metaiodobenzylguanidine uptake and a significant reduction in noradrenergic nerves in the treated region compared with the control region, with a corresponding reduction in tissue tyrosine hydroxylase activity. CONCLUSIONS: We conclude that the absence of a catecholamine-induced reduction in MBF reserve and contractile reserve in the TMR-treated region with associated evidence of neuronal injury indicates that the relief of exercise-induced ischemia after TMR most likely results from reversal of paradoxical catecholamine-induced vasoconstriction. These findings may have implications in selecting patients who would benefit from TMR.

Metastasis-associated in colon cancer-1 in gastric cancer: Beyond metastasis.

Metastasis-associated in colon cancer-1 (MACC1) is an oncogene that was first identified in colon cancer. The upstream and downstream of MACC1 form a delicate regulatory network that supports its tumorigenic role in cancers. Multiple functions of MACC1 have been discovered in many cancers. In gastric cancer (GC), MACC1 has been shown to be involved in oncogenesis and tumor progression. MACC1 overexpression adversely affects the clinical outcomes of GC patients. Regarding the mechanism of action of MACC1 in GC, studies have shown that it promotes the epithelial-to-mesenchymal transition and accelerates cancer metastasis. MACC1 is involved in many hallmarks of GC in addition to metastasis. MACC1 promotes vasculogenic mimicry (VM) via TWIST1/2, and VM increases the tumor blood supply, which is necessary for tumor progression. MACC1 also facilitates GC lymphangiogenesis by upregulating extracellular secretion of VEGF-C/D, indicating that MACC1 may be an important player in GC lymphatic dissemination. Additionally, MACC1 supports GC growth under metabolic stress by enhancing the Warburg effect. In conclusion, MACC1 participates in multiple biological processes inside and outside of GC cells, making it an important mediator of the tumor microenvironment.

Mechanism of inducible regional dysfunction during dipyridamole stress.

BACKGROUND: We hypothesized that increased myocardial oxygen demand resulting from hypotension and reflex tachycardia unmasking a reduced endocardial myocardial blood flow (MBF) reserve is the mechanism of dipyridamole-induced regional dysfunction in chronic coronary artery disease. METHODS AND RESULTS: Ameroid constrictors were placed around the proximal coronary arteries and their major branches in 15 dogs to create chronic coronary stenosis. Seven days later, radiolabeled microsphere-derived MBF and 2-dimensional echocardiography-derived percent wall thickening (%WT) were measured at rest and after 0.56 mg/kg dipyridamole. Dipyridamole caused an increase (mean, 21%) in the rate-pressure product secondary to reflex tachycardia resulting from mild systemic hypotension. %WT in myocardial segments with an endocardial MBF reserve (dipyridamole/resting MBF) of 1.5 to 2.5 (n=35) did not change after dipyridamole, whereas it decreased in segments with an endocardial MBF reserve of <1.5 (n=30) and increased in those with an endocardial MBF reserve of > or =2.5 (n=45) (P<0.05). Most (80%) segments with endocardial MBF reserve of <1.5 and 14% with an endocardial MBF reserve of 1.5 to 2.5 showed inducible dysfunction after dipyridamole, whereas none of the segments with an endocardial MBF reserve of > or =2.5 showed this finding. A sigmoid relation (y=-6.74/[1+exp (19.9. [x-1.84])]+1.35. x, r=0.93, P<0.0001) was noted between endocardial MBF reserve and Delta%WT. In contrast, neither the epicardial MBF reserve nor the endocardial/epicardial MBF ratio during hyperemia was associated with inducible regional dysfunction. CONCLUSIONS: Increased myocardial oxygen demand resulting from hypotension and reflex tachycardia unmasking a reduced endocardial MBF reserve is the primary mechanism of dipyridamole-induced regional dysfunction in chronic coronary artery disease.

Detection of noncritical coronary stenosis at rest without recourse to exercise or pharmacological stress.

BACKGROUND: Currently, the detection of noncritical coronary stenoses requires some form of stress. We hypothesized that these stenoses can be detected at rest without recourse to stress by assessing adaptive changes that occur distally in the microcirculation. METHODS AND RESULTS: Phasic changes in myocardial video intensity (VI) were measured at rest with continuous high-mechanical-index (MI) contrast echocardiography in 15 open-chest dogs. Data were acquired at baseline and in the presence of different degrees of noncritical coronary stenosis. In 6 of these dogs, capillary blood volume was also measured at baseline using high-MI intermittent imaging with triggering performed separately at both end diastole and end systole. During continuous high-MI imaging, a significant increase in systolic VI was noted with coronary stenoses that resulted in progressive increases in the systolic/diastolic VI ratio with greater degrees of stenosis (P=0.003), with a mildly quadratic relation noted between the two: y=1.3. 10(-6). x(2)+0.01x+0.32, P<0.001, r=0.76, SEE=0.14. There was no difference in capillary blood volume between end diastole and end systole at baseline. CONCLUSIONS: Capillary blood volume does not change between diastole and systole in vivo. Phasic changes in VI are noted at baseline during high-MI continuous imaging. The systolic component is negligible at baseline but increases with increasing levels of noncritical coronary stenosis because of adaptive changes in the microcirculation distal to the stenosis. Thus, the measurement of phasic changes in myocardial VI has the potential to detect coronary stenosis at rest without recourse to any form of stress.

Detection of coronary stenosis and myocardial viability using a single intravenous bolus injection of BR14.

OBJECTIVES: The aim of the study was to determine whether coronary stenosis can be detected and myocardial viability assessed after myocardial infarction from a single venous bolus injection of BR14, a new ultrasound contrast agent. BACKGROUND: BR14 is an ultrasound contrast agent that, like (201)Tl, demonstrates redistribution. Whether this principle can be used to determine myocardial viability is not known. METHODS: Non-critical (n = 6) or flow-limiting (n = 4) stenoses were placed on coronary arteries of 10 open-chest dogs, which then underwent 2 h of coronary occlusion followed by reperfusion through the stenosis. Hyperemia was induced to create flow mismatch in the dogs with non-critical stenosis. Hyperemia was not induced in dogs with reduced resting coronary blood flow. All dogs were given 2 ml of BR14 as a bolus injection and serial images were obtained. Myocardial blood flow (MBF) was measured using radiolabeled microspheres. At the end of the experiment, tissue staining was performed to determine infarct size and topography. RESULTS: Initial images demonstrated flow mismatch between the normal bed and that subtended by the stenosis (during hyperemia in dogs without critical stenosis and during rest in those with reduced resting MBF). The perfusion defect size correlated well with radiolabeled microsphere-derived hypoperfused zone (r = 0.89). Regions within the hypoperfused zone that had not undergone necrosis showed redistribution, whereas the necrotic regions showed a persistent defect, the size of which correlated well with infarct size (r = 0.80). CONCLUSIONS: Because of its ability to redistribute, BR14 can define regions of relative hypoperfusion and also discriminate between infarcted and viable tissue within the hypoperfused zone after a single venous injection. This property lends itself to assessing myocardial perfusion during exercise stress.

Dobutamine versus dipyridamole for inducing reversible perfusion defects in chronic multivessel coronary artery stenosis.

OBJECTIVES: We hypothesized that, although the effects of dipyridamole and dobutamine on myocardial blood volume (MBV) and mean microbubble velocity (VEL) are different, the magnitude of perfusion deficit during both forms of stress is the same because both drugs unmask abnormal myocardial blood flow (MBF) reserve. BACKGROUND: Both dipyridamole and dobutamine are used clinically as pharmacologic stress agents to induce reversible perfusion defects in patients with chronic coronary artery disease (CAD), but the basis for doing so for dobutamine is not clear. METHODS: Eleven chronically instrumented closed-chest dogs with multivessel coronary stenosis were studied. Hemodynamics, radiolabeled microsphere-derived MBF, and myocardial contrast echocardiography (MCE)-derived myocardial perfusion were measured at rest, after dipyridamole infusion (0.56 mg x kg(-1)), and at peak dobutamine dose (either 30 or 40 microg x kg(-1) x min(-1)). Abnormal beds were defined as those demonstrating an MBF reserve <3 with dipyridamole. RESULTS: In the presence of either drug, MBV increased more in the normal bed than in the abnormal bed, but the increase was higher in both beds with dobutamine than with dipyridamole. The slope of the relationship between MBF reserve and MBV reserve was greater during dobutamine than dipyridamole (p < 0.05). The converse was true for VEL reserve (p < 0.05). Consequently, the relationship between the ratios of either variable, or the product of the two, between the abnormal bed and normal bed was similar for both drugs. CONCLUSIONS: Although the effects of dipyridamole and dobutamine on MBV and VEL are different, both are equally effective in detecting physiologically relevant coronary stenoses on MCE. Both can therefore be used interchangeably with myocardial perfusion imaging for the detection of CAD.

[Experimental study of the characteristics of renal blood flow with contrast ultrasound].

OBJECTIVE: To study the characteristics of renal blood flow with contrast ultrasound. METHODS: The examination of the renal ultrasonography was performed in 10 dogs after intravenous injection of Quanfuxian (a contrast agent consisting of C3F8 microbubbles). RESULTS: Contrast visualization appeared in the renal cortex and then in the outer to inner medulla at the baseline level after administration of the contrast agent. Notable differences in the values of microvascular volume (A, which was 120.3 in the corted vs 110.8 in the medulla, P>0.05), microcirculatory flow velocity (beta, which was 1.39 in the corted vs 0.54 in the medulla, P<0.05), and microcirculatory flow rate (A x beta, 167.4 in the corted vs 59.5 in the medulla, P<0.05) were found between the corted and the medulla, with also marked difference between the the corted-to-the medulla ratios of beta and A (0.612 vs 0.078, P<0.05). CONCLUSION: Contrast ultrasound of the kidney provides a useful means of renal circulatory flow study.

[Quantification of renal medullary perfusion with contrast-enhanced ultrasound: an experimental study].

OBJECTIVE: To quantitatively evaluate the effects of dopamine (DA) and noradrenaline (NE) on renal medullary perfusion and the differences in perfusion in the outer and inner medulla using contrast-enhanced ultrasound. METHODS AND RESULTS: Contrast-enhanced ultrasound was performed in 10 dogs with simultaneous renal artery flow (RAF) measurement at the baseline level and during application of 3 different doses of DA and NE. During treatment with the 3 doses of DA, the changes of ultrasound-derived parameters (A, beta and A*beta) in the medulla were similar to the changes in the cortex. As compared with the baseline level, the ratios between the cortex and medulla exhibited no significant difference in A, beta and A*beta during DA treatment (P>0.05). No significant difference in ultrasound-derived medullar parameters was noted in dogs with NE treatment from the baseline level (P>0.05). However, a progressive decrease in the ratios of A, beta and A*beta between the cortex and medulla was noted during NE treatment in comparison with the baseline level (P<0.05). The velocity (beta) and perfusion (A*beta) of blood flow in the medulla decreased progressively from the outer medulla to the inner medulla at baseline (P<0.05), while the blood volume (A) remained unchanged (P<0.05). CONCLUSIONS: The changes of blood flow in both the cortex and medulla are identical during DA treatment but different in the presence of NE. The progressive decrease in perfusion from the outer medulla to the inner medulla is attributed to the decrease in the velocity of blood flow.

[Targeted adhesion of platelet receptor-specific microbubble agent to thrombus in vitro].

OBJECTIVE: To examine the thrombus-targeting effect of platelet receptor-specific lipid microbubbles. METHODS: The targeted microbubbles were prepared by coupling Arg-Gly-Asp-Ser (RGDS) with the lipid microbubbles, which were added to the microthrombus generated by platelet aggregation. The effects of the targeted microbubbles on the ultrasonic signal was observed in an artificial thrombus model. RESULTS: The targeted microbubbles were adhesive to the microthrombus, while the non-targeted microbubbles did not possess this property. The ultrasonic signal of the thrombus border was enhanced significantly after the addition of the targeted microbubbles. CONCLUSIONS: Platelet receptor-specific microbubbles possess significant adhesive property to the thrombus and can improve signal-to-noise ratio of the thrombus, suggesting the potential value of the targeted microbubbles for clinical application in the diagnosis and treatment of thrombus.

[Quantitative evaluation of canine renal blood flow with contrast-enhanced ultrasound].

OBJECTIVE: To evaluate the accuracy of contrast-enhanced ultrasound (CEU) in renal blood flow quantification. METHODS: Regional renal perfusion was quantified with CEU in 10 dogs at the baseline level and after treatment with 3 doses of dopamine (3, 8 and 16 mg.kg(-1).min(-1)), and renal arterial flow (RAF) was measured with ultrasonic flow probes deployed directly on the renal artery simultaneously. Normalized RAF was calculated as RAF divided by renal weight (ml.min(-1).g(-1)). RESULTS: Compared with the baseline level, a progressive increase in RAF was induced by dopamine treatment at the doses of 3 and 8 mg.kg(-1).min(-1) (P<0.05), but at a higher dose of 16 mg.kg(-1).min(-1), the increment in RAF was reduced in comparison with that with the two lower doses (P<0.05). The same changes in cortical nutrient blood flow derived from CEU were observed. Significant positive correlation was found between normalized RAF and CEU-derived cortical nutrient blood flow (y=39.8x + 44.3, r=0.88, P<0.001). CONCLUSION: CEU can be used to accurately quantify renal blood flow in dogs.

[Cardioprotective effects of K(ATP) channel opener nicorandil during ischemia/ reperfusion in dogs].

OBJECTIVE: To further confirm the effect of nicorandil in reducing the area of myocardial infarct is through the mediation of activation of the KATP channel but not by its nitrate-like properties, and to determine whether the protective effect is the same or not when the drug is either given immediate after infarction or after reperfusion. METHODS: Thirty-five dogs were randomly divided into five groups as follows. Ischemia/reperfusion (IR) group: the dogs were subjected to 90 minutes of left anterior descending coronary artery(LAD) occlusion followed by 120 minutes reperfusion. Pre-nicorandil (PNIC) group: nicorandil(NIC) 100 microg/kg was administrated by intravenous injection 10 minutes before occlusion, followed by infusion of 10 microg x kg(-1) x min (-1) of the drug till the end of reperfusion. Ischemia nicorandil(INIC) group: NIC 100 microg/kg was administered by intravenous injection 15 minutes after occlusion and 10 microg x kg(-1) x min (-1) of drug intravenously till the end of reperfusion. In the Onset reperfusion treated with nicorandil(RNIC) group: NIC 100 microg/kg was administered intravenously at the onset of reperfusion followed by 10 microg x kg(-1) x min (-1)of drug intravenously up to the end of reperfusion. Glibenclamide(GLIB)+INIC group: before NIC was administered, dogs were pretreated with GLIB 0.3 mg/kg for 10 minutes, and other treatment was the same as INIC group. Hemodynamics data were determined as baseline, 60 minutes post-occlusion, and 120 minutes post-reperfusion. By using 2, 3, 5-triphenyltetrazolium chloride (TTC) staining, the infarct areas were analyzed with image analyzer. RESULTS: The results showed that at 60 minutes post-occlusion, cardiac output (CO) was reduced in every group compared with baseline (all P<0.01), CO value recovered at 120 minutes after reperfusion in both PNIC and INIC group (P>0.05). There were no significant differences in heart rate (HR), mean artery pressure(MAP), mean pulmonary artery pressure(MPAP), pulmonary capillary wedge pressure(PCWP) values among all the groups. A marked reduction in the infarct area was found in PNIC group and INIC group (P<0.01) compared with IR group. Administration of GLIB before INIC shows to have no protective effect (P>0.05). CONCLUSION: Our study shows that nicorandil which is a K ATP channel activator, could mimic the effect of ischemic pre-conditioning of the myocardium, by reducing the area of myocardial infarct.

[An experimental study on renal microvascular perfusion in dogs with acute cardiac insufficiency].

OBJECTIVE: To investigate the changes and the effects of captopril on the renal blood flow and microvascular perfusion in dogs with acute cardiac insufficiency. METHODS: Acute cardial insufficiency was induced by combining occlusion of the left anterior descending artery with right ventricular pacing in 12 mongrel dogs. The ascending aorta and left kidney were dissected and ultrasonic flow probes were placed on ascending aorta and renal artery to monitor cardiac output (CO) and renal blood flow (RBF). Contrast-enhanced ultrasound of the kidney was performed as CO was reduced to 25% (LCO25%) and 50% (LCO50%) from the basic measurement and microvascular flow velocity (beta), microvascular volume (A) and microvascular blood flow (renal cortex) were observed. After CO reduced to 50%, captopril 1 mg/kg and 2 mg/kg were injected successively and contrast-enhanced ultrasound of the kidney were performed again before and after injection. RESULTS: At baseline, CO, RBF, CXbeta (beta of renal cortex), A and A x beta were (1.46 +/- 0.16) ml/min, (107.5 +/- 35.7) ml/min, 1.39 +/- 0.14, 120.3 +/- 14.8 and 167.4 +/- 25.0, respectively. After the LCO25% was reached, RAF, CXbeta, A and A x beta decreased to (72.50 +/- 32.4) ml/min, 0.87 +/- 0.082, 117.6 +/- 13.1, and 102.6 +/- 15.5, respectively. The corresponding values after the LCO50% was reached were (44.1 +/- 17.2) ml/min, 0.61 +/- 0.039, 106.9 +/- 12.0, and 64.7 +/- 8.83, respectively. It is suggested that the volume of the renal microvasculature remained stable until the LCO50% was reached. When captopril 1 mg/kg and 2 mg/kg were injected successively at LCO50%, MAP decreased from (85.4 +/- 7.8) mm Hg to (78.7 +/- 7.3) mm Hg and to (69.1 +/- 6.3) mm Hg (P < 0.05), respectively, while CO increased from 0.73 +/- 0.084 to 0.83 +/- 0.065 and to 0.9 +/- 0.054 (P < 0.05), respectively. RBF increased from (44.1 +/- 17.2) ml/min to 60.3 +/- 17.8 and to 79.4 +/- 17.8 (P < 0.05), respectively. After captopril 1 mg/kg and 2 mg/kg were injected, the increased flow ratios with CO were 0.15 +/- 0.084 and 0.31 +/- 0.011, respectively, and with RBF were 0.29 +/- 089 and 0.522 +/- 0.040, respectively. The increased renal blood flow ratio was higher than that of CO after captopril was used. The corresponding increases were from 0.61 +/- 0.039 to 0.75 +/- 0.020 and to 0.86 +/- 0.027 for CX beta, from 106.9 +/- 11.9 to 115.4 +/- 11.1 and to 116.6 +/- 8.9 for A, from 64.7 +/- 8.83 to 87.0 +/- 8.6 and to 100.6 +/- 8.9 for A x beta, respectively. CONCLUSION: The renal microvasculature plays a role by keeping its volume stable in the protection against renal ischemia when acute cardiac output decreases slightly. The role of captopril to improve renal microvascular perfusion is independent of increased total cardiac output or increased systemic blood pressure.

Direct effects of dobutamine on the coronary microcirculation: comparison with adenosine using myocardial contrast echocardiography.

The direct effects of dobutamine on capillary blood volume (VOL) and blood flow velocity (VEL) are not known. We hypothesized that these would be more similar to that of adenosine because of its effects on the beta(2) receptors on the coronary circulation. A total of 9 open-chest anesthetized dogs were studied after placement of 2 noncritical stenoses at rest and during separate intracoronary administrations of 5 microg/kg(-1)/min(-1) of adenosine and 2 microg/kg(-1)/min(-1) of dobutamine. VOL and VEL were measured using myocardial contrast echocardiography, wall thickening with 2-dimensional echocardiography, and myocardial blood flow (MBF) with radiolabeled microspheres. Dobutamine increased the rate-pressure product significantly, whereas adenosine had no effect on the rate-pressure product. In the normal myocardium, adenosine had no effect on VOL and increases in MBF were all a result of increases in VEL. Dobutamine also caused mostly an increase in VEL and only a 30% increase in VOL indicating modest capillary recruitment. In the bed with stenosis both drugs attenuated increase in MBF by the same amount, which was associated with an attenuation in the increase in VEL secondary to a 15% increase in capillary resistance because of capillary derecruitment. The MBF-wall thickening relation was described for both drugs by the same function: y = 1 - exp(x) with wall thickening being significantly higher for dobutamine compared with adenosine for each level of MBF. We conclude that the increase in MBF in the normal myocardium with intracoronary dobutamine occurs mostly from an increase in VEL rather than from an increase in VOL. In the bed with a noncritical stenosis, the increases in MBF and VEL are similar for both drugs. Similar to intracoronary adenosine, intracoronary dobutamine also caused capillary derecruitment distal to a noncritical coronary stenosis.

A1-receptor blockade: a novel approach for assessing myocardial viability in chronic ischemic cardiomyopathy.

Diminished myocardial function can be seen in chronic coronary stenosis (CS) even in the presence of normal resting myocardial blood flow. We hypothesized that adenosine contributes to myocardial depression in this setting, predominantly through activation of the A(1) adenosine receptor. To test this hypothesis we used aminophylline, a nonselective adenosine receptor antagonist, and 8-cyclopentyl 1,3 dipropylxanthine, a selective A(1) adenosine receptor antagonist, in a canine model of chronic CS. Chronic CS was produced by placement of ameroid constrictors on the left anterior descending and left circumflex coronary arteries in 17 adult mongrel dogs, which resulted in severe left ventricular dysfunction 6 weeks later. Eight dogs without ameroid placement were used as controls (C). Closed-chest echocardiographic short-axis images at the low midpapillary level, hemodynamics, and radiolabeled microsphere-derived myocardial blood flow were obtained before and immediately after injection of either 5 mg/kg(-1) of aminophylline (7 left ventricular dysfunction and 4 C dogs) or 1 mg/kg(-1) of 8-cyclopentyl 1,3-dipropylxanthine (10 left ventricular dysfunction and 4 C dogs). Both 8-cyclopentyl 1,3-dipropylxanthine and aminophylline had no effect in C animals but resulted in a significant transient increase in regional percent wall thickening (P <.05) with a concomitant decrease in end-systolic wall stress (P <.05) in CS animals. There was no change in transmural myocardial blood flow or systemic hemodynamics to explain these results. Thus, adenosine plays a significant role in myocardial dysfunction in chronic ischemia by activation of the A(1) receptor. Aminophylline or a selective A(1) adenosine receptor antagonist can be used to detect viable myocardium and may be safer than dobutamine in severe chronic ischemic heart disease.

Relation between myocardial oxygen consumption and myocardial blood volume: a study using myocardial contrast echocardiography.

Myocardial blood volume (MBV) is the volume of blood residing in myocardial vessels, 90% of which is in capillaries. MBV can be measured in vivo using myocardial contrast echocardiography (MCE). It has been shown that when increases in coronary blood flow (CBF) are not associated with increase in myocardial oxygen consumption (MVO(2)), MBV does not increase. We hypothesized that MBV would increase when increases in CBF are associated with an increase in MVO(2). The atrioventricular node was ablated in 18 dogs and dual-chamber pacing was instituted. In group 1 dogs (n = 9), heart rate was altered from 50 to 150 bpm(-1) in increments of 20 bpm(-1) in random order. In group 2 dogs (n = 9), heart rate was kept constant, and dobutamine was infused at doses of 5, 10, 20, 30, and 40 microg/kg(-1)/min(-1). During each intervention, hemodynamic parameters and MVO(2) were measured, and MCE was performed. MVO(2) increased more (P <.01) with inotropic compared with chronotropic stimulation, resulting in a parallel increase in CBF. MBV fraction and MCE-derived myocardial blood flow increased significantly with increases in MVO(2) (P <.05 and P <.001, respectively) when dobutamine was infused, but remained unchanged when heart rate alone was increased. We conclude that when MVO(2) is increased substantially, the resulting increase in CBF and MCE-derived myocardial blood flow is mediated, in part, by an increase in MBV. Thus, capillary recruitment plays an important role in the physiologic regulation of CBF. Lack of increase in MBV during dobutamine stress may indicate the presence of coronary stenosis or microvascular disease.