American journal of physiology. Heart and circulatory physiology
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Am. J. Physiol. Heart Circ. Physiol. · Aug 2007
Continuous inhalation of carbon monoxide induces right ventricle ischemia and dysfunction in rats with hypoxic pulmonary hypertension.
We aimed to investigate the toxicity of carbon monoxide (CO) in rats with right ventricle (RV) remodeling induced by hypoxic pulmonary hypertension (PHT). A group of Wistar rats was exposed to 3-wk hypobaric hypoxia (H). A second group was exposed to 50 ppm CO for 1 wk (CO). ⋯ PHT and RV hypertrophy were still present in the H+CO group, and fibroses localized in the RV were detected. Similar lesions were observed in an additional group exposed simultaneously to hypoxia and 50 ppm CO over 3 wk. We demonstrated that rats with established PHT were more sensitive to CO, which dramatically alters the RV adaptive response to PHT, leading to ischemic lesions.
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Am. J. Physiol. Heart Circ. Physiol. · Jul 2007
Evaluation of a noninvasive continuous cardiac output monitoring system based on thoracic bioreactance.
Noninvasive cardiac output (CO) measurement can be useful in many clinical settings where invasive monitoring is not desired. Bioimpedance (intrabeat measurement of changes in transthoracic voltage amplitude in response to an injected high-frequency current) has been explored for this purpose but is limited in some clinical settings because of inherently low signal-to-noise ratio. Since changes in fluid content also induce changes in thoracic capacitive and inductive properties, we tested whether a noninvasive CO measurement could be obtained through measurement of the relative phase shift of an injected current (i.e., bioreactance). ⋯ The measurements of noninvasive CO measurement and cardiopulmonary bypass pump correlated to each other (r = 0.84) despite the large variation in CO and temperatures. Similarly, in patients, mean CO values were 5.18 and 5.17 l/min as measured by SGC and the noninvasive CO measurement system, respectively, and were highly correlated over the range of values studied (r = 0.90). Preclinical and clinical data demonstrate the feasibility of using blood flow-related phase shifts of transthoracic electric signals to perform noninvasive continuous CO monitoring.
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Am. J. Physiol. Heart Circ. Physiol. · Jun 2007
Cardioprotection by adenosine A2A agonists in a canine model of myocardial stunning produced by multiple episodes of transient ischemia.
We sought to determine whether administration of a very low, nonvasodilating dose of a highly selective adenosine A(2A) receptor agonist (ATL-193 or ATL-146e) would be cardioprotective in a canine model of myocardial stunning produced by multiple episodes of transient ischemia. Twenty-four anesthetized open-chest dogs underwent either 4 (n=12) or 10 cycles (n=12) of 5-min left anterior descending coronary artery (LAD) occlusions interspersed by 5 or 10 min of reperfusion. Left ventricular thickening was measured from baseline through 180 min after the last occlusion-reperfusion cycle. ⋯ During occlusion, there was severe dyskinesis with marked LAD zone thinning in all animals. After 180 min of reperfusion following the last cycle, significantly greater recovery of LAD zone thickening was observed in A(2A) receptor agonist-treated vs. control animals in both the 4-cycle (91 +/- 7 vs. 56 +/- 12%, respectively; P<0.05) and the 10-cycle (65 +/- 9 vs. 8 +/- 16%, respectively; P<0.05) occlusion groups. The striking amount of functional recovery observed with administration of low, nonvasodilating doses of adenosine A(2A) agonist ATL-193 or ATL-146e supports their further evaluation for the attenuation of postischemic stunning in the clinical setting.
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Am. J. Physiol. Heart Circ. Physiol. · Jun 2007
Restoration of impaired endothelium-dependent coronary vasodilation in failing heart: role of eNOS phosphorylation and CGMP/cGK-I signaling.
In congestive heart failure (CHF), coronary vascular relaxation is associated with endothelial dysfunction and nitric oxide (NO) deficiency. This study explored the reversibility of this process in hearts recovering from CHF and its related mechanisms. Dogs were chronically instrumented to measure cardiac function and coronary blood flow (CBF). ⋯ However, myocardial NOx recovered to 78% of control and phosphorylated eNOS was fully restored in CR, despite the fact that eNOS mRNA expression and protein levels remained lower than control. Furthermore, the endothelium-independent CBF response to nitroglycerin did not change in CHF; however, it increased by 75% in CR, in conjunction with a near threefold increase in the phosphorylation of vasodilation-stimulated phosphoprotein (VASP) at Ser(239) in recovering hearts. Thus the complete restoration of endothelium-dependent coronary vascular relaxation during cardiac recovery from CHF was mediated by 1) a restoration of phosphorylated eNOS for partial recovery of the NO production and 2) an increase in cGMP/cGMP-dependent protein kinase-I pathway signaling activity for the enhancement of coronary vascular smooth muscle relaxation in response to NO.
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Am. J. Physiol. Heart Circ. Physiol. · Jun 2007
Apoptotic signaling induces hyperpermeability following hemorrhagic shock.
Hemorrhagic shock (HS) disrupts the endothelial cell barrier, resulting in microvascular hyperpermeability. Recent studies have also demonstrated that activation of the apoptotic signaling cascade is involved in endothelial dysfunction, which may result in hyperpermeability. Here we report involvement of the mitochondrial "intrinsic" pathway in microvascular hyperpermeability following HS in rats. ⋯ This, along with the in vivo transfection of the proapoptotic peptide BAK (BH3), resulted in hyperpermeability (as visualized by intravital microscopy), release of mitochondrial cytochrome c into the cytoplasm, and activation of caspase-3. Conversely, transfection of the BAK (BH3) mutant had no effect on hyperpermeability. Together, these results demonstrate involvement of the mitochondrial intrinsic apoptotic pathway in HS-induced hyperpermeability and that the attenuation of this pathway may provide an alternative strategy in preserving vascular barrier integrity.