Category Archives: Cardiac function

Figure 4 shows responses of isolated perfused rat hearts to perfusion with Krebs-Henseleit buffer at 15 ml/min at a Po, of 325 to 350 mm Hg (ie, 95% 02 + 5% COJ for 10 min followed by hypoxia (95% Na + 5% CO*), resulting in a Pos of 40-50 mm Hg for 30 min, and then reoxygenation with 95% 0*+5% COa for 20 min. At the beginning and at the end of this protocol, hearts were tested for their ability to dilate in response to ACh and NTG, compared with initial control responses. Hypoxia and reoxygenation clearly resulted in a marked decrease in vasorelaxation in response to ACh but not to NTG. (more…)

Figure 3 illustrates vasoactive responses to ACh and nitroglycerin (NTG) in isolated rat hearts perfused for 50 min at control flows (15 ml/min) or subjected to ischemia at 2.2 ml/min (to produce an 85% reduction in global coronary flow) for 30 min, followed by 20 min of reperfusion at 15 ml/ min. All hearts were then tested for their dilator capacity to ACh and NTG. In control hearts isolated from rats given 0.9% NaCl (ie, control-I-vehicle), both ACh and NTG produced a full vasorelaxation after addition of U-46619, a TXA* mimetic, at the arrows. However, in hearts subjected to ischemia-reperfusion but given 0.9% NaCl (ie, ischemia + vehicle), ACh produced only a partial vasorelaxation (35%) whereas NTG fully relaxed the coronary vasculature. Not shown are responses to A23187, which also showed a partial vasorelaxation, comparable to that of ACh. These findings indicate an endothelial dysfunction in the rat coronary vasculature following ischemia and reperfusion. (more…)

Another circulatory condition resulting in impairment of endothelial-derived vasorelaxation is myocardial ischemia and reperfusion injury. An important factor response for myocardial necrosis is postischemic reperfusion injury. Classically, the explanation for this phenomenon entails the release of lipid and peptide mediators that act as chemoat-tractant and chemokinetic agents to recruit neutrophils to the site of the ischemic coronary vasculature and cause them to stick to the endothelium. (more…)

The most logical explanation for all these results is that TNF stimulates the endothelium to synthesize surface proteins (eg, ELAM) that interfere with either the synthesis or release of EDRF. This type of response may be important in situations in which TNF is released into the blood, such as endotoxin shock. It also occurs in the absence of white blood cells (lymphocytes, monocytes, macrophages, neutrophils), which are the major source of cytokines like TNF, since epithelial and endothelial cells can also produce these cytokines (eg, TNF, interleukin-1) which have similar biologic effects. (more…)

The responses to ACh and ADP were significantly depressed (p<0.001) after incubation with TNF. However, the responses to A23187 and NaN02 were not altered by TNF. Thus, non-receptor-mediated endothelium-dependent as well as endothelium-independent dilators elicit normal responses after TNF incubation. This confirms the receptor-mediated aspect of the defect in endothelium-dependent dilation by TNF. (more…)

Figure 1 illustrates representative recordings of developed force in isolated rings of cat coronary artery with an intact endothelium. The responses on the left are those obtained prior to addition of TNF. It is evident that all endothelium-dependent dilators (eg, ACh, ADP, and the calcium iono-phore A23187) as well as the endothelium-independent dilator (eg, acidified sodium nitrite [NaNOj) relax these coronary artery rings. ACh acts on the endothelium via M2 or M3 muscarinic receptors to release EDRF; ADP also acts through its own specific receptors to release EDRF, but A23187 releases EDRF independendy of endothelial cell receptors. NaN02 at pH 2 actually releases NO, the major form of EDRF, and hence dilates vascular smooth muscle direcdy (ie, without the obligatory role of EDRF). (more…)

Additionally, superoxide radicals inactivate EDRF once EDRF is released from endothelial cells, thus preventing EDRF, thought to be nitric oxide (NO), from reaching the vascular smooth muscle cell membrane. This anti-EDRF effect of superoxide radicals can be prevented by superoxide dismutase (SOD). However, superoxide radicals can originate in a variety of cell types, including endothelial cells, since SOD can preserve endothelium-mediated vasodilator responses even in the absence of leukocytes. These mechanisms of induction of endothelial dysfunction may be of considerable significance in ischemia and shock states. (more…)

A variety of stimuli can influence the pathophysiology of ischemia, hypoxia, and shock states. Thus, in endotox-emia, macrophages and other cell types become activated and can then release tumor necrosis factor (TNF), a polypeptide cytokine that is cytotoxic for certain cell types and that produces hypotension, hypoglycemia, hyperkalemia, and hemoconcentration. Second, during myocardial ischemia and reperfusion, neutrophils release superoxide free radicals, which are thought to mediate myocardial cell injury. (more…)