This study was performed to determine the reproducibility of the ionic and electrical changes associated with serial ischemic episodes. We used ion-selective and bipolar plunge electrodes to determine the changes in left ventricular extracellular potassium (

In silicosis, alveolar macrophages (AM) are thought to induce chronic inflammation and fibrosis by release of cytokines. Rats were exposed to aerosols of alpha-quartz and examined 4 to 9 mo later for persistence of silica particles and release of tumor necrosis factor-alpha (TNF-alpha) from macrophages. Silica particles were detected in AM, lung parenchyma, and thoracic lymphoid organs, whereas extrathoracic lymphoid tissues and organs were free of the mineral. When AM were tested functionally, no spontaneous release of TNF-alpha was observed. However, upon in vitro stimulation of AM from silicotic rats with a low concentration of lipopolysaccharide (10 ng/ml), abundant TNF-alpha production was found that was higher and occurred more rapidly than with AM from sham-exposed animals. Peritoneal macrophages, which did not have contact with silica particles, displayed a similarly enhanced TNF-alpha release in response to low doses of lipopolysaccharide. These data demonstrate a state of systemic preactivation ("priming") of macrophages that supports the notion that silicosis is associated with a general immunostimulation.

In experimental animals, the calcium channel-blocking agents lessen the arrhythmogenic, ionic, metabolic, and electrical changes that occur during acute myocardial ischemia. To date, these effects have been studied separately, and the effects of these agents on local activation have not been correlated with ionic or metabolic effects. In open-chest, anesthetized swine, we used bipolar and ion-selective plunge electrodes to simultaneously measure ischemia-induced changes in left ventricular local activation, extracellular K+ ([KIIe), and extracellular pH (pHe) The effects of verapamil (0.2 mg/kg) on these variables were studied during a series of 10 min occlusions of the left anterior descending coronary artery. Compared with control occlusions, verapamil (1) slowed the rise in [K']e at the center of the ischemic zone and at its lateral margin and decreased the peak [K'+] by 0.9 mM at the center (p < .05) and by 0.1 mM at the margin (p = .10); (2) slowed the development of acidosis and decreased the peak level of acidosis beyond that expected solely as a result of serial occlusions by 0.19 pH units at the center (p < .05) and by 0.07 pH units at the margin (p = .10); and (3) slowed the development of local activation delay and often prevented the local activation block that was observed during control occlusions. Effects on local activation became less marked at [K']e levels greater than 9.0 mM, and the effects of verapamil on local activation were not explained solely by its effects on the local rise in [K+]

The pathogenesis of silicosis results, in part, from interactions between silica particles and alveolar macrophages (AM) with release of cytokines and other mediators. Different arachidonic acid metabolites have been shown to promote or to suppress inflammation and fibrosis. We designed experiments to study the production of cyclooxygenase metabolites and tumor necrosis factor-alpha (TNF-alpha) from macrophages during active silicosis. Macrophages were harvested from rats 5 to 7 mo after an 8-day silica aerosol exposure. Upon in vitro culture of AM, the spontaneous release of prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and prostaglandin D2 (PGD2) of silica-exposed animals was higher than that of sham-exposed animals. Moreover, AM from silicotic rats displayed an increased sensitivity to low concentrations of lipopolysaccharide (LPS, 10 ng/ml) and released copious amounts of PGE2 and TXB2. When compared with similarly enhanced release of TNF-alpha from AM of silica-exposed rats, PGE2 production occurred later and started to increase when TNF-alpha production declined. Addition of the cyclooxygenase blocker indomethacin augmented TNF-alpha production, whereas the addition of PGE2 counteracted TNF-alpha release. Also peritoneal macrophages, which did not have direct contact with silica particles, released enhanced levels of PGE2 in response to low LPS doses. We conclude that AM and other macrophages from silica-exposed rats are preactivated and display an enhanced prostanoid production that could serve anti-inflammatory or immunomodulating roles in silicosis.

The ,3-adrenergic and calcium channel blocking agents are known to reduce heart rate and alter myocardial contractility. More recent evidence suggests that both agents affect the metabolic consequences of ischemia, independent of their effects on heart rate and contractility. We used a low-flow model of ischemia in swine with heart rate held constant by atrial pacing. Blood was shunted from the carotid artery to the left anterior descending coronary artery through a controlled-flow roller pump to assess the threshold flow for the rise in extracellular potassium ([K4Ie) and fall in extracellular pH (pHe) associated with ischemia during control situations and after the administration of either propranolol or verapamil. We also measured the changes in activation delay and contractility associated with graded flow reductions in the presence and absence of these drugs. We found that when heart rate is held constant, 1) verapamil shifts the threshold flow for [K4Ie and pH, to lower levels, but propranolol does not; 2) verapamil lessens activation delay, while propranolol aggravates the delay; and 3) verapamil reduces afterload and selectively depresses contractility in the reperfused ischemic zone. We conclude that the calcium channel blockers and the f-adrenergic-blocking agents have different effects and possibly different modes of action and should not be considered interchangeable when evaluating therapeutic options for patients with ischemic heart disease. (Circulation 1989;79: 939-947) T he ,3-adrenergic-blocking agents and the calcium channel blocking agents are both used in the treatment of patients with effortinduced ischemial2 due to coronary artery disease. The beneficial effects of these agents are attributed to their ability to reduce heart rate and contractility, thereby lessening the myocardial oxygen requirement. In addition, there is evidence to suggest that both the 8-adrenergic-and the calcium channel blocking agents may alter the metabolic consequences of reduced coronary blood flow independently of changes in heart rate or contractility.3,4 after the complete interruption of coronary blood flow5-8 been attributed to this mechanism. These effects would be expected to allow the myocardium to tolerate lower levels of coronary blood flow without becoming ischemic.Our recent studies9 have shown that the changes in extracellular potassium concentration ([K']e) and extracellular pH (pHe) are the most sensitive markers of ischemia when coronary blood flow is progressively reduced. As such, they provide a means for assessing the effects of physiologic and pharmacologic interventions on the coronary blood flow associated with the onset of ischemia. The present experiments were conducted to determine if propranolol or verapamil or both were capable of altering the coronary flow associated with the first change in[K4]e and pHe when heart rate was held constant. We also studied the effects of these drugs on myocardial activation during the progressive reduction of coronary blood flow because it is known th...