Inhibition of eicosanoid-mediated coronary constriction during myocardial ischemia.

Thromboxane A2 and cysteinyl leukotrienes are highly effective microvessel constrictors in normally perfused myocardium. Their release during acute coronary thrombosis might augment myocardial underperfusion. The constrictor action of these substances could be modified substantially, however, by concomitant myocardial ischemia. We compared the effects of the two eicosanoid constrictors in normally perfused and ischemic myocardium of 24 open-chest, pentobarbital-anesthetized pigs. Left anterior descending coronary flow was measured after intracoronary bolus injections of the stable thromboxane A2 analog U46619 (1-10 micrograms) or leukotriene D4 (LTD4, 1-10 micrograms). Each dose was given before and during myocardial ischemia induced by a snare adjusted to produce 63 +/- 2% decrease in coronary flow for 10 min. Marked dose-independent inhibition of eicosanoid-induced coronary flow decrease occurred during ischemia. With 10 micrograms U46619, coronary flow decrease in the unoccluded state (25 +/- 2 from 55 +/- 4 ml/min pretreatment baseline) was virtually eliminated during snare occlusion (1 +/- 1 from 21 +/- 3 ml/min pretreatment baseline, P less than 0.001). Similar results occurred with LTD4. Distal coronary pressure during ischemia indicated a lack of microvessel responsiveness to the eicosanoids rather than a buffering of resistance change by the snare. U46619 and LTD4 did induce transient, small reductions in regional shortening fraction during ischemia. Our data suggest that eicosanoid-induced constriction of myocardial resistance vessels is not a likely complication of acute coronary thrombosis. However, eicosanoids could depress residual contractility in moderately ischemic regions.

Unique coronary vasodilator induction by leukotriene D4.

Coronary blood flow (CBF) and myocardial contractility decrease markedly in response to intracoronary administration of leukotriene D4 (LTD4). With steady infusion, however, both CBF and contractility escape, approaching preinfusion values despite ongoing LTD4 administration. To clarify the mechanism of this escape, we reinfused plasma from the coronary vein draining the myocardial area receiving LTD4. Introducing this plasma into a coronary artery caused a marked rise in coronary flow for the duration of the plasma infusion. Coronary flow reduction with vasopressin or mechanical occlusion matching that caused by LTD4 failed to elicit vasodilator production. Thus a unique coronary vasodilator factor is induced by LTD4. Whole blood or platelet-rich plasma incubated with LTD4 in vitro produced the same pattern of coronary dilation on intracoronary infusion; LTD4 incubation with platelet-poor plasma failed to elicit a vasodilation. The vasodilator factor is stable and is not potassium, a prostaglandin, catecholamine, histamine, serotonin, adenosine, adenosine diphosphate, or platelet-activating factor. Production of this leukotriene-induced vasodilator factor may account for the escape from LTD4-induced coronary constriction.

Gentamicin-induced hypomagnesemia.

There have been several case reports of hypomagnesemia associated with gentamicin therapy. A cause and effect relationship between gentamicin and hypomagnesemia has been difficult to establish in these cases due to: 1) large doses of gentamicin; 2) concomitant administration of other antibiotics and cytotoxic agents; 3) failure to monitor drug levels; and 4) poor oral intake. To test for a direct cause and effect relationship and to determine the frequency of gentamicin-induced hypomagnesemia, we administered the drug for 10 days to six healthy, well-fed, subhuman primates. Five of the six animals developed a mean decrease in serum magnesium of 0.34 mg/dl (P = 0.03) after 10 days of therapy. Four of the five had levels in the frankly hypomagnesemic range (less than 1.4 mg/dl). Urine magnesium values were inappropriately elevated in relation to serum magnesium concentrations. It is concluded that gentamicin-induced hypomagnesemia may occur more commonly than has been previously appreciated. Serial monitoring of serum magnesium in patients receiving gentamicin is recommended.

Sympathetic nervous system "switch off" with severe hypothermia.

Hypothermia occurs frequently in the critically ill patient, yet little is known about the endogenous catecholamine response to this stress. To study this problem, we measured heart rate (HR), mean arterial blood pressure (MAP), and plasma levels of norepinephrine (NE) and epinephrine (Epi) in subhuman primates (baboons) during progressive hypothermia from 37 degrees to 29 degrees C and then during rewarming to 37 degrees C. As the core temperature decreased from 37 degrees to 33 degrees C, HR and MAP increased significantly (p less than 0.05), but as core temperature further decreased from 33 degrees to 29 degrees C, the HR and MAP fell to prehypothermic levels. Plasma concentrations of NE and Epi increased significantly (p less than 0.01) as core temperature fell from 37 degrees to 31 degrees C, but as core temperature dropped from 31 degrees to 29 degrees C, plasma NE and Epi levels decreased towards prehypothermic concentrations. These findings indicate that the sympathetic nervous system (SNS) responds quickly to hypothermia but may be "switched off" at a threshold temperature of about 29 degrees C. We speculate that hypotensive patients with temperatures less than or equal to 29 degrees C may benefit from infusions of exogenous catecholamines, especially if there have been only minimal benefits achieved with conventional therapy such as fluids, and an increase in ambient temperature.

"Bovine ketosis" in a nondiabetic postpartum woman.

A 19-yr-old woman developed ketoacidosis 7 wk after the delivery of her first child. Despite breast feeding, she had been on a weight reduction diet resulting in a loss of 12 kg/body wt. With the development of a urinary tract infection, the patient became dehydrated and was found to be in ketoacidosis (arterial pH was 7.25 and PaCO2 was 17 mm Hg). The patient did not use alcohol and was nondiabetic. Therapy with adequate calories, intravenous fluids, and an appropriate antimicrobial agent resulted in prompt normalization of the laboratory abnormalities and resolution of the patient's symptoms. The hypothesis is advanced that the postpartum status of the patient put her at particular risk for development of ketoacidosis and that this may represent the first reported episode of "bovine ketosis" in a human.

The significance of serial measurements of serum complement C3 and C4 components and DNA binding capacity in patients with lupus nephritis.

Eighteen patients with systemic lupus erythematosus (SLE) and proliferative glomerulonephritis, underwent serial serum determinations of C3, C4, and native DNA binding capacity, as well as repeat renal biopsy 7 to 48 months (median 25 months) following initial biopsy. Highly significant correlations were found between serum C3 levels and renal histologic changes (P less than 0.0001), and between serum C3 levels and DNA binding capacity (P less than 0.03). Histologic deterioration correlated with depressed C3 levels, while improvement was associated with normalization of C3 levels. No correlation between renal histologic changes and either serum C4 levels or DNA binding capacity was found. The data suggest that the serum level of C3 is the best index of activity of lupus nephritis.