The rat in sepsis and endotoxic shock.

Compared to the experimental studies, interpretation of eicosanoid levels in human sepsis is complicated by a large number of uncontrolled variables. Further clinical studies are needed to establish the relationship between the septic rat model and the human septic condition. The rat model is useful for uncovering fundamental pathophysiologic processes and should be useful in developing therapeutic interventions in human circulatory shock. Studies on the rat model offered the first indication that eicosanoids were involved in the shock syndrome (Cook et al., 1980). This led to clinical trials to determine the role of these mediators in human sepsis (Reines et al. 1982). The rat affords a model system which allows for pharmacologic manipulation and testing of a large number of hypotheses in a practical and cost effective manner. The recent evidence that leukotrienes are released during circulatory shock in the rat and that attenuation of this release alters the pathophysiologic outcome (Ball et al., 1986), lays the groundwork for future clinical studies. Finding that eicosanoids and leukotrienes are elevated in rat models of adult respiratory distress syndrome (Hammarstrom, 1983) has opened further new areas of clinical inquiry. Although rat models involving bolus endotoxin administration have not been predictive of the human septic syndrome, they have proven useful in the determination of the cellular sources and mechanisms of eicosanoid and leukotriene action. From the evidence presented, the septic shock rat model would seem to be the best model in predicting the outcome of therapies in human sepsis. Limited clinical trials have assessed the therapeutic efficacy of pharmacologic agents which alter eicosanoid and leukotriene metabolism in sepsis. In view of the continued high mortality of patients with septic shock and the failure of conventional therapies (Sprung et al., 1984; DuToit et al. 1985), further clinical and experimental studies are desirable.

The guinea pig as a model in shock research.

Studies described in this review characterize the guinea pig as useful for modeling pathophysiologic changes associated with a variety of shock states, including thermal injury. There are basic similarities in the hemodynamic and metabolic responsiveness of humans and guinea pigs to thermal trauma. Guinea pigs are readily available, relatively inexpensive, and easily maintained in the laboratory in accordance with specific nutrition-environmental requirements. The inherent tractability of the guinea pig, coupled with small body size, facilitates cardiorespiratory monitoring without anesthetic restraint. A limitation to using the guinea pig is the amount of information that can be obtained from one animal, but we have demonstrated that with the use of microtechnology, both hemodynamic and metabolic alterations in shock can be characterized in individual guinea pigs. Experimental models using guinea pigs can also be successfully utilized to investigate potential resuscitative and therapeutic modalities in shock.

Endogenous opioids do not mediate HCl-induced myocardial dysfunction.

We evaluated the hypothesis that increased endogenous opioid activity mediates part or all of the left ventricular contractile and pump dysfunction previously demonstrated in HCl-induced metabolic acidemia. Eighteen Western newborn lambs were catheterized and instrumented; pacing wires were sutured to the right atrial appendage; a catheter mounted micromanometer pressure transducer was inserted into the left ventricle; and a 2.5 F thermistor was inserted into the distal abdominal aorta. The lambs were studied 3 days after surgery. Metabolic acidemia was produced with an infusion of 0.5 N HCl into the inferior vena cava. Inhibition of endogenous opioids was achieved with a bolus of 2 mg/kg of intravenous naloxone, which was demonstrated to inhibit morphine sulfate-induced myocardial dysfunction. The effects of opioid inhibition were contrasted with our previously published results after restoration of a normal arterial pH with intravenous sodium bicarbonate. In agreement with our previous study, we found that reducing the arterial pH from 7.41 +/- 0.01 to 6.97 +/- 0.04 was associated with a 45% reduction in cardiac output which resulted from a 50% reduction in stroke volume. These changes in turn were mediated by a 35% reduction in the maximal first derivative of left ventricular pressure and/or a 63% increase in systemic vascular resistance which we used to estimate contractility and afterload, respectively. Left ventricular end diastolic pressure increased during acidemia. Although opioid inhibition produced a consistent increase in the maximal first derivative of left ventricular pressure, this increase was relatively small and was not associated with a significant change in cardiac output, stroke volume, or systemic vascular resistance.

C57BL/6J-bgJ (beige) mice: differential sensitivity in the tail flick test to centrally administered mu- and delta-opioid receptor agonists.

The antinociceptive effects of two mu-opioid receptor agonists, morphine and [D-Ala2, MePhe4, Gly-ol5]enkephalin (DAGO), and a selective delta-receptor agonist, [D-Pen2, L-Pen5]enkephalin (DPLPE), were determined in C57BL/6J-bgJ (beige) and control mice (CRS-CDl and C57BL/6By) using a standard tail-flick assay. The antinociceptive response of C57BL/6J-bgJ mice to intracerebro-ventricularly administered morphine and DAGO was significantly reduced compared to controls, but there was no difference in the antinociceptive response to DPLPE. These results suggest that there is a genetic deficit of mu-opioid receptor number or a genetically-induced alteration in receptor function in regions of C57BL/6J-bgJ brains involved in antinociception, that delta-opioid receptors can mediate antinociception in mice, and that the C57BL/6J-bgJ strain may offer a practical new animal model for studying the function of opioid receptor subtypes.

The newborn rabbit: a model for studying hypoxemia-induced renal changes.

The newborn rabbit was used as an experimental model for studying renal changes during normocapnic hypoxemia. Renal extraction of p-aminohippuric acid (PAH), as assessed in 15 normoxemic and 8 hypoxemic rabbits amounted to 54.6 +/- 3.7 and 45.7 +/- 4.6%, respectively (NS). Changes in glomerular filtration rate (GFR), and renal blood flow (RBF) as assessed by inulin and PAH clearances, respectively, were determined during normoxemia and subsequent hypoxemia in 8 additional anesthetized and mechanically ventilated newborn rabbits. Normocapnic hypoxemia (PaO2 = 38.6 +/- 2.1 mm Hg) induced a significant fall in GFR from 2.10 +/- 0.21 to 1.51 +/- 0.18 ml/kg/min (p less than 0.01), in filtration fraction (p less than 0.01) and U/P inulin ratio (p less than 0.01). RBF, renal vascular resistance and urine flow rate did not change significantly. In comparison with other immature animal species the newborn rabbit appears a valuable and inexpensive model for the study of acute hypoxemia-induced renal changes.

Postnatal development of a demyelinating disease in avian spinal cord chimeras.

Xenogeneic spinal cord chimeras were constructed by grafting fragments of quail neural primordium into chick embryos at 2 days of incubation. Hatched birds displayed normal motor behavior for about 5 to 7 weeks, whereupon they developed a neurological syndrome; in the grafted spinal cord the pathological signs of the disease were very similar to those of the active plaques of multiple sclerosis and of the lesions of experimental allergic encephalomyelitis and neuritis, including Ia expression by brain capillary endothelia, rupture of the blood-brain barrier, leukocytic infiltration in the nervous tissue, and demyelination. In the animals at the most advanced stage of the disease an autoimmune attack occurred on the host's nervous system with the same histopathological signs.

Elevated plasma vasopressin in cardiomyopathic hamsters.

Hamsters of the BIO 14.6 strain characteristically develop cardiomyopathy as they age, and hamsters of this strain have overt signs of heart failure by 11 months of age. Plasma levels of the posterior pituitary hormone arginine-vasopressin (AVP) were found to be elevated (approximately 2-fold) in 11 month old BIO 14.6 hamsters, compared to age-matched hamsters of a control strain. AVP appeared inappropriately elevated in these animals, since they were neither hyperosmotic nor markedly hypotensive. The elevated levels of AVP observed in these animals appears to contribute to vasomotor tone, since intravenous administration of a specific antagonist of the vasoconstrictor action of AVP [d(CH2)5Ome(TYR)AVP] elicited a fall in arterial pressure (9 +/- 2 mm Hg, n = 6, p less than 0.05). The AVP antagonist had no effect on arterial pressure in hamsters of a control strain, and vehicle administration had no effect on arterial pressure in either strain. These data indicate that inappropriately elevated levels of AVP contribute to the cardiovascular state of myopathic hamsters. Since elevated plasma AVP has been noted in human congestive heart failure, these results suggest that AVP may contribute to the cardiovascular status during congestive heart failure.

Experimental studies on prenatal treatment of congenital anomalies.

Development of fetal animal models for congenital anomalies helps elucidate the pathophysiological consequences of the disease process as well as the efficiency of prenatal intervention in ameliorating the disease. The experimental work that supports the pathophysiological rationale for in-utero correction of diaphragmatic hernia and urinary tract obstruction is reviewed in this article.

Human interdental plaque-pH data and rat caries tests: results with the same substances.

Interdental plaque-pH telemetry measures, in vivo, H-ion concentration at the level of the enamel surface under an undisturbed layer of plaque. It is better suited to test non- or hypo-acidogenic products than are rat caries tests. These products can, with a very high probability, be considered non- or hypocariogenic ("safe, or friendly, for teeth"), no matter how frequently they are consumed. Plaque-pH telemetry is poorly suited for judging the effectiveness of agents directed at enamel - e.g., topical fluoride, remineralizing solutions, etc. - or agents which may have long-term effects on plaque composition. Plaque-pH telemetry is able to demonstrate the effects of different meal patterns and the form and texture of foods on oral clearance and plaque pH.

Nulceoprotein changes in the hearts of cardiomyopathic turkeys.

The possible involvement of nuclear proteins in the pathogenesis of a spontaneously occurring model of congestive cardiomyopathy in turkeys was examined. This model is characterised by cardiac hypertrophy and dilatation, reduced cardiac output and depressed contractility. The protein composition of myocardial nuclei was compared in normal (n = 9) and cardiomyopathic (n = 18) turkeys, 70 to 140 days old. Myopathic hearts as a group have a higher histone content (1.75 +/- 0.09 (SD) mg . mg DNA-1 vs 1.65 +/- 0.07 in controls, P less than 0.01) and histone/nonhistone protein (NHP) ratio (1.07 +/- 0.07 vs 0.95 +/- 0.02 in controls, P less than 0.01). The latter was independent of age and correlated well with the degree of cardiac dilatation. The electrophoretic patterns of chromatin proteins was decreased in myopathic hearts. This decrease was primarily accounted for by lower NHP phosphorylation (5.78 +/- 1.38 pmol 32P . mg prot-1 . 15 min-1 vs 8.33 +/- 0.81 in controls, P less than 0.01). DEAE-Sephacel chromatography separated cyclic AMP-dependent and -independent nuclear protein kinases with similar substrate specificities but lower specific activities in myopathic hearts. SDS-polyacrylamide similar substrate specificities but lower specific activities in myopathic hearts. SDS-polyacrylamide gel electrophoresis of phosphorylated nucleoproteins revealed differences in the lower molecular species of NHPs between control and myopathic hearts. There was a significant correlation between NHP phosphorylation and degree of cardiac dilatation (r = -0.78) or contractility as reflected by left ventricular systolic time intervals (r = -0.57). These results suggest that development of this model of spontaneous cardiomyopathy is associated with, and may, in part, be secondary to changes in the composition and function of myocardial nucleoproteins.