The goals of this study were 1) to quantitate the effects of atherosclerosis on physiological and pharmacological endothelium-dependent vasoactive responses in coronary arterioles downstream from arterial lesions and 2) to determine if administration of L-arginine, the precursor for endothelium-derived relaxing factor, would restore normal endothelium-dependent function. Dietary-induced atherosclerosis was induced in pigs, and vasomotor responses of isolated, cannulated coronary arterioles (30-70 ,um in diameter) were assessed by measuring diameter changes in vitro. To assess pharmacological alterations of endothelium-dependent responses, dose-response curves were constructed to ADP, serotonin, and histamine. To assess physiological alterations in endothelial function, different flow rates were established across the vessel. Arteriolar diameters were measured in vessels from normal and atherosclerotic pigs under control conditions, after administration of L-arginine, and after endothelial denudation. In arterioles from normal pigs, administration of serotonin, histamine, or ADP produced dose-dependent vasodilation, which was abolished by endothelial denudation. In arterioles from atherosclerotic pigs, administration of histamine, serotonin, and ADP produced dilation at only the highest doses (10-6_10-7 M), and the extent of dilation was only 20-30%Yo of that observed in arterioles from normal pigs. Initiation of flow also produced vasodilation in arterioles from normal pigs that was completely abolished after endothelial denudation. In arterioles from atherosclerotic pigs, flow-induced responses were absent. These abnormal physiological and pharmacological responses (i.e., blunted vasodilation to pharmacological stimulation and to flow) were restored after administration of L-arginine for 40 minutes. The vascular responses after administration of L-arginine were not different from those observed under control conditions in arterioles from normal pigs. In addition, L-arginine did not restore vasodilation to the endothelium-dependent agonists in denuded segments. From these data in arterioles downstream from atherosclerotic lesions, we conclude that 1) the ED50 and maximal responses of endothelium-dependent vasodilation to ADP, histamine, and serotonin are attenuated; 2) the physiological response to flow, that is, flow-mediated endothelium-dependent vasodilation, is absent; and 3) the abnormality in arteriolar responsiveness during large vessel disease involves an impairment of the synthesis and/or release of endothelium-derived relaxing factor. (Circulation Research 1992;70:465-476) KEY WoRDs * coronary circulation * coronary microcirculation * endothelium-dependent responses * atherosclerosis * vasodilation, flow-induced * arteriole * endothelium-derived relaxing factor A therosclerosis is known to potentiate the vasoconstrictor responses of arteries to several ago-

Ultrastructural studies on blood leukocytes of the channel catfish, Ictalurus punctatus, show the presence of heterophils (neutrophils), small lymphocytes, monocytes, and thrombocytes. Monocytes cannot always be distinguished from large lymphocytes. Cells resembling macrophages or transitional forms between monocytes and macrophages are occasionally seen. Blood eosinophils and basophils are not found. Thrombocytes and small lymphocytes are the most abundant leukocytes, while monocytes are the least frequently encountered leukocyte. Glycogen, present in all leukocytes, is most abundant in heterophils and least abundant in monocytes. Although monocytes are similar to heterophils in size and shape, a greater amount of rough endoplasmic reticulum, free ribosomes, and fewer granules are observed in monocytes. Heterophils possess oval or elongate granules, which often contain a crystalline or striated structure; small tubules which resemble smooth endoplasmic reticulum, and cristae which traverse the long axes of the mitochondria are frequently seen. Small lymphocytes are characterized by the presence of pseudopodia, many free ribosomes, numerous large mitochondria, dictyosomes (Golgi), and long profiles of rough endoplasmic reticulum. The dictyosomes are often associated with a large zone of exclusion. Bundles of microtubules are observed near the elongated ends of thrombocytes. Deep indentations of the plasmalemma, which give the appearance of vacuoles, are also seen in thrombocytes.

Insulin-like growth factor (IGF) binding protein 5 (IGFBP-5) mRNA was studied in intestines of rats with peptidoglycan-polysaccharide enterocolitis by Northern analysis and in situ hybridization. IGFBP-5 mRNA was increased 2.4 ± 0.5-fold in inflamed rat colon compared with controls and was highly expressed in smooth muscle. Cultured rat intestinal smooth muscle cells were used to study the regulation of IGFBP-5 and type I collagen synthesis. IGF-I (100 ng/ml) increased IGFBP-5 mRNA (1.9 ± 0.1-fold) and collagen type α1(I) mRNA (1.6 ± 0.2-fold) in cultured smooth muscle cells. IGF-I induced a dose- and time-dependent increase in IGFBP-5 in conditioned medium by Western ligand blot and by immunoblot. IGF-I did not affect the IGFBP-5 mRNA decay rate after transcriptional blockade. Cycloheximide abolished IGFBP-5 mRNA. In conclusion, IGFBP-5 mRNA is expressed by intestinal smooth muscle and is increased during chronic inflammation. IGF-I increases IGFBP-5 and collagen mRNAs in intestinal smooth muscle cells.

Microscopic studies of human adrenal glands from 58 autopsy specimens, ranging in age from one month gestation to 69 years, revealed a pertinent developmental pattern in the establishment of definitive zonation. This pattern was established using the following criteria: (1) relationship of age to the developing zones; ( 2 ) times of formation of definitive zonation; and (3) the morphological determination of developmental patterns based on staining characteristics.Using these criteria, development was divided into five phases: (1) condensation of coelomic epithelium; ( 2 ) secondary proliferation of coelomic epithelium; (3) finding of PAS-positive material within the fetal cortex; ( 4 ) decline and disappearance of the fetal cortex; and (5) establishment and stabilization of the definitive zonular patterns.Significant features occurring in this development were: (1) the origin of both permanent and fetal cortex from proliferation of coelomic epithelium; ( 2 ) the appearance of PAS-positive granules surrounding a homogenous mass in the fetal cortex and the zona reticularis during maturation and organization; and (3) the gradual establishment of definitive zones by proliferation of the permanent cortex, maturation of the fetal cortex, and growth of the medulla; with the adult structure of the adrenal gland achieved by the eleventh to fifteenth year without any apparent major involution or hemorrhage.

The structural characteristics of the supraorbital ridge in three extent primate species and fossil Neanderthals are described in this study. Surface morphology and patterns of trabecular organization as observed in cross-sectional collections of Pupio, Mucucu and Pun are compared with similar traits encountered in the Pech de 1'Aze infant, Gibraltar child, and La Quina 5, La Chapelle-aux-Saints, Broken Hill, Skhul V, Skhul IX, Tabun I and Gibraltar adult Neanderthals. Periods of rapid appositional growth of the browridges by means of fine cancellous bone formation and its subsequent remodeling and consolidation are temporally correlated with dental development and eruption sequences. The purpose of this report is (1) t o identify surface indicators of trabecular organization and browridge formation in Neanderthals, (2) to compare these data with similar information about macaques, chimpanzees, and olive baboons, and (3) to demonstrate how these comparisons can be used in addressing developmental, functional, and evolutionary questions about browridge formation and craniofacial morphogenesis in primates. was determined on the basis of dental eruption sequence and attrition status (Krogman, '30; Schultz, '35; Bramblett, '69).The nature of the bone surface in the brow region of each of the skulls was noted; samples of bone were then removed from the supraorbital region of the non-hominid skulls and prepared and analyzed using standard light microscopy and scanning electron microscopy techniques. RESULTS MacroscopicFigures la,b-3a,b show variations of a surface pattern that we observed in the supraorbital region of several monkey, ape and fossil hominid skulls. This trait, described as "vermiculate bone" by Tappen ('731, was found along portions of the supraorbital margin in the Gibraltar child, Skhul V, Skhul IX, Tabun I, and Broken Hill skulls; Tappen ('73, '78) has described the trait in the brow region of numerous Neanderthal specimens. We encountered variations of the pattern in the supraorbital region of many of the macaque and chimpanzee skulls considered during this analysis. The vermiculate pattern is absent or virtually '