Thickening In Response Research Articles

R-Ras is a global regulator of vascular regeneration that suppresses intimal hyperplasia and tumor angiogenesis

R-Ras is a small GTPase of the Ras family that regulates cell survival and integrin activity. Despite a number of in vitro studies, the in vivo function of R-Ras remains unclear. Here, we used R-Ras-null mice to explore the in vivo function of this small GTPase. Our results show a role for R-Ras as a regulator of vascular differentiation that primarily affects the remodeling of blood vessels. We show that R-Ras-null mice, although otherwise phenotypically normal, mount excessive vascular responses. We found that in vivo R-Ras expression is largely confined to fully differentiated smooth muscle cells, including those of blood vessels, and to endothelial cells. Challenging the R-Ras-null mice with arterial injury or tumor implantation showed exaggerated neointimal thickening in response to the injury and increased angiogenesis in the tumors. In wild-type mice, R-Ras expression was greatly reduced in hyperplastic neointimal smooth muscle cells and in angiogenic endothelial cells. Forced expression of activated R-Ras suppressed mitogenic and invasive activities of growth factor-stimulated vascular cells. These results establish an unexpected role for R-Ras in blood vessel homeostasis and suggest that R-Ras signaling may offer a target for therapeutic intervention in vascular diseases.

Arterial enlargement, tortuosity, and intimal thickening in response to sequential exposure to high and low wall shear stress

We investigated the effects of sequential and prolonged exposure to high and low wall shear stress on arterial remodeling using a rabbit arteriovenous fistula (AVF) model. Blood flow was increased by approximately 17-fold to 20-fold when the AVF was open, and returned to normal when the AVF was occluded. Repeated opening and closing of the AVF resulted in sequential exposure of the artery to high and low wall shear stress. High flow and high wall shear stress induced arterial dilatation, elongation, and tortuosity, without intimal thickening. The common carotid artery was elongated 37% after 4 weeks of high flow, and was shortened 10% after 6 weeks of normal flow. Subsequent cycles of high flow induced less elongation, with less shortening after return to normal flow. Enlargement of the distal segment was more dramatic than in the proximal segment, despite exposure to the same volume of flow and the same initial high wall shear stress after creation of the AVF. The distal carotid segment enlarged more than did the proximal segment during each exposure to high flow. In segments of carotid artery exposed to low wall shear stress (<5 dynes/cm 2) intimal thickening developed. These changes were maximal in the distal carotid segment, just before the AVF. Each cycle of low wall shear stress induced intimal thickening accompanied by medial hyperplasia. Intimal thickening was inhibited during periods of high flow when wall shear stress was high. Three cycles of flow alteration induced three layers of intimal thickening in the distal arterial segment, two layers of intimal thickening in the middle segment, and one layer of intimal thickening in the proximal segment. Long-term exposure to low wall shear stress induced severe intimal thickening and medial hyperplasia in different segments. Thus the response of the carotid artery afferent to an AVF varies along the length of the artery, with maximum enlargement, elongation, and tortuosity in the distal segment, just proximal to the AVF. Similarly, intimal thickening in response to low wall shear stress is maximal in the distal carotid artery. It appears that intimal thickening is related to local levels of low wall shear stress, and occurs when wall shear stress chronically falls to less than 5 dynes/cm 2.

The effect of the nonspecific nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester on the choroidal compensatory response to myopic defocus in chickens.

Chick eyes show rapid compensation to retinal defocus. One component of this mechanism involves changes in the thickness of the choroid: when the retina is exposed to myopic defocus, the choroid thickens, pushing the retina forward; conversely, when the eye is exposed to hyperopic defocus, the choroid thins. The underlying mechanism(s) for these changes are unknown. We tested the hypothesis that nitric oxide might play a role. We examined the effect of the nonspecific nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on the compensatory choroidal thickening in response to myopic defocus using two visual paradigms: first, in previously form-deprived "recovering" eyes and, second, in eyes wearing +15 D spectacle lenses. L-NAME was injected intravitreally after removal of the diffuser or immediately before putting on the lenses. In addition, we looked at the effect of L-NAME on experimentally thickened choroids (induced by 1 week of recovery from deprivation myopia or 1 week of +15 D lens wear) and on choroids of normal eyes. Eyes were measured using A-scan ultrasonography before the injections and at subsequent intervals for several days. As a control for the injection procedure, eyes with the same visual conditions were injected with saline. Fellow eyes were untreated and uninjected. L-NAME inhibited choroidal thickening in both previously form-deprived eyes (2 vs. 117 microm; p < 0.001) and eyes wearing +15 D lenses (3 vs. 137 microm; p < 0.02). The effect was rapid, transient, and dose dependent (ED50, 0.26 micromoles). L-NAME produced thinning in experimentally thickened choroids (recovering: -116 microm; lenses: -219 microm) and in normal choroids (-47 microm) within 7 hours. Nitric oxide may play a role in modulating choroidal thickness. The mechanism is as yet unknown.

Importance of Adipocytokines in Obesity-Related Diseases

To elucidate the biological characteristics of adipose tissue, we analyzed the gene expression profile of visceral and subcutaneous fat. Unexpectedly, adipose tissue, especially visceral fat, expressed a variety of genes for secretory proteins. About 30% of the genes expressed in visceral adipose tissue encoded secretory proteins and most were biologically active molecules, which we called adipocytokines. We found plasminogen activator inhibitor type 1 and heparin binding EGF-like growth factor. Production of these atherogenic adipocytokines was shown to increase with the accumulation of visceral fat, which may be one of the mechanisms of vascular disease in visceral obesity. We found a unique and novel collagen-like protein, adiponectin, encoded by the most abundantly expressed gene in adipose tissue, termed apM1 (adipose most abundant gene transcript-1). Plasma levels of adiponectin ranged from 0.3 to approximately 3 mg/dl but were decreased in patients with visceral obesity, type 2 diabetes and coronary artery disease (CAD). Screening for mutations in the adiponectin gene revealed that patients carrying a missense mutation showed markedly decreased plasma levels of adiponectin and had CAD. These data suggest that hypoadiponectinemia may be considered an important risk factor for CAD. Cell biology studies revealed that adiponectin has a potent inhibitory effect on the expression of adhesion molecules in endothelial cells and an inhibitory effect on the expression in macrophages. In order to confirm these antidiabetic and antiatherogenic functions of adiponectin, we developed adiponectin knockout mice. Adiponectin knockout mice showed severe insulin resistance and impaired glucose metabolism when fed a high-fat, high-sucrose diet. Knockout mice also developed intimal thickening in response to endothelial injury.

Copper chelation represses the vascular response to injury.

The induction of an acute inflammatory response followed by the release of polypeptide cytokines and growth factors from peripheral blood monocytes has been implicated in mediating the response to vascular injury. Because the Cu2+-binding proteins IL-1alpha and fibroblast growth factor 1 are exported into the extracellular compartment in a stress-dependent manner by using intracellular Cu2+ to facilitate the formation of S100A13 heterotetrameric complexes and these signal peptideless polypeptides have been implicated as regulators of vascular injury in vivo, we examined the ability of Cu2+ chelation to repress neointimal thickening in response to injury. We observed that the oral administration of the Cu2+ chelator tetrathiomolybdate was able to reduce neointimal thickening after balloon injury in the rat. Interestingly, although immunohistochemical analysis of control neointimal sections exhibited prominent staining for MAC1, IL-1alpha, S100A13, and the acidic phospholipid phosphatidylserine, similar sections obtained from tetrathiomolybdate-treated animals did not. Further, adenoviral gene transfer of the IL-1 receptor antagonist during vascular injury also significantly reduced the area of neointimal thickening. Our data suggest that intracellular copper may be involved in mediating the response to injury in vivo by its ability to regulate the stress-induced release of IL-1alpha by using the nonclassical export mechanism employed by human peripheral blood mononuclear cells in vitro.

Down-regulation of the ERK1 and ERK2 mitogen-activated protein kinases using antisense oligonucleotides inhibits intimal hyperplasia in a porcine model of coronary balloon angioplasty.

Neointimal hyperplasia is a central feature in the pathogenesis of a variety of vascular pathologies. Mitogen-activated protein kinases (MAPK) are involved in the downstream transduction of signals from receptors for many of the molecules known to be instrumental in this process and thus represent a potential target for the modification of the proliferative response. We examined the hypothesis that down-regulation of MAPK would inhibit neointima formation in a porcine coronary injury model. Balloon angioplasty was performed on 38 coronary arteries from 23 large white pigs. Antisense oligonucleotides to the p42 and p44 MAPK were locally delivered to the site of injury immediately after balloon injury. At 7 or 21 days, arteries were harvested for morphometry, determination of cell proliferation and assessment of MAPK protein levels. At 7 days, neointima formation was significantly reduced compared to controls (corrected intima/media ratio (IMR) 1.01+/-0.13 vs. 1.61+/-0.07, P<0.01) and this was associated with a 58% and 23% down-regulation of p42 and p44 protein levels, respectively. Intimal and medial proliferation rates were also reduced by 32% and 26%, respectively. At 21 days however, the effect of the treatment on MAPK protein levels was no longer significant and this correlated with a loss of the effects on IMR and cell proliferation. Down-regulation of MAPK inhibits early smooth muscle cell (SMC) proliferation and neointimal thickening in response to arterial injury, implying that it plays an important role in determining the early vascular response to injury. Inhibitory effects were less apparent at 21 days after a single delivery of oligonucleotide, implying that more sustained local delivery may be required to achieve longer term therapeutic benefit.

Structural evolution of the southernmost segment of the West European Variscides: the South Portuguese Zone (SW Iberia)

The South Portuguese Zone (SPZ) represents the southernmost unit of the Iberian Massif. It is mainly composed of three structural domains, from north to south, the Beja–Acebuches Ophiolitic Complex (BAOC), The Pulo do Lobo Antiform (PLA) and the Iberian Pyrite Belt (IPB).This study proposes a structural analysis of the Spanish part of the SPZ that allows us to point out two main kinds of deformation; one accommodated by early top-to-the-south and following sinistral strike-slip tectonics in the northern part of the SPZ and the other by top-to-the-south thrusting in a wide southern branch. This transition, underlining the strain partitioning, is analysed by lattice preferred orientation of quartz using the texture goniometry method. It shows that the deformation is accommodated in the PLA at low to middle temperature by basal and prismatic 〈a〉 slip. Quartz textures suggest increasing thermal conditions of deformation from thrust to strike-slip tectonics.Our work within the IPB allows us to present a sequence of deformation showing a primary south-verging ductile thrusting and coeval crustal thickening in response to the thin-skinned tectonics. The progressive deformation generated backthrusts while it turns shallower southward. These features are summarised in an interpretative cross-section of the SPZ that underlines the main structural style of deformation, the fore-mentioned southward propagating thin-skinned thrusts.

Raloxifene and estrogen inhibit neointimal thickening after balloon injury in the carotid artery of male and ovariectomized female rats.

The effects of raloxifene and 17alpha-ethinyl estradiol (EE2) on intimal thickening in response to balloon injury were tested in male and ovariectomized female rats. In male rats, oral raloxifene and EE2, administered either by gavage or in the diet, inhibited arterial intimal thickening in response to balloon injury to a maximum of approximately 60 and 50%, respectively. The effect of oral raloxifene to decrease cholesterol was observed at doses (> or = 3 mg/kg/day) higher than those required to inhibit intimal thickening (> or = 0.03 mg/kg/day). Coadministration of the estrogen receptor antagonist, ICI 182,780 (5 mg/kg/day, s.c.), blocked the inhibition of balloon injury by raloxifene and EE2. Direct adventitial delivery of raloxifene (0.03 mg/kg/day) and EE2 (0.001 mg/kg/day) to the vascular wall inhibited intimal thickening by 63 and 53%, respectively. In ovariectomized female rats, oral raloxifene (0.01-3.0 mg/kg/day) and EE2 (0.08 mg/kg/day) inhibited intimal thickening to a maximum of 32 and 60%, respectively. Together, these data suggest that raloxifene and EE2, inhibit balloon arterial injury in the rat through direct effects on the vascular wall that involve the estrogen receptor and are at least partially independent of serum cholesterol.

Loss of expression of the beta subunit of soluble guanylyl cyclase prevents nitric oxide-mediated inhibition of DNA synthesis in smooth muscle cells of old rats.

We compared the effects of NO donors and cGMP analogues on the growth of aortic smooth muscle cells (SMCs) derived from newborn, adult (aged 3 months), and old (aged 2 years) rats. We found that the NO donor S-nitroso-N-acetylpenicillamine failed to block DNA synthesis in SMCs from old rats but was effective in SMCs from newborn and adult rats. However, cGMP analogues were inhibitory in all 3 SMC types. We demonstrated that in SMCs from old rats, NO was unable to increase the concentration of intracellular cGMP, suggesting that either cGMP synthesis was defective or cGMP degradation was enhanced. Western blot analysis revealed that SMCs from old rats do not express the beta subunit of soluble guanylyl cyclase. To confirm the importance of this observation in vivo, we balloon-injured the carotid arteries of adult and old rats. Whereas soluble guanylyl cyclase was expressed at the same level in the media of injured vessels and uninjured vessels of both groups, its expression in the intimas of old rats was reduced by 70% compared with intimas from adult animals. Furthermore, N(omega)-nitro-L-arginine, an inhibitor of NO synthesis, enhanced the intimal thickening in injured vessels in adult rats but not in old rats. We conclude that the loss of NO responsiveness in aged rats is due to the lack of the beta subunit of soluble guanylyl cyclase, and we speculate that this defect contributes to the enhanced intimal thickening in response to injury in old animals.

Cyclic GMP-dependent protein kinase regulates vascular smooth muscle cell phenotype.

Nitric oxide (NO) and cyclic guanosine 3',5'-monophosphate (cGMP) have been reported to prevent vascular smooth muscle cell (VSMC) proliferation and have beneficial effects to reduce intimal thickening in response to arterial injury. The purpose of this study was to determine whether the downstream effector molecule of NO-cGMP signaling, cyclic GMP-dependent protein kinase (PKG), regulates phenotypic modulation and proliferation in cultured rat aortic VSMC. PKG-expressing VSMC lines were created by transfection of PKG-deficient cell lines and characterized. All forms of PKG, i.e. PKG-I alpha and PKG-I beta, as well as the constitutively active catalytic domain of PKG-I, transformed dedifferentiated 'synthetic' VSMC to a more contractile-like morphology. PKG expression resulted in an increased production of the contractile phenotype marker proteins, smooth muscle myosin heavy chain-2, calponin and alpha-actin and restored the capacity of cAMP and cGMP analogues to inhibit platelet-derived growth factor (PDGF)-induced cell migration. On the other hand, PKG expression had no significant effects on PDGF-induced cell proliferation. These results suggest that PKG expression contributes to the regulation of a contractile-like phenotypic expression in cultured VSMC, and the suppression of PKG expression during cultured growth in vitro may permit the modulation of cells to a more synthetic, dedifferentiated phenotype.

Expression and function of a recombinant PDGF B gene in porcine arteries.

Platelet-derived growth factor (PDGF) B is a mitogen and chemoattractant for smooth muscle cells in vitro, and expression of a recombinant PDGF B gene in porcine arteries stimulates intimal thickening. To define the mechanisms by which PDGF B gene expression induces intimal thickening in vivo, we examined its effects on smooth muscle cell proliferation and migration, extracellular matrix synthesis, and inflammatory cell infiltration in intimal lesions of pig arteries after direct gene transfer of a recombinant PDGF B gene. PDGF B gene expression was associated with rapid formation of an intima, including 3- to 10-fold increases in intimal thickness and intima-to-media area ratio 4 to 21 days after gene transfer compared with control transfected arteries. Intimal smooth muscle cell proliferation was detected at 2 days, peaked at 7 days (P < .01), and declined by 14 days, although the total number of intimal nuclei progressively increased to 21 days (P < .01). Calculations of expected-to-observed ratios of intimal cells, based on BrdC proliferation indexes, demonstrated that the increases in intimal cell number on days 2 through 7 could not be accounted for by proliferation alone, suggesting that recombinant PDGF BB acts to stimulate cell proliferation and migration of smooth muscle cells into the intima. Extracellular matrix deposition and procollagen synthesis were observed after 7 days (P < .01) and were associated with a decline in cell density in the intima, suggesting that extracellular matrix synthesis may contribute to progressive intimal thickening in response to PDGF B gene expression. There was minimal accumulation of inflammatory cells, including macrophages and CD3(+) lymphocytes, in transfected arteries. These data suggest that PDGF B gene expression promotes intimal expansion by both proliferation and migration of smooth muscle cells followed by synthesis of extracellular matrix and therefore acts through several mechanisms to play a role in the pathogenesis of intimal lesions in vivo.

Pituitary factors in blood plasma are necessary for smooth muscle cell proliferation in response to injury in vivo.

Intimal thickening in response to vascular injury is inhibited in animals previously subjected to hypophysectomy. We have investigated the nature and cell kinetics of this effect in a balloon catheter model of injury to the rat carotid artery. The ability of injury to stimulate [3H]thymidine labeling 48 hours after injury was almost completely eliminated in hypophysectomized (hypox) compared with control animals (0.1% versus 32.1%). Total DNA content of the developing neointima 14 days after injury was only 30% of the values found in ballooned carotid arteries of normal rats. If hypox rats were treated with recombinant human growth hormone, the proliferative response was not restored. There are two possible general explanations for the reduction of proliferative response in hypox animals: 1) that smooth muscle cells in the hypox animals have lost the ability to respond to the stimulus of injury or 2) that the ability of the smooth muscle cells to respond has not been reduced by prior hypophysectomy, but that the response itself requires the presence of pituitary-dependent factors. Transplantation experiments were performed in vivo to distinguish between these possibilities. Carotid arteries in inbred Lewis rats were excised 1 hour after balloon injury to give platelets the opportunity to adhere. These vessels were then transplanted from hypox into control animals and vice versa. At 48 hours, proliferation of smooth muscle cells in "control-to-hypox" transplants was 0.3% compared with 14.3% in "control-to-control" transplants, whereas vessels from hypox rats increased their indices to 4.8% if transplanted into control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Toward a new tectonic model for the Late Proterozoic Araçuaí (SE Brazil)-West Congolian (SW Africa) Belt

The Araçuaí Belt is a Late Proterozoic (Brasiliano Cycle) geotectonic unit which was developed along the southeastern margin of the São Francisco Craton (SE Brazil) and was formerly considered as being an ensialic orogen. It is correlated with the Pan-African West Congolian Belt (SW Africa) in many reports. In the western domain of the belt, the Macaúbas Group—the most important supracrustal sequence related to the evolution of the Araçuaí Belt —comprises the Terra Branca and Carbonita Formations, which consist of littoral glacial sediments to shelf turbidites. These formations grade upward and eastward to the Salinas Formation, consisting of distal turbidites related to submarine fans, pelagic sediments, and a rock association (the Ribeirão da Folha Facies) typical of an ocean-floor environment. Banded iron formations, metacherts, diopsidites, massive sulfides, graphite schists, hyperaluminous schists, and ortho-amphibolites, intercalated with quartz-mica schists and impure quartzites, characterize the most distinctive and restricted volcano-sedimentary facies yet found within the Salinas Formation. Ultramafic slabs were tectonically emplaced within the Ribeirão da Folha Facies. Eight whole rock samples of meta-ultramafic rocks and ortho-amphibolites yielded a SmNd isochronic age of 793 ± 90 Ma ( ϵ Nd(T) = +4.1 ± 0.6. MSWD = 1.76 ). The structures of the northern Araçuaí Belt are marked by a doen-dip stretching lineation (western domain) related to frontal thrusts which controlled tectonic transport from east to west; stretching lineation rakes decrease in the eastern tectonic domain, indicating dominant oblique to transcurrent motion; the northern arch of the belt is characterized by major high-dip transcurrent shear zones. Our tectonic model starts with marked fracturing, followed by rifting that took place in the São Francisco-Congo Craton around 1000 ± 100 Ma (ages of basic intrusions and alkaline anorogenic granites). A sinistral transfer zone was established at the north rn boundary of the belt, controlling the ellargement of the Araçuaí-West Congolian rift, with the neighbouring northern cratonic region remaining essentially unaffected by compressional stresses. A period of ocean-floor spreading took place at about 800 Ma. Rift closure started at about 750 Ma and led to the reversal of motion along former extensional structures. The main Brasiliano-Pan-African orogenic period took place between 700 and 550 Ma and was marked by regional metamorphism and deformation related to both thrusting and transcurrent movements, and emplacement of syntectonic grranites derived from anatectic melts trigered by collisional crustal thickening. In this period, ultramafic slabs were emmlaced within the Ribeirão da Folha Facies, and both may represent an ophiolite-type suite. Late- to post-tectonic (500 to 550 Ma) intrusive granites were generated and emplaced in the Brazilian side along a major zone of crustal thickening in response to the last stages of collision.

Strain variations in an ancient accretionary complex: Implications for forearc evolution

Strain magnitudes and orientations and incremental strain histories are characterized throughout the Kodiak Formation, a portion of a Late Cretaceous‐early Tertiary accretionary prism. The results of these analyses are used to evaluate the history of underplating, penetrative strain, and unroofing in the forearc of the southwest Alaskan convergent margin. Five major deformation events are recognized in the Kodiak Formation: (1) layer‐parallel extension and layer‐parallel shear (D1) related to underthrusting, (2) seaward verging fold and thrust deformation (D2) with development of both a slaty cleavage (S2) and a downdip stretching lineation (L2) related to underplating and early penetrative strain within the wedge, (3) development of a regional scale antiform (D3), (4) development of a shear zone along the northwest limb of the D3 antiform (D4), and (5) right‐lateral strike‐slip faulting and penetrative right‐lateral simple shear in the seaward half of the Kodiak Formation (D5). Based on sharp differences in structural style and the magnitude and orientation of strain associated with D2, the Kodiak Formation has been subdivided into three structural units informally called the landward, central, and seaward belts. The structural variations observed in these three belts correspond to differences in structural relief of 1–5 km associated with the D3 antiform; the lowest D2 structural level is in the core of the antiform (central belt) and progressively higher structural levels are exposed on both limbs (landward and seaward belts). The regional distribution of incremental strain histories associated with D2, D3, D4, and D5 has been quantified by using syntectonic fibers in pressure shadows around spherical pyrite framboids. From the highest to the lowest structural level, D2 strain is characterized by (1) an increase in the magnitude of finite strain, (2) a change in the orientation of finite extension from nearly vertical to gently northwest plunging, (3) a change in the incremental extension direction from nearly vertical to moderately northwest plunging, and, finally, (4) a change in the strain history from coaxial to noncoaxial with a sense of rotation consistent with southeast directed thrusting. We interpret these D2 strain patterns to reflect a strain field that was fixed relative to the basal decollement, with coaxial subhorizontal shortening in the interior of the prism and noncoaxial strain (probably simple shear) near the base. Subsequent variations in the orientation of incremental extension associated with D3 are consistent with relatively rapid, vertical translation of the accreted sequences relative to the D2 strain field. We specifically propose two periods of wedge thickening in response to a combination of underplating and penetrative strain. These two wedge thickening events correspond with episodes of subaerial exposure and erosional unroofing in the Late Cretaceous and middle Tertiary.

Histamine-induced coronary spasm in regions of intimal thickening in miniature pigs: roles of serum cholesterol and spontaneous or induced intimal thickening.

The pathogenesis of histamine-induced coronary spasm was examined angiographically and morphometrically in Göttingen miniature pigs. In five of 36 consecutive pigs that were 4 to 5 months of age, coronary spasm was provoked by the intracoronary administration of histamine, and the left coronary arteries were examined histologically without endothelial denudation (group 1). Endothelial balloon denudation of the major branch of the left coronary artery was performed in 31 of 36 pigs and five died during the procedure. The remaining 26 pigs were randomly allotted to one of two groups, one fed a cholesterol-supplemented (group 2, n = 13) and one fed a regular low-cholesterol diet (group 3, n = 13). After 3 months, serum cholesterol increased significantly from 57 +/- 6 to 222 +/- 27 mg/dl (p less than .01) in group 2, but remained unchanged (48 +/- 5 to 55 +/- 6 mg/dl) in group 3. Percent narrowing of the coronary diameter induced by 10 micrograms/kg ic histamine after administration of the H2 blocker cimetidine (60 mg/kg iv) was 39 +/- 3% and 24 +/- 2% (p less than .05 between groups 2 and 3) at the nondenuded site and 78 +/- 3% and 74 +/- 4% at the denuded site in groups 2 and 3, respectively (p less than .01 between nondenuded and denuded sites). Histamine-induced percent narrowing of the coronary diameter after cimetidine in group 1, 2, and 3 pigs correlated well with the degree of intimal thickness on an exponential curve (r = .92, p less than .001). Since percent narrowing at the intact site was 27% (n = 19) in all three groups, predicted histamine-induced percent narrowing at the spastic site, applying the geometric theory, was 33 +/- 3%. Accordingly, enhanced constriction of the coronary artery with intimal thickening in response to histamine can largely be explained by the acquired hyperresponsiveness of the vascular wall to autacoids. This phenomena, not related to the level of serum cholesterol, may be uniquely linked to the basic pathology of evolution of atherosclerosis.

Effect of background illumination on evoked potentials of the visual system in the turtle

We discovered an enhancing effect of background illumination on amplitude and total duration of electrical reactions of the tectum of the midbrain and pallial thickening in response to a flash and electrical stimulation of the optic nerve. This effect is analogous to the phenomenon of photic potentiation known for the visual system of mammals. Changes of evoked potentials in the contralateral pallial thickening and tectum were fairly stable and survived throughout the course of the entire period of illumination (up to 30 min). The effect was intensified with an increase of illumination intensity. Intensification of response on the part of the tectum and pallial thickening during steady illumination was accompanied by a weakening of slow background electrical activity. During the action of background illumination, the excitability of the tectum rose considerably with direct electrical stimulation. The influence of prolonged illumination on responses of the tectum and pallial thickening was more clearly detected at submaximal strengths of stimulation of the optic nerve or tectum. All of the effects of photic potentiation are confined to centers contralateral to the illuminated eye. This indicates the absence of diffuse effects on excitability of the turtle brain.