Lack of adequate attention to elevated blood pressure in an urban hypertensive population.

BACKGROUND: Efforts directed at improving blood pressure (BP) control and outcomes of hypertension require insight into how physicians diagnose and manage hypertension in various practice settings, especially in the non-continuity setting. METHODS: Retrospective, cross-sectional study. Chart review of records of hypertensive patients, and patients with elevated BP, who visited the Urgent Care Center (UCC) of an urban teaching hospital. We examined patients' characteristics associated with the diagnosis and treatment of hypertension. RESULTS: Complaint of hypertension, request for medication refill, history of hypertension and high stages of hypertension, were associated with attention to BP. Complaint of hypertension and request for medication refill were associated with prescription for antihypertensive medications. Eighty percent of stage I, 50% of stage II, and 30% of stage III levels of BP did not have their BP addressed. Attention to the blood pressure reading was significantly associated with referral for follow-up care. CONCLUSIONS: Providers do not adequately acknowledge elevated BP in the UCC. Progress in the fight against hypertension will require a change in the practice of hypertension care in the non-continuity setting to recognize elevated blood pressures during patient encounters.

Cytoskeletal organization and cell motility correlates with metastatic potential and state of differentiation in prostate cancer.

The actin cytoskeleton is the key cellular machinery responsible for cellular movement. Changes in the organization and distribution of actin and actin binding protein are necessary for several cellular processes such as focal adhesion formation, cell motility and cell invasion. Here we examined differences in cytoskeletal protein distribution, cell morphometry and cell motility of metastatic and non-metastatic cells. Correlations were found between metastatic potential phenotypic properties such as cell motility, cell spreading and cytoskeletal organization in prostate cancer. As a cell progresses from a normal state to a malignant state, it loses its ability to function normally and also become poorly differentiated. Differentiation therapy is concerned with the redirection of malignant cells toward a terminal, non-dividing state using non-cytotoxic agents. Two well acknowledged differentiation agents, retinoic acid (RA) and diflouromethylomithine (DFMO) were examined for their ability to alter cellular phenotypes associated with metastatic potential in rat prostate cancer cell lines. The results of these studies indicate that there are sub-cellular differences between non-metastatic and highly metastatic cells relative to cytoskeletal organization. We also show that treatment of highly metastatic cells with either RA or DFMO significantly alters cell morphology, cell morphometry and motility to states similar to non-metastatic cells.

Enhanced nitric oxide synthesis reverses salt-induced alterations in blood flow and cGMP levels.

To understand the role of nitric oxide in salt-induced hypertension, we evaluated cardiovascular, hemodynamic and biochemical parameters in Dahl salt-sensitive rats fed low (0.3%) and high (8.0%) sodium diets. Two high salt groups received 1.25 and 2.5 g/L l-arginine in their drinking water. After three weeks of treatment, blood pressure was greater in the high salt groups. l-arginine did not modify salt-induced hypertension. Eicosapentaenoic acid (EPA) caused a smaller depressor response compared to normotensive rats. The increase in blood pressure was associated with decreases in aortic and renal blood flows. In renal artery, the reduction was counteracted by both l-arginine doses; whereas in the aorta, only the higher l-arginine one restored blood flow. The salt-induced reduction in aortic cyclic GMP level was only overcome by the higher l-arginine treatment. These data suggest that at the dose levels tested, nitric oxide reverses the reduction in cGMP and blood flow, but not the blood pressure changes associated with salt-induced hypertension.

Influence of changes in gravity on the response of lung and vascular cells to ischemia/reperfusion in vitro.

Gravity and other physical forces (e.g., shear stress or mechanical stretch) will affect organ and cellular function, e.g., blood flow distribution, gas exchange, alveolar size and mechanical stresses within the lung. Microgravity produced marked alterations in lung blood flow and ventilation distribution while hypergravity exaggerated the regional differences in lung structure and function. Microgravity was found to decrease the metabolic activity in cardiac cells, WI-38 embryonic lung cells, and human lymphocytes. These studies show that changes in gravity will affect several aspects of organ and cellular function and produce major changes in blood flow and tissue/organ perfusion. However, these past studies have not addressed whether ischemia-reperfusion injury will be exacerbated or, ameliorated by changes in the gravity environment, e.g., space flight. Currently, nothing is known about how gravity will affect the susceptibility of different lung and vascular cells to this type of injury. Ischemia injury is the underlying cause of many clinical disorders with high morbidity and mortality. The subsequent reperfusion (reoxygenation) further compounds the initial ischemic stress. Understanding the possible exacerbation of transient ischemia under the stress of space flight or an increase in gravity is critical. We conducted studies that examined whether alterations in gravity affect the susceptibility of cells to ischemia-reperfusion injury, using an in vitro anoxia-reoxygenation model.

Wound healing following injury to vascular smooth muscle cell cultures is modulated by culture under hypergravity.

Anticipated hazards for crewmembers in future long-term space flights may result in a variety of injuries including fractures, deep punctures or cuts. The microgravity environment of space may complicate the wound healing process. Myofibroblasts have been proposed to play a role in wound contraction; these cells develop from tissue fibroblasts sue fibroblasts develop numerous features found in vascular smooth muscle cells (SMC), ultrastructural features, expression of alpha-SM actin and microfilament bundles. These changes have been shown to be inducible by TGF beta 1. Previous studies have also shown that TGF beta 1 is capable of initiating and regulating critical events in bone fracture, soft tissue, dermal wound healing. Several studies have suggested that bFGF may also be involved in the wound healing process, and that the interactions of bFGF with TGF beta 1 control the overall repair of a wounded tissue. The formation (angiogenesis) and/or repair of blood vessels is also essential for wound healing. Both TGF beta 1 and bFGF have been shown to affect both angiogenesis and vascular injury repair. However, the response of cells following injury, in a microgravity or hypergravity (HG) environment has not been evaluated. We assessed the influence of HG (centrifugation at 6G) and clinostat rotation at 30 rpm (CR) on the response of SMC to a denudation injury. We also examined the possible involvement of c-myc, c-fos and TGF beta 1 in meeting the response of SMC to wounding.

Plasma 25-hydroxyvitamin D concentrations are inversely associated with blood pressure of Dahl salt-sensitive rats.

Dietary salt is a contributing factor to the development of hypertension in individuals who are salt-sensitive. The vitamin D endocrine system has been reported to modulate vascular structure and function. Since elderly hypertensive females with low plasma renin activity, typical of salt-sensitivity, had significantly lower 25-hydroxyvitamin D concentrations compared with normotensive elderly and young females, we have used Dahl salt-sensitive and salt-resistant rats fed high (80 g/kg diet) and low (3 g/kg diet) salt diets as models to examine the relationship between salt-sensitivity and 25-hydroxyvitamin D, the precursor of the hormonal form of vitamin D, 1,25-dihydroxyvitamin D. Plasma 25-hydroxyvitamin D concentrations of salt-resistant rats were unaffected by a high salt diet, but plasma 25-hydroxyvitamin D concentrations of salt-sensitive rats were significantly reduced within three weeks to lower than 25%. There was a negative association between plasma 25-hydroxyvitamin D concentrations of salt-sensitive rats and the number of days that the rats were fed a high salt diet (r = -0.98, P < 0.02) and a positive association between blood pressure and the number of days that the rats were fed a high salt diet (r = 0.97, P < 0.05). An inverse relationship was found between plasma 25-hydroxyvitamin D concentrations and blood pressure (r = -0.99, P < 0.01). Spontaneously hypertensive rats did not have low plasma 25-hydroxyvitamin D concentrations, suggesting that reduction of plasma 25-hydroxyvitamin D concentration might be specific to salt-induced hypertension.

Possible mechanisms of salt-induced hypertension in Dahl salt-sensitive rats.

Genetic factors, diet, and salt sensitivity have all been implicated in hypertension. To further understand the mechanisms involved in salt-induced hypertension, cardiovascular, hemodynamics, and biochemical parameters in Dahl salt-sensitive rats were evaluated in animals on high- and low-sodium diets. During a 4-week treatment period, blood pressure was significantly elevated in the high (8.0%) salt group compared to the low (0.3%) salt group (p< or =0.05 for weeks 2 and 4, respectively). No significant changes were observed in heart rate. The increase in blood pressure was associated with significant increases in lower abdominal aortic and renal vascular resistance, along with a reduction in blood flow. A fourfold increase in arginine vasopressin was observed in animals on the high-salt diet. In contrast, there was no effect on plasma sodium, potassium, or aldosterone levels during the treatment period. As measured in isolated aortic rings, the high-salt diet also caused a significant elevation in stimulated norepinephrine release and a reduction in cyclic GMP levels. These data suggest that salt-induced elevation in blood pressure is due to activation of both the sympathetic and arginine vasopressin systems via mechanisms involving decreased cyclic GMP generation in vascular smooth muscle.

Is there a difference in hypertensive claim rates among Medicaid recipients?

The purpose of this study was to determine whether there are racial differences in the rates of prevalence and new claims to Medicaid for hypertension treatment in a population of uniformly low economic status--i.e., Georgia Medicaid recipients. Age-specific and age-adjusted prevalence rates of hypertension in 1991 and the first 1991 claim rates by race and gender were calculated. Gender-specific black-to-white risk ratios, using the Mantel-Haenszel pooled point estimate (RMH) and the corresponding test-based 95 percent confidence interval (CI) were also calculated. African-American females were more likely than African-American males, or whites of either sex to have hypertension diagnoses. For newly claimed cases, the gender-specific black-to-white risk ratios were significant in malignant hypertension for both females (RMH = 1.9, 95 percent CI 1.4-2.5) and males (RMH = 2.0, 95 percent CI 1.2-3.7) and in unspecified hypertension for females (RMH = 1.5, 95 percent CI 1.4-1.6), but were less significant in unspecified hypertension for males, and in benign hypertension for both sexes. Using Medicaid data may have caused underestimation of the prevalence and incidence of hypertension among Medicaid recipients; however, significant racial differences in the "occurrence" of hypertension still existed among them. Factors other than the household income status may be responsible for much of the excess risk of hypertension in the black Medicaid population.

Lipids, lipoproteins and coronary heart disease in minority populations.

Despite recent advances in both prevention and treatment, cardiovascular disease (CVD) remains the leading cause of mortality in the US. The Framingham Study was a landmark in defining CHD-related risk factors; unfortunately, very few minorities were included. A major preventable risk factor for CHD continues to be lipid abnormalities, but its association within minority populations is unclear. The few studies that have examined the association of hyperlipidemia with CHD in minorities have shown that total cholesterol was a predictor of CHD risk (e.g., black men aged 35-64). Several researchers have reported higher levels of HDL for black men and women compared to white men and women. Since HDL was shown to be inversely related to CHD, this discrepancy in HDL is hypothesized to account for the lower than expected mortality rate. Lipoprotein(a) has been identified as an independent risk factor for CHD; blacks have considerably higher levels than whites. Data also indicate the following: Hispanics have lower CVD mortality rates than the general population despite having known risk factors (e.g., obesity, diabetes, low socioeconomic status); Hispanic women have lower levels of HDL cholesterol; Native-American populations have lower prevalence of CHD associated with lower LDL-cholesterol and higher HDL-cholesterol. Understanding epidemiologic and pathophysiologic data regarding differences between various racial groups should help reduce CVD-related morbidity and mortality in minority populations.

Inhibition of steroidogenesis by luteal cells of early pregnancy in the rat in response to in vitro administration of a gonadotropin-releasing hormone agonist.

Previous studies from this laboratory have demonstrated that the administration of a gonadotropin-releasing hormone agonist (GnRH-Ag) in vivo in early or mid-pregnancy to rats induces antifertility effects by suppressing the luteal production of progesterone (P4) within 24h with a concomitant increase in luteal lipid droplets and decreases in the luteal cytochrome P450 side chain cleavage (P450scc) enzyme and its mRNA content. These observations suggest a direct inhibitory effect of GnRH-Ag on the corpus luteum. Here we demonstrate a suppressive effect of GnRH-Ag in vitro on the basal P4, pregnenolone (P5) and 20 alpha-dihydroprogesterone (20 alpha-DHP) production by luteal cells obtained during early pregnancy in rats. We further studied its effect on two key enzymes, namely P450scc and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), which participate in the conversion of cholesterol to P5 and conversion of P5 to P4, respectively. We observed that two doses of GnRH-Ag, 10(-4) and 10-7 M, suppress the basal P4 production in vitro after 12 h of incubation by luteal cells; P4 remained suppressed after 48 h of incubation. Basal P5 production was also suppressed after luteal cells were incubated for 12 h with 10(-4) M and 10(-7) M GnRH-Ag, but incubation for 48 h with GnRH-Ag failed to alter P5 production by these cells. 20 alpha-DHP production was suppressed after incubating the luteal cells with both doses of GnRH-Ag for 12 h. GnRH-Ag inhibited P450scc activity after 12 h of incubation and 3 beta-HSD protein content at all time periods measured. These results suggest that GnRH exerts a direct inhibitory effect on luteal steroidogenesis. This inhibition is due to its suppressive effect on P450scc and/or 3 beta-HSD and not due to an increase in P4 metabolites.

Biometric assessment of prostate cancer's metastatic potential.

Currently, no protocol exists that can assess the metastatic potential of prostate adenocarcinoma. The reason for this is partly due to the lack of information on cellular changes that result in a tumor cell's becoming metastatic. In this investigation, attempts were made to devise a method that correlated with the metastatic potential of AT-1, Mat-Lu, and Mat-LyLu cell lines of the Dunning R-3327 rat prostatic adenocarcinoma system. To accomplish this, we applied BioQuant biometric parameters, i.e., area, shape factor, and cell motility. AT-1 had a lower shape factor and a greater area as compared with the more highly metastatic Mat-Lu subline. No significant difference in area or shape factor was detected between the AT-1 cell line and the highly metastatic Mat-LyLu line. However, the lowly metastatic AT-1 line had less motility as compared with the Mat-Lu and Mat-LyLu lines. This study revealed that metastatic potential could be partially predicted via area and shape factor and accurately predicted via cell motility.

Adhesion and invasion potential of rat prostatic cancer cells: correlation with metastatic potential.

This investigation examined the ability of low-metastatic AT-1 and high-metastatic ML and MLL cell lines to adhere to a monolayer of bovine aortic endothelial cells and fibronectin substratum and penetrate a matrigel basement membrane matrix. Cell area, shape factor, and motility as influenced by fibronectin were also examined using these cell lines. The ability of these cells to adhere to fibronectin and traverse matrigel matrix correlated with their metastatic potential. In addition, fibronectin increases cell circularity and reduces cell area as metastatic potential increases within AT-1 to ML or MLL cell lineages.

Influence of low density lipoproteins on vascular smooth muscle cell growth and motility: modulation by extracellular matrix.

Low density lipoproteins (LDL) are thought to play a major role in cardiovascular diseases such as atherosclerosis. Much remains to be done to understand the cellular effects of LDL and how the extracellular matrix (ECM) influences these effects. We found that LDL produced a dose dependent increase in vascular smooth muscle cell (SMC) proliferation. The ECM altered the proliferative response of SMC to LDL: on collagen I there was a 66% inhibition, endothelial cell derived-ECM a 2-fold increase, and collagen IV no difference in proliferation compared to paired controls. LDL affected SMC motility (cell area and shape factor) but the extent and direction of the effect depended on whether the cells were cultured on uncoated or coated dishes. LDL treated cultures had a 5-fold lower migration rate but net movement was not different, suggesting that LDL decreased SMC random movement. There was a dose-dependent accumulation of lipid by SMC incubated with LDL and, subsequently, cytoplasmic lipid droplets were observed. Cells cultured on uncoated plates showed an increased cholesterol content as a function of LDL concentration. In contrast, cells cultured on a collagen IV matrix showed no net change in cholesterol content over the range of LDL concentrations studied. Hence, the uptake of LDL cholesterol appears to be completely inhibited by this matrix. These studies indicate that the influence of LDL on several SMC parameters is modulated by ECM components.

Racial differences in mortality from cardiovascular disease in Atlanta, 1979-1985.

Mortality from cardiovascular disease (CVD) for the period 1979 to 1985 in the Atlanta metropolitan population was reviewed for racial differences. About 28% of the population was black in 1980. Of 22,585 deaths from hypertension, stroke, ischemic heart disease, and atherosclerosis, 78.7% occurred among whites and 21.3% among blacks. Overall, ischemic heart disease accounted for 47.7% of these four types of CVD deaths for both races and sexes. Age-specific and age-adjusted rates were compared. Among these four causes of death, blacks have the greatest excess of deaths from hypertension over whites for both males and females; the excesses were more than 200% when the rates were age-adjusted. The excess risk of death from hypertension occurred for all ages in blacks, with an excess of about 10 times in 30- to 49-year-olds. An excess risk from stroke also occurred in blacks below the age of 75; the risk reversed afterward. The age-specific mortality rates revealed an excess from ischemic heart disease only between the ages of 30 and 59 years and from atherosclerosis between 40 and 59 years of age for black men. This age-related crossover in females did not occur until the age of 75 years for deaths attributed to these causes. These data suggest that blacks were at highest risk for all four causes at younger age groups.

Extracellular matrix mediated growth and differentiation in human pigment epithelial cell line 0041.

Efforts to grow differentiated pigment epithelial cells have led to a characterization of the growth kinetics of spontaneously established, continuously growing, human retinal pigment epithelial (PE) cell line 0041 on several biomatrices. These substrates were prepared from (a) placental and amniotic membrane, (b) commercially available basement membrane matrix (Matrigel), (c) dishes coated with extracellular matrix secreted by endothelial cells (ECM), (d) dishes coated with collagen IV and/or laminin, (e) dishes coated with collagen I and/or fibronectin. Our findings suggest that tissue culture plastic and dishes coated with collagen IV alone promote higher cell densities, while highest plating efficiency (24 hrs) was seen on tissue culture plastic and Matrigel. The highest degree of differentiation (epithelioid appearance, apical villi and junctional complexes) was seen in cells plated on dishes coated with collagen IV and extracellular matrix secreted by endothelial cells. Cells were epithelioid and polarized on those two substrates; they expressed fine finger-shaped villi and the highest degree of cell contact (in the form of junctions). Cells grown on Matrigel looked like fibroblasts and became deeply pigmented; however, the nature of the pigment remains to be determined. Collagen IV and ECM coated dishes, therefore, are most suitable for cultures of human PE cell line 0041 because they provide higher cell densities while retaining the differentiated state. This is the first report where an established pigmented epithelial cell line has been induced to become differentiated by use of extracellular matrices and extracellular matrix components.

Stimulation of vascular cell proliferation by beta-galactoside specific lectins.

An investigation was conducted to assess the effects of various beta-galactoside specific lectins on the growth of vascular cells in vitro. The plant lectins from peanut (Arachis hypogaea), mushroom (Agaricus bisporus), and coral tree (Erythrina corallodendron) were used in these studies with the ultimate purpose of comparing those findings with data derived with the lectin isolated from rat lung. Peanut lectin was added to confluent and subconfluent cultures of smooth muscle cells (SMC), pulmonary arterial (PEC), and aortic endothelial cells (BAEC) at concentrations of 2, 3.5, and 7.0 micrograms/ml. There was a dose-dependent increase in cell proliferation for both confluent and subconfluent SMC, with maximal stimulation noted between 3.5 and 7 micrograms/ml of peanut lectin. A dose-dependent stimulation of PEC proliferation was also found with maximal stimulation between 3.5 and 7.0 micrograms/ml. Peanut lectin did not stimulate BAEC to multiply. The stimulation of PEC and SMC by peanut lectin could be prevented by the addition of 50 mM lactose. Peanut and mushroom lectin stimulated the proliferation of sparse cultures of SMC in a dose-dependent fashion in both standard (10% fetal bovine serum, or FBS) or low (0.5% FBS) serum to about the same degree. Coral tree lectin did not have a significant stimulation of proliferation under either serum conditions. The incorporation of [3H]thymidine into the DNA of PEC was increased 30 and 150% by peanut lectin and lung galaptin, respectively, under standard serum conditions. However, under low serum conditions, both lectins increased incorporation by about the same extent (93 and 78% for peanut lectin and galaptin, respectively). Both lectins produced a 30% increase in DNA synthesis by SMC under standard serum conditions, and about a 200% increase under low serum conditions. These studies indicate that beta-galactoside specific lectins such as lung galaptin have mitogenic activity toward vascular cells.

Movement of Entamoeba histolytica trophozoites in rat cecum and colon intact mucus blankets and harvested mucus gels.

Entamoeba histolytica trophozoites were centrifuged into mucus gels harvested from in vivo loops of rat cecum and proximal colon. Frank ameba movement was not detected in the colonic mucus, but attenuated motility was measured in the cecal mucus. The harvested rat cecal mucus had significantly lower apparent viscosity and neutral glycoprotein concentration values than the colonic mucus. A shape factor method was developed to assess the motility of amebae in mucus gels and intact mucus blankets. Shape factor data obtained from harvested mucus gel and intact mucus blanket experiments indicated that such mucus severely attenuated trophozoite movement with the attenuation being greater with colonic than with cecal mucus. Entamoeba trophozoites are known to be able to generate a pseudopod force of 3.3 x 10(-6) Newtons. Latex microspheres of the size range of Entamoeba trophozoites were forced through cecal and colonic mucus gels under gravity. Colonic mucus gels could withstand a force of 3.3 x 10(-6) Newtons while cecal mucus could not, suggesting that the ameba movement that was observed in cecal mucus involved mechanical penetration of the mucus by the ameba pseudopodia and did not require prior gel dissolution by Entamoeba enzymes.

In vitro and in vivo effects of endothelial cell-derived growth factor.

Endothelial cells in culture produce a growth factor with an apparent molecular weight of 10,000 to 30,000 daltons. This material, the endothelial cell-derived growth factor ( ECDGF ), can replace the requirement of 3T3 and smooth muscle cells for exogenous mitogens. ECDGF , added to plasma-derived serum, a platelet deficient preparation of plasma, supports growth of these cells to confluency. Lyophilized preparations of the ECDGF stimulate migration of smooth muscle cells into an in vitro wound. The same material induces an angiogenic response when implanted on the chick chorioallantoic membrane. Thus two requirements of an angiogenic response, migration and proliferation, are supplied by endothelial cell products.

Neovascular responses induced by cultured aortic endothelial cells.

Neovascularization was studied in the chorioallantoic membrane of the chick embryo after implantation of bovine aortic endothelial and smooth muscle cells, Swiss and BALB/c 3T3 cells and human diploid fibroblasts cultured separately on microcarrier beads. Quantitative analysis of neovascularization indicated a 3 1/2-fold increase in the number of blood vessels responding to endothelial cells while smooth muscle cells induced a twofold increase when compared to the response of beads without cells. Skin fibroblasts and Swiss 3T3 cells did not elicit a comparable response. The marked angiogenic response induced by endothelial cells was characterized by a 137% increase in total vessel length and a 35% increase in average vessel area when compared to controls. Two of the properties required for an angiogenesis factor--stimulation of cellular migration and proliferation--can also be demonstrated using endothelial cell-conditioned medium in cell culture systems. Medium from cultured bovine aortic endothelium stimulates DNA synthesis, proliferation, and migration of smooth muscle cells. In addition, conditioned media from both endothelial cells and smooth muscle cells produced an angiogenic response in the chorioallantoic membrane assay, which was comparable to that produced by intact cells growing on microcarrier beads. Similar responses were not evident with medium conditioned by other cell types. These results indicate the potential importance of endothelial cells and endothelial cell products in regulating blood vessel growth.