Is there a need for a '100 questions exercise' to enhance fisheries and aquatic conservation, policy, management and research? Lessons from a global 100 questions exercise on conservation of biodiversity.

Recent global and regional exercises have been undertaken to identify 100 questions of relevance to policy makers that, if answered, would improve decision making and conservation actions. These were intentionally broad, but all included themes and questions of relevance to aquatic and fisheries professionals (e.g. exploitation, habitat alteration, effectiveness of protected areas, migratory connectivity and environmental effects of aquaculture). Here, the content of the global 100 question exercise relevant to aquatic and fisheries issues is summarized and a critical analysis is provided. Many of the questions addressed in apparently unrelated themes and topics (e.g. terrestrial, agriculture and energy policy) have potential relevance to fisheries and aquatic habitats, which underlines the connectivity between terrestrial and aquatic realms. Given the intimate link between aquatic environmental problems and human activities (including culture and economics), greater understanding of the human dimension is required to inform decision making. Stakeholder perspectives need to be included as a core component of the fisheries management triangle (i.e. managing fish, habitat and people). The benefits and risks of conducting a global 100 questions exercise with an exclusive focus on questions of relevance to fisheries and aquatic practitioners are also considered. There is no question that evidence-based approaches to conservation are essential for addressing the many threats that face aquatic ecosystems and reverse the imperilment trends among ichthyofauna. It is still unclear, however, as to the extent to which 100 questions exercises will help to achieve conservation and management targets for aquatic resources. A global 100 questions exercise that focused on fisheries and aquatic issues would certainly help to generate interest and awareness sufficient to justify such an exercise.

Oxidative stress and renal dysfunction in salt-sensitive hypertension.

Hypertension is a risk factor for the development of end-stage renal disease. The mechanisms underlying hypertensive nephropathy are poorly understood. There is evidence, however, that in hypertension there is an accumulation of partially reduced oxygen and its derivatives, known collectively as reactive oxygen species, which may contribute to progressive renal dysfunction. In the present study, we assess the contribution of oxidative stress in the development of salt-dependent hypertensive nephrosclerosis. Going beyond previous end point studies, which inferred renal function either indirectly or only qualitatively, we have determined oxidative stress concurrently with direct and quantitative measurements of renal function (via inulin and p-aminohippuric acid clearances). Moreover, in this time-dependent study, the measurements have been taken under low- as well as high-salt diets. As was expected from previous studies, in the Dahl salt-sensitive rat, a high-salt diet (8% NaCl) resulted in the development of hypertension, in a decreased glomerular filtration rate, and in a decreased renal plasma flow as compared with the normotensive control, the Dahl salt-resistant rat. In addition, however, we found clear evidence for the accumulation of reactive oxygen species in renal tissue homogenates of Dahl salt-sensitive rats on the high-salt diet. Our time-dependent protocol also indicated that renal oxidative stress follows, in time, the development of hypertension. We also found that after 2 weeks of increased salt loading, Dahl salt-sensitive rats excreted less cyclic guanosine monophosphate and NO(x) than Dahl salt-resistant rats on the same diet. It is known that urinary cyclic guanosine monophosphate and NO(x) represent the activity and stable derivatives of renal NO., respectively, and that they closely correlate with renal vascular resistance. Therefore, our results suggest that, in the Dahl salt-sensitive rat, increased oxidative stress is associated with salt-dependent hypertensive nephrosclerosis and that decreased NO. bioavailability may represent a common factor responsible for the vascular and glomerular dysfunction.

Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia.

Homocysteine is a risk factor for the development of atherosclerosis and its thrombotic complications. We have employed an animal model to explore the hypothesis that an increase in reactive oxygen species and a subsequent loss of nitric oxide bioactivity contribute to endothelial dysfunction in mild hyperhomocysteinemia. We examined endothelial function and in vivo oxidant burden in mice heterozygous for a deletion in the cystathionine beta-synthase (CBS) gene, by studying isolated, precontracted aortic rings and mesenteric arterioles in situ. CBS(-/+) mice demonstrated impaired acetylcholine-induced aortic relaxation and a paradoxical vasoconstriction of mesenteric microvessels in response to superfusion of methacholine and bradykinin. Cyclic GMP accumulation following acetylcholine treatment was also impaired in isolated aortic segments from CBS(-/+) mice, but aortic relaxation and mesenteric arteriolar dilation in response to sodium nitroprusside were similar to wild-type. Plasma levels of 8-epi-PGF(2alpha) (8-IP) were somewhat increased in CBS(-/+) mice, but liver levels of 8-IP and phospholipid hydroperoxides, another marker of oxidative stress, were normal. Aortic tissue from CBS(-/+) mice also demonstrated greater superoxide production and greater immunostaining for 3-nitrotyrosine, particularly on the endothelial surface. Importantly, endothelial dysfunction appears early in CBS(-/+) mice in the absence of structural arterial abnormalities. Hence, mild hyperhomocysteinemia due to reduced CBS expression impairs endothelium-dependent vasodilation, likely due to impaired nitric oxide bioactivity, and increased oxidative stress apparently contributes to inactivating nitric oxide in chronic, mild hyperhomocysteinemia.

Salt-induced hypertension in Dahl salt-resistant and salt-sensitive rats with NOS II inhibition.

Although recent evidence suggests that reduced nitric oxide (NO) production may be involved in salt-induced hypertension, the specific NO synthase (NOS) responsible for the conveyance of salt sensitivity remains unknown. To determine the role of inducible NOS (NOS II) in salt-induced hypertension, we treated Dahl salt-resistant (DR) rats with the selective NOS II inhibitor 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT) for 12 days. Tail-cuff systolic blood pressures rose 29 +/- 6 and 42 +/- 8 mmHg in DR rats given 150 and 300 nmol AMT/h, respectively (P < 0.01, 2-way ANOVA) after 7 days of 8% NaCl diet. We observed similar results with two other potent selective NOS II inhibitors, S-ethylisourea (EIT) and N-[3-(aminomethyl)benzyl]acetamidine hydrochloride (1400W). Additionally, AMT effects were independent of alterations in endothelial function as assessed by diameter change of mesenteric arterioles in response to methacholine using videomicroscopy. We, therefore, conclude from these data that NOS II is important in salt-induced hypertension.

Cell-surface protein disulfide isomerase catalyzes transnitrosation and regulates intracellular transfer of nitric oxide.

Since thiols can undergo nitrosation and the cell membrane is rich in thiol-containing proteins, we considered the possibility that membrane surface thiols may regulate cellular entry of NO. Recently, protein disulfide isomerase (PDI), a protein that catalyzes thio-disulfide exchange reactions, has been found on the cell-surface membrane. We hypothesized that cell-surface PDI reacts with NO, catalyzes S-nitrosation reactions, and facilitates NO transfer from the extracellular to intracellular compartment. We observed that PDI catalyzes the S-nitrosothiol-dependent oxidation of the heme group of myoglobin (15-fold increase in the rate of oxidation compared with control), and that NO reduces the activity of PDI by 73.1 +/- 21.8% (P < 0.005). To assess the role of PDI in the cellular action of NO, we inhibited human erythroleukemia (HEL) cell-surface PDI expression using an antisense phosphorothioate oligodeoxynucleotide directed against PDI mRNA. This oligodeoxynucleotide decreased cell-surface PDI content by 74.1 +/- 9.3% and PDI folding activity by 46.6 +/- 3.5% compared with untreated or "scrambled" phosphorothioate oligodeoxynucleotide-treated cells (P < 0.0001). This decrease in cell-surface PDI was associated with a significant decrease in cyclic guanosine monophosphate (cGMP) generation after S-nitrosothiol exposure (65.4 +/- 26.7% reduction compared with control; P < 0.05), with no effect on cyclic adenosine monophosphate (cAMP) generation after prostaglandin E1 exposure. These data demonstrate that the cellular entry of NO involves a transnitrosation mechanism catalyzed by cell-surface PDI. These observations suggest a unique mechanism by which extracellular NO gains access to the intracellular environment.

S-Transnitrosation reactions are involved in the metabolic fate and biological actions of nitric oxide.

S-Nitrosothiols are a group of potent, bioactive compounds that form through the reaction of nitric oxide (NO) with thiols in the presence of oxygen. These compounds are naturally occurring in vivo, stabilize NO and potentiate its biological effects. S-Nitrosoglutathione is the most abundant intracellular S-nitrosothiol, and the kinetics for its formation favors de novo synthesis. In this analysis, we studied the formation of S-nitrosothiols by S-transnitrosation, or exchange of -NO for -H between sulfur atoms; we synthesized S-nitroso-glutathionyl-Sepharose 4B beads (SNO-4B) as a reagent with which to measure S-transnitrosation reactions. We detected a maximum of 1.57 +/- 0.24 pmol NO/bead (n = 5) after S-nitrosation of the beads with acidified nitrite. The stability of the S-NO bond was dependent on temperature, but not pH over the 5 to 9 range (except at pH 9 at 37 degrees ), with an estimated t1/2 of 30 hr at 22 degrees C and of approximately 2 wk at 4 degrees C. We demonstrated that SNO-4B transfers -NO to glutathione and to cysteine rapidly and in a pH-dependent manner. The initial rate of transfer of -NO from SNO-4B to glutathione at room temperature was 0.53, 3.03 and 5.14 microM/min at pH 5.0, 7.4 and 9.0, respectively (P < .05). Under the same conditions, the initial rate of -NO transfer to cysteine was 0. 72, 3.71 and 4.69 microM/min at pH 5.0, 7.4 and 9.0, respectively (P < .05). There was no appreciable S-transnitrosation between SNO-4B and bovine serum albumin. We further demonstrated that SNO-4B evokes significant vasodilator and platelet inhibitory responses in plasma-free systems and activates platelet soluble guanylyl cyclase. These data suggest a mechanism by which to explain the metabolic fate and distribution of NO among thiol pools in the vasculature, and implicate S-transnitrosation at the cell surface in NO signal transduction.

Recombinant human macrophage colony-stimulating factor reduces plasma cholesterol and carrageenan granuloma foam cell formation in Watanabe heritable hyperlipidemic rabbits.

Previous studies have demonstrated that short-term administration of recombinant human macrophage colony-stimulating factor (rhM-CSF) reduces plasma cholesterol in rabbits, nonhuman primates, and human subjects. This study extended the dose schedule of rhM-CSF to 8 weeks of continuous intravenous infusion (CIV) in the Watanabe heritable hyperlipidemic (WHHL) rabbit and expanded the scope to include an assessment of macrophage-derived foam cell development. Ten male WHHL rabbits were injected subcutaneously with 1% carrageenan to promote formation of a macrophage-rich foam cell granuloma. Rabbits were infused with either vehicle or rhM-CSF at 100 micrograms/kg per day (weeks 1 through 5) followed by 300 micrograms/kg per day (weeks 6 through 8). rhM-CSF (100 micrograms/kg per day) decreased total plasma cholesterol by 45% at 2 weeks compared with controls. The gradual return of plasma cholesterol toward control concentrations over the subsequent 3 weeks correlated with the appearance of circulating antibodies specific to rhM-CSF. Granuloma weights at harvest (8 weeks after infusion) were significantly lower (2.8 +/- 0.7 g, mean +/- SEM) in rhM-CSF-treated rabbits relative to controls (7.1 +/- 1.5 g, P < .05). Granulomas from rabbits treated with rhM-CSF contained lower concentrations of cholesterol (2.0 +/- 0.7 versus 6.1 +/- 1.5 micrograms/mg, P < .03) and cholesteryl ester (0.7 +/- 0.4 versus 3.9 +/- 1.2 micrograms/mg, P < .03) than controls. Histological evaluation revealed that granulomas from the rhM-CSF-treated rabbits were more fibrous and contained fewer foam cells than those from controls.(ABSTRACT TRUNCATED AT 250 WORDS)

PPACK attenuates plasmin-induced changes in endothelial integrity.

In order to determine whether plasmin affects endothelial cell integrity directly, confluent bovine aortic endothelial cells were treated with plasminogen and a plasminogen activator. The permeability of the monolayer to [125I]-albumin was shown to be increased significantly (P < 0.01) with a concomitant decrease in viability. Plasmin activity correlated significantly with endothelial cell permeability (p < 0.004; r = 0.82). Coincubation with D-phenylalanyl-L-prolyl-L-arginyl chloromethylketone, a tripeptide inhibitor of plasmin, reduced the increase in endothelial permeability induced by plasmin by 59% (p = 0.033). Monolayers studied in parallel were stained with rhodamine-phalloidin to visualize F-actin. There were significant morphologic changes in the endothelial monolayers exposed to plasmin compared to control monolayers, and these changes could be attenuated by coincubation with D-phenylalanyl-L-prolyl-L-arginyl chloromethylketone. These studies show that: 1) plasmin induces significant increases in endothelial cell permeability with accompanying morphologic changes; and 2) these deleterious functional and morphologic effects can be attenuated by coincubation with the plasmin inhibitor, D-phenylalanyl-L-prolyl-L-arginyl chloromethylketone.

Effect of thrombin inhibition on the dynamics of thrombolysis and on platelet function during thrombolytic therapy.

To evaluate the effect of thrombin on the dynamics of thrombolysis, we infused rabbits with heparin or hirudin alone or in conjunction with tissue-type plasminogen activator (t-PA) and monitored the kinetics of fibrinolysis and changes in ex vivo platelet aggregation responses over time. Both heparin and hirudin enhanced total fibrinolysis in an ex vivo arteriovenous shunt preparation: 82 +/- 2% and 79 +/- 2%, respectively, compared with 51 +/- 8% for t-PA alone (P less than 0.05) and 50 +/- 4% for t-PA plus aspirin (p less than 0.05). Heparin coadministered with t-PA significantly reduced the half-time for clot lysis compared with t-PA alone (p less than 0.05), whereas hirudin coadministered with t-PA significantly reduced the half-time for clot lysis compared with that for t-PA alone, t-PA plus aspirin, and t-PA plus heparin (5.5 +/- 0.6 versus 12.1 +/- 2.0 versus 12.6 +/- 2.2 versus 10.0 +/- 0.8 minutes, respectively; p less than 0.05). Both heparin and hirudin prevented the increase in ADP-induced platelet aggregation normally seen with t-PA alone (p less than 0.01 by t test; p less than 0.05 by two-way analysis of variance). These data demonstrate that selective, antithrombin III-independent thrombin inhibitors can enhance the efficacy of thrombolysis by modulating the dynamics of the process and preventing platelet activation associated with plasminogen activator therapy.

Thrombolytic therapy causes an increase in vascular permeability that is reversed by 1-deamino-8-D-vasopressin.

BACKGROUND: To examine the effect of plasminogen activator therapy on vascular permeability, we used a modified rabbit mesenteric model of extravascular tissue accumulation of radiolabeled albumin. METHODS AND RESULTS: Albumin deposition was measured after saline, tissue-type plasminogen activator (t-PA; 0.86 mg/kg for 1 hour followed by 0.29 mg/kg for 2 hours), or t-PA plus 1-deamino-8-D-arginine vasopressin (DDAVP; 0.6 mg/kg/hr for 30 minutes) infusion in animals with or without aspirin (ASA; 15-mg/kg bolus) pretreatment. In animals not given ASA, t-PA caused a 240% increase in tissue [125I]albumin accumulation over time (p less than 0.001). DDAVP prevented the rise in albumin accumulation normally seen with t-PA alone (p less than 0.05) in animals not given ASA. In animals pretreated with ASA, t-PA similarly caused an increase in tissue albumin accumulation, but this was significantly attenuated from that of animals not given ASA (p less than 0.03). Interestingly, DDAVP failed to block the response to t-PA in the animals given ASA. Because increases in vascular permeability correlated with increases in bleeding time (r = 0.37, p less than 0.03), these data suggest that the effect of plasmin generation on vascular permeability may contribute to the bleeding tendency seen with thrombolytic therapy. The ability of DDAVP to reverse the bleeding tendency and bleeding time may be due in part to its reversal of the increased vascular permeability induced by the administration of plasminogen activators. CONCLUSIONS: These data show that plasminogen activation causes an increase in vascular permeability that is inhibited by DDAVP; ASA blunts this action of t-PA and prevents the DDAVP blockade of the increase in permeability induced by t-PA in this rabbit model.

Bleeding time prolongation with streptokinase and its reduction with 1-desamino-8-D-arginine vasopressin.

The mechanism by which treatment with thrombolytic agents causes bleeding is not known. Recently, frequency of bleeding events has been shown to correlate with bleeding time, particularly in individuals treated with aspirin. We examined the effects of streptokinase (20,000-60,000 IU/kg) on bleeding time in 40 rabbits pretreated with aspirin, a model for fibrinolytic therapy. We then tested the effects of 1-desamino-8-D-arginine vasopressin (DDAVP) (0.3 microgram/kg), an agent known to reduce bleeding time in a variety of bleeding disorders, in 20 rabbits and compared the results with those of a control group of rabbits receiving normal saline placebo. Aspirin increased the bleeding time from a baseline mean +/- SEM value of 119 +/- 15 to 191 +/- 34 seconds in the control group and from 114 +/- 6 to 188 +/- 18 seconds in the experimental group. The addition of streptokinase increased the bleeding time to 592 +/- 119 seconds in the control group and 810 +/- 114 seconds in the experimental group (p = NS). Subsequent infusion of DDAVP decreased the bleeding time in the experimental group to 302 +/- 29 seconds (p less than 0.01 versus streptokinase) compared with 572 +/- 79 seconds (p = NS versus streptokinase) in the control animals given saline placebo. In a subset of rabbits receiving aspirin and streptokinase (40,000-60,000 IU/kg), samples were obtained for platelet aggregation (n = 16), von Willebrand factor antigen concentration (n = 17), and von Willebrand factor multimer distribution (n = 14). Maximal rates of ADP-induced platelet aggregation were not affected by DDAVP infusion, nor was the plasma concentration of von Willebrand factor antigen, quantified by an immunoradiometric assay, significantly affected by DDAVP infusion. Furthermore, the von Willebrand factor multimer ratio decreased with DDAVP administration. These findings indicate that aspirin and streptokinase combined result in a marked increase in bleeding time that can be reduced by DDAVP. This effect of DDAVP is not accompanied by an increase in platelet aggregation response, plasma von Willebrand factor antigen concentration, or von Willebrand factor multimer ratio.

Temporal effects of thrombolytic agents on platelet function in vivo and their modulation by prostaglandins.

To examine the temporal effects of plasmin generated in vivo on platelet function, we infused tissue-type plasminogen activator (t-PA) in rabbits over 3 hours and measured ex vivo platelet aggregation. We noted an initial increase in the aggregation response to ADP occurring 30 minutes after the start of infusion. This enhanced response was short-lived and by 180 minutes was reduced, compared with pretreatment levels. Baseline aggregation response was restored by 240 minutes. This pattern of aggregation response to t-PA infusion was also seen with thrombin as the agonist. Coinfusion of either prostaglandin I2 or prostaglandin E1 abolished the initial hyperaggregable phase induced by t-PA; the hypoaggregable phase occurred earlier (after 60 minutes) and persisted throughout the 1-hour recovery period. Similarly, streptokinase infused for 1 hour also increased platelet aggregation at early times and then reduced aggregation responses after the first hour. Plasma plasmin activity increased as expected with t-PA infusion alone, peaking at 30 minutes and returning to baseline by the first hour. Interestingly, prostaglandin E1 blunted the rise in plasma plasmin activity. This same dose of prostaglandin E1 or prostaglandin I2 used alone did not appreciably alter platelet function at any time during the experiment. Our data show that therapeutic doses of t-PA or streptokinase produce a biphasic effect on platelet aggregation response in the rabbit. Coinfusion of either of the antiplatelet agents, prostaglandin E1 or prostaglandin I2, abolishes the hyperaggregable phase and prolongs the inhibitory effects on platelet aggregation produced by t-PA. These data suggest that the effects of thrombolytic agents on platelet function are complex and can be modulated by antiplatelet prostaglandins.

Plasma membrane enrichment with cis-unsaturated fatty acids enhances LDL metabolism in U937 monocytes.

The mechanism by which dietary cis-unsaturated fatty acids lower low density lipoprotein (LDL) cholesterol is unknown. Because cis-unsaturated fatty acids incorporated into cell membranes increase membrane fluidity and, as a result, can alter membrane-dependent cell functions, we examined LDL binding, uptake, and degradation in upregulated U937 monocytes enriched in membrane oleate, a monounsaturated fatty acid, and membrane linoleate, a polyunsaturated fatty acid. The same parameters were also examined in upregulated U937 monocytes enriched in membrane stearate, a saturated fatty acid, and in upregulated, unmodified U937 monocytes. Monocytes enriched in cis-unsaturated fatty acids exhibited augmented LDL binding, internalization, and degradation compared with both stearate-enriched monocytes and unmodified monocytes. The molar potency of linoleate in augmenting LDL metabolism was 50% greater than that of oleate. Enrichment with oleate and linoleate resulted in a decrease in the fatty acyl mole-weighted melting point of the plasma membrane and an increase in plasma membrane fluidity, as indicated by a reduction in the steady-state fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene incorporated into the membrane. Stearate-enriched monocytes exhibited a slight increase in the plasma membrane fatty acyl mole-weighted melting point and essentially no change in plasma membrane fluidity. Thus, one mechanism by which cis-unsaturated fatty acids lower LDL cholesterol may involve alteration in membrane lipid composition and physical properties, thereby leading to an increase in cellular clearance of this atherogenic lipoprotein.

Effect of dietary fat saturation and cholesterol on low density lipoprotein degradation by mononuclear cells of Cebus monkeys.

The mechanism by which dietary unsaturated fatty acids lower low density lipoprotein (LDL) cholesterol is unknown. Unsaturated fatty acids incorporated into the cell membrane can increase membrane fluidity and, as a result, dramatically alter membrane-dependent cell functions. Therefore, we examined the effect of long-term dietary consumption of corn oil and coconut oil with and without cholesterol in amounts equivalent to those of a typical Western diet on the degradation of human LDL by peripheral blood mononuclear cells in Cebus albifrons monkeys. Cellular LDL degradation was dramatically enhanced in the mononuclear cells isolated from animals fed corn oil in comparison with those from animals fed coconut oil. The addition of cholesterol to the diets resulted in a slight attenuation of LDL degradation in the corn oil group while no effect was noted in the coconut oil group. Crossover LDL binding and degradation experiments with LDL isolated from animals fed corn oil diets and coconut oil diets demonstrated increased binding and degradation of LDL in mononuclear cells from animals fed corn oil diets. Enhanced mononuclear cell LDL degradation was accompanied by increased cellular cis-unsaturated fatty acyl content, increased membrane fluidity, and decreased plasma cholesterol. Increased cellular cis-unsaturated fatty acyl content with its concomitant increase in membrane fluidity mirrored the dietary lipid profile of the host animal. A linear relationship was observed between cellular LDL degradation and both cellular cis-unsaturated fatty acyl content and membrane fluidity. These observations parallel results noted in whole-animal LDL catabolic studies with these same animals described elsewhere. These data suggest a novel mechanism by which dietary unsaturated fatty acids exert their LDL-lowering effect.

Atrial natriuretic factor-specific antibody as a tool for physiological studies. Evidence for role of atrial natriuretic factor in aldosterone and renal electrolyte regulation.

Numerous studies have shown that administration of atrial natriuretic factor (ANF) increases urinary sodium excretion and urine flow, decreases blood pressure, and inhibits renin and aldosterone release. However, the role of endogenous ANF in the regulation of renal sodium excretion, blood pressure, plasma renin activity, and aldosterone level remains to be elucidated. To examine this issue, endogenous ANF was blocked by administering rat ANF-(99-126) specific antiserum (Ab) to anesthetized rats (n = 7). Control animals received either no injection (time controls, n = 10) or preimmune serum (n = 8). Blockade of endogenous ANF caused a 28 +/- 0.09%, 47 +/- 0.08%, and 51 +/- 0.08% fall in sodium excretion at 15, 30, and 45 minutes after Ab injection (p less than 0.05, p less than 0.01, p less than 0.01, respectively). Urine flow fell 35 +/- 7% at 45 minutes after ANF inhibition (p less than 0.05). Plasma ANF levels were suppressed to undetectable levels. However, there were no changes in blood pressure throughout the experiment nor plasma renin concentration when measured at 45 minutes after Ab injection. Interestingly, plasma aldosterone concentration increased significantly (by approximately 50%, p less than 0.025), in response to Ab. Completeness of blockade was demonstrated by the absence of sodium excretion response to exogenous ANF (500 ng). In either the time control or the preimmune serum group, urinary excretion, blood pressure, plasma ANF, plasma renin concentration, and plasma aldosterone concentration were unchanged throughout the experiment. In contrast to the Ab group, a challenge with exogenous ANF (500 ng) increased sodium excretion by 2.17 mueq/min in the preimmune serum group.(ABSTRACT TRUNCATED AT 250 WORDS)

Frequency of hypercholesterolemia after cardiac transplantation.

Cardiac transplant patients are prone to accelerated coronary atherosclerosis. The mechanism by which this process occurs is not yet known, although immunologically mediated arterial injury is thought to play a primary role in its pathogenesis. Despite immunosuppressive potency, patients treated with cyclosporin A remain at significant risk for the development of accelerated atherosclerosis. It is hypothesized that cyclosporin A's hepatotoxic effects might contribute to the atherosclerotic process by impairing low density lipoprotein hepatic clearance in transplant patients, which would be reflected in a more atherogenic lipoprotein profile. To test this hypothesis, serum cholesterol levels were analyzed after transplantation. Significant and progressive increases in total cholesterol and in the total-to-high density lipoprotein cholesterol ratio were found. This atherogenic lipoprotein profile may contribute to accelerated atherosclerosis in cardiac transplant patients treated with cyclosporin A.

Unsaturated fatty acids enhance low density lipoprotein uptake and degradation by peripheral blood mononuclear cells.

The precise mechanism by which unsaturated fatty acids lower low density lipoprotein cholesterol is not known. Because cis-unsaturated fatty acids incorporated in cell membranes increase membrane fluidity and can thereby dramatically alter membrane-dependent cellular functions, we examined the effect of linoleate and oleate incorporation in peripheral blood mononuclear cell membranes on the physical properties of the membrane and concomitantly on low density lipoprotein uptake and degradation. We found that membrane enrichment with linoleate increased the rate of low density lipoprotein degradation in both freshly isolated and derepressed mononuclear cells. Enrichment with oleate led to similar increases in degradation. "Specific" low density lipoprotein uptake by derepressed cells was also enhanced by linoleate and oleate incorporation. Enrichment with both of these fatty acids produced an increase in membrane fluidity, as indicated by a reduction in the steady-state fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene incorporated in the membrane. In contrast, stearate enrichment had little effect on uptake or degradation of low density lipoprotein, nor did it affect membrane fluidity. These data point to a novel mechanism for the reduction in low density lipoprotein produced by unsaturated fatty acids that involves their physical effects on cell membranes as it relates to metabolism of the lipoprotein.

Acute renal denervation produces a diuresis and natriuresis in young SHR but not WKY rats.

Clearance experiments were conducted to determine the effect of acute unilateral renal denervation (DNX) on renal hemodynamics and salt and water excretion in anesthetized 6-wk-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto genetic control rats (WKY). Before DNX, SHR had higher mean arterial pressure (33%) and renal vascular resistance (RVR) (57%) and lower glomerular filtration rate (GFR) (10%); urine flow and sodium excretion were similar. Following DNX in SHR, sodium and water excretion increased by 138 and 62%, respectively (P less than 0.001); GFR and RVR were unchanged. In contrast, DNX in WKY did not affect urine flow (0%) or sodium excretion (-21%). These strain differences were observed in Okamoto-Aoki rats from two sources. Effective DNX was indicated by 95% reduction of norepinephrine content 3 days after DNX in both strains. Six-week-old Sprague-Dawley and Munich-Wistar rats, in contrast to WKY, responded to DNX with a natriuresis (+182%) and diuresis (+95%) (P less than 0.001). Renal function was unaffected by sham DNX in SHR. Our results indicate that efferent renal nerve activity has little tonic influence on the renal vasculature in these young rats. Augmented neurotransmitter release and/or tubular responsiveness may be involved in fluid and electrolyte retention and the pathogenesis of hypertension in SHR. Conversely, blunted renal neuroeffector responses may prevent WKY from developing hypertension.