Baseline cardiovascular risk in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: The Strategic Timing of AntiRetroviral Treatment (START) trial has recruited antiretroviral-naïve individuals with high CD4 cell counts from all regions of the world. We describe the distribution of cardiovascular disease (CVD) risk factors, overall and by geographical region, at study baseline. METHODS: The distribution of CVD risk factors was assessed and compared by geographical region among START participants who had a baseline electrocardiogram (n = 4019; North America, 11%; Europe/Australia/Israel, 36%; South America, 26%; Asia, 4%; Africa, 23%; median age 36 years; 26% female). RESULTS: About 58.3% (n = 2344) of the participants had at least one CVD risk factor and 18.9% (n = 761) had two or more. The most common CVD risk factors were current smoking (32%), hypertension (19.3%) and obesity (16.5%). There were significant differences in the prevalence of CVD risk factors among geographical regions. The prevalence of at least one risk factor across regions was as follows: North America, 70.0%; Europe/Australia/Israel, 65.1%; South America, 49.4%; Asia, 37.0%; Africa, 55.8% (P-value < 0.001). Significant regional differences were also observed when risk factors were used as part of the Framingham and Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) risk scores or used to define a favourable risk profile. CONCLUSIONS: CVD risk factors are common among START participants, and their distribution varies by geographical region. Better understanding of how and why CVD risk factors develop in people with HIV infection and their geographical distributions could shed light on appropriate strategies for CVD prevention and may inform the interpretation of the results of START, as CVD is expected to be a major fraction of the primary endpoints observed.

Effect of statin therapy in reducing the risk of serious non-AIDS-defining events and nonaccidental death.

BACKGROUND: Excessive inflammation persists despite antiretroviral treatment. Statins decrease cardiovascular (CV) disease risk by reducing low-density lipoprotein cholesterol and inflammation. We performed an exploratory analysis to evaluate whether statin therapy decreased risk of non-AIDS-defining events and nonaccidental death. METHODS: A total of 3601 subjects not on a statin from the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort were included. Outcome was time to first clinical event (CV event, renal or hepatic disease, incident diabetes, thrombotic/embolic event, nontraumatic fracture, non-AIDS-defining malignancy, serious bacterial infection, or nonaccidental death); event categories were also analyzed separately. Inverse probability of treatment and censoring weighted Cox proportional hazard models were used to assess the causal statin effect. Differential statin effects by baseline covariates were evaluated. RESULTS: Over 15 135 person-years (PY) of follow-up, 484 subjects initiated statins; 616 experienced an event (crude event rate, 4.4/100 PY on a statin and 4.1/100 PY not on a statin); the unadjusted hazard ratio (HR) was 1.17 (95% confidence interval [CI], .91-1.50). In a final weighted model, the adjusted HR (AHR) was 0.81 (95% CI, .53- 1.24). Results for other clinical events were similar, except for malignancies (AHR, 0.43 [95% CI, .19-.94]) and bacterial infections (AHR, 1.30 [95% CI, .64-2.65]). No differential statin effects by baseline covariates were detected. CONCLUSIONS: Although statin therapy was not associated with a reduction in time to all non-AIDS-defining event or nonaccidental death, it was associated with a statistically significant 57% reduction in non-AIDS-defining malignancies. Confirmatory studies are needed to evaluate statin-associated reduction in risk of cancer and non-AIDS-associated morbidities.

The effect of inhibition of prostaglandin synthesis on urinary sodium excretion in the conscious dog.

Studies were performed to determine the effect of decreased endogenous release of renal prostaglandins on urinary sodium excretion. Two structurally dissimilar inhibitors of prostaglandin synthesis were employed, and studies were performed in conscious dogs allowed to recover from prior surgical instrumentation. Either meclofenamate (2 mg/kg) or the competitive prostaglandin inhibitor RO 20-5720 (1 mg/kg) was given to seven unanesthetized dogs undergoing a water diuresis. The administration of either prostaglandin inhibitor did not alter glomerular filtration rate, renal plasma flow, urinary volume, or potassium excretion. Sodium excretion, however, increased from 32 to 130 mueq/min (P less than 0.02). Essentially, the entire increase in sodium excretion was due to an increase in urinary sodium concentration from 7.7 to 28.3 meq/liter (P less than 0.02). On a different day, the same animals were studied before and after administration of the diluent of the prostaglandin inhibitor. No change was noted in sodium excretion or any other parameter. Thus, these findings suggest that prostaglandin inhibition in the conscious dog is associated with a natriuresis without a change in urinary volume or potassium excretion during water diuresis. This may indicate that the natruiresis was due to diminished sodium reabsorption beyond the distal tubule.

Further studies on segmental sodium transport in the rat kidney during expansion of the extracellular fluid volume.

The present studies were designed to further investigate the possibility of heterogeneity of nephron function during Ringer loading in the rat, and to determine the specific nephron segment responsible for this finding. As in previous studies from this laboratory with smaller rats (50-125 g), net addition of sodium between late distal tubule and papillary base (6.9 vs. 10.4% of the filtered load, respectively, P <0.005) was found in more mature rats (170-230 g). In contrast, there was net reabsorption of sodium between these two segments in nonvolume-expanded animals, 1.70 vs. 0.45% of the filtered sodium load, P <0.005. Because nephron heterogeneity of sodium transport during extracellular volume expansion is the most likely explanation for these findings, further studies were performed to determine the specific juxtamedullary nephron segment responsible for the net addition pattern between late distal tubule and papillary base in Ringer-loaded animals. First, a comparison was made of sodium delivery to the late proximal tubule of superficial nephrons vs. the delivery rate to the bend of Henle's loop of juxtamedullary nephrons in both hydropenia and Ringer loading. Fractional sodium delivery was quite comparable between the superficial and juxtamedullary nephrons in both hydropenia and Ringer loading although the absolute level was much greater in both groups of nephrons in the Ringer studies. Chlorothiazide (15 mg/kg loading and 15 mg/kg per h) given during Ringer loading markedly increased late distal sodium delivery, 19% of the filtered load, but did not prevent net addition of sodium at the papillary base. In contrast, furosemide (5 mg/kg loading and 5/mg/kg per h) given during Ringer loading completely reversed the segmental pattern, 35.5 and 28.8% at late distal tubule and papillary base, respectively, P <0.005. These studies demonstrate that the net addition of sodium between late distal tubule and papillary base during Ringer loading is not limited to immature rats and that the segmental pattern does not occur in non-volume-expanded animals. Further, the reversal of the net addition pattern with furosemide, but not chlorothiazide, and the comparable proximal nephron delivery rates in Ringer loading suggest that the loop of Henle of juxtamedullary nephrons reabsorbs less sodium than the same portion of superficial nephrons in this setting. A model is proposed to explain this finding.

Direct measurement of papillary collecting duct sodium transport in the rat. Evidence for heterogeneity of nephron function during Ringer loading.

It has been suggested that collecting duct sodium transport was inhibited by extracellular volume expansion. To directly evaluate this possibility, micropuncture of the papillary collecting duct of young rats was performed during hydropenia and Ringer loading. The possibility of heterogeneity of nephron function was evaluated during Ringer and hyperoncotic albumin loading by comparing the delivery of sodium to the end of the distal tubule of superficial nephrons with papillary base delivery. During hydropenia (n = 14), sodium delivery to the base averaged 0.95% of the filtered sodium load and reabsorption along the collecting duct was noted from base to tip in each collection pair averaging 0.80% of the filtered load. During Ringer loading, sodium delivery to the base was markedly greater than in hydropenia, 11.8 vs. 0.95% of the filtered load (P less than 0.001). Yet, sodium reabsorption was also much greater, 6 vs. 0.8% (P less than 0.001). In 13 paired collections, during Ringer loading, sodium delivery to the papillary base, 12.2% of the filtered load, was consistently greater than late distal tubular delivery from superficial nephrons. 8% (P less than 0.005). In contrast, reabsorption of sodium from late distal tubule to papillary base was found during albumin infusion, 6.2 vs. 3.1% (P less than 0.001). Therefore, these studies demonstrate that: (a) the delivery of sodium to and reabsorption along the papillary collecting duct were markedly greater during Ringer loading than in hydropenia; (b) the amount of sodium delivered to the papillary base was greater than the delivery to the end of the distal tubule of superficial nephrons during Ringer loading, suggesting that deeper nephrons deliver more sodium to the collecting duct in this setting; and (c) the difference in sodium excretion between Ringer loading and hyperoncotic albumin infusion is due to events occurring between the late distal tubule of superficial nephrons and the base of the papillary collecting duct.

Uterine blood flow and uterine renin secretion.

Experiments were carried out in pregnant nephrectomized rabbits to determine the relationship between uterine blood flow and uterine renin secretion. Uterine blood flow was measured by the percentage distribution of radioactive microspheres injected into the left ventricle which lodged in uterus and placenta, and cardiac output was measured by dye dilution. In 40 animals, 24 hr after nephrectomy, uterine blood flow was 4.7+/-0.4% of cardiac output and absolute flow 32.4+/-3 ml/100 g per min. Plasma renin activity (PRA) in uterine vein, 994+/-182 ng/100 ml per hr, was higher than in carotid artery, 832+/-143 (P < 0.025). With reduction of uterine blood flow from 4.7+/-0.5 to 1.95+/-0.3% of cardiac output and absolute flow from 30.8+/-4.6 to 8.8+/-2 ml/100 g per min, uterine vein PRA rose from 1434+/-234 to 4430+/-300 (P < 0.001), and carotid artery PRA from 1009+/-200 to 2300+/-350 (P < 0.01). Hemorrhagic hypotension caused uterine vein PRA to increase from 913+/-293 to 3638+/-1276 (P < 0.001) and carotid artery PRA from 774+/-252 to 1730+/-433 (P < 0.01). Uterine blood flow expressed as a percentage of cardiac output remained constant after hemorrhage, 5.5+/-0.9 and 6.3+/-0.8%, although absolute flow fell from 37+/-7.7 to 29+/-3.6 ml/100 g per min because of the large fall in cardiac output which occurred.Angiotensin, 10 ng/kg per min, caused no significant change in blood pressure or cardiac output but increased uterine blood flow from 4.1+/-0.6 to 8.4+/-1% (P < 0.005) of cardiac output with absolute flow increasing from 37.4+/-7 to 73.2+/-10 ml/100 g per min (P < 0.001). The increase in uterine blood flow during angiotensin was abolished by the prior administration of propranolol. Isoproterenol, 0.5 mu/min, increased uterine blood flow from 3.5+/-0.6 to 6.4+/-1.2% of cardiac output (P < 0.02) with absolute flow increasing from 25+/-5 to 51+/-12 ml/100 g per min (P < 0.05). Norepinephrine, 500 ng/min, caused no significant change in uterine blood flow. These findings suggest that uterine renin might be involved in regulating uterine blood flow, secretion being increased in response to a reduction in flow with the resultant rise in circulating or local angiotensin, through beta adrenergic stimulation, increasing uterine blood flow.

The effect of changes in perfusion pressure on uteroplacental blood flow in the pregnant rabbit.

The effect of perfusion pressure on uteroplacental blood flow was determined in pregnant rabbits utilizing the radioactive microsphere method. Control mean arterial pressure, 93 mm Hg +/- 2.6 SEM, was raised by carotid ligation to 109 +/- 4.1 mm Hg and then reduced with antihypertensive drugs to 74 +/- 1.3 mm Hg. Over this range of pressure there was no significant change in cardiac output, 605 +/- 36, 523 +/- 37, and 540 +/- 39 ml/min; or uteroplacental blood flow, 30 +/- 3.2, 27 +/- 5.2, and 29 +/- 4.5 ml/min, respectively. When prostaglandin synthesis was inhibited with either indomethacin or meclofenamate (2 mg/kg), uterine vascular resistance was higher but maintenance of uteroplacental flow occurred over a perfusion pressure of 89 +/- 6.7-115 +/- 9.3 mm Hg. With more severe hypotension induced with trimethaphan, control arterial pressure fell from 92 +/- 2.4 to 39 +/- 0.9 mm Hg, cardiac output fell from 514 +/- 17 to 407 +/- 22 ml/min (P less than 0.025) and uteroplacental blood flow fell from 6.1 +/- 0.9 to 2.5 +/- 0.9% of cardiac output (P less than 0.05), which represented an absolute fall from 32.4 +/- 5 to 10.6 +/- 3 ml/min (P less than 0.025). There was no significant change in renal blood flow expressed as percentage of cardiac output, 14.9 +/- 2 and 13 +/- 1.5%, or in absolute flow, 75 +/- 7.7 and 54 +/- 7 ml/min with trimethaphan-induced hypotension. These studies indicate that uteroplacental blood flow is maintained relatively constant over a range of perfusion pressure of 60-140 mm Hg in both normal and prostaglandin-inhibited pregnant rabbits. However, with reduction in pressure to 36-42 mm Hg, uteroplacental blood flow falls, expressed as a percentage of cardiac output and in absolute flow.

Uterine prostaglandin E secretion and uterine blood flow in the pregnant rabbit.

Studies were performed in pregnant rabbits to assess the effect of inhibition of prostaglandin synthesis on uterine blood flow. Cardiac output and uteroplacental blood flow (UPBF) were measured using radiolabeled microspheres. Prostaglandin E (PGE) concentration was measured by radioimmunoassay in the uterine vein and peripheral artery of the pregnant nephrectomized rabbit. Either meclofenamate or indomethacin 2 mg/kg were utilized to inhibit prostaglandin synthesis. Systemic arterial pressure increased from 86 mm Hg to 98 mm Hg (P less than0.0001) after prostaglandin inhibition. Cardiac output was unchanged after the inhibition of prostaglandin synthesis, 326 ml/min to 7.8 ml/min. Uterine vein PGE concentration was extremely high, 172.4 ng/ml, with concomitant peripheral arterial PGE 2.1 NG/ML. Intravenous administration of either meclofenamate or indomethacin reduced uterine vein PGE to 23 ng/ml (P less than 0.01) and arterial PGE to 1.0 ng/ml (P less than 0.05). Male and nonpregnant female rabbits had lower arterial PGE, 0.37 ng/ml (P less 0.05). Studies in non-nephrectomized pregnant animals demonstrated that uteroplacental secretion of PGE was greater than five times renal secretion. These studies demonstrate that the rabbit uteroplacental unit is a rich source of PGE and suggest that production of the vasoactive lipid may have a key role in regulating UPBF during pregnancy.

A comparison of the segmental analysis of sodium reabsorption during Ringer's and hyperoncotic albumin infusion in the rat.

Studies were designed to compare the segmental analysis of sodium reabsorption along the nephron during volume expansion with either 10% body weight Ringer's or 0.6% body weight hyperoncotic albumin. Total kidney and nephron glomerular filtration rate increased similarly with both, but urinary sodium excretion (12.7 vs. 4.0 mueq/min, P < 0.001) and fractional sodium excretion (5.0 vs. 1.6%, P < 0.001) increased to a greater extent with Ringer's. Fractional reabsorption of sodium in the proximal tubule was diminished in both groups but to a significantly greater extent during Ringer's (P < 0.005). Absolute reabsorption was inhibited only in the Ringer's group. Delivery of filtrate out of the proximal tubule was greater in the Ringer's studies, 45 vs. 37 nl/min (P < 0.001). However, both fractional and absolute sodium delivery to the early and late distal tubule were not significantly different in the two groups. Fractional reabsorption in the collecting duct decreased from 96% in hydropenia to 31% during Ringer's but fell only slightly to 80% in the albumin studies. Absolute collecting duct reabsorption was also greater in the albumin studies, 0.55 vs. 0.21 neq/min (P < 0.001), which could totally account for the difference in urinary sodium excretion between the two groups. (22)Na recovery in the final urine after end distal microinjections was 71% during Ringer's infusion and 34% during albumin (P < 0.001). From these data we conclude that: (a) Ringer's solution has a greater inhibitory effect on proximal tubular sodium reabsorption, and (b) in spite of this effect, differences in mucosal to serosal collecting duct sodium transport are primarily responsible for the greater natriuresis during Ringer's infusion.

Mechanism of the redistribution of renal cortical blood flow during hemorrhagic hypotension in the dog.

Studies were performed to define the mechanisms involved in the redistribution of renal cortical blood flow to inner cortical nephrons which occurs during hemorrhagic hypotension in the dog. The radioactive microsphere method was utilized to measure regional blood flow in the renal cortex. Renal nerve stimulation decreased renal blood flow 40% but had no effect on the fractional distribution of cortical blood flow. Pretreatment with phenoxybenzamine, phentolamine, propranolol, or atropine did not alter the redistribution of cortical flow during hemorrhage. A reduction in renal perfusion pressure by aortic constriction caused a qualitatively similar alteration in regional blood flow distribution as occurred during hemorrhage. When perfusion pressure was kept constant in one kidney by aortic constriction followed by hemorrhage, no redistribution occurred in the kidney with a constant perfusion pressure while the contralateral kidney with the normal perfusion pressure before hemorrhage had a marked increase in the fractional distribution of cortical flow to inner cortical nephrons. Additionally, retransfusion had no effect on the fractional distribution of flow in the kidney in which perfusion pressure was maintained at the same level as during hemorrhage while in the contralateral kidney in which pressure increased to normal there was a redistribution of flow to outer cortical nephrons. These studies indicate that the redistribution of renal cortical blood flow which occurs during hemorrhage is not related to changes in adrenergic activity but rather to the intrarenal alterations which attend a diminution in perfusion pressure.

Studies on the mechanism of reduced urinary osmolality after exposure of renal papilla.

Studies were performed in Munich-Wistar rats to determine whether changes in papillary plasma flow might be responsible for the concentrating defect which occurs after exposure of the extrarenal papilla. Papillary plasma flow was measured by (125)I-albumin accumulation. Initial studies in hydropenic animals revealed that papillary plasma flow was 40% higher in the kidney with the exposured papilla, 41 vs. 29 ml/min per 100 g of papilla (P < 0.001). This increase in papillary plasma flow was detectable 15 or 45 min after removing the ureter. Because it was unclear whether the rise in papillary plasma flow was a cause or the result of the fall in urine osmolality, similar studies were performed in animals undergoing a water diuresis. In this setting, papillary plasma flow still increased on the exposed side compared to the control side, 81 vs. 60 ml/min per 100 g, despite similarly low urine osmolalities of 155 and 174 mosmol/kg, respectively. This finding is compatible with the possibility that papillary exposure per se causes an increase in papillary plasma flow and that this hemodynamic alteration may lead to a reduction in urinary osmolality secondary to washout of the medullary interstitium. A final group of hydropenic rats was given either indomethacin or meclofenamate before removing the ureter. In these studies, there was no difference in either the papillary plasma flow or the urine osmolality between control and exposed kidneys. It is therefore suggested that opening the ureter induces an increase in papillary plasma flow by some mechanism which may involve an alteration in prostaglandin synthesis.

Effect of renal vasodilatation on the distribution of cortical blood flow in the kidney of the dog.

Studies were performed to evaluate the validity of using the radioactive microsphere technique to measure regional blood flow in the renal cortex. A technique was developed in which the renal cortex was divided into four equal zones, and the fractional and absolute distribution of blood flow in these zones was determined. It was consistently found that approximately 70% of the renal blood flow was distributed to the two outer cortical zones with the remaining 30% going to the two inner cortical zones. In addition, there was a reproducible pattern of distribution of blood flow in different areas of the same kidney after a single injection of microspheres and in the same area of the kidney after multiple injections of microspheres. Using this method, the distribution of renal blood flow was determined before and during the intrarenal administration of either acetylcholine (40 mug/min) or bradykinin (5 mug/min). Both agents decreased the per cent of blood flow to outer cortical zone 1, caused no change in zone 2, and increased the fractional blood flow in inner cortical zones 3 and 4. When this data was evaluated in terms of total blood flow, there was no change in zone 1, an increase in zone 2 commensurate with the change in total blood flow, and a marked increase in inner cortical zones 3 and 4 which accounted for 60 and 65% of the increase in total blood flow during acetylcholine and bradykinin administration, respectively.Therefore, the natriuresis of renal vasodilatation is associated with a redistribution to inner cortical nephrons.

Studies on the mechanism of sodium excretion during drug-induced vasodilatation in the dog.

The administration of vasodilating agents such as bradykinin and acetylcholine cause an increase in urinary sodium excretion. Yet the mechanisms involved in this natriuretic effect are not clear. Recent studies with another renal vasodilator, secretin have shown this drug also causes a profound increase in renal blood flow but without major changes in sodium excretion. To attempt to delineate the basis of this difference in sodium excretion with these drugs, the renal functional effects of secretin and bradykinin were compared at an equivalent vasodilating dose. Bradykinin increased renal blood flow from 222 to 342 ml/min, urine volume from 0.2 to 1.2 ml/min, and urine sodium excretion from 28 to 115 mueq/min. Urine osmolality fell from 1,230 to 401 mosmol/kg. Secretin caused a comparable increase in renal blood flow (216 to 325 ml/min) while changes in urine flow, sodium excretion, and urine osmolality were significantly less. In further studies papillary plasma flow was estimated using the albumin accumulation technique. Control papillary plasma flow was 29 ml/min per 100 g. Bradykinin increased urinary sodium excretion 108 mueq/min and decreased urinary osmolality from 1,254 to 516 mosmol/kg in association with a rise in papillary plasma flow to 62 ml/min per 100 g. Urine sodium excretion, urinary osmolality, and urine flow rate, as well as papillary plasma flow rate (32 ml/min per 100 g) were unchanged from control when secretin was administered. Studies with acetylcholine were qualitatively similar to those of bradykinin. Renal blood flow increased from 150 to 248 ml/min, urinary sodium excretion increased from 20 to 243 mueq/min, urinary osmolality decreased from 1,237 to 411 mosmol/kg and papillary plasma flow increased from 39 to 52 ml/min per 100 g. It is suggested that the natriuretic effect of some vasodilators is due, at least in part, to alterations in medullary hemodynamics, as evidenced by the increase in papillary plasma flow seen with bradykinin and acetylcholine, but not secretin.

The measurement of nephron filtration rate and absolute reabsorption in the proximal tubule of the rabbit kidney.

Micropuncture studies were performed in the rabbit to determine nephron filtration rate and absolute fluid reabsorption in the proximal tubule in order to compare the latter value with data obtained with the in vitro microperfusion technique. New Zealand white rabbits, 2-2.8 kg, were studied. Nephron filtration rate was 21 nl/min (n equal to 48) and absolute reabsorption along the length of the accesible portion of the proximal convoluted tubule was 10.3 nl/min. Correcting this value for tubular length gives a fluid reabsorption of approximately 1.9 nl/mm per min. In view of the marked difference between the in vivo and in vitro techniques and the various sources of error with each, this is reasonably similiar to the value of 1.3 nl/mm per min obtained in the isolated proximal convoluted tubule.

The effect of bradykinin on proximal tubular sodium reabsorption in the dog: evidence for functional nephron heterogeneity.

In a previous study we have found that acetylcholine, a renal vasodilator, inhibits fractional and absolute reabsorption of sodium in the proximal tubule of the dog. To delineate whether this effect on proximal tubular sodium reabsorption was related to alterations in renal hemodynamics or to a direct tubular action of the drug, free-flow micropuncture studies were performed in the dog in which the tubular fluid to plasma inulin ratio and nephron filtration rate were determined before and during the administration of a structurally different renal vasodilator, bradykinin. This agent increased sodium excretion from 12 to 96 muEq/min and decreased total kidney filtration fraction from 0.35 to 0.25. However, sodium reabsorption in the proximal tubule of the superficial nephrons was unchanged during bradykinin administration. Since it has been shown that a decrease in filtration fraction and presumably peritubular capillary protein concentration will decrease proximal tubular sodium reabsorption, studies were performed to determine whether the fall in total kidney filtration fraction seen with both vasodilators is paralleled by a similar change in the circulation of superficial nephrons. The results of these studies indicate that neither agent altered superficial nephron capillary protein concentration, hematocrit, or filtration fraction. In contrast, a decrease in capillary protein concentration, hematocrit, and filtration fraction was consistently demonstrated during the intrarenal infusion of 7.5-15 ml/min of Ringer's solution while an increase in these parameters occurred during the i.v. administration of norepinephrine, 60 mug/min. In the Ringer's infusion studies, both fractional and absolute sodium reabsorption in the proximal tubule were decreased concomitant with the fall in capillary protein concentration and hematocrit. THIS DATA SUGGESTS THAT: (a) the hemodynamic effect of renal vasodilatation is not the same in the circulation of all nephrons; (b) the inhibitory effect of acetylcholine on proximal tubular sodium reabsorption is due to a direct tubular action; (c) a decrease in capillary protein concentration and/or hematocrit does decrease proximal tubular sodium reabsorption; (d) although proximal reabsorption of sodium is unchanged in the superficial nephrons during bradykinin administration, a decrease in reabsorption may be present in deeper nephrons in which filtration fraction is decreased.

Studies of the mechanism of oliguria in a model of unilateral acute renal failure.

To further evaluate the mechanism of the oliguria of acute renal failure, a model was utilized in which intense and prolonged vasoconstriction produced the unilateral cessation of urine flow. The radioactive microsphere method was used to measure total and regional blood flow before and after the intrarenal infusion of norepinephrine, 0.75 mug/kg/min, for 2 h in the dog. In the control kidney, renal blood flow increased 32% 48 h after norepinephrine in association with a fall in the fractional distribution of flow to the outer cortex. In the experimental kidney, total renal blood flow fell from 190 ml/min before norepinephrine to 116 ml/min at 48 h (P < 0.025) with a uniform reduction in cortical blood flow. After the administration of 10% body wt Ringer's solution, there was a marked redistribution of flow to inner cortical nephrons in both the control and experimental kidney. In addition, there was a marked increase in total blood flow in both kidneys. On the experimental side, flow rose to 235 ml/min, a value greater than in either the control period (P < 0.05) or at 48 h after norepinephrine (P < 0.001). However, in spite of this marked increase in blood flow, there was essentially no urine flow from the experimental kidney. In separate studies, the animals were prepared for micropuncture. In all studies, the surface tubules were collapsed, and there was no evidence of tubular obstruction or leakage of filtrate. Over 99% of the 15-muM spheres were extracted in one pass through the experimental kidney. An analysis of the forces affecting filtration suggested that an alteration in the ultrafiltration coefficient may be responsible, at least in part, for the anuria in this model. In this regard, transmission and scanning electron microscopy revealed a marked abnormality in the epithelial structure of the glomerulus. It is suggested that a decrease in glomerular capillary permeability may be present in this model of acute renal failure.

Purple grape juice improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease.

BACKGROUND: In vitro, the flavonoid components of red wine and purple grape juice are powerful antioxidants that induce endothelium-dependent vasodilation of vascular rings derived from rat aortas and human coronary arteries. Although improved endothelial function and inhibition of LDL oxidation may be potential mechanisms by which red wine and flavonoids reduce cardiovascular risk, the in vivo effects of grape products on endothelial function and LDL oxidation have not been investigated. This study assessed the effects of ingesting purple grape juice on endothelial function and LDL susceptibility to oxidation in patients with coronary artery disease (CAD). METHODS AND RESULTS: Fifteen adults with angiographically documented CAD ingested 7.7+/-1.2 mL. kg(-1). d(-1) of purple grape juice for 14 days. Flow-mediated vasodilation (FMD) was measured using high-resolution brachial artery ultrasonography. Susceptibility of LDL particles to oxidation was determined from the rate of conjugated diene formation after exposure to copper chloride. At baseline, FMD was impaired (2.2+/-2. 9%). After ingestion of grape juice, FMD increased to 6.4+/-4.7% (P=0.003). In a linear regression model that included age, artery diameter, lipid values, and use of lipid-lowering and antioxidant therapies, the effect of grape juice on FMD remained significant (mean change 4.2+/-4.4%, P<0.001). After ingestion of grape juice, lag time increased by 34.5% (P=0.015). CONCLUSIONS: Short-term ingestion of purple grape juice improves FMD and reduces LDL susceptibility to oxidation in CAD patients. Improved endothelium-dependent vasodilation and prevention of LDL oxidation are potential mechanisms by which flavonoids in purple grape products may prevent cardiovascular events, independent of alcohol content.

Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction.

BACKGROUND: Human immunodeficiency virus protease inhibitors (HIV PIs) are associated with hyperlipidemia, hyperglycemia, and obesity; however, it is not known whether they increase risk of atherosclerotic vascular disease. The purposes of this study were to characterize the lipoprotein abnormalities associated with use of HIV PIs in individuals with HIV infection and to determine the pathophysiological significance of these changes by assessing their effect on endothelial dysfunction. METHODS AND RESULTS: This was a cross-sectional study of 37 adults with HIV-1 infection who were receiving antiretroviral therapy. Twenty-two were taking HIV PIs (group 1); 15 were not (group 2). Lipids and lipoproteins were measured by enzymatic techniques and nuclear magnetic resonance spectroscopic analysis. Flow-mediated vasodilation (FMD) of the brachial artery was measured by high-resolution ultrasound. Subjects in both groups were similar in regard to age, time since diagnosis of HIV infection, and CD4 cell count. Group 1 subjects had higher total cholesterol (5.68 versus 4.42 mmol/L, P=0.007) and triglyceride (4.43 versus 1.98 mmol/L, P=0.009) levels, characterized by elevated levels of IDL and VLDL. Subjects in group 1 had impaired FMD (2.6+/-4.6%), indicative of significant endothelial dysfunction. Group 2 subjects had normal FMD (8.1+/-6.7%, P=0.005). In group 1, chylomicron, VLDL, IDL, and HDL cholesterol levels predicted FMD. CONCLUSIONS: Use of HIV PIs is associated with atherogenic lipoprotein changes and endothelial dysfunction. Because these metabolic and vascular changes predispose to atherosclerosis, monitoring and treatment of dyslipidemia in patients taking these medications is warranted.

Echocardiography for hemodynamic assessment of patients with advanced heart failure and potential heart transplant recipients.

OBJECTIVES: This study sought to assess the accuracy of Doppler echocardiographic techniques for the determination of right heart catheterization hemodynamic variables in patients with advanced heart failure and in potential heart transplant recipients. BACKGROUND: Doppler echocardiographic techniques permit the noninvasive acquisition of hemodynamic variables traditionally used for the assessment of patients with advanced heart failure and potential heart transplant candidates. However, the accuracy of these techniques has not been sufficiently well documented for clinical application in individual patients. METHODS: Echocardiographic data required for estimation of mean right atrial, pulmonary artery and mean left atrial pressures and cardiac output were obtained. Right heart catheterization was performed immediately after Doppler echocardiographic data were acquired, before any intervention that might have altered the subject's hemodynamic status. RESULTS: A complete Doppler echocardiographic hemodynamic data set was acquired in 21 (84%) of 25 subjects. For all variables, invasive and noninvasive hemodynamic values were highly correlated (p < 0.001), with minimal bias and narrow 95% confidence limits. An algorithm constructed from the noninvasive hemodynamic variable values identified all patients with adverse pulmonary vascular hemodynamic variables (i.e., transpulmonary gradient > or = 12 mm Hg, pulmonary vascular resistance > or = 3 Wood units or pulmonary vascular resistance index > or = 6 Wood units x m2). This algorithm identified 12 (71%) of 19 patients for whom right heart catheterization was unnecessary. CONCLUSIONS: Doppler echocardiographic estimates of hemodynamic variables in patients with advanced heart failure are accurate and reproducible. This noninvasive methodology may assist with monitoring and optimization of medical therapy in patients with advanced heart failure and may obviate the need for routine right heart catheterization in potential heart transplant candidates.

The effects of lipid-lowering and antioxidant vitamin therapies on flow-mediated vasodilation of the brachial artery in older adults with hypercholesterolemia.

OBJECTIVES: The goal of this study was to determine the long-term effects of statins and antioxidant vitamins on flow-mediated vasodilation of the brachial artery in older adults with hypercholesterolemia. BACKGROUND: Lipid-lowering therapy and antioxidant vitamins improve endothelium-dependent vasodilation in young and middle-aged adults with hypercholesterolemia, but their effects in older adults are not known. METHODS: Two double-blind, placebo-controlled studies were performed in individuals > or =70 years old with low-density lipoprotein cholesterol (LDL-C) > or =140 mg/dl. In the first study, 37 subjects were randomized to receive (group 1) pravastatin for six months then pravastatin and vitamin E for six additional months or (group 2) vitamin E for six months, then pravastatin and vitamin E for six additional months. In the second study, additional 17 subjects sequentially received simvastatin for six months, then simvastatin and vitamins C and E for six additional months. Flow-mediated vasodilation of the brachial artery was measured by high-resolution ultrasound. RESULTS: At baseline, subjects in both studies were similar in age (mean +/- SD, 75.8 +/- 4.2 years), gender, systolic blood pressure, total cholesterol (261.6 +/- 37.4 mg/dl), LDL-C (180.3 +/- 28.1 mg/dl), high-density lipoprotein cholesterol and triglycerides levels. Flow-mediated vasodilation was severely impaired (2.2 +/- 3.9%). Both statins reduced total and LDL-C levels (p < 0.001); however, neither statin, antioxidant vitamin regimen nor the combination of statins and antioxidant vitamins improved flow-mediated vasodilation of the brachial artery. At baseline, nitroglycerin-mediated vasodilation also was impaired (10.7 +/- 5.6%) and did not change in either study. CONCLUSIONS: Older adults with hypercholesterolemia have impaired flow-mediated vasodilation of the brachial artery that does not improve after one year of therapy with statins and antioxidant vitamins, despite significant lipid-lowering.