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M S Paller

Publications and source records attributed to M S Paller.

70 records · Page 4Linked to original sources
PubMed1986

Ethane production as a measure of lipid peroxidation after renal ischemia.

After renal ischemia, oxygen free radicals are formed and produce tissue injury, in large part, through peroxidation of polyunsaturated fatty acids. We used an in vivo method to monitor lipid peroxidation after renal ischemia, the measurement of ethane in expired gas, to determine the time course of lipid peroxidation and the effect of several agents to limit lipid peroxidation after renal ischemia. In anesthetized rats there was no significant increase in ethane production during 60 min of renal ischemia. During the first 10 min of renal reperfusion, there was a prompt increase in ethane production from 2.9 +/- 1.3 to 6.3 +/- 1.9 pmol/min (P less than 0.05). Ethane production was significantly increased during the first 50 min of reperfusion and then rapidly tapered to base-line levels. Preischemic administration of allopurinol to prevent superoxide radical generation or the superoxide radical scavenger superoxide dismutase prevented the increase in ethane production during postischemic reperfusion. These studies confirm that there is increase lipid peroxidation following renal ischemia that can be prevented by agents which limit the formation or accumulation of oxygen free radicals. This in vivo method for measuring lipid peroxidation could also be employed to study the effects of ischemia on lipid peroxidation in other organs, as well as to monitor lipid peroxidation in other forms of injury.

Allopurinol↗
PubMed1986

Beneficial effects of renal denervation and prazosin on GFR and renal blood flow after cyclosporine in rats.

We have previously shown that both acute infusion of cyclosporine and chronic intraperitoneal cyclosporine result in decreased renal blood flow in rats. This effect of cyclosporine infusion was mediated via the sympathetic nervous system. In this study, renal denervation was found to also prevent the decrease in glomerular filtration rate after cyclosporine infusion. Male Sprague-Dawley rats underwent unilateral renal denervation and three days later inulin clearance was measured following infusion of cyclosporine (20 mg/kg). GFR fell by 43% in innervated kidneys, but remained normal in denervated kidneys. In addition, administration of the alpha-adrenergic antagonist prazosin prevented the rise in serum creatinine and the fall in renal blood flow associated with chronic cyclosporine administration (20 mg/kg intraperitoneally for 7 days). These findings further support the hypothesis that sympathetic nervous system-mediated vasoconstriction is responsible for renal dysfunction in rats after acute and chronic cyclosporine administration.

Animals↗
PubMed1986

The role of intensive dialysis in acute renal failure.

The efficacy of vigorous dialysis in the management of acute renal failure remains controversial. In order to examine the beneficial role of vigorous dialysis, a prospective study was carried out in 34 patients paired by acute renal failure etiology and treated with sufficient dialysis to maintain predialysis blood urea nitrogen and serum creatinine below either 60 and 5 mg/dl (intensive) or 100 and 9 mg/dl, respectively (non-intensive). Serum creatinine was at least 8 mg/dl in all patients prior to random assignment to intensive or non-intensive dialysis. Mean predialysis blood urea nitrogen and serum creatinine, respectively, were 60 +/- 23 and 5.3 +/- 1.5 mg/dl in the intensively dialyzed group and 101 +/- 18 and 9.1 +/- 1.4 mg/dl in the non-intensively dialyzed group (both p less than .001). Predialysis serum bicarbonate and blood pH were lower and serum phosphate higher in the non-intensively dialyzed patients. Daily weight changes, increases in blood urea nitrogen, protein and calorie intakes were similar. While hemorrhagic episodes tended to be more frequent in non-intensively dialyzed patients, overall complication rates were not different between the two groups. Mortality rates, which were 58.8% in the intensive and 47.1% in the non-intensive groups, also were not different. On the other hand, urine output prior to dialysis did influence survival. It is concluded that, within the limits of the study, there is no advantage to intensive dialysis in the management of acute renal failure.

Acute Kidney Injury↗
PubMed1985

Effect of cyclosporine administration on renal hemodynamics in conscious rats.

The effect of acute and chronic administration of cyclosporine on systemic and renal hemodynamics was studied in conscious rats. Infusion of cyclosporine in a dose of 20 mg/kg (Cy 20) resulted in a significant fall in renal blood flow (RBF) (3.4 vs. 6.5 ml/min/g, P less than 0.05) and a rise in renal vascular resistance (RVR) (36.9 vs. 20.6 mm Hg/ml/min/g, P less than 0.05). Infusion of cyclosporine at a dose of 10 mg/kg (Cy 10) did not result in a significant change in RBF or RVR. Both doses of cyclosporine resulted in stimulation of plasma renin activity (PRA) from control values of 5.6 +/- 0.8 ng/ml/hr to 11.6 +/- 2.0 with 10 mg/kg and 26.7 +/- 5.6 with 20 mg/kg. Urinary 6-keto-PGF1 alpha excretion increased from control values of 14.0 +/- 2.0 ng/6 hr to 22.7 +/- 2.2 with 10 mg/kg and 25.0 +/- 2.0 with 20 mg/kg. Similar effects on RBF, RVR, PRA, and 6-keto-PGF1 alpha excretion were seen after chronic administration of cyclosporine (20 mg/kg i.p. for 7 days). Pretreatment of animals with captopril did not prevent the fall in RBF after cyclosporine, suggesting that the vasoconstriction was not mediated by angiotensin II. Animals treated with meclofenamate demonstrated reduction in RBF with 10 mg/kg cyclosporine (4.3 vs. 7.0 ml/min/g, P less than 0.05), suggesting that prostaglandins protect against the vasoconstrictor effect of cyclosporine. Administration of phenoxybenzamine after cyclosporine improved RBF (5.0 vs. 3.4 ml/min/g) and restored RVR to normal. Similarly, renal denervation dramatically reduced the fall in RBF after cyclosporine (innervated right kidney 3.6 vs. denervated left kidney 6.0 ml/min/g, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Cardiovascular and endocrine effects of potassium in spontaneously hypertensive rats.

Although potassium is known to lower blood pressure in a number of forms of experimental and human hypertension, the mechanism for this effect remains unclear. We studied several possible mechanisms for this effect in the spontaneously hypertensive rat (SHR). Fourteen-week-old SHR were given 0.5% KCl in the drinking water. This potassium supplement resulted in a 16-mmHg fall in mean arterial pressure and a 22% decrease in peripheral vascular resistance. Plasma potassium increased 0.4 meq/l, while muscle potassium was unchanged. Potassium supplementation resulted in no change in plasma renin activity, plasma aldosterone, or plasma norepinephrine. Urinary excretion of prostaglandin (PG) E2 and 6-keto-PGF1 alpha was also not altered by potassium supplementation. Potassium-supplemented SHR were found to have no difference in sodium excretion compared with control SHR, and plasma volume was similar in both groups. The pressor response to angiotensin II and norepinephrine was not substantially affected by potassium supplementation. Furthermore, baroreflex control of heart rate was not altered by potassium supplementation. Finally, potassium supplementation resulted in no change in mesenteric artery angiotensin II receptor number or receptor affinity. Therefore, although potassium lowers blood pressure in the SHR by decreasing peripheral vascular resistance, the mechanism of this effect on vascular resistance remains unknown.

Angiotensin II↗
PubMed1985

Decreased pressor reactivity to angiotensin II in cirrhotic rats. Evidence for a post-receptor defect in angiotensin action.

We used a model of cirrhosis in the rat, produced by inhalation of carbon tetrachloride for 6 weeks, to investigate the mechanism of resistance to the pressor effects of angiotensin II. The pressor response to angiotensin II was significantly lower in conscious cirrhotic animals than in controls. On the other hand, cirrhotic animals had normal pressor responses to norepinephrine, indicating that a generalized defect in vascular reactivity does not cause the decreased pressor response to angiotensin II. Enhanced baroreceptor activity was not the cause of the decreased pressor response to angiotensin II, since baroreflex control of heart rate after angiotensin II was similar in cirrhotics and controls. Pretreatment with either the converting enzyme inhibitor captopril to reduce circulating angiotensin II or the prostaglandin synthesis inhibitor meclofenamate failed to normalize the response to angiotensin II. Thus, neither prior occupancy of receptors with endogenous angiotensin II nor the production of vasodilatory prostaglandins was responsible for the decreased angiotensin II response. Studies of angiotensin II binding by mesenteric artery smooth muscle particles showed that, in cirrhotic animals, receptor affinity for angiotensin II, was significantly lower than in controls (kd: cirrhosis 1.11 +/- 0.09 nM, control 0.94 +/- 0.13 nM; P less than 0.02), whereas receptor number was significantly increased (cirrhosis 315 +/- 42 fmol/mg protein, control 277 +/- 43 fmol/mg protein, P less than 0.01). However, total binding of AII by vascular receptors from cirrhotics was no different than in controls, since the decrease in affinity negated the increase in receptor number.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1985

Free radical scavengers in mercuric chloride-induced acute renal failure in the rat.

Oxygen free radicals have recently been found to mediate cell injury after ischemia in the kidney. We sought to determine whether oxygen free radicals mediate damage in mercuric chloride (HgCl2)-induced acute renal failure, a toxic model of acute renal failure. Neither superoxide dismutase nor allopurinol, which scavenges or inhibits production of superoxide radical, respectively, provided protection against renal dysfunction after HgCl2. Similarly, the hydroxyl radical scavengers tryptophan, N-acetyl-tryptophan, and ascorbic acid were unable to protect against HgCl2. However, dimethylthiourea and dimethyl sulfoxide, both hydroxyl radical scavengers, were beneficial. Dimethylthiourea completely prevented the rise in plasma creatinine concentration after HgCL2. In control rats plasma creatinine concentration rose from 0.4 mg/dl to 3.2 +/- 0.8, 5.1 +/- 1.0, and 6.1 +/- 1.6 mg/dl at 24, 48, and 72 hours after HgCl2. Dimethylthiourea-treated rats had plasma creatinine concentration less than 0.5 mg/dl at all times. Furthermore, a mixture of HgCl2 and equimolar amounts of dimethylthiourea was less toxic than HgCl2 alone. Dimethyl sulfoxide attenuated the HgCl2-induced rise in creatinine concentration: 1.3 +/- 0.2, 3.2 +/- 0.3, and 3.1 +/- 0.2 mg/dl at 24, 48, and 72 hours after HgCl2. Measurement of kidney malondialdehyde content after HgCl2 provided no evidence for oxygen free radical-mediated lipid peroxidation. We conclude that there is no convincing role for oxygen free radicals in the pathogenesis of HgCl2-induced acute renal failure. The ability of dimethylthiourea and dimethyl sulfoxide to protect against HgCl2-induced renal dysfunction may be related to their ability to form complexes with Hg2+.

Acute Kidney Injury↗
PubMed1984

Role of angiotensin II, alpha-adrenergic system, and arginine vasopressin on arterial pressure in rat.

Three pressor systems regulate arterial pressure (MAP): angiotensin II (ANG II), the alpha-adrenergic system, and arginine vasopressin (AVP). In this study we determined the ability of each system to support MAP in the conscious rat when the other two systems were inactivated. After administration of the converting-enzyme inhibitor teprotide (CEI) and the alpha-adrenergic receptor antagonist phenoxybenzamine (POB), MAP decreased 40% as a result of a 45% decrease in peripheral vascular resistance (PVR). Despite hypotension, plasma AVP levels were not increased, and an AVP pressor antagonist (AVP-A) did not result in a further decrease in MAP. Thus the profound hypotension after POB plus CEI was the result of inhibition of all three systems. POB, rather than CEI, prevented AVP release since following hypotensive hemorrhage, plasma levels reached 51 +/- 13 pg/ml with CEI but only 4.7 +/- 0.8 pg/ml with POB. To study the pressor effect of AVP alone, AVP was infused in POB plus CEI-treated rats. AVP increased MAP (from 68 +/- 4 to 92 +/- 5 mmHg; P less than 0.005) and plasma AVP (to 13.8 +/- 1.9 pg/ml). Since POB inhibited both the AVP and the alpha-adrenergic system, the role of ANG II alone was determined in POB-treated rats. In the presence of ANG II MAP was 97 +/- 1 mmHg. To study the alpha-adrenergic system, MAP was determined in CEI plus AVP-A-treated rats. In the presence of an intact alpha-adrenergic system MAP was 101 +/- 1 mmHg. We conclude that PVR and MAP are profoundly decreased in the absence of all three pressor systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1984

Mechanism of decreased pressor responsiveness to ANG II, NE, and vasopressin in pregnant rats.

The mechanism of decreased pressor responsiveness to pressor agents was examined serially throughout pregnancy in conscious rats. Rats, 15 and 20 days pregnant, showed marked blunting of the pressor response to graded doses of angiotensin, whereas after only 5 days of pregnancy there was a normal response and at 10 days an intermediate pressor response. A role for prior occupancy of vascular angiotensin II receptors for the blunted pressor response was made less likely by the observation that treatment with captopril to decrease endogenous angiotensin II did not improve the angiotensin II pressor response in 15-day pregnant rats. Studies of smooth muscle receptor binding of angiotensin II showed that, in pregnancy, receptor affinity and number was not changed. Inhibition of prostaglandin synthesis with meclofenamate increased the pressor response to angiotensin II toward normal in pregnant animals. The blunted vascular response in pregnancy was not specific for angiotensin since pregnant animals showed a similar decrease in the response to both norepinephrine and arginine vasopressin. Furthermore, meclofenamate increased the pressor response to norepinephrine and vasopressin in pregnant rats. We conclude that pressor hyporesponsiveness in pregnancy is not specific for angiotensin II and is not caused by alterations in vascular receptor occupancy or binding. In pregnancy there is a decreased pressor response to all three major pressor agents that is improved by inhibition of prostaglandin production.

Angiotensin II↗
PubMed1984

Mechanism of decreased vascular reactivity to angiotensin II in conscious, potassium-deficient rats.

Chronic potassium deficiency in the rat results in a decrease in the pressor sensitivity to exogenous angiotensin II (AII). To define the mechanism of this resistance to AII, studies were performed in conscious rats after 14-21 d of dietary potassium deficiency. The pressor response to graded doses of AII was 50% less in potassium-deficient than control animals. In contrast, the pressor response to graded doses of norepinephrine was preserved in potassium-deficient rats; therefore, the decreased response to AII was not due to a generalized defect in vascular reactivity. Pretreatment with either the converting enzyme inhibitor, teprotide, or the prostaglandin synthesis inhibitor, indomethacin, failed to normalize the response to AII. Thus, neither prior receptor occupancy with endogenous AII nor the presence of vasodilatory prostaglandins caused the decreased AII response in potassium deficiency. Since the pressor response to AII involves angiotensin interaction with its vascular receptor, binding studies of mesenteric artery and uterine smooth muscle AII receptors were performed. Scatchard analysis showed that potassium deficiency resulted in a decrease in binding affinity (50% increase in Kd) in both uterine (6.00 vs. 3.82 nM; P less than 0.05) and vascular (1.39 vs. 0.973 nM; P less than 0.005) smooth muscle. Furthermore, despite increased circulating AII, there was an increase in AII receptor number in potassium-deficient uterine (308 vs. 147 fmol/mg protein; P less than 0.005) and vascular (470 vs. 316 fmol/mg protein; 0.05 less than P less than 0.1) smooth muscle. Although potassium deficiency resulted in alterations in receptor-binding parameters, the changes in binding affinity and number were directionally opposite, so that in potassium deficiency there was either no change or an increase in total AII binding. We conclude that the decrease in angiotensin pressor sensitivity in potassium-deficient rats is mediated by a postreceptor defect since it occurs subsequent to the binding of AII to its vascular smooth muscle receptor.

Angiotensin II↗
PubMed1984

Oxygen free radicals in ischemic acute renal failure in the rat.

During renal ischemia, ATP is degraded to hypoxanthine. When xanthine oxidase converts hypoxanthine to xanthine in the presence of molecular oxygen, superoxide radical (O-2) is generated. We studied the role of O-2 and its reduction product OH X in mediating renal injury after ischemia. Male Sprague-Dawley rats underwent right nephrectomy followed by 60 min of occlusion of the left renal artery. The O-2 scavenger superoxide dismutase (SOD) was given 8 min before clamping and before release of the renal artery clamp. Control rats received 5% dextrose instead. Plasma creatinine was lower in SOD treated rats: 1.5, 1.0, and 0.8 mg/dl vs. 2.5, 2.5, and 2.1 mg/dl at 24, 48, and 72 h postischemia. 24 h after ischemia inulin clearance was higher in SOD treated rats than in controls (399 vs. 185 microliter/min). Renal blood flow, measured after ischemia plus 15 min of reflow, was also greater in SOD treated than in control rats. Furthermore, tubular injury, judged histologically in perfusion fixed specimens, was less in SOD treated rats. Rats given SOD inactivated by prior incubation with diethyldithiocarbamate had plasma creatinine values no different from those of control rats. The OH X scavenger dimethylthiourea (DMTU) was given before renal artery occlusion. DMTU treated rats had lower plasma creatinine than did controls: 1.7, 1.7, and 1.3 mg/dl vs. 3.2, 2.2, and 2.4 mg/dl at 24, 48, and 72 h postischemia. Neither SOD nor DMTU caused an increase in renal blood flow, urine flow rate, or solute excretion in normal rats. The xanthine oxidase inhibitor allopurinol was given before ischemia to prevent the generation of oxygen free radicals. Plasma creatinine was lower in allopurinol treated rats: 2.7, 2.2, and 1.4 mg/dl vs. 3.6, 3.5, and 2.3 mg/dl at 24, 48, and 72 h postischemia. Catalase treatment did not protect against renal ischemia, perhaps because its large size limits glomerular filtration and access to the tubular lumen. Superoxide-mediated lipid peroxidation was studied after renal ischemia. 60 min of ischemia did not increase the renal content of the lipid peroxide malondialdehyde, whereas ischemia plus 15 min reflow resulted in a large increase in kidney lipid peroxides. Treatment with SOD before renal ischemia prevented the reflow-induced increase in lipid peroxidation in renal cortical mitochondria but not in crude cortical homogenates. In summary, the oxygen free radical scavengers SOD and DMTU, and allopurinol, which inhibits free radical generation, protected renal function after ischemia. Reperfusion after ischemia resulted in lipid peroxidation; SOD decreased lipid peroxidation in cortical mitochondria after renal ischemia and reflow. We concluded that restoration of oxygen supply to ischemic kidney results in the production of oxygen free radicals, which causes renal injury by lipid peroxidation.

Acute Kidney Injury↗
PubMed1983

Anticytoplasmic antibodies in antinuclear antibody-negative lupus erythematosus. Correlation with clinical course.

A patient with clinical manifestations of systemic lupus erythematosus (SLE) and without antinuclear antibodies was found to have anticytoplasmic antibodies. These anticytoplasmic antibodies were directed against ribosomal ribonucleoprotein, and the titer of anticytoplasmic and anti-ribosomal ribonucleoprotein antibodies correlated with the clinical course of the patient's illness. The importance of detecting anticytoplasmic antibodies and their role in producing disease in patients with SLE is discussed.

Adolescent↗
PubMed1983

Role of vasopressin in support of blood pressure in potassium deficient rats.

Arginine vasopressin (AVP) has been found to contribute to the maintenance of blood pressure (BP) in the rat. Since potassium deficiency results in alterations in systemic hemodynamics, the role of AVP in the control of BP was studied after 14 to 21 days of dietary potassium deficiency. When potassium deficient and control rats were allowed free access to water, plasma osmolality (301.4 +/- 1 vs. 293.4 +/- 3 mOsm/kg; P less than 0.02) and plasma AVP (3.5 +/- 0.2 vs. 2.4 +/- 0.2 pg/ml; P less than 0.02) were increased in potassium deficient animals. To determine the role of this increase in AVP in the maintenance of BP, BP was determined in rats made polydipsic by adding glucose to the drinking water. In both control and potassium deficient rats, increased fluid intake resulted in increased urine output, decreased urinary and plasma osmolality, and a decrease in plasma AVP. While there was no change in BP in control rats when fluid intake was increased, BP fell from 103.9 +/- 1.8 to 96 +/- 2.6 mm Hg (P less than 0.05) in potassium deficient rats with increased fluid intake. To confirm that the decrease in plasma AVP caused the decrease in BP in potassium deficient rats, an AVP pressor antagonist was employed. Following the administration of the AVP pressor antagonist, there was no change in BP in control animals. In contrast, BP fell from 104.3 +/- 1.9 to 98.3 +/- 2.5 mm Hg; P less than 0.05 in potassium deficient rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Pathogenesis of sodium and water retention in edematous disorders.

Edema is a collection of fluid within the body's interstitial space which occurs when there is an alteration of the Starling forces which control transfer of fluid from the vascular compartment to surrounding tissue spaces. Generalized edema results when altered Starling forces affect all capillary beds, such as occurs in cardiac failure, cirrhosis, and nephrotic syndrome. Common to these conditions is the development of increased total body sodium and water content. The kidneys play an essential role in the retention of this sodium and water. In this article we shall discuss the signals the kidneys receive for sodium and water retention in these edematous disorders (afferent mechanisms). We shall also examine the means by which the kidney responds to these signals and retains sodium and water (efferent mechanisms). As shall become apparent these edematous states may share many of the same afferent and efferent mechanisms for sodium and water retention.

Blood Volume↗
PubMedDate not supplied

Hemodynamic effects of alterations in potassium.

Potassium is the major intracellular cation. Despite this fact, the systemic and renal hemodynamic effects of alterations in either serum K or in total body K are only partially understood. In isolated preparations acute K excess causes vasodilation while acute K deficiency results in vasoconstriction. Although chronic K excess may decrease arterial pressure in experimental models of hypertension, no definitive conclusions can be stated on the effect of K excess in hypertensive patients. In normotensive animals, chronic K depletion is associated with decreased systemic vascular resistance and increased renal vascular resistance. Although a number of studies have shown that K depletion ameliorates experimental hypertension, no definitive conclusions can be stated on the effect of K depletion in hypertensive patients. The vasodilatory effect of K depletion appears to be a direct effect on vascular smooth muscle since it is associated with an increase in total body Na as well as an increase in cardiac output and in renin ane arginine vasopressin levels. Although renin levels are increased in K deficient rats to a value comparable to na-depleted rats, angiotensin antagonism results in a substantially smaller decrease in arterial pressure than in Na-depleted rats (11 +/- 1.6 vs 24 +/- 3.4 mm Hg, p less than 0.01). This relative resistance to the pressor effect of angiotensin also results in a blunted pressor sensitivity to exogenous angiotensin II. Since changes in K balance appear to have a major effect on the control of hemodynamics, further studies are warranted to determine whether alterations in K balance would be useful in the treatment of hypertension.

Animals↗