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Biomedical subjects

R M Zusman

Publications and source records attributed to R M Zusman.

At least 55 records · Page 3Linked to original sources
PubMed1982

Gut-mediated hypercalcemia in rabbits bearing VX2 carcinoma: new mechanism for tumor-induced hypercalcemia.

The VX2 carcinoma-bearing rabbit is an animal model for tumor-induced hypercalcemia, thought to be due to increased bone destruction effected by prostaglandin E2. The present experiments suggest that the pathophysiology of the hypercalcemia differs from that previously proposed. Tumor was transplanted intramuscularly into 2.5- to 3-kg male New Zealand White rabbits, which were conditioned to a 1.5% calcium diet and treated with daily subcutaneous injections of dichloromethane diphosphonate (10 mg . kg-1 . day-1), a potent inhibitor of bone resorption, or 0.9% NaCl (2 ml . kg-1 . day -1). The diphosphonate had no significant effect on plasma Ca2+ in either group. After day 31, half the animals of each group were fed a calcium-free diet. This normalized the plasma Ca2+ in each VX2-bearing rabbit within 3 to 4 days but had little effect in control rabbits. In a second series of experiments, VX2-bearing rabbits maintained on standard rabbit chow were treated for 11 days with parenteral indomethacin (30--60 mg/day) or 0.9% NaCl. Although indomethacin normalized the markedly elevated urinary excretion of prostaglandin E2, both treatment groups became severely hypercalcemic. Dietary calcium restriction promptly restored to normal the plasma Ca2+ concentration. In a third series of experiments, rabbits were fed standard rabbit chow and treated with oral indomethacin (40 mg/day) while control-rabbits were pair fed in identical chow. Transplantation of VX2 tumor into both groups caused hypercalcemia. We conclude that the hypercalcemia produced by this tumor strain is indomethacin resistant and dependent on an increase in gastrointestinal calcium absorption, not on skeletal calcium mobilization.

Animals↗
PubMed1981

Hemodialysis using prostacyclin instead of heparin as the sole antithrombotic agent.

Anticoagulation during hemodialysis is necessary to prevent clotting of the blood on contact with the dialysis membrane. Heparin is the usual anticoagulant used, but systemic anticoagulation may persist for hours, and hemorrhage is common. We successfully used an infusion of prostacyclin, which has an in vitro half-life of three to five minutes, as the sole anticoagulant in 10 patients on long-term hemodialysis and in one patient undergoing dialysis for acute renal failure (this patient bled severely on three occasions when heparin was used). Prostacyclin was infused intravenously for 10 minutes before dialysis and into the arterial line of the dialyzer during dialysis. We adjusted the rate of infusion into the dialyzer to prevent prostacyclin-induced hypotension. Each patient completed 240 minutes of dialysis and received a total of 423 +/- 91 ng of prostacyclin per kilogram of body weight (mean +/- S.E.M.; range, 56 to 780). Prostacyclin caused no clinically important changes in the intrinsic clotting system, and there were no hemorrhages or clotting of the coil. We conclude that prostacyclin can safely replace heparin as the sole antithrombotic agent during hemodialysis and may be more advantageous if anticoagulation is contraindicated.

Acute Kidney Injury↗
PubMed1981

Effects of prostacyclin infusion in uremic patients: hematologic and hemodynamic responses.

The effects of sequential prostacyclin infusions at 2, 4, and 8 ng/kg/min for 1 hr were determined in six patients with chronic renal failure. Diastolic blood pressure decreased in a dose-dependent fashion from 74 +/- 4 mm Hg (mean +/- SEM) to 70 +/- 4, 66 +/- 5, and 55 +/- 5 during the 2, 4, and 8 ng/kg/min infusions, respectively; systolic blood pressure was not affected by prostacyclin. The fall in diastolic blood pressure was associated with a progressive rise in heart rate from 77 +/- 3 to 91 +/- 4 bpm and lowering of body temperature from 36.7 +/- 0.1 to 36 +/- 0.2 degrees. The threshold concentration of adenosine diphosphate that evoked reversible and irreversible platelet aggregation increased progressively from 1.2 to 2.8 and from 2.8 to 6 microM, respectively, during the prostacyclin infusions. Prostacyclin infusions had no effect on prothrombin time, activated partial thromboplastin time, or platelet count, but template bleeding time increased (not statistically significantly) from 5.8 to 12.3 min. In three of six patients, the 8 ng/kg/min infusion was terminated prematurely due to nausea, vomiting, and/or hypotension. We conclude that platelet aggregability can be inhibited in patients with chronic uremia by infusing 4 ng/kg/min prostacyclin without causing untoward side effects. When infused at hemodynamically tolerable doses, prostacyclin might serve as an in vivo inhibitor of platelet aggregation during hemodialysis or cardiopulmonary bypass.

Adult↗
PubMed1980

Regulation of prostaglandin E2 synthesis by angiotensin II, potassium, osmolality, and dexamethasone.

We investigated the regulation of cellular prostaglandin E2 (PGE2) biosynthesis in rabbit renomedullary interstitial cells in tissue culture. Arachidonic acid markedly stimulated PGE2 biosynthesis by these cells. Repeated exposure to arachidonic acid, resulted in progressively less stimulation of PGE2 biosynthesis. Potassium and dexamethasone diminished PGE2 biosynthesis by decreasing the rate of arachidonic acid release from the endogenous arachidonic acid storage pool. Hyperosmolality, like angiotensin II, bradykinin, and arginine vasopressin, stimulated PGE2 biosynthesis by increasing the rate of arachidonic acid release. Inhibitors of protein synthesis diminished angiotensin II-, bradykinin-, and arginine-vasopressin-stimulated PGE2 biosynthesis by decreasing hormone-stimulated arachidonic acid release. The effects of potassium, dexamethasone, arachidonic acid, and hyperosmolality on PGE2 biosynthesis were unaffected by protein synthesis inhibitors. Hormone-stimulated phospholipase activation is dependent on protein synthesis, whereas potassium, hyperosmolality, and dexamethasone alter the release of arachidonic acid from cellular lipids via a mechanism that is independent of protein synthesis.

Angiotensin II↗
PubMed1980

Identification of an angiotensin receptor in rabbit renomedullary interstitial cells in tissue culture. Correlation with prostaglandin biosynthesis.

High affinity binding sites of angiotensin II (A II) have been characterized in rabbit renomedullary interstitial cells in tissue culture. Binding was rapid, specific, and saturable. Scatchard analysis of steady state saturation binding data at 22 degrees C indicated a single binding site with an equilibrium dissociation constant of 3.1 mM. The binding inhibition activities of analogues of angiotensin II correlated with their biological potencies: [Sar1, Ala8]A II greater than [des-Asp1]A II greater than greater than 3--8 hexapeptide. The biologically inactive 1--7 heptapeptide failed to displace the labeled angiotensin II from its binding sites. Angiotensin II directly stimulated prostaglandin E2 biosynthesis by the rabbit renomedullary interstitial cells in tissue culture. The concentration of angiotensin II that resulted in half maximal stimulation of prostaglandin E2 biosynthesis (6.5 nM) correlated with the concentration of angiotensin II that resulted in half maximal occupancy of binding sites (3.1 nM). The relative potency of [des-Asp1] A II as a stimulus for prostaglandin E2 biosynthesis was proportional to its relative binding inhibition activity. These findings demonstrate the biological significance of the angiotensin II binding sites in the rabbit renomedullary interstitial cells in tissue culture and suggest that the cells may provide a homogeneous model tissue for the study of the angiotensin receptor.

Angiotensin II↗
PubMed1979

Effect of indomethacin and adrenocorticotrophic hormone on renal function in man: an experimental model of inappropriate antidiuresis.

The effect of prostaglandin synthesis inhibition on basal and ACTH-stimulated adrenal and renal function was investigated in normal volunteers. Data were collected during control and experimental study periods (13 days each). Adrenocorticotrophic hormone (Cosyntropin, 80 U/day) was administered i.v. on days 8 and 9 of each period. Indomethacin (150 mg/day) was given on days 5 through 13 of the experimental period. The subjects ate a constant diet containing 9 mEq of sodium, 100 mEq of potassium, and 2,500 ml of fluid daily. Indomethacin markedly inhibited urinary PGE excretion and plasma PGE concentration. The effect of ACTH alone as compared to the effect of ACTH and indomethacin showed: plasma sodium concentration, 139 +/- 1 vs. 131 +/ 3 mEg/liter (P less than 0.01, mean +/- SEM); plasma osmolality, 287 +/- 3 vs. 270 +/- 3 mOsm/liter (P less than 0.01); free water clearance, 97 +/- 66 vs. -1100 +/- 380 ml/24hr (P less than 0.01); urine volume, 2,000 +/- 60 vs. 950 +/- 200 ml/day (P less than 0.01); and urine osmolality 282 +/- 12 vs. 720 +/- 144 mOsm/liter (P less than 0.01). We conclude that the effects of ACTH and prostaglandin synthesis inhibition interact to result in inappropriate antidiuresis.

Adrenal Glands↗
PubMed1979

Relationship of human urinary and plasma kinins to sodium-retaining steroids and plasma renin activity.

In these studies we have shown that: 1. urinary kallikrein is an index of sodium-retaining steroid activity and may participate in the anti-natriuretic and kaliuretic effects of these hormones; 2. urinary kinin excretion is independent of changes in urinary kallikrein excretion; 3. levels of plasma bradykinin are highly correlated with levels of plasma renin activity probably because both respond to changes in extracellular fluid volume; and, 4. plasma bradykinin may act to antagonize angiotensin II to maintain normal blood pressure in hyper-reninemic states.

Adolescent↗
PubMed1979

Characterization of an angiotensin binding site in rabbit renomedullary interstitial cells in tissue culture: correlation with prostaglandin biosynthesis.

High affinity binding sites for angiotensin II have been identified and characterized in rabbit renomedullary interstitial cells in tissue culture. Binding studies were performed using monoiodinated angiotensin II of high specific activity; the angiotensinase inhibitors dithiothreitol and phenylmethylsulfonylfluoride were added to the incubation medium to retard degradation of the labeled hormone. Uptake of 125I angiotensin II was maximal at pH 7.4 and Scatchard analysis indicated a single binding site with a KD of 3.1 nM. Binding to a particulate preparation of the cells was rapid and reversible. Competition for binding by angiotensin II analogs correlated with their biologic potencies: (Sar1Ala8) AII greater than AII greater than (desAsp1) AII greater than greater than 3-8 hexapeptide. The 1-7 heptapeptide was completely ineffective in displacing the labeled angiotensin II from its binding sites. Angiotensin II directly stimulated prostaglandin (PG) biosynthesis by the renomedullary cells in tissue culture; the concentration of angiotensin II that resulted in half maximal stimulation of PG biosynthesis (6.5 nM) was similar to the concentration of angiotensin II that resulted in half maximal occupancy of binding sites (3.1 nM). These results suggest that the renomedullary cells may provide a model homogeneous tissue for the study of the angiotensin receptor and the hormonal regulation of prostaglandin biosynthesis.

Angiotensin II↗
PubMed1978

The kallikrein-kinin system in Bartter's syndrome and its response to prostaglandin synthetase inhibition.

The kallikrein-kinin system was characterized in seven patients with Bartter's syndrome on constant metabolic regimens before, during, and after treatment with prostaglandin synthetase inhibitors. Patients with Bartter's syndrome had high values for plasma bradykinin, plasma renin activity (PRA), urinary kallikrein, urinary immunoreactive prostaglandin E excretion, and urinary aldosterone; urinary kinins were subnormal and plasma prekallikrein was normal. Treatment with indomethacin or ibuprofen which decreased urinary immunoreactive prostaglandin E excretion by 67%, decreased mean PRA (patients recumbent) from 17.3+/-5.3 (S.E.M.) ng/ml per h to 3.3+/-1.1 ng/ml per h, mean plasma bradykinin (patients recumbent) from 15.4+/-4.4 ng/ml to 3.9+/-0.9 ng/ml, mean urinary kallikrein excretion from 24.8+/-3.2 tosyl-arginine-methyl ester units (TU)/day to 12.4+/-2.0 TU/day, but increased mean urinary kinin excretion from 3.8+/-1.3 mug/day to 8.5+/-2.5 mug/day. Plasma prekallikrein remained unchanged at 1.4 TU/ml. Thus, with prostaglandin synthetase inhibition, values for urinary kallikrein and kinin and plasma bradykinin returned to normal pari passu with changes in PRA, in aldosterone, and in prostaglandin E. The results suggest that, in Bartter's syndrome, prostaglandins mediate the low urinary kinins and the high plasma bradykinin, and that urinary kallikrein, which is aldosterone dependent, does not control kinin excretion. The high plasma bradykinin may be a cause of the pressor hyporesponsiveness to angiotensin II which characterizes the syndrome.

Adolescent↗
PubMed1977

Prostaglandin E2 biosynthesis by rabbit renomedullary interstitial cells in tissue culture. Mechanism of stimulation by angiotensin II, bradykinin, and arginine vasopressin.

The mechanism of hormone-stimulated prostaglandin E2 biosynthesis was investigated in rabbit renomedullary interstitial cells in tissue culture. Angiotensin II, bradykinin, and arginine vasopressin stimulated arachidonic acid release and subsequent prostaglandin biosynthesis. Indomethacin completely inhibited prostaglandin biosynthesis without affecting arachidonic acid release. Mepacrine, a phospholipase inhibitor, inhibited arachidonic acid release without affecting subsequent synthesis of prostaglandin E2. Our studies suggest that arachidonic acid release via hormone-activated phospholipase or acylhydrolase (or both) is the mechanism of hormone-stimulated prostaglandin E2 biosynthesis.

Angiotensin II↗