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Biomedical subjects

R A Branch

Publications and source records attributed to R A Branch.

At least 163 records · Page 9Linked to original sources
PubMed1982

Comparison of the pulmonary, hepatic and renal extraction of PGI2 and 6-keto-PGE1.

Prostaglandin (PG) I2 and 6-keto-PGE1 were infused into the aortic arch, femoral vein, renal artery and portal vein in anesthetized dogs over a dose range to produce a stable decrease in systemic blood pressure after 7 min of infusion. Mesenteric artery blood flow was measured continuously with a non-cannulating electromagnetic flow probe. Parallel log dose-response relationship were seen for decreases in blood pressure and increases in mesenteric blood flow with both prostaglandins when infused into the aortic arch. The dose responses for intra-aortic and intravenous infusion of PGI2 were not different but were shifted to the right with intrarenal and intraportal infusions. With 6-keto-PGE1 the dose responses after intravenous, intrarenal and intraportal infusions were all shifted to the right. By comparing doses which reduced blood pressure by 10 mm Hg, the extraction of the PGs by the lungs, kidney and liver was calculated PGI2 had no significant pulmonary extraction. 31% renal and 75% hepatic extraction. In contrast, 6-keto-PGE1 had extractions of 40, 66 and 51% for pulmonary, renal, and hepatic vascular beds, respectively. We conclude that 6-keto-PGE1 is reasonably well extracted by the lungs, kidney, and liver.

Alprostadil↗
PubMed1982

Familial Bartter's syndrome and the effect of indomethacin in one family member.

A Japanese family in which a father, daughter and son had hypokalemia and hyperreninemia was investigated. Both father and daughter had reduced vascular sensitivity to angiotensin II; in addition, the daughter had juxtaglomerular cell hyperplasia and dwarf glomeruli. These features are consistent with Bartter's syndrome occurring in 2 successive generations in 1 family. The 12-year-old girl had growth retardation in spite of normal growth hormone secretion. No chromosomal abnormalities were found. Indomethacin administration to this patient in doses sufficient to reduce urinary prostaglandin excretion resulted in a marked improvement of polydipsia and polyuria, and an increase in serum sodium, potassium and chloride concentrations. Even though plasma aldosterone concentrations were reduced to within the normal range, serum potassium concentrations remained low, and plasma renin activity (PRA) remained elevated. Thus it is not likely that hypokalemia is induced only by aldosteronism. These results suggest that prostaglandins are the major determinant of polydipsia, polyuria and high plasma aldosterone levels and contribute to the hypokalemia observed in this patient. However, the failure of complete correction of the hypokalemia and the persistence of the raised PRA with a significant reduction of the prostaglandins suggest the possibility that additional factors are involved in the pathogenesis of Bartter's syndrome.

Adult↗
PubMed1982

Furosemide disposition in cirrhosis.

Furosemide disposition after rapid intravenous injection (80 mg) was studied in 10 normal healthy subjects and eight patients with cirrhosis and ascites. In the cirrhotic patients the elimination half-life was modestly longer (81.0 +/- 8.0 min and 60.2 +/- 5.8 min). This prolongation was not associated with a difference in systemic clearance (156 +/- 7 ml/min in normal and 142 +/- 16 ml/min in cirrhotic subjects), rather it was a reflection of alterations in furosemide distribution. The steady-state volume of distribution was increased from 8.5 +/- 0.4 l in the healthy subjects to 12.1 +/- 1.3 l in the cirrhotic subjects; estimation in terms of unbound drug indicated an approximately 50% smaller value in cirrhosis. These observations were quantitatively consistent with the increased percentage of furosemide in plasma in the unbound form in the patients (10.2 +/- 1.0%) compared to in the normal subjects (4.0 +/- 0.1%). The 24-hr percentage urinary recovery of unchanged drug (58.8 +/- 2.8% and 53.1 6.5%) and the glucuronide metabolite (17.8 +/- 1.5 and 21.3 +/- 3.4) were on the same order in the normal and cirrhotic groups. The lack of major effects of cirrhosis on furosemide disposition suggests that changes in furosemide diuretic efficacy in such patients is a result of altered dynamic factors rather than altered disposition.

Adult↗
PubMed1982

Low dose intrarenal infusions of PGE2, PGI2, and 6-keto-PGE1 vasodilate the in vivo rat kidney.

The renal vascular effects of prostaglandin E2 (PGE2), 6-keto-PGE1, and PGI2 were investigated in indomethacin-pretreated rats. These prostanoids were infused directly into the left renal artery at rates ranging from 0.01 to 1.0 microgram/min, while renal blood flow and mean arterial blood pressure were constantly monitored. PGE2, 6-keto-PGE1, and PGI2 produced reductions in mean arterial blood pressure with threshold doses of 1.0, 0.3, and 0.03 microgram/min (P less than 0.01), respectively, and maximal vasodepressor responses of 18.9 +/- 4.3, 37.0 +/- 7.8, and 58.7 +/- 8.2 mm Hg (P less than 0.01), respectively. In addition, all three prostanoids caused a dose-related reduction in renal vascular resistance with a threshold dose of 0.01 microgram/min (P less than 0.05). The maximal reductions in renal vascular resistance were 2.59 +/- 0.52, 4.41 +/- 1.20, and 5.29 +/- 1.06 mm Hg/(ml per min) for PGE2, 6-keto-PGE1, and PGI2 (P less than 0.01), respectively. Whereas PGE2 an 6-keto-PGE1 produced dose-dependent increases in renal blood flow (maximal increases of 1.5 +/- 0.3 and 1.0 +/- 0.3 ml/min, respectively (P less than 0.01), PGI2 nonsignificantly increased renal blood flow at low doses and decreased renal blood flow at higher infusion rates (P less than 0.01). These data indicate that the in vivo rat kidney, similar to the kidneys of other species, is vasodilated by low doses of PGE2, PGI2, and 6-keto-PGE1.

Alprostadil↗
PubMed1982

Effects of indomethacin on beta adrenoreceptor-stimulated renin release in the dog.

The hypothesis that prostaglandins participate in beta adrenoreceptor-stimulated renin release was tested by examining the effects of prostaglandin synthesis inhibition on renal nerve stimulation (0.5-5.0 Hz)-induced renin release. In phentolamine (5 micrograms/kg/min, intrarenal artery)-treated dogs (n = 6), renal nerve stimulation produced a frequency-related increase in renal renin secretion rate, without altering renal blood flow. In phentolamine plus propranolol (0.3 mg/kg i.v. bolus + 5 micrograms/kg/min infusion)-treated dogs (n = 6), renal nerve stimulation-induced renin release was inhibited by 86% (P less than .03), 75% (P less than .03) and 73% (P less than .02) at 1, 2 and 5 Hz, respectively. In contrast to propranolol, blockade of prostaglandin synthesis with indomethacin (8 mg/kg i.v. bolus) failed to alter the renin secretory response to renal nerve stimulation in phentolamine-treated animals. These results indicate that, in a situation of intrarenal alpha adrenoreceptor blockade, renal nerve stimulation induces renin secretion by a beta adrenoreceptor mechanism that is independent of prostaglandin biosynthesis.

Animals↗
PubMed1982

Assessment of the extent to exogenous prostaglandin I2 is converted to 6-keto-prostaglandin E1 in human subjects.

6-Keto-prostaglandin (PG) E1 has been suggested as a possible active metabolite of PGI2. The objective of this study was to evaluate whether 6-keto-PGE1 might mediate the biological responses of exogenous PGI2 in man. Toward this end, a novel gas chromatographic-mass spectrometric assay for 6-keto-PGE1, was developed. Selective ion monitor traces from human plasma detected levels that were at the lower limit of sensitivity for this assay and positive mass spectral identification was not possible. An infusion of PGI2 (8 ng/kg/min) which caused systemic hemodynamic changes did not alter plasma levels of 6-keto-PGE1. We conclude that exogenous PGI2 is not converted to an appreciable extent to 6-keto-PGE1 in man and, therefore, 6-keto-PGE1 biosynthesis is unlikely to be responsible for the biological effects of infused PGI2.

Adult↗
PubMed1982

Acute renal artery constriction increases renal prostaglandin I2 biosynthesis and renin release in the conscious dog.

The relationship between renal prostaglandin (PG)I2 biosynthesis and renin release was examined in conscious dogs before and during renal artery constriction. Dogs were chronically instrumented with femoral vein, femoral artery and left renal vein catheters and an inflatable cuff and electromagnetic flow probe were positioned on the left renal artery. After 2 days, mean arterial blood pressure, heart rate, renal blood flow and renal secretion rates of renin and 6-keto-PGF1 alpha were determined before and 10 min after a reduction in renal blood flow. Plasma levels of 6-keto-PGF1 alpha, measured by a gas chromatographic-mass spectrometric assay, were used as an index of PGI2 synthesis. A 38% reduction in renal blood flow did not significantly alter mean arterial blood pressure, heart rate or arterial levels of plasma renin activity or 6-keto-PGF1 alpha. In contrast, renal artery constriction increased renal venous plasma levels of both renin activity and 6-keto-PGF1 alpha by 308% (P less than .002) and 132% (P less than .05), respectively. As a consequence, the renal secretion rate of renin was increased from 80 +/- 40 to 917 +/- 231 ng of angiotensin I . min-1 . hr-1 (P less than .02) and the renal secretion rate of 6-keto-PGF1 alpha was increased from -2.1 +/- 1.1 to 9.0 +/- 3.6 ng/min (P less than .05). In addition, there was a significant correlation between the renal secretion rates of renin and 6-keto-PGF1 alpha (r = 0.688; P less than .013; n = 12). These data indicate a close association between the renal biosynthesis and PGI2 and renin release and are consistent with the concept that PGI2 participates in the release of renin.

6-Ketoprostaglandin F1 alpha↗
PubMed1981

Effect of precursors of the 1, 2, and 3 series prostaglandins on renin release and renal blood flow in the dog.

The precursors of the monoene, diene, and triene series of prostaglandins, eicosatrienoic acid, arachidonic acid, and eicosapentaenoic acid, respectively, were infused at 3 X 10-6, 10-5, and 3 x 10-5 g/kg/min directly into the renal artery of non-filtering, denervated kidneys of conscious propranolol-treated dogs. Renal blood flow was measured with an electromagnetic flow probe around the renal artery and renal renin secretion rate from blood samples taken from catheters in the aorta and renal vein. The highest dose of arachidonic acid increased renal blood flow by 54 +/- 19% and increased renin secretion rate seven-fold. Eicosatrienoic acid produced a smaller increase in renal blood flow but did not significantly increase renin secretion rate. Eicosapentaenoic did not change either blood flow or renin secretion rate. We conclude that compared with arachidonic acid the precursors of the 1 and 3 series of prostaglandins are not significantly involved in the regulation of renal blood flow or renin secretion.

8,11,14-Eicosatrienoic Acid↗
PubMed1981

Meperidine disposition in man: influence of urinary pH and route of administration.

The effects of route of administration and altered urinary pH on the disposition of meperidine and its metabolite normeperidine were investigated in six normal, nonsmoking young men from 23 to 31 yr old. Meperidine (21.75 mg) was injected intravenously simultaneous with the same dose of deuterated (2H5) drug given orally in solution or by injection into the deltoid muscle. After intravenous administration with no control of urinary pH, meperidine blood levels declined triexponentially over 24 hr with a terminal half-life (t1/2) of 4.9 to 9.4 hr and a clearance of 472 to 686 ml/min. The 48-hr urinary recoveries of meperidine and normeperidine were about 7% and 12%. Urinary acidification with ammonium chloride reduced these amounts to less than 1% and about 7%, whereas urinary alkalinization increased them to about 20% and 24%. These pronounced changes had negligible effects on the blood concentration/time profiles. Plasma levels were proportional to the blood concentrations with a ratio of about unity for meperidine and a value 25% greater for normeperidine. Absorption after intramuscular injection was complete and followed a first-order process with t1/2 ranging from 7 to 13 min. Accordingly, maximum blood levels were achieved within 5 to 15 min and the concentration was essentially the same as after intravenous dosing. In contrast, oral bioavailability was incomplete, ranging from 47% to 73%, and at a much slower rate, with peak concentrations being observed after about 1 hr. Absorption was biphasic and was preceded by a 5- to 10-min lag period. Normeperidine blood concentration after intravenous dosing reached a maximum within 2 to 4 hr and remained at this value through 12 hr before modestly declining by 24 hr. After oral dosing the peak level was achieved more rapidly and sharply. Thus, presystemic elimination occurs after oral dosing within meperidine consistent in value with the measured blood clearance which, therefore, probably reflects only hepatic metabolism.

Administration, Oral↗
PubMed1981

Indomethacin decreases arterial blood pressure and plasma renin activity in rats with aortic ligation.

Severe renovascular hypertension was produced in rats by complete aortic ligation between the origin of the renal arteries. Six days after coarctation, a carotid cannula was implanted and mean arterial blood pressure (MABP) and plasma renin activity (PRA) were determined. Subsequently, indomethacin (5 mg/kg in oil) or vehicle was administered subcutaneously three times in the following 24-hour period. On day 7, MABP and PRA were again determined. Indomethacin reduced MABP from 179.0 +/- 6.7 to 156.5 +/- 8.8 mm Hg (P less than 0.002, n = 11) and PRA from 21.2 +/- 7.3 to 9.3 +/- 2.9 ng AI/ml per hr (P less than 0.045, n = 10), whereas vehicle treatment did not alter either MABP or PRA (n = 6). There was a significant association between the decrease in MABP and the percentage decrease in PRA following indomethacin treatment (r = 0.766, P less than 0.016). A similar study was performed in aortic ligated rats in which the left kidney was removed at the time of ligation. In these animals, 6 days after surgery, MABP and PRA were 128.0 +/- 5.9 mm Hg and 0.11 +/- 0.06 ng AI/ml per hr (n = 6), respectively, and indomethacin had no effect on either MABP or PRA. These data provide evidence that the prostaglandin system is involved in the release of renin and in the pathogenesis of elevated blood pressure in this model of renin-dependent hypertension.

Animals↗
PubMed1981

6-Keto-prostaglandin E1 is more potent than prostaglandin I2 as a renal vasodilator and renin secretagogue.

Several studies indicate that prostaglandin (PG) I2 is involved in the control of renin release. This investigation was performed to determine if the active possible metabolite of PGI2, 6-keto-PGE1, is also a renin secretagogue. The relative potencies of PGI2, 6-keto-PGE1 and 6-keto-PGF1 alpha on renin secretion rate (RSR) and renal blood flow (RBF) were assessed in nonfiltering, beta adrenoreceptor blocked kidneys of seven anesthetized dogs. Intrarenal infusions of both PGI2 and 6-keto-PGE1 significantly augmented RSR in a dose-related fashion. However, 6-keto-PGE1 was approximately 5 times more potent than PGI2, producing significantly greater increases in RSR at doses from 3 X 10(-9) to 3 X 10(-8 g/kg/min (P < .03). At low infusion rates (less than 3 X 10(-8) g/kg/min), 6-keto-PGE1 enhanced RBF to a greater extent than PGI2. However, with infusion rates of 3 X 10(-8) g/kg/min, these eicosanoides enhanced RBF to an equal extent. Thus, in comparison to PGI2, 6-keto-PGF1 induced a greater increase in RSR for equivalent increases in RBF. 6-keto-PGF 1 alpha had no effect on either RSR or RBF at any of the doses infused. We conclude that, in the canine kidney, 6-keto-PGE1 is more potent than PGI2 in stimulating the juxtaglomerular cells to secrete renin.

Alprostadil↗
PubMed1981

Disposition of furosemide in functionally hepatectomized dogs.

To assess the role of the liver in the elimination of furosemide, the disposition kinetics of the diuretic after intravenous administration were studied in dogs with total devascularization of the liver and sham-operated animals. Functional hepatectomy caused no significant changes in either the renal or the nonrenal clearances of furosemide; renal = 124.2 +/- 27.1 (mean +/- SE) and 106.6 +/- 17.5 ml/min and nonrenal = 148.2 +/- 11.4 and 112.6 +/- 21.0 ml/min in sham-operated and hepatectomized dogs, respectively. Devascularization of the liver had no effect on the plasma binding of furosemide which was 90.0% in the sham-operated and 88.2% in the hepatectomized animals. The steady-state volume of distribution of furosemide was relatively small, 0.70 +/- 0.09 liters/kg in control dogs and hepatectomy resulted in a reduction in this volume (0.58 +/- 0.09 liters/kg). This indicates that the liver is a significant organ for distribution of furosemide in the dog. Urinary recoveries of parent drug (43.2% of the dose in sham-operated dogs ad 49.1% in hepatectomized animals) and of its glucuronide (4.3% in sham-operated and 5.5% in hepatectomized dogs) were not influenced by hepatic devascularization. These findings demonstrate that, although nonrenal clearance accounts for about 50% of the elimination of furosemide, the liver does not play a significant role in this process in the dog.

Animals↗
PubMed1981

The differential localization of various drug metabolizing systems within the rat liver lobule as determined by the hepatotoxins allyl alcohol, carbon tetrachloride and bromobenzene.

Rats were pretreated with allyl alcohol, carbon tetrachloride or bromobenzene to induce histopathological evidence of periportal, midzonal to centrilobular, and centrilobular hepatic necrosis. The amount of various drug metabolizing enzyme systems present after necrosis was determined indirectly by measuring the rate of metabolism for specific substrates in vitro. The chemically induced hepatocellular injury of these toxins produced variable but significant alterations in hepatic drug metabolism. The changes in enzymatic activity related well with the area of the lesion produced by each toxin. Thus, these hepatotoxins appear to be useful as probes to determine the hepatolobular distribution of the various drug metabolizing enzyme systems studied. Aniline hydroxylase and p-nitroanisole o-demethylase were concentrated in the midzonal and periportal zones, while aminopyrine N-demethylase was more uniformly distributed along the cytochrome P-450 gradient. Glucuronyltransferase was more heavily concentrated in the periportal-midzonal area, acetyltransferase was centrilobular-midzonal and glutathionetransferase was concentrated in the midzonal region. Thus, as is the case for cytochrome P-450, there appears to be a high degree of regional organization for all of the drug metabolizing enzymes within the hepatic lobule.

1-Propanol↗