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Biomedical subjects

R A Branch

Publications and source records attributed to R A Branch.

At least 91 records · Page 5Linked to original sources
PubMed1990

Interaction between angiotensin II and adenosine in mediating the vasoconstrictor response to intrarenal hypertonic saline infusions in the dog.

Intrarenal artery infusion of hypertonic saline induces a sustained renal vasoconstriction that is most likely mediated by tubuloglomerular feedback. The purpose of this study was to investigate the contribution of angiotensin II and adenosine to this response in normal-salt and salt-deplete states. Intrarenal infusions of hypertonic saline to sodium-deplete dogs caused a renal vaso-constrictor response that was observed between 5 and 10 min into the infusion. This response was attenuated in dogs on a normal-salt diet and in salt-deplete dogs receiving captopril. Intravenous infusion of subpressor doses of angiotensin II to dogs either on a normal-salt intake or on a salt-deplete diet but receiving captopril, restored the vasoconstrictor response to hypertonic saline. The vasoconstrictor response in the presence of an angiotensin II infusion in each of these two groups of dogs was abolished by an intrarenal artery infusion of the adenosine receptor blocker, theophylline. These experiments are consistent with the hypothesis that intrarenal infusion of hypertonic saline enhances the endogenous production of adenosine and that the ability of adenosine to reduce renal blood flow is dependent on the presence of angiotensin II.

Adenosine↗
PubMed1990

Mechanisms of amphotericin B-induced reduction of the glomerular filtration rate: a micropuncture study.

Amphotericin B infusions cause acute reductions in renal plasma flow and glomerular filtration rate. The exact mechanism by which these changes occur has not been identified fully, nor have the effects of the drug on the renal microcirculation been studied adequately. In this study, we examined the effect of intrarenal amphotericin B infusions (0.05 mg/kg/min) on glomerular hemodynamics in the anesthetized rat. Amphotericin B did not affect systemic blood pressure and slightly increased hematocrit (5%), but significantly decreased renal blood flow and glomerular filtration rate by 40 and 35%, respectively. Glomerular micropuncture revealed decreases in single nephron plasma flow and glomerular filtration rate (from 142 +/- 12 to 89 +/- 14 and from 35.3 +/- 2.2 to 22.8 +/- 2.8 nl/min, respectively). These changes were due to significant increases in pre- and postglomerular resistances (from 1.91 +/- 0.17 to 3.95 +/- 0.38 and from 1.30 +/- 0.10 to 2.08 +/- 0.12 10(10) dyn.sec.cm-5, respectively), and to a significant decrease in the glomerular capillary ultrafiltration coefficient which fell from 0.043 +/- 0.008 to 0.032 +/- 0.009 nl/(sec.mm Hg). These results provide further insight into the mechanisms of the acute renal effects of amphotericin B, and suggest possible mediators that may be involved in these effects.

Amphotericin B↗
PubMed1990

Use of a database computer program to identify trends in reporting of adverse drug reactions.

A computerized system for concurrent monitoring and reporting of adverse drug reactions (ADRs) in a university hospital is described. The program, which began in 1988, was developed in collaboration with the hospital's pharmacy and therapeutics committee and quality assurance committee. Quality assurance nurses review patients' charts every three days during hospitalization; if an ADR is detected, the nurse completes an ADR report form. A computer database is used to sort and store 15 data elements taken from each ADR form. Individual pharmacists and hospital review committees evaluate the recorded ADRs. The database can present the data for analysis by different variables such as patient age, clinical service, and implicated drugs. Retrieval of such data permits easier evaluation of trends in ADR reports and identification of reactions that should be reported to FDA. Educational programs for staff members can be targeted to address problems occurring within the institution. During the first nine months of the program 340 ADRs were reported; 15 reports were submitted to FDA, and serious problems were reviewed at medical grand rounds. A bimonthly newsletter that reviews recently reported ADRs was begun. The monitoring program has facilitated rapid detection and evaluation of ADRs.

Drug-Related Side Effects and Adverse Reactions↗
PubMed1989

Adenosine inhibits renin release induced by suprarenal-aortic constriction and prostacyclin.

The purpose of this study was to determine whether adenosine can attenuate the renin release response to a reduction in renal perfusion pressure. To this end, the secretion rate of renin was measured in six beta-blocked dogs at ambient arterial blood pressure and after a reduction of renal perfusion pressure to 80 mm Hg. These measurements were made during a control period, an intrarenal infusion of adenosine at 10 and 30 micrograms/min, and a recovery period. During the control and recovery periods renal artery hypotension significantly increased the secretion rate of renin. However, during the intrarenal infusions of adenosine, renin secretion rate did not increase significantly. Analysis of variance indicated that both doses of adenosine reduced the renin response to renal artery hypotension. In another six dogs with a single nonfiltering kidney, we again measured renin secretion during a control period, the intrarenal infusion of adenosine at 10 and 30 micrograms/min, and a recovery period; however, in this study PGI2 was used to stimulate renin release. Adenosine also significantly attenuated the renin release response to PGI2. We conclude that adenosine can inhibit the renin release response to both renal artery hypotension and PGI2 and that this effect is most likely mediated by a direct action of adenosine on juxtaglomerular cells. Also, since PGI2 may be a mediator of the renin response to renal artery hypotension, the data are consistent with the hypothesis that adenosine inhibits the renin response to renal artery hypotension by attenuating the response of juxtaglomerular cells to PGI2.

Adenosine↗
PubMed1989

Methylxanthines augment the renin response to suprarenal-aortic constriction.

In a previous study we discovered that the adenosine receptor antagonist, caffeine, increases plasma renin activity and blood pressure in renin-dependent renovascular hypertension. The purpose of the present investigation was to determine whether methylxanthines augment the increase in renin secretion induced by a reduction in renal perfusion pressure and, if so, whether this effect is mediated by a direct action on juxtaglomerular cells. Accordingly, we examined the effects of infusions of caffeine and theophylline directly into the renal artery on the increase in renin secretion induced by suprarenal aortic constriction. All studies were conducted in dogs receiving an intravenous infusion of propranolol to prevent changes in renin secretion mediated indirectly via the sympathetic nervous system. Caffeine (5 mg/min) increased the renin response to suprarenal aortic constriction about 10-fold without significantly affecting renal hemodynamics or excretory function. Theophylline (5 mg/kg), on the other hand, did not significantly increase the renin response to a reduction in renal perfusion pressure, but did increase urine flow and sodium excretion about 10-fold. However, in the non-filtering, beta-adrenoceptor blocked, canine kidney, theophylline markedly increased the renin response to suprarenal aortic constriction. These results indicate that methylxanthines can potentiate the renin response to a reduction in renal perfusion pressure most likely by directly affecting the juxtaglomerular cells; however, since increased sodium delivery to the macula densa inhibits renin release, the extent to which methylxanthines affect the renin response to renal artery hypotension depends on how vigorous the diuretic response is to a given methylxanthine.

Adrenergic beta-Antagonists↗
PubMed1989

Propranolol's metabolism is determined by both mephenytoin and debrisoquin hydroxylase activities.

The relative contributions of the debrisoquin and mephenytoin isozymes of hepatic cytochrome P-450 to the stereoselective metabolism of propranolol have been studied in a panel of volunteers of known oxidative phenotypes. Six subjects were extensive metabolizers of both debrisoquin and mephenytoin (EM). Four subjects were poor metabolizers of debrisoquin but rapid for mephenytoin (PMD). Five subjects were poor metabolizers of mephenytoin but rapid for debrisoquin (PMM), and one individual had a deficiency for both test compounds (PMD/M). Partial metabolic clearances of each propranolol enantiomer to 4-hydroxypropranolol (4-OH-P), the sulfate, and glucuronide conjugates of 4-OH-P, naphthoxylactic acid (NLA) and propranolol glucuronide, were estimated after a single oral dose of racemic propranolol (80 mg). The partial metabolic clearance of both enantiomers to total 4-OH-P in the PMD group was 75% less than in the EM and PMM groups, indicating the contribution of the debrisoquin isozyme to this route of metabolism. The R/S ratios for the clearance to 4-OH-P were similar between EM and PMD (2.5 +/- 0.5 vs 2.5 +/- 0.4, respectively), implying that the different enzymes involved in ring hydroxylation (i.e., the debrisoquin isozyme and other hydroxylases) have similar stereoselective preferences. The partial metabolic clearance to NLA was 55% less in the PMM group than in the EM and PMD groups, indicating that S-mephenytoin 4-hydroxylase contributes to the metabolic conversion of propranolol to NLA. The R/S ratios for the clearance to NLA were close to unity in all groups. The partial metabolic clearance to propranolol glucuronide also did not exhibit stereoselectivity and was similar in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Aryl Hydrocarbon Hydroxylases↗
PubMed1989

Impaired hepatic elimination of paranitrophenol and its metabolites in the rat following chronic ethanol pretreatment.

Chronic ethanol feeding has been shown to enhance hepatic microsomal drug oxidation in humans and in laboratory animals. However, the effects of chronic ethanol administration on drug conjugation are less conclusive. We have studied the effects of chronic ethanol feeding on (a) the conjugation and elimination of p-nitrophenol (PNP) by the isolated perfused rat liver, (b) the formation of PNP glucuronide by hepatic microsomal PNP-glucuronyltransferase in vitro and (c) the hepatic content of UDP-glucuronic acid (UDPGA). PNP elimination from the isolated perfused rat liver was best described as a combination of parallel saturable and first-order processes. Ethanol pretreatment did not influence the former but resulted in a 48% reduction in the rate of elimination by the latter. This was associated with a significant reduction in recovery of PNP-glucuronide from bile, but no change in concentrations of PNP glucuronide or sulfate in perfusate. Michaelis constants and Vmax for PNP-glucuronyltransferase in native and solubilized microsomes and UDPGA concentrations in liver were not influenced by ethanol pretreatment. These results suggest that chronic ethanol treatment reduces PNP elimination in the intact liver primarily via a reduction in the biliary excretion of PNP glucuronide without altering glucuronidation per se.

Animals↗
PubMed1989

Role of sodium in the protective effect of ticarcillin on gentamicin nephrotoxicity in rats.

Coadministration of sodium ticarcillin with an aminoglycoside is known to reduce the nephrotoxicity of the aminoglycoside. However, it is not known whether the penicillin or the obligatory sodium load confers protection. To investigate this, gentamicin has been administered intraperitoneally in doses of 50, 60, or 80 mg/kg per day for 12 days in groups of rats receiving either a normal or a low sodium intake. Alterations in creatinine clearance have been measured. Salt depletion resulted in an enhanced nephrotoxic response with a shift in the dose-response curve to the left. Administration of sodium ticarcillin to rats with a salt-depleted intake at a dose sufficient to replace sodium intake conferred an equal degree of protection to rats with a normal salt intake. We report that the obligatory salt supplement with ticarcillin is sufficient to account for the renal sparing effect of the combination treatment without having to infer a direct chemical interaction of penicillin with the aminoglycoside.

Animals↗
PubMed1989

Sodium status influences chronic amphotericin B nephrotoxicity in rats.

The nephrotoxic potential of amphotericin B (5 mg/kg per day intraperitoneally for 3 weeks) has been investigated in salt-depleted, normal-salt, and salt-loaded rats. In salt-depleted rats, amphotericin B decreased creatinine clearance linearly with time, with an 85% reduction by week 3. In contrast, in normal-salt rats creatinine clearance was decreased but to a lesser extent at week 2 and 3, and in salt-loaded rats creatinine clearance did not change for 2 weeks and was decreased by 43% at week 3. All rats in the sodium-depleted group had histopathological evidence of patchy tubular cytoplasmic degeneration in tubules that was not observed in any normal-salt or salt-loaded rat. Concentrations of amphotericin B in plasma were not significantly different among the three groups at any time during the study. However, at the end of 3 weeks, amphotericin B levels in the kidneys and liver were significantly higher in salt-depleted and normal-salt rats than those in salt-loaded rats, with plasma/kidney ratios of 21, 14, and 8 in salt-depleted, normal-salt, and salt-loaded rats, respectively. In conclusion, reductions in creatinine clearance and renal amphotericin B accumulation after chronic amphotericin B administration were enhanced by salt depletion and attenuated by sodium loading in rats.

Amphotericin B↗
PubMed1989

Zonal distribution of paracetamol glucuronidation in the isolated perfused rat liver.

1. The lobular distribution of paracetamol conjugation was studied using antegrade and retrograde perfusion of isolated rat liver. After addition of 25 mg of paracetamol, recovery of sulphate from antegrade perfusions was greater than from retrograde perfusions indicating periportal predominance of this metabolic pathway. 2. Recovery of sulphate was greater than recovery of glucuronide after addition of 25 mg of paracetamol during both antegrade and retrograde perfusions. Recovery of sulphate was similar after addition of 25 or 100 mg of paracetamol, whereas recovery of the glucuronide was increased at the higher dose, indicating a higher capacity for glucuronidation than for sulphation, but a higher affinity for sulphation. 3. Recovery of glucuronide from antegrade and retrograde perfusions was similar after addition of 25 mg of paracetamol, but was greater from antegrade perfusions after addition of 100 mg. This indicates that drug concentration may be an important determinant of the zonal distribution of drug metabolism. Factors other than localization of drug-metabolizing enzymes, such as competition with other metabolic pathways or availability of cofactors, may also influence the apparent zonal distribution of drug metabolism.

Acetaminophen↗
PubMed1989

Caffeine potentiates the renin response to furosemide in rats. Evidence for a regulatory role of endogenous adenosine.

Adenosine is a potent inhibitor of renin release. It has therefore been suggested that endogenous adenosine may play a role in the regulation of renin release. Sodium-chloride transport at the level of the macula densa has been proposed as the primary source of endogenous adenosine. Evidence to support a modulatory role of adenosine on renin release in vivo is, however, limited. We therefore wanted to determine if: 1) adenosine modulates furosemide-induced renin release and 2) sodium-chloride reabsorption at the macula densa is essential for adenosine actions. To test these hypotheses, three groups of rats were pretreated either with saline or the adenosine receptor antagonists caffeine or 1,3-dipropyl-8-(p-sulfophenyl)xanthine (both at a dose of 30 mg/kg followed by 450 micrograms/kg/min). Rats then received furosemide (50 mg/kg i.v.). In the vehicle group, furosemide increased urinary volume, sodium and potassium excretion and increased plasma renin activity from 6 +/- 1 to 45 +/- 11 ngAl/ml/hr. Caffeine and 1,3-dipropyl-8-(p-sulfophenyl)xanthine potentiated the increase in plasma renin activity produced by furosemide (to 120 +/- 15 and 147 +/- 21 ng Al/ml/hr, respectively), whereas having no significant effects on urinary volume, sodium excretion or blood pressure. These results suggest that furosemide-induced renin release in vivo is restrained by endogenous adenosine. In as much as furosemide blocks sodium-chloride transport in the thick ascending limb of Henle's loop and the macula densa cells, it appears that under the conditions of this study sodium transport across these segments is not essential to initiate adenosine-mediated mechanisms.

Adenosine↗
PubMed1989

Inhibition of renal vasoconstriction induced by intrarenal hypertonic saline by the nonxanthine adenosine antagonist CGS 15943A.

The hypothesis that intrarenal infusions of hypertonic saline induce endogenous release of adenosine to result in renal vasoconstriction has been investigated in salt-deplete dogs using the nonxanthine adenosine receptor antagonist, CGS 15943A. Intrarenal artery infusions of CGS 15943A induced dose-dependent reductions in the renal vasoconstrictor response to bolus doses of adenosine into the renal artery, without altering base-line blood pressure or renal blood flow. Infusion rates of 10 micrograms/min induced an approximate 50% reduction in response, whereas 100 micrograms/min produced a substantially greater response. There was no inhibition of the renal vasoconstrictor response to angiotensin II and norepinephrine by CGS 15943A at a rate of 100 micrograms/min. Changes in RBF after intrarenal infusion of hypertonic saline were compared between further series of salt-deplete dogs receiving intrarenal artery infusions of either vehicle or CGS 15943A (100 micrograms/min). An initial infusion of hypertonic saline to both groups of dogs induced renal vasodilation followed by vasoconstriction. In dogs subsequently infused with CGS 15943A (100 micrograms/min), the initial renal vasodilation response was similar, but there was an abolition of the later vasoconstrictor response. In contrast, the renal blood flow response to hypertonic saline was unchanged in the vehicle-infused dogs. We conclude that CGS 15943A can selectively block the renal blood flow response to exogenous adenosine without altering baseline renal vascular tone and that the ability of CGS 15943A to abolish the renal vasoconstrictor response to intrarenal hypertonic saline is consistent with the hypothesis that endogenous release of adenosine is involved in mediating the reduction in renal blood flow.

Adenosine↗
PubMed1988

Effects of thromboxane synthase inhibitors on renal function.

In general the effects of thromboxane A2(TXA2) on renal function are opposite those produced by other prostanoids. TXA2 synthase inhibitors decrease the biosynthesis of TXA2 and may increase the production of other prostanoids by causing endoperoxide shunting. Therefore, in situations of increased kidney arachidonate mobilization, inhibition of renal TXA2 synthase might alter renal function by reducing TXA2 production and/or increasing prostaglandin (PG) biosynthesis. This hypothesis was tested by comparing the changes in renal function induced by suprarenal aortic constriction in anesthetized dogs pretreated with either a TXA2 synthase inhibitor (UK38,485; n = 7 or OKY1581; n = 7) or vehicle (0.1 M Na2CO3; n = 9). Several renal function parameters were compared in control versus treated animals by analysis of variance. Neither UK38,485 (1 mg/kg, i.v.) nor OKY1581 (10 mg/kg, i.v.) significantly altered renal artery hypotension-induced changes in mean arterial blood pressure, heart rate, renal blood flow, renal vascular resistance, glomerular filtration, filtration fraction, urine flow rate, sodium excretion rate, fractional sodium excretion, potassium excretion, or fractional potassium excretion. However, both UK38,485 and OKY1581 seemed to attenuate the increase in renal renin secretion rate induced by suprarenal aortic constriction. We conclude that acute administration of TXA2 synthase inhibitors does not modify acute renal artery hypotension-induced changes in either electrolyte excretion or renal hemodynamics. However, acute administration of TXA2 inhibitors attenuates suprarenal aortic constriction-induced increases in renin release in anesthetized dogs by unknown mechanisms.

Acrylates↗