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Biomedical subjects

W R Murphy

Publications and source records attributed to W R Murphy.

At least 19 recordsLinked to original sources
PubMed1997

Assessing the sequence specificity in the binding of Co(III) to DNA via a thermodynamic approach.

The interaction specificities of Co(III) with DNA were investigated via consideration of thermodynamic characteristics of the duplex to single strand transition for DNA oligomers incubated in the presence of [Co(NH3)5(OH2)](ClO4)3. It has previously been demonstrated that incubation of the DNA oligomer [(5medC-dG)4]2 with this cobalt complex leads to coordination of the cobalt center to the DNA, presumably at N7 of guanine bases [D. C. Calderone, E. J. Mantilla, M. Hicks, D. H. Huchital, W. R. Murphy, Jr. and R. D. Sheardy, (1995) Biochemistry 34, 13841]. In this report, DNA oligomers of different sequence were incubated with [Co(NH3)5(OH2)](ClO4)3 via protocols developed previously and the treated oligomers were subjected to thermal denaturation for comparison to the untreated oligomers. The DNA oligomers were designed in order to investigate the sequence specificity, if any, in the reaction of the cobalt complex with DNA. The values of Tm, delta HvH, and delta n (the differential ion binding term) obtained from the thermal denaturations were used to assess the sequence specificity of the interaction. For all oligomers, treated or untreated, Tm and delta HvH vary linearly with log [Na+] and hence the value of delta n is a function of the Na+ concentration. The results indicate no significant reaction between the cobalt complex and oligomers possessing isolated -GA- or -CG- sites; however, the thermodynamic characteristics of DNA oligomers possessing either an isolated -GG- site or an isolated -GC- site were altered by the treatment. Atomic absorption studies of the treated oligomers demonstrate that only the DNA oligomers possessing isolated -GG- or -GC- sites bind cobalt. Hence, the changes in the thermodynamic properties of these oligomers are a result of cobalt binding with a remarkable sequence specificity.

Binding Sites↗
PubMed1997

Processor quality control in laser imaging systems.

Sensitometric techniques for performing processor quality control in laser imaging systems are analyzed in this study. The sensitivity of conventional x-ray films using simulated screen-light sensitometry is compared with helium-neon (HeNe) laser film exposed with a simulated red-light sensitometer, a standalone (reference) laser sensitometer, an experimental (unstable) laser sensitometer, and laser printers. Infrared (IR) laser film exposed with an IR laser diode and a simulated IR sensitometer are also evaluated. It is demonstrated that laser-generated step tablets provide an easy and reliable method of performing laser film processor quality control.

Helium↗
PubMed1995

Binding of Co(III) to a DNA oligomer via reaction of [Co(NH3)5(OH2)]3+ with (5medC-dG)4.

The interaction specificities of cobalt(III) ammines with the self-complementary eight-base pair DNA oligomer (5medC-dG)4 have been investigated. Standard protocol for preparing DNA samples calls for heat annealing the DNA oligomer in phosphate buffer in the absence or presence of cobalt(III) ammine complex for 2 min at 80 degrees C, followed by slow cooling to 25 degrees C. An alternative method for DNA preparation is incubation of the oligomer in the presence of the cobalt(III) complex at 37 degrees C followed by exhaustive dialysis. The conformational properties of the thus-treated DNA oligomer were determined by inspection of the UV and CD spectra at 25 and 95 degrees C and thermal denaturation studies. With heat annealing in the absence of any cobalt(III) complex, (5medC-dG)4 assumes a double-stranded, right-handed B conformation at 25 degrees C. Upon heat annealing in the presence of 200 microM [Co(NH3)6]3+, (5medC-dG)4 assumes a double-stranded, left-handed Z conformation at 25 degrees C. In contrast, the CD and UV spectra of (5medC-dG)4 heat annealed in the presence of 200 microM [Co(NH3)5(OH2)]3+ are consistent with a distorted B-like conformation at 25 degrees C. Incubation of the oligomer in the presence of [Co(NH3)5(OH2)]3+ results in modification of the conformational properties of the oligomer at both 25 and 95 degrees C relative to the untreated oligomer. The extent of modification depends upon the incubation concentration of [Co(NH3)5-(OH2)]3+ and the reaction time. Atomic absorption (AA) analyses of these treated DNA samples indicate a high degree of cobalt association to the oligomer.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1995

Discovery of inhibitors of human renin with high oral bioavailability.

Knowledge of the sequence of a bioactive protein (angiotensinogen) and the availability of a natural product inhibitor lead (pepstatin) were the starting point for discovery of potent penta- and hexapeptide renin inhibitors. Study of the metabolism and disposition of these substances forced the discovery of simpler inhibitors leading to the discovery of oral activity in Terlakiren (22). Modification of physical properties led to the synthesis of aminopiperidine 30, which was identified by oral efficacy profiling. Structural modification to give enzymatic stability produced the bioavailable benzylsuccinate inhibitor 34. Its bioactive monomethylamine metabolite (35, CP-108,671) was subsequently found to have uniformly high oral bioavailability and activity in various species including primates.

Administration, Oral↗
PubMed1994

CP-71,362: a pentapeptide renin inhibitor selective for the canine enzyme.

Most renin inhibitors are primate-specific. In the present paper, we describe the effects of CP-71,362, a pentapeptide which preferentially inhibits canine (and to a lesser extent, rat) plasma renin. Vs. the canine enzyme, its affinity (IC50 = 3.3 x 10(-12) M) is 1000x greater than for rat renin (IC50 = 3.3 x 10(-9) M), and 1000x greater than for human (IC50 = 2.3 x 10(-8) M), cynomolgus monkey (IC50 = 1.6 x 10(-8) M), or guinea pig (IC50 = 5.2 x 10(-8) M) enzyme. In anesthetized, sodium-depleted dogs, intravenous infusion of CP-71,362 (ED50 = 1.1 micrograms/kg/min) resulted in dose-dependent decreases (up to -35 mm Hg) in mean arterial pressure (MAP). The maximum fall in MAP was equivalent to that produced by i.v. captopril (5 mg/kg). Similar falls in MAP were observed in conscious sodium-depleted SHR (ED50 = 5 micrograms/kg/min). Via bolus injection, the action of CP-71,362 was relatively brief in dog, guinea pig, and SHR. We conclude that CP-71,362 is a potent canine/rat renin inhibitor and causes profound MAP lowering in these species.

Animals↗
PubMed1993

Comparison of angiotensin converting enzyme and renin inhibition in rats following myocardial infarction.

Renal and systemic hemodynamics were studied in rats 1 month after induction of myocardial infarction by ligation of the left coronary artery. The mean arterial pressure, heart rate, and cardiac index were not different from controls, but there were striking elevations in heart weight (p < 0.001), left ventricular end diastolic pressure (p < 0.002), and renal vascular resistance (p < 0.01). Renal blood flow and the percent of cardiac output perfusing the kidneys were reduced by 18% (p < 0.01) and 14% (p < 0.01), respectively. Acute angiotensin inhibition was studied at a dose of the converting enzyme inhibitor, enalapril, or the renin inhibitor, CP71362, that lowered the mean arterial pressure by 15 mm Hg in normal rats. In normal rats, enalapril and CP71362 were without effect on renal blood flow (RBF), renal vascular resistance (RR), and RBF as a percent of cardiac output. However, in rats with myocardial infarction, enalapril and CP71362 increased the RBF and RBF as a percent of cardiac output and lowered the RR to levels similar to normal controls (p < 0.02). Enalapril and CP71362 were equally effective in reducing the left ventricular end-diastolic pressure and total peripheral resistance in rats with myocardial infarction. These data demonstrate significant intrarenal vasoconstriction following myocardial infarction in the absence of detectable changes in mean arterial pressure or cardiac index. Converting enzyme inhibition or renin inhibition had similar beneficial effects on cardiorenal function, suggesting that both classes of compounds act by a similar mechanism to improve renal hemodynamics in congestive heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Synergistic effect on reduction in blood pressure with coadministration of the renin inhibitor, CP-80,794, and the angiotensin converting enzyme inhibitor, captopril.

The effects of coadministration of a renin inhibitor, CP-80,794, and an angiotensin converting enzyme inhibitor, captopril, on blood pressure of sodium-depleted guinea pigs was studied. Dose-response curves for CP-80,794 (0.3-3.0 mg/kg i.v.) and captopril (0.03-1.0 mg/kg i.v.) were obtained either alone or in the presence of a submaximal dose of the other inhibitor. The hypotensive response calculated for each compound individually was subtracted from the combined dose response. The results showed that statistically significant synergy with captopril and CP-80,794 occurred when the area rather than the peak drop or duration of change in blood pressure was measured. The degree of the synergy indicated that to achieve the same reduction in blood pressure, the dose of each drug, below the high end of its response range, could be decreased approximately sixfold when administered in combination. It was determined that the plasma pharmacokinetics of CP-80,794 were not altered during coadministration, as plasma concentrations of CP-80,794 were similar in the presence and absence of 0.1 mg/kg i.v. of captopril. These results indicate that by inhibiting sequential enzymes in the renin-angiotensin system, synergistic effects can be produced. The relative safety of each inhibitor could be improved by large reductions in dose when used concurrently.

Analysis of Variance↗
PubMed1991

CP-66,948: an antisecretory histamine H2-receptor antagonist with mucosal protective properties.

CP-66,948 is a histamine H2-receptor antagonist with gastric antisecretory activity and mucosal protective properties. The affinity of CP-66,948 for the guinea pig atria histamine H2-receptor is 15 times greater than that of cimetidine and seven times greater than that of ranitidine. In vivo, the ED50 value for inhibition of gastric acid secretion in pylorus-ligated rats is 2 mg/kg intraduodenally, and in histamine or pentagastrin-stimulated Heidenhain pouch dogs the antisecretory ED50 values are 0.3 mg/kg per os and 1.0 mg/kg per os, respectively. CP-66,948 also inhibits ethanol-induced gastric hemorrhagic lesions in rats following either oral or systemic administration (ED50 values of 12 mg/kg per os and 6 mg/kg subcutaneously). In addition, the mucosal protective activity is independent of prostaglandin synthesis. CP-66,948 inhibits gastric acid secretion in man, and its mucosal protective activity may provide additional benefits in peptic ulcer therapy.

Animals↗
PubMed1989

Combined renin and converting enzyme inhibition in rats.

The effects of combined renin inhibition and converting enzyme inhibition on mean arterial pressure and the plasma renin-angiotensin system were studied in conscious rats. In sodium-replete rats the infusion of the renin inhibitor CP71362 (100 micrograms/kg/min) decreased blood pressure by 13 +/- 1 mm Hg (p less than 0.0001), reduced plasma renin activity to undetectable levels, but did not lower plasma angiotensin II. In rats treated chronically with enalapril (30 mg/kg/day), CP71362 decreased blood pressure by an additional 5 +/- 2 mm Hg (p less than 0.025) and reduced plasma renin activity and angiotensin II concentrations to undetectable levels. The effects of renin inhibition were also tested under conditions where the renin-angiotensin system was stimulated. In rats on a low sodium diet, CP71362 decreased blood pressure by 15 +/- 2 mm Hg (p less than 0.0001), a decrease similar to that in rats on a normal diet. Plasma renin activity was decreased below detectable limits, but plasma angiotensin II concentrations were not reduced. In rats on a low sodium diet treated chronically with enalapril, CP71362 did not further decrease blood pressure although angiotensin II levels were significantly reduced. An additive effect of combined converting enzyme and renin inhibition on blood pressure lowering and inhibition of plasma angiotensin II was found in rats anesthetized with Inactin.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1987

Hemodynamic monitoring for 24 h in unanesthetized rats.

A new technique is described that allows minute-to-minute recordings of cardiac output and arterial pressure in unanesthetized rats for periods of 24 h and longer. Rats were instrumented with electromagnetic flow probes and arterial catheters. An electrical and hydraulic swivel was interposed between the rat and recording apparatus to allow free range of movement. Data were collected and analyzed once each minute by computer. Average 24-h values (mean +/- SD) for the following hemodynamic variables were determined in eight rats [expressed where appropriate as a function of body weight (BW)]: cardiac output (98.1 +/- 14.7 ml/min), cardiac index (29.2 +/- 4.4 ml.min-1.100 g BW-1), mean arterial pressure (92.5 +/- 7.8 mmHg), heart rate (347 +/- 45 beats/min), peak aortic flow (403 +/- 32 ml/min), stroke volume (282 +/- 26 microliters), stroke volume index (84.4 +/- 8.1 microliters/100 g BW), and total peripheral resistance index (3.26 +/- 0.46 mmHg.ml-1.min.100 g BW). These results provide a data base of hemodynamic values for unanesthetized adult, Sprague-Dawley male rats, which has not been previously available. In addition, cardiac index, mean arterial pressure, and total peripheral resistance index demonstrated diurnal variation. Diurnal variation contributed substantially to the overall variance observed within these variables. Hourly variance was also substantial and indicates the use of continuous recordings for short-term experiments.

Animals↗
PubMed1987

Overall hemodynamic pattern in coarctation of the abdominal aorta in conscious rats.

This study was designed to examine the total body hemodynamics of abdominal aortic coarctation hypertension. The study quantitates both regional and organ blood flow and resistance in conscious rats both above and below an experimentally produced coarctation. The experimental group consisted of 10 male Sprague-Dawley rats with a mean pressure gradient of 68 mm Hg across the coarctation. This experimental group was compared with a group of eight control rats with no pressure gradient. Flow measurements were made with radioactively labeled microspheres 4 weeks after aortic constriction. This aortic coarctation produced an increase in cardiac index (22%) and total peripheral resistance (19%). Blood flow through tissues proximal to the coarctation was not different from control; vascular resistance was increased (31%). Flow through the tissues distal to the coarctation was increased (16%); vascular resistance was decreased (-22%). The upper carcass, diaphragm, and brain were the tissues most representative of flow above the coarctation, and the lower carcass and large intestine were the tissues most representative of flow below the coarctation. Coarctation of the aorta produced cardiac hypertrophy and increased microsphere shunting to the lungs.

Animals↗
PubMed1985

Two hemodynamic problems commonly associated with the microsphere technique for measuring regional blood flow in rats.

The purpose of this study was to reevaluate two major steps associated with the radioactive microsphere technique in rats; the hemodynamic effects of the solutions used to inject the microspheres, and the hemodynamic effects of repeated blood withdrawals. With regard to the first, Flaim et al. (1978) have shown that 1.0 ml of 10% dextran injected into the rat may result in a severe pressure drop. The present study showed that even 0.1 ml of 10% dextran caused significant hypotension 46% of the time. Six other mediums were also tested as possible suspending media. It was concluded that a dextrose solution (sp gr 1.3) was the best microsphere injection medium based on the length of time the microspheres stayed mixed in the solution and the minimal hemodynamic alterations caused during injection. With regard to the second concern, cardiac output decreased approximately 7% with each reference sample withdrawal. When volume was replaced with a Ficoll-70 solution, cardiac output decreased less than 3%. These data show that repeated blood withdrawals are possible as long as the volume of blood is replaced. Thus, several isotopes can be injected in the same rat to allow measurement of regional blood flow under different experimental conditions.

Animals↗
PubMed1983

Hemodynamic disturbances in the rat as a function of the number of microspheres injected.

The purpose of this study was to reevaluate the radioactive microsphere technique used to measure blood flow distribution. The rats were conscious when studied. A dextrose solution with specific gravity of 1.3 was used as the suspension media instead of 10% dextran, which has previously been shown to cause hypotension. The microspheres were injected into the left atrium, which provided for maximal mixing with the blood before being ejected into the aortic arch. Ficoll-70 was given after each reference sample as a fluid replacement. With these modifications an injection of 360,000 microspheres or less caused no hemodynamic disturbances, as judged by electromagnetic flowmetry. After 1.4 X 10(6) microspheres had accumulated in the rat (several injections) the only significant hemodynamic disturbance was a decreased heart rate. This study establishes the limits in the rat regarding the number of microspheres that can be injected before hemodynamic disturbances result.

Animals↗
PubMed1982

Measurement of renal artery pressure in the rat.

The objective of this study was to develop and document a simple technique for the direct measurement of renal artery pressure (RAP) in the rat. RAP was recorded in 13 Sprague-Dawley rats using a glass micropipette fitted to a low displacement pressure transducer. Average mean arterial pressure recorded from a femoral artery catheter was 107.2 +/- 3.2 mmHg compared with a RAP of 103.8 +/- 3.7 mmHg (P less than 0.05). To determine whether the measurement affected renal blood flow (RBF), RBF was determined using radiolabeled microspheres, both before and while recording left RAP. No differences existed between the initial left and right RBFs [7.3 +/- 0.4 %CO/gm (percent cardiac output per gram tissue) vs. 7.3 +/- 0.4 %CO/gm, P greater than 0.9]. The micropipette in the left renal artery did not alter left RBF (control, 7.3 +/- 0.4 %CO/gm vs. experimental, 7.6 +/- 0.4 %CO/gm; P greater than 0.2). Right RBF did not change between successive flow determinations (P greater than 0.5) indicating that a change in renal hemodynamics unrelated to the protocol did not occur. The techniques presented provide an accurate, simple method for the direct measurement of RAP in the rat.

Animals↗
PubMed1978

Coronary aneurysms after a febrile illness: probable mucocutaneous lymph node syndrome.

An autopsy of a probable case of MCLS is described. After 10,000 cases have been recorded in Japan, the disease is being recognized in the United States. There may be an overlap with infantile periarteritis nodosa. Pathologic studies of fatal cases of MCLS diagnosed during life have not been reported in this country. Further studies will be necessary to confirm the high incidence of coronary arteritis and aneurysms in this country.

Aneurysm↗
PubMed1976

Sympathetic nerve activity: role in regulation of blood pressure in the spontaenously hypertensive rat.

Sympathetic nerve activity (SNA) and high pressure baroreceptor regulation of SNA were studied in the Okamoto strain of spontaneously hypertensive rat (SHR). Mean arterial pressure (MAP) and SNA were not significantly affected by anesthesia with low doses of pentobarbital (20-25 mg/kg). Thus, most of these studies were performed in anesthetized rats. SNA in visceral sympathetic nerves increased rapidly with age up to 24 weeks and slowly thereafter. MAP increased with SNA, following the same time course. Both SNA and MAP in SHR were significantly greater than that found in normotensive Wistar control rats of comparable ages. Abolition of ganglionic transmission with hexamethonium in both SHR and normotensive controls reduced postganglionic SNA and MAP to comparable levels. In SHR less than 16 weeks old, increased baroreceptor stimulation effectively inhibited SNA with the same sensitivity as found in Wistar control rats. However, older SHR appeared to lose their ability to completely inhibit SNA during induced hypertension, whereas in Wistar control rats as old as 52 weeks, elevation of blood pressure to 165.3 +/- 2.3 mm Hg completely suppressed SNA. These results suggest that SNA may play an important role in the development and maintenance of hypertension in SHR, and that central sympathetic centers, uninhibited by baroreceptor afferents, become active during the development of hypertension in the SHR.

Age Factors↗
PubMed1975

Recurrent myxosarcoma of left atrium.

The surgical treatment of cardiac myxosarcoma is reviewed with emphasis placed on palliative response to radiation therapy. A case of primary myxosarcoma of the left atrium in a 16-year-old girl is presented. The tumor was surgically removed in October, 1967. Recurrently myxosarcoma was removed in August, 1968, at which time involvement of the pulmonary veins and the pericardium was noted. Subsequent to postoperative radiation therapy, the patient remained symptom-free for more than three years. Death occurred 4 1/2 years after the original operation from local and systemic recurrence of the tumor.

Adolescent↗