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R L Webb

Publications and source records attributed to R L Webb.

At least 19 recordsLinked to original sources
PubMed1992

Pharmacologic characterization of an endothelinA (ETA) receptor antagonist in conscious rats.

The present experiments describe the endothelin-1 (ET-1) antagonist activity of BQ123 (cyclic D-Asp-L-Pro-D-Val-L-Leu-D-Trp) in conscious Sprague-Dawley (SD) rats, and we also examined the effect blockade of ETA receptors had on blood pressure in four experimental models of hypertension. Rats were anesthetized with methoxyflurane and instrumented with femoral arterial and venous catheters. In SD rats, BQ123 (0.1-10.0 mg/kg i.v.) administered 5 or 60 min prior to ET-1 inhibited both the magnitude and duration of the ET-1 (0.25 nmol/kg i.v.) pressor response. In addition, BQ123 (10.0 mg/kg) inhibited the pressor response evoked by administration of the ET-1 precursor, proendothelin-1 (1.0 nmol/kg). However, BQ123 (10.0 mg/kg) had no effect on the pressor response evoked by ET-3 (0.75 nmol/kg). In Wistar-Kyoto rats, BQ123 (10.0 mg/kg) reversed the hypertension produced by an infusion of ET-1 (0.01 nmol/kg/min). Administration of BQ123 produced a mild antihypertensive effect in normal- to low-renin models of hypertension, but no blood pressure lowering was observed in high-renin models of hypertension. These studies demonstrated the selectivity of the ETA receptor antagonist, BQ123 for ET-1, but not ET-3-induced pressor responses. Furthermore, ET-1 does not appear to be a major contributing factor to the maintenance of elevated levels of blood pressure in four experimental models of hypertension.

Amino Acid Sequence↗
PubMed1991

Highly selective adenosine A2 receptor agonists in a series of N-alkylated 2-aminoadenosines.

A wide variety of 2-substituted aminoadenosines were prepared for comparison with the moderately A2 receptor selective adenosine agonist 2-anilinoadenosine (CV-1808). High selectivity combined with significant affinity at the A2 receptor in rat membranes was observed for those amines bearing a two-carbon chain to which was attached an aryl, heteroaryl, or alicyclic moiety. 2-(2-Phenethylamino)adenosine (3d), a 14-fold A2 selective compound, was modified by introduction of a variety of substituents in the benzene ring and the side chain. Some of these changes led to improved A2 affinity and increased selectivity. Replacement of the phenyl moiety by cyclohexenyl produced a 210-fold selective agonist 3ag (CGS 22989) whereas the cyclohexanyl analogue 3af (CGS 22492) was 530-fold selective at the A2 site. These compounds showed hypotensive activity in rat models over a range of doses without the bradycardia observed with less selective agonists.

Adenosine↗
PubMed1991

Surgical complications with the cochlear multiple-channel intracochlear implant: experience at Hannover and Melbourne.

The surgical complications for the first 153 multiple-channel cochlear implant operations carried out at the Medizinische Hochschule in Hannover and the first 100 operations at the University of Melbourne Clinic, The Royal Victorian Eye and Ear Hospital, are presented. In the Hannover experience the major complications were wound breakdown, wound infection, electrode tie erosion through the external auditory canal, electrode slippage, a persistent increase in tinnitus, and facial nerve stimulation. The incidence of wound breakdown requiring removal of the package was 0.6% in Hannover and 1.0% in Melbourne. The complications for the operation at both clinics were at acceptable levels. It was considered that wound breakdown requiring implant removal could be kept to a minimum by making a generous incision and suturing the flap without tension.

Australia↗
PubMed1991

Cardiovascular effects of adenosine A2 agonists in the conscious spontaneously hypertensive rat: a comparative study of three structurally distinct ligands.

The hemodynamic responses to 5'-N-ethylcarboxamide adenosine (NECA), a nonselective adenosine agonist, were compared to those elicited by the sodium salt of 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido adenosine (CGS 21680C) and N6-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl adenosine (CGS 24012), two structurally dissimilar selective A2 agonists in conscious spontaneously hypertensive rats (SHR). Dose-related reductions in mean arterial pressure occurred after bolus administration of NECA, CGS 21680C and CGS 24012. Dose-dependent tachycardia was seen with both CGS 21680C and CGS 24012, whereas NECA produced a biphasic response on heart rate. At high doses (3 and 10 micrograms/kg), NECA evoked an immediate and dramatic fall in heart rate, followed by a more gradual and long-lasting tachycardia. At equihypotensive doses, both CGS 21680C and CGS 24012 produced significant increases in cardiac output, but NECA had no effect. Although each of the adenosine agonists reduced total peripheral resistance, the greatest change was produced by CGS 21680C. Hindquarter, renal and mesenteric vascular resistances were significantly reduced by both CGS 21680C and CGS 24012, whereas only mesenteric vascular resistance was reduced with NECA. CGS 24012 reduced renal vascular resistance to the greatest extent and produced a concomitant significant increase in renal blood flow. Marked elevation in plasma renin activity occurred with CGS 24012 and CGS 21680C, whereas no change was seen after NECA. The hemodynamic responses to NECA, CGS 21680C and CGS 24012 were significantly reduced by the adenosine antagonist, 8-(p-sulfophenyl) theophylline, suggesting that these agents act through stimulation of adenosine receptors in the conscious SHR. Furthermore, blockade of the beta adrenergic receptor with metoprolol (1 mg/kg, i.v.) significantly attenuated the increase in heart rate produced by NECA, CGS 21680C and CGS 24012. The cardiovascular pattern of responses to the two selective A2 agonists, CGS 21680C and CGS 24012, are distinct from those of NECA, the nonselective adenosine agonist. The responses to both CGS 21680C and CGS 24012 indicate that systemic vasodilation, with resultant cardioexcitation and stimulation of renin release, are the predominant hemodynamic effects of selective A2 agonists in the conscious SHR. In contrast, the cardiovascular effects produced by NECA are mediated by activation of both A1 and A2 receptors.

Adenosine↗
PubMed1991

Angiotensin-converting enzyme inhibitor versus angiotensin II, AT1 receptor antagonist. Effects on smooth muscle cell migration and proliferation after balloon catheter injury.

The angiotensin-converting enzyme (ACE) inhibitor, benazeprilat and the angiotensin II (Ang II), AT1-specific receptor antagonist, DuP753, were compared for their effects on intimal lesion formation as well as smooth muscle cell (SMC) proliferation and migration in Sprague Dawley rats after carotid balloon injury. Both the ACE inhibitor (benazeprilat, 3 mg/kg/day) and the AT1 antagonist (DuP 753, 10 mg/kg/day) significantly reduced intimal lesion formation after balloon injury (by 35% and 49%, respectively). Medial SMC proliferation after injury was reduced 53% by the AT1 antagonist; however, the ACE inhibitor had no effect on SMC proliferation. SMC migration was reduced 94% by the AT1 antagonist and 68% by the ACE inhibitor. These data demonstrate the importance of Ang II in SMC proliferation and migration after balloon injury. They also demonstrate that in the balloon injury model, the ACE inhibitor reduced intimal lesion size by inhibiting SMC migration alone without affecting SMC proliferation. A more pronounced reduction in lesion size was obtained after AT1 antagonism, however, when both SMC migration and proliferation were inhibited.

Angiotensin II↗
PubMed1991

Treatment modality patterns and transplantation among the United States pediatric end-stage renal disease population: a longitudinal study.

Between 1985 and 1988, there were 3,393 children (Medicare insured) under age 20 who began treatment for chronic ESRD. Patterns of modality use, modality switch, mortality rates, and various aspects of transplantation were analyzed for different age and incident groups of this pediatric cohort. The pediatric cohort as a whole exhibited a distinct pattern of modality use when compared to adults in general, a point evidenced most clearly by their substantially higher rates of transplantation. Furthermore, notable differences were found within the pediatric cohort when the younger than 5, 5-9, 10-14, and 15- to 19-year-old age groups were analyzed separately. Younger pediatric patients, particularly those younger than 5 years, received peritoneal dialysis as initial ESRD therapy more frequently than their older pediatric counterparts. This result would be expected given vascular access problems often associated with very young patients. In addition, those patients younger than 5 years who began RRT with some form of hemodialysis had the highest likelihood of switching to CAPD/CCPD within the first year of therapy. Conversely, older pediatric patients were most likely to begin RRT therapy with some form of hemodialysis. By day 91, slightly over half of the 15- to 19-year-old age group was utilizing center hemodialysis; the CAPD/CCPD, other peritoneal, and functioning transplant modalities each contained about 10% of the patients with the remainder falling into the death and unknown dialysis categories. The overall pattern of switching to transplantation during the first year of RRT was similar for pediatric patients initiating RRT with center hemodialysis versus peritoneal dialysis (CAPD/CCPD), but differed by age group within each dialysis type. Pediatric patients on peritoneal dialysis were somewhat more likely to receive a transplant during the first year of ESRD compared to hemodialysis, although the difference was small. Mortality rates during the first year for patients who began treatment with center hemodialysis versus CAPD/CCPD were similar. The well-documented dominance of transplantation as a method of RRT for pediatric patients was further verified by this study. Results show that transplantation was implemented rapidly during the initial months of ESRD. Nearly 50% of surviving pediatric patients had a functioning transplant at 1 year following onset and 64% at 3 years. These percentages were exceeded for the 5- to 9-year-old age group, of which 74% had a functioning graft 3 years following onset.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1990

2-(Arylalkylamino)adenosin-5'-uronamides: a new class of highly selective adenosine A2 receptor ligands.

The synthesis and receptor-binding profiles at adenosine receptor subtypes for a series of 2-(arylalkylamino)-adenosin-5'-uronamides is described. Halogenated 2-phenethylamino analogues such as 3e show greater than 200-fold selectivity for the A2 receptor subtype on the basis of rat brain receptor binding. The general structure-activity relationship of this series of compounds is discussed both in terms of potency at A2 receptors as well as receptor subtype selectivity. It is possible to introduce a hydrophilic carboxyalkyl substituent to this series such as in CGS 21680A (3h) and still retain good potency and selectivity for A2 receptors. In addition, functional data in a perfused working rat heart model shows that these compounds possess full agonist properties at A2 receptors with 3h having a greater than 1500-fold separation between A2 (coronary vasodilatory) and A1 (negative chronotropic) receptor mediated events.

Adenosine↗
PubMed1990

Recent trends in cadaveric renal transplantation.

1. Cadaveric transplantation increased steadily from 1981 through 1986 and then leveled off. The gap between patients awaiting transplant and cadaveric transplants performed increased rapidly after 1986. 2. There has been a trend in the age distribution of cadaveric transplant recipients toward transplantation of older patients. The number of cadaveric transplants to patients 50 and over continued to increase after 1986, while the number to patients under 50 declined. The proportion of transplants to patients 60 and over has shown a particularly dramatic increase. 3. The rate of transplantation is highest in the pediatric age group and declines with age. The rate of transplantation increased in all age groups until 1986 and then declined in all age groups except the 50 and over group. The magnitude of the decline is greatest in the younger age groups. 4. Among all dialysis patients, males have a higher rate of transplantation than females, and Whites have a higher rate than Blacks. These differences in rates increase with increasing recipient age. There are moderate trends toward decreased differences by sex and increased differences by race. 5. Repeat transplants make up about 15% of all cadaveric transplants in 1988, with higher proportions of repeat transplants in the younger age groups. The transplantation rates for repeat transplants has been declining relative to that for first transplants when the relevant pool of dialysis patients is used. For the 50 and over age group, the repeat transplant rate was 3.6 times as high as the first transplant rate in 1988. 6. Compared to the general population, cadaver transplant donors are younger, less often female, and less often Black. There has been a trend toward older donors and toward a smaller difference by sex. 7. There has been a trend toward fewer nephrectomies and splenectomies prior to transplantation. 8. There are no clear time trends in sharing of organs among transplant centers and only a slight increase in the proportion of transplants with 0 HLA-antigen mismatches.

Age Factors↗
PubMed1990

Hemodynamic effects of adenosine agonists in the conscious spontaneously hypertensive rat.

The present studies examined the underlying hemodynamic mechanisms contributing to the reduction in blood pressure observed in conscious spontaneously hypertensive rats after systemic administration of adenosine agonists. The effects produced by i.v. and i.a. injections of 2-phenylaminoadenosine [CV-1808, adenosine (A2) selective agonist], 5'-N-ethylcarboxamide adenosine (NECA, nonselective agonist), 2-chloroadenosine (2-CADO, A1 selective agonist) and cyclopentyladenosine (CPA, A1 selective agonist) were evaluated and compared to those of hydralazine. All agents produced hypotensive effects after bolus i.v. injection. Although CPA, NECA and 2-CADO elicited dose-dependent bradycardia, CV-1808 and hydralazine increased heart rate. These effects, with the exception of the hydralazine-evoked responses, were attenuated by prior treatment with 8-(p-sulfophenyl)theophylline (2 mg/kg/min), whereas both CV-1808 and hydralazine produced regional vasodilation, significant increases in blood flow occurred only after CV-1808 (3-30 micrograms/kg). The regional hemodynamic responses to NECA were more complex; low doses (0.1-1 microgram/kg) produced consistent reductions in regional vascular resistance, whereas at the highest dose renal vasoconstriction occurred. Although regional vasodilation occurred after 2-CADO, mesenteric vasoconstriction was observed subsequent to CPA administration. Whereas a significant increase in renin release was evident in animals treated with CV-1808 and hydralazine, no change occurred in response to the NECA-, 2-CADO- or CPA-induced hypotension. We conclude that the predominant hemodynamic response after selective activation of A2 receptors is one of regional vasodilation and hypotension leading to a reflex increase in heart rate and renin release.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Chloroadenosine↗
PubMed1989

Purification and characterization of human recombinant precursor interleukin 1 beta.

We have purified the 31-kDa precursor of human interleukin 1 beta (proIL1 beta) from recombinant Escherichia coli expressing the protein. The recombinant precursor was characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, spectroscopy, Western blot, and for biological and receptor binding activity. The protein migrates at the expected molecular weight on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and analytical gel filtration columns. The specific activity of the recombinant precursor is less than 10(2) units/mg in the EL4 thymoma assay compared with 5 x 10(8) units/mg for the recombinant 17-kDa mature protein. The inactivity of the precursor is attributable to the inability of the protein to bind the IL1 receptor on EL4 cells as shown by receptor competition studies using 125I-labeled 17-kDa IL1 beta. Inactivity of the IL1 beta precursor is not due to degradation of the protein in either the bioactivity or receptor binding assays. The inactive IL1 beta precursor is converted to an active form following proteolysis with chymotrypsin which generates a carboxyl-terminal fragment of 17 kDa that is 6 orders of magnitude more active than the starting IL1 beta precursor. Removal of the first 114 amino acids from proIL1 beta generates a fully active molecule. In contrast, removal of the first 77 amino acids by treatment with trypsin only partially restores activity. The resultant 22-kDa protein exhibits a 600-fold increase in both biological and receptor binding activity, demonstrating a direct correlation between the ability of sequences within the pro-region to inhibit biological activity and inhibit binding to the IL1 receptor. Far-UV circular dichroism spectroscopy indicates that proIL1 beta is similar in secondary structure to mature IL1 beta; both proteins are nonhelical beta sheet proteins.

Circular Dichroism↗
PubMed1989

Degradation of atrial natriuretic peptide: pharmacologic effects of protease EC 24.11 inhibition.

Several processes participate in the clearance of atrial natriuretic peptide (ANP) from the circulation, one of which is enzymatic degradation. Endoprotease EC 3.4.24.11 (NEP 24.11), present within the kidney in high concentration, has been shown in vitro to degrade ANP. Phosphoramidon and thiorphan, two potent NEP 24.11 inhibitors, have been shown to prevent the enzymatic degradation of ANP. The purpose of the present study was to determine if phosphoramidon or thiorphan would alter the in vivo time course of the pharmacologic effects of ANP. The magnitude and duration of the ANP-induced increase in urine output and sodium and cyclic GMP excretion were examined with and without either thiorphan or phosphoramidon. Six separate groups of anesthetized rats received either a low, medium, or high infusion rate of thiorphan or phosphoramidon. Renal responses to ANP were potentiated and prolonged during the low phosphoramidon infusion (3 Ki) and the medium thiorphan infusion (150 Ki). At high inhibitor infusion rates in the anesthetized rat, ANP elicited a marked depressor response. In the conscious spontaneously hypertensive rat (SHR), a 15-min intravenous (i.v.) infusion of ANP (1 microgram/kg/min) lowered mean arterial pressure (MAP 23 +/- 6 mm Hg), with an approximately 35-min duration of action. A simultaneous i.v. infusion of phosphoramidon (high dose) produced both a potentiation (33 +/- 3 mm Hg) and a prolongation (greater than 65 min to return to baseline) of the depressor response. These data lend support to the hypothesis that enzymatic breakdown of ANP may play an important role in regulating the actions of atrial natriuretic peptide.

Animals↗
PubMed1989

CGS 21680C, an A2 selective adenosine receptor agonist with preferential hypotensive activity.

CGS 21680C (2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethyl-carboxamido adenosine) a 2-substituted analog of the riboside uronamide, 5'-N-ethylcarboxamido adenosine and the related analog CGS 21577 (2-phenethylamino-5'-N-ethylcarboxamido adenosine), have high in vitro affinity for brain striatal adenosine A2 receptors (IC50 values = 22 and 13 nM, respectively). Both compounds were considerably less active at A1 receptors with CGS 21577 and CGS 21680C having respective IC50 values of 0.76 and 3.1 microM. The former compound was thus 59-fold selective for A2 receptors whereas CGS 21680C was 140-fold selective. In contrast, the reference A2 selective ligand, CV 1808 (2-phenylaminoadenosine), showed only 8-fold selectivity as an A2 ligand, having an IC50 of 115 nM in the [3H]-5'N-ethylcarboxamide adenosine assay and an IC50 of 910 nM at the N6-[3H] cyclohexyladenosine site. Further examination of CGS 21680C showed that the compound was without effect on binding to 17 other putative neurotransmitter/neuromodulator sites indicating its selectivity as an adenosine receptor ligand. In an isolated perfused working rat heart model, CGS 21680C effectively increased coronary flow with an ED25 value of 1.8 nM. The corresponding value for CGS 21577 was 3 nM whereas that for CV 1808 was 110 nM. The EC25 for eliciting bradycardia for all three compounds was greater than 1000 nM. The effects of all three compounds could be reversed by treatment with the xanthine adenosine antagonist, xanthine amine congener.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1988

Popliteal artery injury complicating arthroscopic menisectomy.

Inadvertent popliteal artery injury during arthroscopic menisectomy is an unusual occurrence. Prompt diagnosis and treatment are essential to achieve a good outcome, as illustrated in two of the five patients described herein. Pitfalls in diagnosis led to late recognition and therapy in three patients, with subsequent serious complications; namely, arteriovenous fistula, false aneurysm, and amputation. On the basis of this limited but poignant experience, we propose an outline of steps in management to help others avoid similar problems. If popliteal injury is suspected, we advise exploration immediately to avoid a potential limb-loss crisis. Heparin should be given as soon as diagnosis is made. A posterior incision in the knee crease, rather than the conventional medial approach, gives expedient exposure for precise repair. We also advise passing a no. 3 thrombectomy catheter distally to rule out or retrieve any clot that may have embolized. A completion angiogram is also helpful. Compartment pressure may be measured, but if any doubt exists, a three-compartment fasciotomy should be performed.

Amputation, Surgical↗
PubMed1988

Design, synthesis, and biological activity of a peptide mimic of vasopressin.

Our molecular modeling studies suggested that the conformational effects of the "cystine-line" residue Pmp1-Cys6 on the cyclohexapeptide ring of the vasopressin antagonist [Pmp1,D-Phe2,Val4]AVP might be mimicked by substitution of D-aminoadipic acid at position 6 and cyclization of its side-chain carboxyl to the alpha-amine of residue 2. The peptide was prepared with DL-aminoadipic acid, and following cyclization, the two diastereomeric peptides were separated and purified by preparative high-performance liquid chromatography. The structure of each was confirmed by amino acid analysis and fast atom bombardment mass spectrometry. The chirality of the aminoadipic acid residue of each peptide was determined by chiral gas chromatography. The circular dichroism spectrum of each peptide was run and compared with the appropriate agonist and antagonist peptide standards. These peptides demonstrated in vitro poor V2-receptor affinity and an inability to inhibit or stimulate vasopressin-induced adenylate cyclase formation, suggesting that they lack one or more key features of the agonist/antagonist pharmacophore.

Adenylyl Cyclase Inhibitors↗
PubMed1988

Effects of two nonsulfhydryl angiotensin-converting enzyme inhibitors, CGS 14831 and CGS 16617, on myocardial damage and left-ventricular hypertrophy following coronary artery occlusion in the rat.

The present study was designed to examine the effects of two new angiotensin-converting enzyme (ACE) inhibitors, CGS 14831 and CGS 16617 (3 mg/kg i. v. 1 min prior to occlusion and 4 and 24 h after occlusion), on myocardial ischemic (MI) damage and left-ventricular hypertrophy in rats. Administration of CGS 14831 or CGS 16617 inhibited angio-tensin-I-induced pressor responses by 40-100% for 4 h after each dose. Myocardial creatine phosphokinase (CK) levels were 10.6 +/- 0.6 U/mg protein in sham-MI animals, and following coronary artery occlusion for 48 h were decreased to 4.1 +/- 0.2 U/mg protein in MI + vehicle animals (p less than 0.01). CGS 14831 and CGS 16617 attenuated the decrease in CK content and resulted in 47 and 40% sparing, respectively, of the left-ventricular free wall. Neither agent attenuated the left-ventricular hypertrophy which developed following coronary artery occlusion. These data indicate that the nonsulfhydryl ACE inhibitors CGS 14831 and CGS 16617 have a significant cardioprotective effect in rats surviving 48 h, and suggest a potential therapeutic usefulness of these agents for the treatment of ischemia-induced heart failure.

Angiotensin-Converting Enzyme Inhibitors↗