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Biomedical subjects

D G Taylor

Publications and source records attributed to D G Taylor.

At least 19 recordsLinked to original sources
PubMed1992

Structure-activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors.

A series of renin inhibitors was synthesized that contained a 2-amino-4-thiazolyl moiety at the P2 position. These derivatives are potent inhibitors of monkey renin in vitro and are selective in that they only weakly inhibit the closely related aspartic proteinase, bovine cathepsin D. Four compounds exhibited oral blood pressure lowering activity in high-renin normotensive monkeys. One of these compounds, 22 (PD 134672), was selected for further evaluation in renal hypertensive monkeys, on the basis of its superior efficacy and duration of action in the in vitro assays and the normotensive primate model.

Animals↗
PubMed1992

Endothelin and structurally related analogs distinguish between endothelin receptor subtypes.

The endothelin (ET) analog ET-1[1,3,11,15-Ala] was compared with ET-1, ET-2, ET-3 and sarafotoxins (SRTX) S6b and S6c for receptor binding and function. All the peptides exhibited high affinity binding and contracted rabbit pulmonary artery with near equal potency. In rat aorta both ET-3 and ET-1 [1,3,11,15-Ala] bound with much lower affinity than ET-1 while ET-3 displayed weak contractile potency and ET-1 [1,3,11,15-Ala] and SRTX-c were inactive. In rat left atria, ET-1 [1,3,11,15-Ala] and SRTX-c were weak inhibitors of binding and were also functionally inactive, whereas ET-1, ET-2, ET-3, and SRTX-b were equipotent in producing contractile responses. The data support the idea of there being a predominance of ETA receptors in rat aorta and ETB receptors in rabbit pulmonary artery. In rat left atria, the ET receptor could not be readily classified into ETA or ETB and suggests the existence of a new receptor subtype.

Animals↗
PubMed1992

Importance of secondary structure for endothelin binding and functional activity.

ET-1[16-Phe] and ET-1[12-Pro] were prepared in order to investigate the importance of secondary structure of ET-1 for receptor binding and function. ET-1[16-Phe] displayed the greatest binding and contractile potency of the ET-analogs tested in rabbit pulmonary artery, rat aorta, and rat left atria. ET-1[12-Pro] also exhibited low nanomolar binding in these tissues but showed less contractile activity than ET-1[16-Phe] or ET-1. The results indicate that the helical region between residues Lys9 and Cys15 of ET-1 is not critical for receptor binding and functional activity. However, replacement of His16 with Phe altered the charge characteristics of the C-terminal region of ET-1 producing the most potent ET-1 analog yet reported.

Animals↗
PubMed1992

Modeling transient exchange in mesentery.

In this paper, a mathematical model of interstitial transport and microvascular exchange within a rigid mesenteric tissue segment is employed to simulate the transient exchange of fluid and plasma proteins following two systemic disturbances: hypoproteinemia and venous congestion. In each case, the model system behavior is studied as a function of interstitial plasma protein transport mechanisms and mesothelial transport properties. Plasma protein washout was generally predicted in cases of hypoproteinemia. However, following venous congestion, the transient change in interstitial plasma protein content also depended on the relative sieving properties of the filtering and draining boundaries. When these boundaries display similar sieving characteristics, the interstitial plasma protein content increases following the disturbance. Such behavior may have some bearing on transient exchange in the hepatic microcirculation during venous congestion.

Biological Transport↗
PubMed1992

Reduction of canine myocardial infarct size by CI-959, an inhibitor of inflammatory cell activation.

CI-959, a cell-activation inhibitor that prevents the formation of oxygen-derived free radicals by inflammatory cells, was studied to determine its effects on myocardial infarct size and subsequent scar formation in dogs. The left circumflex coronary artery was occluded for 90 min, followed by 6 h of reperfusion. Drug infusion was started 15 min before reperfusion at a loading dose of 8 mg/kg i.v., followed immediately by 2 mg/kg i.v. infused over 80 min. The infarct size, assessed by TTC staining techniques, was significantly reduced in 12 dogs treated with CI-959 (23.3 +/- 3.6% of the area at risk) when compared to 11 vehicle-treated animals (35.5 +/- 4% of the area at risk, p less than 0.05). This reduction in infarct size was not attributed to changes in regional myocardial blood flow, as measured by radioactive microspheres, or to a reduction in myocardial oxygen demand, as estimated by changes in the rate-pressure product. The scar thickness, measured after a 6-week recovery period in 9 animals treated with CI-959, was not significantly reduced in comparison with 11 controls. In vitro, CI-959 effectively inhibited oxygen free radical formation by canine neutrophils. The results of this study show that CI-959 significantly reduces the myocardial infarct size without causing scar thinning, which might lead to ventricular aneurysm, and suggests the most likely mechanism for its beneficial action is the prevention of formation of toxic oxygen radicals.

Animals↗
PubMed1992

Renal hemodynamic and excretory responses to PD 123319 and losartan, nonpeptide AT1 and AT2 subtype-specific angiotensin II ligands.

Angiotensin receptor subtypes have been described and pharmacologically characterized. DuP 753 (losartan) selectively antagonizes the angiotensin type 1 receptor, whereas PD 123319 selectively binds to an angiotensin type 2 receptor. These studies compared the renal response to treatment with the nonpeptides, DuP 753 and PD 123319, and the peptide antagonist, saralasin, in anesthetized mongrel dogs. Saralasin and DuP 753 increased renal blood flow and were mildly natriuretic. DuP 753 was roughly 10-fold less potent than saralasin. PD 123319 had no effect on renal hemodynamics, but produced dose-related increases in urine volume and free water clearance. PD 123319 had no effect on circulating vasopressin levels, suggesting the change in water handling by the kidney was not due to inhibition of vasopressin release. A direct effect of PD 123319 at the level of the renal tubule has not been ruled out. This is the first report of a renal functional response to an angiotensin type 2 receptor ligand and suggests that the angiotensin type 2 receptor may be related to water handling by the kidney.

Angiotensin II↗
PubMed1991

Structure-activity studies of the C-terminal region of the endothelins and the sarafotoxins.

Peptides corresponding to the C-terminal 16-21 hexapeptide of the endothelins (-His-Leu-Asp-Ile-Ile-Trp) and sarafotoxins (a-c) (-His-Gln-Asp-Val-Ile-Trp) were prepared to study the role of the individual amino acids in receptor recognition and activation. Receptor binding in rabbit aorta, rabbit pulmonary artery, and rat heart ventricle is reported for all analogues. In addition, selected C-terminal hexapeptides have been evaluated functionally in two tissues (rabbit pulmonary artery and rat left atria). The C-terminal carboxylate, indole nitrogen, and nature of the aromatic residue are all important for receptor binding, but N-terminal acetylation has no effect. L-Amino acids are required in positions 19 and 21, whereas D-amino acids are tolerated in 17 and 18. D-Amino acids in positions 16 and 20 enhance the binding affinity of the hexapeptide in all three tissues. The nature of the basic residue at position 16 is important. Glu and Asn are acceptable substitutions for Asp18, although Ala leads to a substantial loss in binding. The binding of the C-terminal hexapeptide of SRTX-a, -b, and -c is less than ET[16-21] and this appears to be primarily due to the substitution of Gln for Leu17. None of the 16-21 hexapeptides showed any functional activity in the tissues studied.

Amino Acid Sequence↗
PubMed1991

Effects of quinapril, a new angiotensin converting enzyme inhibitor, on left ventricular failure and survival in the cardiomyopathic hamster. Hemodynamic, morphological, and biochemical correlates.

The effect of chronic therapy with quinapril on the temporal progression of left ventricular failure and survival was assessed in the CHF 146 cardiomyopathic (CM) hamster, which is an idiopathic model of congestive heart failure. Age-matched Golden Syrian (GS) hamsters served as normal controls. Quinapril was administered in the drinking water at average daily doses of 10.2, 112.4, and 222.4 mg/kg/day. In untreated CM hamsters, in vitro left ventricular performance progressively deteriorated with increasing age beginning at roughly 180 days. This decline in left ventricular performance was accompanied by a decrease in coronary flow and an increase in left ventricular volume. Administration of quinapril from 180 to 300 days of age prevented the decline of in vitro left ventricular contractile performance and coronary flow and also reduced the age-dependent increases in left ventricular volume. The cardioprotective effects of quinapril were observed at doses of 112.4 and 222.4 mg/kg/day but not at 10.2 mg/kg/day. Lung angiotensin converting enzyme activity was significantly inhibited by quinapril in GS and CM hamsters at 240 and 300 days of age at all dose levels. In contrast, significant inhibition of ventricular angiotensin converting enzyme activity was observed consistently at doses of 112.4 and 222.4 mg/kg/day quinapril but not at 10.2 mg/kg/day. In the survival protocol, CM and GS hamsters were treated with vehicle or quinapril (100 mg/kg/day) from 180 to 522 days of age. During the initial 210 days of treatment (from 180 to 390 days of age) 78.3% of the vehicle-treated CM hamsters died compared with 27.7% of quinapril-treated CM hamsters. Quinapril increased the median survival time of CM hamsters by 32.9% (112 days). It is concluded that chronic quinapril therapy exerts a significant cardioprotective effect and also increases survival.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Development of a high renin model of hypertension in the cynomolgus monkey.

Hypertension was produced in cynomolgus monkeys by reducing blood flow to the left kidney by 60% via renal artery stenosis (2-kidney, 1-clip). Significant increases in mean arterial blood pressure (MABP) were observed within two to three weeks. Maximum increase (from 95 +/- 6 mmHg to 130 +/- 7 mmHg) occurred at about four to six weeks following renal artery stenosis and was sustained for more than 24 weeks. Plasma renin activity (PRA) was elevated concomitantly with the increase in MABP. PRA was raised to 42 +/- 3 ng angiotensin I/ml/hr six weeks after renal artery stenosis from a control PRA of 3 +/- 0.7 ng angiotensin I/ml/hr. At six months post renal artery stenosis, PRA was 33.4 +/- 4.2 ng angiotensin I/ml/hr. The angiotensin II (AII) receptor antagonist saralasin, the angiotensin I converting enzyme inhibitor captopril, and the renin inhibitor CGP 38,560 produced sustained reductions in MABP. The antihypertensive response to the renin inhibitor CGP 38,560 was associated with a reduction in PRA of greater than 99%, and a greater than 90% reduction in immunoreactive AII. These studies demonstrate that high-renin hypertension can be induced in the cynomolgus monkey. This pathological model provides a useful method for investigating the antihypertensive effects of agents which antagonize the renin-angiotensin system in a nonhuman primate.

Angiotensin II↗
PubMed1991

Evidence for a functional tissue renin-angiotensin system in the rat mesenteric vasculature and its involvement in regulating blood pressure.

Electrical stimulation of the isolated rat mesenteric vascular bed resulted in a frequency-dependent pressor response, which could be potentiated by increasing concentrations of renin substrate (synthetic tetradecapeptide). This potentiating effect appeared to be mediated by tissue conversion of renin substrate to angiotensin II because the response 1) could be mimicked by angiotensin II, 2) was accompanied by an increase in angiotensin II production and 3) was blocked by the angiotensin converting enzyme (ACE) inhibitor quinaprilat and the angiotensin II receptor antagonist saralasin ([Sar1,Ile5,Ala8]angiotensin II). To assess the role of this tissue renin-angiotensin system in contributing to blood pressure regulation, spontaneously hypertensive rats were administered the prodrug ACE inhibitor quinapril at a dose of 10 mg/kg/day for 7 days. Such administration resulted in a reduction in systolic blood pressure of 48 +/- 3 mm Hg, a greater than 95% inhibition of serum ACE activity, and a significant attenuation of the potentiating effect of renin substrate on electrically evoked contractions of isolated mesenteric beds. Significant reductions in blood pressure and the potentiating effect of renin substrate on the isolated mesenteric vasculature were still observed 24 and 48 hr after the last dose of quinapril. In contrast, serum ACE activity returned to normal levels within 48 hr after the last dose of quinapril. These results suggest that the changes in tissue renin-angiotensin system, and not the circulating system, are closely related to the blood pressure lowering effect of the ACE inhibitor, quinapril.

Angiotensin II↗
PubMed1990

In vivo replication and reversion to wild type of a neutralization-resistant antigenic variant of hepatitis A virus.

Six seronegative owl monkeys were intravenously inoculated with an antigenic variant (S18) of hepatitis A virus that is highly adapted to growth in cell culture and resists neutralization by monoclonal antibodies due to replacement of aspartic acid 70 of capsid protein VP3 with histidine. Each developed hepatitis 22-33 days after inoculation. Virus in feces, serum, and liver was quantified by radioimmunofocus assay. Viremia developed 7-11 days after inoculation, in parallel with fecal shedding of virus, and persisted for a mean of 20.5 days. Although the antigenic variant was recovered from feces or liver of three animals, virus in liver at the time of enzyme elevations was predominantly wild-type antigenic phenotype. Virus was not recovered from liver 96 days after challenge. These studies further define virologic events in hepatitis A and show that in vivo replication of an antigenic variant was restricted compared with that of wild-type virus.

Animals↗
PubMed1978

An inexpensive microcomputer-based stopped-flow data acquisition system.

A low-cost (less than $2,500) microcomputer-controlled data acquisition system for use with a stopped-flow instrument is described. Data acquisition, reduction, signal averaging, kinetic modeling, and plotting are performed under software control. Applications to biological and inorganic systems are presented.

Computers↗
PubMed1978

Screening test for complement activation by counterimmunoelectrophoresis.

This report describes the use of counterimmunoelectrophoresis (CIE) as a method of detecting activation of the complement system. With this technic small amounts of C3 split products (C3c/d) can be detected in plasma samples by specific precipitation with antiserum in less than two hours. The CIE technic is a highly sensitive, rapid method for detecting activation of the complement system in the presence of normal concentrations of C3 measured hemolytically or by radial immunodiffusion (RID) in human disease. A clinical investigation was carried out in 40 patients with systemic rheumatic diseases and 116 normal healthy individuals. The following observations were made: (1) plasmas and sera from normal individuals had normal total complement hemolytic activity (CH50), hemolytic active C4 (C4H50) and C3 (C3H50); (2) in 30% of the serum samples it was possible to identify the presence of C3 split products, in contrast to only 2.5% of the plasma samples obtained simultaneously; (3) in the specimens from patients who had rheumatic disease activity, C3 split products were identified by CIE in all cases except one in the presence of normal C3 protein measured by RID.

Adult↗
PubMed1978

Metabolism of cyclohexane carboxylic acid by Alcaligenes strain W1.

Thirty-three microorganisms capable of growth with cyclohexane carboxylate as the sole source of carbon were isolated from mud, water, and soil samples from the Aberystwyth area. Preliminary screening and whole-cell oxidation studies suggested that, with one exception, all of the strains metabolized the growth substrate by beta-oxidation of the coenzyme A ester. This single distinctive strain, able to oxidize rapidly trans-4-hydroxycyclohexane carboxylate, 4-ketocyclohexane carboxylate, p-hydroxybenzoate, and protocatechuate when grown with cyclohexane carboxylate, was classified as a strain of Alcaligenes and given the number W1. Enzymes capable of converting cyclohexane carboxylate to p-hydroxybenzoate were induced by growth with the alicyclic acid and included the first unambiguous specimen of a cyclohexane carboxylate hydroxylase. Because it is a very fragile protein, attempts to stabilize the cyclohexane carboxylate hydroxylase so that a purification procedure could be developed have consistently failed. In limited studies with crude cell extracts, we found that hydroxylation occurred at the 4 position, probably yielding the trans isomer of 4-hydroxycyclohexane carboxylate. Simultaneous measurement of oxygen consumption and reduced nicotinamide adenine dinucleotide oxidation, coupled with an assessment of reactant stoichiometry, showed the enzyme to be a mixed-function oxygenase. Mass spectral analysis enabled the conversion of cyclohexane carboxylate to p-hydroxybenzoate by cell extracts to be established unequivocally, and all of our data were consistent with the pathway: cyclohexane carboxylate --> trans-4-hydroxycyclohexane carboxylate --> 4-ketocyclohexane carboxylate --> p-hydroxybenzoate. The further metabolism of p-hydroxybenzoate proceeded by meta fission and by the oxidative branch of the 2-hydroxy-4-carboxymuconic semialde-hyde-cleaving pathway.

Alcaligenes↗
PubMed1978

Effects of R-28935 on sympathetic nervous activity in anesthetized cat.

Intravenous administration of erythro-1-(1-[2-(1,4-benzodioxan-2-yl)-2-OH-Et]-4-piperidyl)-2-benzimidazolinone (R-28935) (25--100 microgram/kg) produced a dose-related decrease in spontaneous electrical activity recorded in the splanchnic and renal nerves. Reductions in sympathetic nerve activity were paralleled by hypotension and bradycardia. R 28935-induced depressor responses were not affected by baroreceptor denervation, piperoxan, yohimbine or phentolamine. Results support the idea that R-28935 decreased resting blood pressure and heart rate through a reduction in central sympathetic outflow which does not involve alpha-adrenergic receptor activation.

Animals↗