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Biomedical subjects

W J Louis

Publications and source records attributed to W J Louis.

At least 73 records · Page 4Linked to original sources
PubMed1992

Pressor dose responses and baroreflex sensitivity in quadriplegic spinal cord injury patients.

OBJECTIVE: To assess the relative contribution of impaired baroreceptor reflexes and enhanced cardiovascular reactivity to the exaggerated blood pressure rises which occur in quadriplegic spinal cord injury patients with automatic hyperreflexia. DESIGN: Pressor dose responsiveness was evaluated by determining the steady-state dose of phenylephrine, alpha-methylnoradrenaline and angiotensin II required to achieve a blood pressure rise of 20 mmHg and the steady-state dose of isoprenaline required to increase heart rate by 20 beats/min in eight quadriplegic spinal cord injury patients and eight control subjects. RESULTS: The dose of phenylephrine alpha-methylnoradrenaline and angiotensin II to achieve a rise in blood pressure of 20 mmHg was significantly reduced in the spinal cord injury group, whilst the dose of isoprenaline required to raise heart rate by 20 beats/min did not differ significantly from the control group. Baroreceptor sensitivity, assessed by straight line regression of change in heart period with change in blood pressure during steady-state infusions of phenylephrine, did not differ statistically between the two groups, but the results could not exclude some evidence of impairment in the spinal cord injury patients. Baroreceptor sensitivity was much less variable in spinal cord injury patients than in controls. CONCLUSIONS: These findings suggest that quadriplegic patients with spinal cord injury have exaggerated pressor responses with significantly less variability in baroreflex sensitivity. The former probably contributes to the autonomic hyperreflexia seen in these patients. The latter provides some support to the suggestion that centrally mediated psychogenic responses contribute to the variability in baroreceptor sensitivity seen in normal subjects.

Adult↗
PubMed1992

Steady-state pharmacokinetics and pharmacodynamics of cilazapril in the presence and absence of cyclopenthiazide.

Twenty-two patients with essential hypertension received a single dose of 2.5 mg cilazapril and were then randomised into a double-blind parallel group study to receive either placebo, 1.25 mg cilazapril + 0.5 mg cyclopenthiazide (CPTZ), 2.5 mg cilazapril + 0.5 mg CPTZ, or 2.5 mg cilazapril alone for 1 month. After oral administration of a single dose of 2.5 mg cilazapril, the active diacid cilazaprilat appeared rapidly in the plasma (Tmax 2.0 +/- 0.2 h). With the radioinhibitor assay used in this study, a single elimination phase of cilazaprilat was evident, with a half-life (t1/2) of 2-3 h. At steady state, the pharmacokinetics of cilazaprilat were similar to single-dose administration and were not altered by CPTZ. The Cmax and area under the curve (AUC) of cilazaprilat were directly proportional to dose. Cilazapril administration in the dose range of 1.25-2.5 mg produced a dose-proportional inhibition of angiotensin-converting enzyme (ACE) activity that was maximum 2 h after drug administration. The degree of ACE inhibition correlated with the plasma concentration-time profile of cilazaprilat and the maximum decrease in blood pressure (BP). The EC50 for ACE inhibition by cilazaprilat was 7.7 ng/ml after acute treatment and was not significantly altered during chronic administration or by concomitant administration of CPTZ. There was no evidence of a dose-related antihypertensive effect of cilazapril at steady state and, with the small numbers of subjects used in this study, there was no evidence of 24-h BP control with monotherapy.

Aged↗
PubMed1992

Single-dose and steady-state pharmacokinetics and pharmacodynamics of perindopril in hypertensive subjects.

In a double-blind, placebo-controlled, parallel group study, 24 essential hypertensive subjects were randomised to receive either placebo or 2, 4, or 8 mg perindopril. Perindopril, its deesterified metabolite, perindoprilat, and perindoprilat glucuronide were separated with an ion-exchange resin and determined by a radioimmunoassay (RIA). Pharmacokinetic and pharmacodynamic parameters were estimated for 96 h after the first dose and after 4-week once-daily treatment. Perindopril peak levels were achieved in less than or equal to 2 h after dosing with an elimination t1/2 of 1-2 h. Peak levels of perindoprilat were achieved more slowly, reaching a maximum level 5-8 h after dosing, and had an elimination t1/2 of 40 h. Levels of the perindopril glucuronide peaked approximately 0.5 h later than perindopril, with an elimination t1/2 of approximately 2 h. Perindopril, perindoprilat, and its glucuronide conjugate followed linear kinetics in the dose range of 2-8 mg, and there was no evidence of accumulation with chronic dosing. Perindopril 4 and 8 mg produced significant decreases in predose blood pressure (BP) with chronic dosing, with maximal decreases occurring 5-7 h after dosing. Perindopril also produced a prolonged dose-dependent inhibition of plasma angiotensin-converting enzyme (ACE) activity that was maximum after 4 h and had not fully recovered by 48 h after a single dose.

Aged↗
PubMed1992

Comparison of the pharmacokinetics and pharmacodynamics of perindopril, cilazapril and enalapril.

1. The pharmacokinetic and pharmacodynamic responses to enalapril, perindopril and cilazapril have been studied in essential hypertensives (2, 4 and 8 mg perindopril and 2.5 mg cilazapril, single dose and steady state) and normotensive volunteers (10 mg enalapril, single dose). 2. Plasma levels of the active diacid compounds reached similar peaks after single dose administration of the drugs. However, perindoprilat levels persisted for 5 days whereas cilazaprilat levels were not detectable beyond 12 h. 3. The higher levels of perindoprilat were associated with a greater inhibition of plasma angiotensin-converting enzyme (ACE) activity in both acute and steady state studies. 4. The potency of the active diacids in inhibiting plasma ACE activity was perindoprilat greater than cilazaprilat greater than enalaprilat. 5. There was a close relationship between plasma concentration, ACE inhibition and blood pressure decrease. Although both cilazapril and perindopril administration reduced blood pressure in hypertensive subjects, only perindopril exerted 24 h blood pressure control at the doses used.

Adult↗
PubMed1992

Evaluation of the predicted secondary structure of bacteriorhodopsin. Prediction of the bovine rhodopsin secondary structure and its sequence similarity with bacteriorhodopsin.

The secondary structure of bacteriorhodopsin (bacR) is predicted using the Chou and Fasman method in conjunction with the hydropathic index of Kyte and Doolittle. The predicted bacR structure was compared with the structure determined by Henderson et al. (1990) using electron diffraction and was found to correlate extremely well. The secondary structure of bovine rhodopsin (bovR) was then predicted using the same techniques. The proposed transmembrane regions of bovR were then examined and found to have sequence similarity with those transmembrane regions of bacR.

Amino Acid Sequence↗
PubMed1991

Validation of a solid-phase extraction high-performance liquid chromatographic assay for doxazosin.

The determination of doxazosin by high-performance liquid chromatography with fluorescence detection is described. Propanolol was used as the internal standard. Plasma samples were treated with methanol to precipitate the proteins. Doxazosin was isolated with C18 reversed-phase extraction columns. The determination limit is 1 ng/ml of plasma, while the extraction columns can be reused frequently. The method is applied to clinical trial samples.

Adrenergic alpha-Antagonists↗
PubMed1991

Pharmacology of celiprolol.

The pharmacology of celiprolol and its relationship to some other beta-adrenoceptor antagonists is described. Celiprolol is a potent beta blocker on beta 1-adrenoceptors and exhibits cardioselectivity both in vitro and in vivo in the pithed rat, but shows no significant in vitro alpha 1-blocking action. Celiprolol differs from atenolol in that it has an intrinsic sympathomimetic activity (ISA) for beta 1-adrenoceptors, which is reflected in its relative lack of negative inotropic effects in humans. In the pithed rat, celiprolol's ISA was demonstrated at much lower doses than for pindolol, even though pindolol has a similar potency to celiprolol in antagonizing the heart rate effects of isoproterenol. It was completely blocked by propranolol, indicating that celiprolol behaves like a partial agonist for beta 1-adrenoceptors, whereas the ISA developed by pindolol was only partially blocked by propranolol. These data suggest a different mechanism for the development of ISA between celiprolol and pindolol.

Adrenergic beta-Agonists↗
PubMed1991

Diurnal blood pressure variation in quadriplegic chronic spinal cord injury patients.

1. Measurement of blood pressure and heart rate over a 24 h period was performed in 10 quadriplegic spinal cord injury patients and 10 immobilized, neurologically intact orthopaedic subjects by using the Spacelabs 90207 automated ambulatory monitoring system. 2. Systolic and diastolic blood pressure fell significantly at night in orthopaedic subjects but not in quadriplegic patients, and night-time blood pressures were similar in both groups. 3. Cumulative summation of differences from a reference value (cusum analysis) confirmed a markedly diminished diurnal blood pressure variation in the quadriplegic patients. 4. These findings could not be accounted for on the basis of blood pressure variations during chronic postural change. 5. Heart rate fell significantly at night in both groups. 6. The findings suggest that the increase in blood pressure during waking hours in neurologically intact subjects is a consequence of a diurnal variation in sympathetic activity (absent in quadriplegic patients with sympathetic decentralization) which is independent of changes in physical activity.

Adult↗
PubMed1991

Altered alpha 1-adrenoceptor-mediated responses in atria of rats with chronic left ventricular infarction.

Phosphoinositide (PI) turnover, chronotropic and inotropic responses to alpha 1-adrenoceptor activation, and alpha 1-adrenoceptor density were studied in atria from rats with left ventricular myocardial infarction (LVMI) and noninfarcted rats. LVMI was produced after surgical ligation of the left coronary artery in 8-week-old Wistar rats. Rats were killed 4 weeks after this operation when rats with LVMI had developed significant hypertrophy of both ventricles and atria. Phenylephrine 0.1 mM to 1 mM, with propranolol 0.3 mM, produced a concentration-dependent increase in heart rate (HR) in right atria from noninfarcted rat hearts, and this response was significantly reduced in rats with LVMI. In electrically driven left atria, the concentration-dependent, phenylephrine-induced positive inotropic responses observed with propranolol added were also significantly impaired in rats with LVMI as compared with those of noninfarcted rats. In contrast, neither PI turnover in response to phenylephrine in the presence of propranolol nor alpha 1-adrenoceptor density was reduced in rats with LVMI. These results suggest that the impaired alpha 1-adrenoceptor-induced chronotropic and inotropic responses in atria from rats with LVMI are not due to downregulation of alpha 1-adrenoceptors or to impaired activation of PI turnover after alpha 1-adrenoceptor stimulation, but to impairment of one or more biochemical responses distal to PI hydrolysis or changes in coupling mechanisms other than hydrolysis of PIs.

Animals↗
PubMed1991

Antibiotic-induced release of endotoxin in chronically bacteriuric patients.

A novel in vivo model for the study of antibiotic-induced release of endotoxin from gram-negative bacteria is described. The model uses the chronically colonized urinary tracts of patients whose spinal cords have been injured. At baseline, the organisms were present in the range of 1 x 10(3) to 2 x 10(7) CFU/ml, and the concentration of endotoxin ranged from 2 x 10(-1) to 1 x 10(3) ng/ml in 44 studies. In 10 control studies, the concentration of endotoxin and the numbers of viable gram-negative bacteria over time changed by an average of less than 0.15 log10 units from the baseline values. At 2 h after antibiotic administration, the average decrease in CFU was 0.93 log10 units, and because antibiotics cause the release of endotoxin, an average increase in endotoxin concentration of 0.59 log10 units was noted in 21 studies with susceptible bacteria. Similar changes in response to antibiotic exposure were seen in studies with susceptible Pseudomonas bacteria in comparison with those seen in studies with susceptible members of the family Enterobacteriaceae. These results provide evidence that this novel model may be useful for comparing the effects of antibiotics with different modes of action, both as single agents and in combination, on the concentration of endotoxin in relation to changes in the numbers of bacteria, under conditions of bacterial replication and antibiotic exposure more closely resembling those found in vivo than is possible in other models.

Anti-Bacterial Agents↗
PubMed1991

Quantitative Limulus lysate assay for endotoxin and the effect of plasma.

The effects of plasma and chromogenic substrate on the kinetics of the endotoxin-activated Limulus amoebocyte lysate (LAL) assay were determined. A linear correlation was observed between the rate of development of turbidity (optical density 405) with the LAL reagent and the concentration of endotoxin over a four log ten-fold range. Like chromogenic substrate, the addition of dilution and heat treated plasma to the reaction resulted in an increase in optical density proportional to the concentration of plasma present. The presence of the treated plasma also resulted in an accelerated increase in optical density with comparable results when testing plasma at different concentrations and, additionally, serum. This accelerated increase in optical density may not be recognised in assays that monitor the progress of the reaction at a single time point and may confound assays of plasma samples that use chromogenic substrate. Plasma obtained from endotoxin sensitive and resistant strains of mice showed similar effects. The use of kinetic methodology means that a quantitative assay for endotoxin in plasma can be achieved, its variability comparable with that seen with semiquantitative serial dilution but with greater economy of the LAL reagent.

Chromogenic Compounds↗
PubMed1990

The effect of ketanserin on cardiovascular reflexes in conscious normotensive and spontaneously hypertensive rats.

The effect of ketanserin (3 mg/kg i.v.) on the baroreceptor heart rate reflex and the Bezold-Jarisch reflex was examined in conscious Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In the control situation (before ketanserin treatment), reflex bradycardia in response to phenylephrine (baroreflex) and phenyldiguanide (Bezold-Jarisch reflex) were impaired in SHR as compared with WKY, while reflex tachycardia in response to nitroprusside was similar in the two groups. However, after ketanserin administration in SHR, there was a reversal of the baroreflex-mediated tachycardia in response to nitroprusside into a bradycardic response. The nitroprusside-induced bradycardia was not caused by the release of 5-HT stimulating chemosensitive vagal afferents since the 5-HT3 receptor antagonist MDL 72222 did not block this response. In the same SHR, the Bezold-Jarisch reflex evoked by phenyldiguanide and the phenylephrine-induced bradycardia were potentiated by ketanserin. All the above effects of ketanserin were less evident in the WKY. Ketanserin did not alter vagal efferent function in anaesthetized SHR since it did not affect bradycardia induced by electrical stimulation of the vagus nerve. Therefore, it is suggested that ketanserin has sensitised cardiac vagal afferent mechanisms in SHR, which led to a normalization of reflex bradycardic function to a level normally observed in conscious normotensive WKY (i.e. prior to ketanserin treatment).

Animals↗
PubMed1990

Increase in galanin and neuropeptide Y mRNA in locus coeruleus following acute reserpine treatment.

Galanin and neuropeptide Y are known to coexist with noradrenaline in neurones of the locus coeruleus. Furthermore, reserpine depletes noradrenaline from, and increases the synthesis and activity of the catecholamine-synthesizing enzyme tyrosine hydroxylase in, this nucleus. We have found by in situ hybridization of specific 35S-labelled oligonucleotide probes that a single dose of reserpine (10 mg/kg) induced a significant (70-145%) and long-lasting (up to at least 3 days) increase in the amount of galanin and neuropeptide Y mRNA in the locus coeruleus (along with the characteristic increase in tyrosine hydroxylase mRNA). These results suggest a similar reserpine-sensitive mechanism of galanin, neuropeptide Y and tyrosine hydroxylase gene regulation.

Animals↗
PubMed1990

Intrathecal kynurenate reduces arterial pressure, heart rate and baroreceptor-heart rate reflex in conscious rats.

In the present study, an excitatory amino acid (EAA) pathway in the spinal cord which maintains sympathetic vasomotor tone in conscious rats has been investigated. To this end, the cardiovascular effects of an intrathecally administered EAA antagonist, kynurenate (KYN), were studied in conscious rats. KYN (0.5 mumol in 10 microliters) caused a dramatic reduction in mean arterial pressure (MAP) and heart rate (HR) that persisted for 2-3 h, and also resulted in extensor paralysis of the hindlimbs. The time courses of fall in MAP and HR and hindlimb paralysis were similar. Baroreceptor-HR reflex activity was also markedly impaired after KYN, suggesting functional diminution of sympathetic outflow at the level of the spinal cord after blockade of EAA receptors by KYN. Xanthurenate, a metabolite of KYN without EAA antagonistic properties, produced negligible effects at the same dose of KYN. While these findings do not identify the putative EAA pathway, they do provide the first demonstration that this system is tonically active in conscious rats.

Animals↗
PubMed1990

Role of metabolic risk factors in cardiovascular prognosis of systemic hypertension.

There is an increasing awareness of the need to manage multiple risk factors in hypertensive patients, and of possible adverse metabolic effects of antihypertensive drugs which may counteract their ability to reduce the risk of cardiovascular disease. Data collected from the Austin Hospital Hypertension Clinic support previous observations that the incidence of cardiovascular risk factors such as plasma lipid abnormalities are high in hypertensive patients, and although it is becoming easier to control blood pressure in these patients, modification of other risk factors is difficult. The use of diuretics in doses lower than those conventionally prescribed has been advocated as a means of reducing the adverse metabolic effects. However, data from this study suggest that although low-dose hydrochlorothiazide therapy (25 to 50 mg/day) may be as effective as conventional doses of captopril in reducing blood pressure, adverse metabolic effects on plasma potassium, glucose and uric acid levels remain a problem. Indapamide, a relatively new diuretic when used at a fixed dose (2.5 mg/day), appears to be devoid of significant adverse metabolic effects and is a useful alternative to thiazide diuretics. An integrated approach to the management of multiple cardiovascular risk factors is important in hypertensive patients and should include non-pharmacologic methods and the selection of antihypertensive drugs that do not have adverse metabolic effects.

Antihypertensive Agents↗
PubMed1990

Influence of food on the bioavailability of a sustained-release verapamil preparation.

The effects of food on the bioavailability of a sustained-release (SR) formulation of verapamil (SR-verapamil; Isoptin SR) were determined in an open, three-way single-dose study involving 12 volunteers receiving (in randomized order) the SR preparation (1 X 240 mg) either fasting or with food and a conventional formulation of verapamil (3 X 80 mg) fasting. Compared with the conventional formulation, SR-verapamil had a reduced Cmax, prolonged tmax, and unchanged t1/2, consistent with its SR formulation. The AUC was 80% of the conventional preparation. Concomitant food administration significantly prolonged the tmax of SR-verapamil from 7.3 +/- 3.4 to 11.7 +/- 6.3 h, but had little effect on Cmax, t1/2, or AUC. Similar results were obtained with the metabolite, norverapamil. Food administration also had little effect on the blood pressure and ECG effects of SR-verapamil. Cautions regarding taking this preparation with food therefore appear to be unnecessary.

Adult↗
PubMed1990

Excitotoxin-induced degeneration of rat vagal afferent neurons.

The inferior vagal or nodose ganglion contains the perikarya of vagal afferent neurons that function as cardiopulmonary and abdominal visceral receptors as well as aortic arch baroreceptors. In this study we have sought to utilize the axon-sparing properties of the excitotoxins kainic acid, N-methyl-D-aspartic acid and alpha-amino-3-hydroxy-4-isoxazolepropionic acid to destroy the perikarya of these sensory neurons and thus selectively de-afferent the vagus in the rat. Kainic acid (0.5 nmol/microliters, 2 X 2 microliters) was applied topically to both nodose ganglia and the rats were allowed to recover for 7-8 days. Baroreceptor heart rate reflex activity was assessed in these conscious rats. Baroreceptor heart rate reflex gain was reduced (-51%) in kainic acid-treated rats, as was the maximal reflex bradycardia induced by the pressor agent, phenylephrine. Kainic acid treatment did not alter resting mean arterial pressure or heart rate. Vagal efferent neurons were spared by kainic acid treatment since bradycardic responses to electrical stimulation of the peripheral end of a cut vagus were not impaired. Histological studies showed marked destruction of perikarya within the nodose ganglia of kainic acid-treated rats: inflammatory and degenerative changes were evident at 2 days, and at 10 days there was considerable loss of neuronal cell bodies, but sparing of axons. Topical application to the nodose ganglion of alpha-methyl-DL-aspartic acid (6.8 nmol/microliters, 2 X 2 microliters), a non-excitotoxic dicarboxylic acid, failed to alter baroreflex sensitivity or produce perikaryal degeneration in nodose ganglia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗