Biomedical subjects

W J Louis

Publications and source records attributed to W J Louis.

At least 19 recordsLinked to original sources

PubMed1998

Acute effects of blood pressure elevation on insulin clearance in normotensive healthy subjects.

Reduced clearance of insulin from plasma contributes to the hyperinsulinemia associated with essential hypertension (EH); however, the association between impaired insulin clearance and EH remains unexplained. Whether elevated blood pressure (BP) affects insulin clearance is unknown; therefore, we used the hyperinsulinemic euglycemic clamp to determine the effects of BP elevation on insulin clearance and sensitivity in eight healthy volunteers. Placebo infusion increased mean BP by 2.6+/-1.6 mm Hg, which was significantly less than rises produced by phenylephrine, an alpha1-adrenoceptor agonist (+11+/-1.8 mmHg, P<.05), or by angiotensin II (+13+/-1.3 mmHg, P<.01). Although beta-adrenoceptor stimulation with isoproterenol did not change mean BP (+3.6 mm Hg, P=NS), it significantly increased systolic pressure (+23+/-2.8 mm Hg versus +2.3+/-4.6 mm Hg with placebo P<.01). Insulin secretion (ie, C-peptide concentrations) was not affected by any of the treatments; however, phenylephrine significantly reduced the metabolic clearance rate of insulin (MCRinsulin) (16.6+/-1.0 mL/kg per minute with placebo versus 13.6+/-0.7 mL/kg per minute with phenylephrine, P<.01) and thereby increased plasma insulin concentrations (66+/-5.1 microU/mL with placebo versus 79+/-4.1 microU/mL with phenylephrine, P<.05). Phenylephrine also increased glucose utilization (42+/-5.8 micromol/kg per minute during placebo versus 58+/-4.8 micromol/kg per minute during phenylephrine, P<.05); however, this was proportional to the increased insulin concentrations; therefore, insulin sensitivity was unchanged. MCRinsulin and plasma insulin concentrations were not affected by angiotensin II; however, glucose utilization increased to 51+/-2.7 micromol/kg per minute (P<.01 versus placebo), indicating insulin sensitivity was increased. MCRinsulin was unaffected by isoproterenol. Thus, alpha-adrenergic stimulation but not increased BP per se is a potent regulator of insulin clearance and plasma insulin concentrations.

Adrenergic alpha-Agonists↗

PubMed1997

[3H]2-(2-Benzofuranyl)-2-imidazoline, a highly selective radioligand for I2-imidazoline receptor binding sites. Studies in rabbit kidney membranes.

2-(2-Benzofuranyl)-2-imidazoline (2-BFI) has recently been characterised as a selective ligand for the I2-type of imidazoline-receptor binding site(s) (I2-RBS). The present studies determined the relative levels of specific [3H]2-BFI binding to membrane homogenates of brain and kidney from rat, guinea pig and rabbit and identified the pharmacological characteristics of [3H]2-BFI binding sites in rabbit kidney membranes. Rabbit kidney membranes had the highest relative density of specific [3H]2-BFI binding of all tissues studied (2000 fmol/mg protein). Rabbit brain and guinea pig kidney had moderate levels of specific [3H]2-BFI binding (350-500 fmol/mg protein), while rat kidney and guinea pig and rat brain displayed much lower densities of binding (40-65 fmol/mg protein). Studies of [3H]2-BFI binding kinetics in rabbit kidney homogenates revealed binding to two distinct sites with Kd values of 0.10 +/- 0.01 nmol/l and 1.00 +/- 0.36 nmol/l respectively. Equilibrium saturation studies were also consistent with the presence of two binding sites-[3H]2-BFI (0.01-20 nmol/l) bound to sites with affinities of 0.10 +/- 0.01 nmol/l and 0.92 +/- 0.13 nmol/l and binding densities of 470 +/- 80 and 840 +/- 60 fmol/mg protein (n = 3), representing 36 and 64% respectively. Drug inhibition studies revealed that L-adrenaline; alpha 1-adrenoceptor drugs (prazosin, L-phenylephrine) and alpha 2-adrenoceptor drugs (rauwolscine, methoxyidazoxan, 2-(2,4-(O-methoxyphenyl)-piperazin-1-yl)-ethyl-4, 4-dimethyl-1,3-(2H,4H)-isoquinolindione (ARC-239) had extremely low affinities for [3H]2-BFI binding sites (IC50 > or = 10 mumol/l). Putative I1-RBS compounds, p-aminoclonidine, moxonidine, imidazole-4-acetic acid and cimetidine, inhibited [3H]2-BFI binding to rabbit renal membranes with low to very low affinities (Ki values 3 to > or = 100 mumol/l), suggesting [3H]2-BFI does not label I1-RBS in rabbit kidney membranes. I2-RBS compounds-2- (4,5-dihydroimidaz-2-yl)-quinoline (BU224), 2-(4,5-dihydroimidaz-2-yl)-quinoxaline (BU239), idazoxan and cirazoline-potently inhibited [3H]2-BFI binding (Ki values 0.37-1.6 nmol/l), confirming the labelling of I2-RBS. Inhibition of [3H]2-BFI binding by certain compounds was consistent with their interaction with two binding site populations-for example (drug, Ki values) guanabenz, 0.65 nmol/l and 0.17 mumol/l; naphazoline, 0.94 nmol/l and 2.8 mumol/l; amiloride, 76 nmol/l and 26 mumol/l rilmenidine, 150 nmol/l and 50 mumol/l; and clonidine, 230 nmol/l and 70 mumol/l. The high affinity of amiloride for a high proportion (85%) of the binding is consistent with the presence of the I2A-subtype of I-RBS in rabbit kidney. These results demonstrate that [3H]2-BFI is a highly selective and high affinity radioligand for I2-RBS which should be useful for the further characterisation of these sites in mammalian tissues.

Animals↗

PubMed1997

Effects of dietary lipid modification on adrenoceptor-mediated cardiovascular responsiveness and baroreflex sensitivity in normotensive subjects.

To examine the effects of short-term dietary lipid modification on alpha- and beta-adrenoceptor-mediated cardiovascular responsiveness, 19 normal volunteers consumed either a high-fat or a low-fat diet for 2 weeks in an open, randomized, crossover study of 6 weeks' duration. Diets were balanced for sodium and potassium content. Adrenoceptor-mediated cardiovascular responsiveness was assessed by measuring blood pressure and heart rate responses to incremental infusions of phenylephrine and isoprenaline. Baroreflexes were studied by examining heart rate responses to phenylephrine and to the Valsalva manoeuvre. Total plasma cholesterol and low-density lipoprotein cholesterol levels both fell significantly (by 22% and 26%, respectively), on the low-fat compared with the high-fat diet, as did resting supine blood pressures and heart rate (by 6 mmHg systolic and 3 mmHg diastolic, and 5 beats/min). These changes were accompanied by a significant reduction in the systolic blood pressure response to isoprenaline. Blood pressure responses to phenylephrine and baroreflex sensitivity did not change. These results suggest that dietary fat intake alters cardiac beta-adrenergic reactivity without significant effects on vascular alpha-adrenoceptor mediated responses or baroreflexes.

Adult↗

PubMed1997

Computerized neuropsychological tests in the early detection of dementia: prospective findings.

This longitudinal study examines the sensitivity of 2 computerized neuropsychological tests, delayed matching to sample and paired associate learning, to early dementia of the Alzheimer type (DAT). Normal controls, patients in the early stages of DAT, and individuals with questionable dementia (QD) were studied. At 6 and 12 months after initial presentation, almost half of the QD group exhibited lower scores on the computerized subtests, maintaining their scores on standard testing. Over the same period NC subjects maintained their performance levels, while DAT patients continued to deteriorate. Linear discriminant function analyses of the computerized subtests at 6 and 12 months correctly classified 100% of the early DAT patients. Eighty-four and 79 percent of normal controls were correctly classified at 6 and 12 months respectively. Further development of these subtests for the detection of early dementia and the documentation of ongoing change in DAT is warranted. The findings are discussed in terms of the special sensitivity of these tests to the neuropathology of Alzheimer's Disease.

Aged↗

PubMed1996

Inositol hexakisphosphate binding sites in rat heart and brain.

1. Inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) and inositol hexakisphosphate (InsP6) are produced in response to stimulation of cardiac alpha 1-adrenoceptors. While the role of Ins(1,4,5)P3 and Ins(1,4,5)P3 receptors is well-defined in many tissues including brain, the functional role of the putative InsP6-InsP6 receptor system in cardiac function is less clear. Using quantitative autoradiography, this study examined the characteristics and regional localization of [3H]-InsP6 binding sites in rat heart and compared the affinity of a range of inositol polyphosphates for [3H]-InsP6 and [3H]-Ins(1,4,5)P3 binding sites in heart and brain. 2. [3H]-InsP6 bound to a single, high affinity site in sections of rat heart (KD ranging from 22 +/- 1.9 nM in right atria to 35 +/- 2.6 nM in the interventricular septum, n = 7). The maximal number of binding sites (Bmax) ranged from 5.1 +/- 0.48 to 12 +/- 1.8 pmol mg-1 protein in left atrium and left ventricle, respectively. Inositol phosphates inhibited binding of [3H]-InsP6 with the order of potency: InsP6 > Ins(1,4,5)PS3 > inositol 1,3,4,5-tetrakisphosphate > or = inositol pentakisphosphate > Ins(1,4,5)P3 > > inositol mono- and bisphosphates, consistent with the labelling of an InsP6 binding site. 3. The Ins(1,4,5)P3 analogue, Ins(1,4,5)PS3, originally investigated as a putative selective radioligand for the Ins(1,4,5)P3 receptor, was a potent inhibitor of [3H]-InsP6 binding in all heart regions (K1 = 170-260 nM). The K1 of Ins(1,4,5)PS3 for the inhibition of [3H]-Ins(1,4,5)P3 binding in rat brain (60-220 nM) was similar to that observed for the inhibition of [3H]-InsP6 binding in heart, suggesting that Ins(1,4,5)PS3 is not a specific ligand for either Ins(1,4,5)P3 or InsP6 receptor binding sites. 4. Previous studies have detected [3H]-InsP6 binding in mitochondrial and sarcoplasmic reticulum fractions of heart and links between InsP6 and cardiac mitochondrial Ca2+ regulation have been proposed, suggesting further studies are warranted to determine the functional role(s) of InsP6 and InsP6 receptor binding sites in cardiac tissue.

Animals↗

PubMed1996

Insulin as a pressor agent: effects of 'physiological' insulin concentrations on finger blood pressure.

Epidemiological evidence has linked essential hypertension with impaired tissue sensitivity to insulin (i.e. insulin resistance) and actions which could contribute to elevated blood pressure include renal sodium and water retention, sympathetic nervous system stimulation and effects on vascular smooth muscle cell growth and cation balance. Although insulin has pressor effects in some animal models, similar changes in human studies have only been demonstrable with supraphysiological insulin concentrations. We have recently measured finger blood pressure during a two stage hyperinsulinaemic euglycaemic clamp that produced insulin concentrations within the 'physiological' range. The plasma insulin concentration increased from 7.0 +/- 0.3 mu U.ml(-1) to 28.9 +/- 0.6 mu U.ml(-)and then to 101 +/-1.7 mu U.ml(-1) during the procedure and was associated with an increase in fingers but not arm systolic blood pressure during both low dose (i.e.+ 9.9 +/- 1.9 mmHg vs + 7.5 +/- 2.7 mmHg with control,p <0.05) and high dose insulin (21.9 +/- 2.3 mmHg vs 14.6 +/- 3.1 mmHg, p <0.01). Thus it appears that 'physiological' concentrations of insulin have pressor effects on finger systolic blood pressure that are not detectable more proximally and it is possible that such changes could contribute to the development of sustained elevations of blood pressure.

Adult↗

PubMed1995

Differential characteristics and localisation of [3H]oxazoline and [3H]imidazoline binding sites in rat kidney.

Comparative autoradiography revealed that the imidazolines [3H]p-aminoclonidine and [3H]idazoxan labelled high densities of alpha 2A-adrenoceptor sites in the inner medulla and inner stripe of the outer medulla of rat kidney. In contrast, the oxazoline [3H]rilmenidine labelled a high density of non-adrenergic sites in the cortex and outer stripe of the outer medulla, a lower density in the inner stripe and inner medulla and a low density of alpha 2A-adrenoceptor sites in inner medulla. The existence of novel, non-adrenergic oxazoline sites of potential functional importance in rat kidney has important implications for the classification of imidazoline receptors.

Adrenergic alpha-Antagonists↗

PubMed1995

Distribution of nonadrenergic [3H]rilmenidine binding in rat brain and kidney.

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Adrenergic alpha-2 Receptor Agonists↗

PubMed1995

Effect of dorsal periaqueductal grey lesion on baroreflex and cardiovascular response to air-jet stress.

Certain areas within the periaqueductal grey (PAG) have been implicated in cardiovascular regulation. The influence of excitotoxic lesions of the caudal dorsal periaqueductal grey on the baroreceptor-heart rate reflex and the cardiovascular response to air-jet stress was examined in awake Wistar-Kyoto rats. Pressor (11 +/- 2 mmHg) and tachycardic (25 +/- 4 beats/min) responses to air-jet were not influenced by the lesion. Similarly, the resting MAP and HR were unchanged. However, the gain of the baroreflex was reduced from -3.9 +/- 0.1 to -2.8 +/- 0.3 beats/min per mmHg and the upper threshold was increased from 120 +/- 5 to 135 +/- 7 mmHg in the lesioned group. These observations suggest that although the caudal dorsal PAG does not appear to exert a tonic influence on vasomotor tone or mediate the air-jet response, it may provide a facilitatory input to the baroreceptor-heart rate reflex.

Animals↗

PubMed1995

Quantitative autoradiographic localization in rat brain of alpha 2-adrenergic and non-adrenergic I-receptor binding sites labelled by [3H]rilmenidine.

alpha 2A-Adrenergic receptor (AR) and non-adrenergic imidazoline receptor (I-R) binding sites have been previously characterized in rat cerebral cortex membranes using the N-substituted oxazoline, [3H]rilmenidine ([3H]Ril) [King, P.R. et al., Eur. J. Pharmacol., 218 (1992) 101-108]. In the present study, in vitro autoradiography was used to quantify the regional distribution of these receptors throughout the rat neuroaxis. The distribution and relative density (fmol/mg tissue) of I-Rs was examined in the presence of 1 microM adrenaline to block the adrenergic component of 40 nM [3H]Ril binding and non-specific binding was measured in the presence of another oxazoline, Bay a6781 (10 microM). Both alpha 2A-ARs and I-Rs were broadly, but heterogeneously, distributed. In forebrain, high levels of [3H]Ril-labelled alpha 2A-AR sites were observed in the anterior olfactory nucleus, the piriform, entorhinal and perirhinal cortices, lateral septum, bed nucleus of the stria terminalis, several thalamic nuclei, the amygdala and the arcuate, dorsomedial and posterior hypothalamic nuclei. In hindbrain, alpha 2A-AR sites were concentrated in locus coeruleus, lateral parabrachial nucleus, nucleus of the solitary tract and area postrema. I-R sites accounted for 50% or more of specific [3H]Ril binding (40 nM) in most cortical and hypothalamic nuclei, nucleus of the solitary tract, cranial motor nuclei and most spinal cord layers. The highest densities of I-Rs were found in the arcuate, dorsomedial and posterior hypothalamic nuclei, the locus coeruleus, the area postrema, the cranial motor nuclei and associated with spinal motor neurones. A very high concentration of I-Rs was also detected in the pineal gland. The distribution of alpha 2-AR sites determined resembled that reported with [3H]p-aminoclonidine which appears to specifically label alpha 2-ARs and not I1-R sites in rat brain sections, and [3H]methoxyidazoxan which is a selective alpha 2-AR antagonist. The regional and cellular distribution of I-R binding sites was unlike the distribution of putative I1-R sites labelled by [3H]clonidine in human brain, although comparable autoradiographic mapping studies in rat brain have not been done using this ligand. The regional and cellular distribution of [3H]-labelled I-R binding sites had both similarities and differences to that reported using the imidazoline ligand, [3H]idazoxan, with common labelling of areas such as area postrema, arcuate and interpeduncular nuclei and pineal gland with the two ligands, and differential relative binding levels ([3H]Ril > [3H]idazoxan) associated with hippocampal pyramidal cells and brainstem and spinal motor neurones.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic alpha-2 Receptor Agonists↗

PubMed1995

Effects of pravastatin on cardiovascular reactivity to norepinephrine and angiotensin II in patients with hypercholesterolemia and systemic hypertension.

This study was conducted to examine the effects of short-term cholesterol reduction on cardiovascular reactivity in mildly hypertensive patients. Seven male and 7 female patients, aged 34 to 68 years, received pravastatin (40 mg/day) or matched placebo for 3 weeks in a randomized, double-blind, crossover study. Cardiovascular reactivity was assessed by measurement of blood pressure (BP) responses to incremental infusions of angiotensin II and norepinephrine, by cold pressor testing and isometric exercise. Compared with placebo, pravastatin caused significant reductions in plasma total and low-density lipoprotein cholesterol levels, which averaged 20% and 31%, respectively (both p < 0.0001), and in diastolic BP responses (expressed as the infusion rate required to raise BP by 20 mm Hg) to both angiotensin II (7.3 +/- 3.0 vs 9.7 +/- 4.7 ng/kg/min, p = 0.05) and norepinephrine (0.15 +/- 0.13 vs 0.38 +/- 0.33 micrograms/kg/min, p = 0.03). Systolic BP responses were similar with both treatments. Body weight, resting BP, and maximal BP responses to physical stressors were similar with each treatment.

Adult↗

PubMed1995

Efficacy of pravastatin in combination with captopril in hypertensive patients.

OBJECTIVE: To determine the efficacy of pravastatin in the treatment of primary hypercholesterolaemia in patients being treated with captopril for hypertension. DESIGN: A double-blind parallel group study comparing 12 weeks of pravastatin therapy (20-40 mg/day) with placebo. PARTICIPANTS: 25 patients (age, 37-73 years) with mild-to-moderate hypertension and hypercholesterolaemia (total cholesterol level, 5.5-8.8 mmol/L). RESULTS: Pravastatin reduced total cholesterol levels by 22% (from 7.1 +/- 0.29 [SEM] to 5.5 +/- 0.25 mmol/L; P < 0.001) and low-density-lipoprotein cholesterol levels by 32% (from 5.0 +/- 0.32 to 3.4 +/- 0.28 mmol/L; P < 0.001) in four weeks and these levels were maintained for the 12 weeks of therapy. Pre-pravastatin values returned three weeks after stopping therapy. Levels of total cholesterol, cholesterol fractions and triglycerides remained constant or deteriorated in the placebo group. Pravastatin therapy was well tolerated. An integrated coronary risk score showed a 40% reduction in risk. CONCLUSION: This study indicates that pravastatin (combined with captopril) is an effective cholesterol-lowering drug, but that treatment needs to be maintained.

Adult↗

PubMed1995

Atrial fibrillation after coronary artery bypass grafting is associated with sympathetic activation.

BACKGROUND: We prospectively investigated the role of sympathetic activation in the etiology of atrial fibrillation following coronary artery bypass grafting. METHODS: Continuous ambulatory monitoring was performed for 80 hours in 131 patients after coronary artery bypass grafting. Right atrial plasma norepinephrine levels were assessed preoperatively and every 4 hours for 48 hours postoperatively. RESULTS: Of the 131 patients, 50% (65) had development of atrial fibrillation and 36% (47) required treatment. Onset of atrial fibrillation was preceded by a significant increase in sinus rate and atrial ectopic activity. On multivariate logistic regression, elevated mean postoperative norepinephrine levels (5.78 +/- 2.83 versus 3.57 +/- 1.31 nmol/L; p < 0.0001), increased age (68.9 +/- 5.7 versus 63.8 +/- 8.7 years; p = 0.02), and decreased postoperative magnesium levels (0.79 +/- 0.09 versus 0.83 +/- 0.10 mmol/L; p = 0.02) were independently associated with the occurrence of atrial fibrillation. CONCLUSIONS: Elevated norepinephrine levels suggest that sympathetic activation may be important in the pathogenesis of atrial fibrillation after coronary artery bypass grafting, and this underlines the importance of beta-adrenoceptor blockade as prophylaxis.

Aged↗

PubMed1995

The effect of levcromakalim (BRL 38227) on bladder function in patients with high spinal cord lesions.

The effects of the potassium channel opener levcromakalim (BRL 38227) 7.5 micrograms kg-1 were examined on urodynamic variables and blood pressure during inflow and voiding cystometry in six high spinal cord lesion patients. Levcromakalim administration significantly increased the duration of bladder contraction (197 +/- 128 s to 267 +/- 167 s, P < 0.05) and also reduced blood pressure (126 +/- 13/67 +/- 9 mm Hg to 104 +/- 25/52 +/- 12 mm Hg) but was without effect on other urodynamic parameters. Because of concerns about hypotensive responses, further studies involving higher doses of levcromakalim should be considered only if the drug was administered intravesically.

Adult↗

PubMed1994