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Biomedical subjects

B R Walker

Publications and source records attributed to B R Walker.

At least 181 records · Page 10Linked to original sources
PubMed1985

Ventilatory responses of hamsters and rats to hypoxia and hypercapnia.

As a fossorial species the hamster differs in its natural habitat from the rat. Experiments were performed to determine possible differences between the ventilatory responses of awake hamsters and rats to acute exposure to hypoxic and hypercapnic environments. Ventilation was measured with the barometric method while the animals were conscious and unrestrained in a sealed plethysmograph. Tidal volume (VT), respiratory frequency (f), and inspiratory (TI) and expiratory (TE) time measurements were made while the animals breathed normoxic (30% O2), hypercapnic (5% CO2), or hypoxic (10% O2) gases. Arterial blood gases were also measured in both species while exposed to each of these atmospheric conditions. During inhalation of normoxic gas, the VT/100 g was greater and f was lower in the hamster than in the rat. Overall minute ventilation (VE/100 g) in the hamster was less than in the rat, which was reflected in the lower PO2 and higher PCO2 of the hamster arterial blood. When exposed to hypercapnia, the hamster increased VE/100 g solely through VT; however, the VE/100 g increase was significantly less than in the rat. In response to hypoxia, the hamster and rat increased VE/100 g by similar amounts; however, the hamster VE/100 g increase was through f alone, whereas the rat increased both VT/100 g and f. Mean airflow rates (VT/TI) were no different in the hamster or rat in each gas environment; therefore most of the ventilatory responses were the result of changes in TI and TE and respiratory duty cycle (TI/TT).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Prostaglandin modulation of the vascular effects of vasopressin in the conscious rat.

Experiments were performed on conscious, male Sprague-Dawley rats to determine whether cyclooxygenase inhibition affects the pressor response to exogenous vasopressin. The rise in arterial blood pressure was tested in response to 1.0, 2.5, 5.0, and 12.5 mU synthetic arginine vasopressin both before and following cyclooxygenase inhibition with either meclofenamate or the structurally dissimilar inhibitor ibuprofen. In addition, time control experiments were also performed where only the saline vehicle for the drugs was administered. In all animals tested, the increase in arterial pressure in response to the highest three concentrations of vasopressin was greater following cyclooxygenase inhibition than before, while the saline vehicle had no effect. The baroreceptor-mediated bradycardia accompanying the rise in blood pressure was variable, but unaffected by meclofenamate or ibuprofen. It is concluded that vasodilator prostaglandins are released in response to pressor levels of vasopressin, which act to modulate the pressor response of the peptide.

Animals↗
PubMed1984

Comparison of muscular pulmonary arteries in low and high altitude hamsters and rats.

Measurements were made of the ratio of medial area to total arterial area in the muscular pulmonary arteries of a fossorial species, the hamster, and a non-fossorial control, the rat. It was found that the medial area was less in hamsters than in rats. In addition, chronic hypoxic exposure resulted in further medial thickening in rats, while the hamster was unaffected. The hamster has previously been shown to have a blunted hypoxic pulmonary pressor response, and the present data indicate that this relative unresponsiveness is associated with less pulmonary vascular smooth muscle. In addition, the insensitivity to hypoxia of the pulmonary vasculature and a lack of vascular luminal narrowing may tend to minimize increases in pulmonary vascular resistance during chronic hypoxia in the hamster, and thus be beneficial adaptations for a burrowing species.

Altitude↗
PubMed1984

Effect of renal impairment and hemodialysis on lorazepam kinetics.

The effect of renal disease on lorazepam kinetics was assessed in three groups: six normal subjects, six patients with renal impairment, and four functionally anephric patients. Subjects received single 1.5- or 3-mg intravenous and oral doses; eight subjects (four normal and four with renal impairment) also received 0.5-mg oral doses three times a day. Lorazepam and lorazepam glucuronide were determined in plasma, urine, and feces by a highly sensitive gas chromatographic method. After single doses, t1/2 and V beta increased in patients, but Cls in the patients (about 85 ml/min) did not differ significantly from that in normals (71 ml/min). Absorption of oral dose was more than 90% and was not impaired by the disease state. Renal and fecal excretion of intact lorazepam accounted for only about 2% of the dose. The major route of drug elimination was hepatic biotransformation to lorazepam glucuronide, an inactive, nontoxic metabolite eliminated by the kidney. In both the normal and renally impaired groups, about 64% of the dose was recovered as glucuronide in urine and less than 0.4% in feces. Fecal excretion contributed very little to the overall elimination of lorazepam and its glucuronide in all groups. Only 8% of the intact drug was removed by 6-hr hemodialysis, but 40% was removed as glucuronide conjugate. Lorazepam kinetics after subchronic dosing were linear. The difference in Clo between the normal and renally impaired groups was not significant. Since the mean steady-state concentration depends on drug clearance only, and since clearance is not altered, no dosage adjustment appears necessary for patients with renal disease.

Administration, Oral↗
PubMed1984

Effects of guanabenz on gastrointestinal absorption of hydrochlorothiazide.

The pharmacokinetics of guanabenz (16 mg) and hydrochlorothiazide (25 mg), administered separately and as a fixed-combination tablet (guanabenz 16 mg/hydrochlorothiazide 25 mg), were compared in a randomized three-period crossover study in 24 healthy men. Plasma concentrations were monitored for 48 h after each administration. No statistically significant differences between the two formulations were noted in mean plasma concentrations or the rate and extent of absorption of guanabenz. The relative bioavailability (Fr) of the combination tablet compared with guanabenz alone was 96%; thus the two formulations were bioequivalent with respect to guanabenz. For hydrochlorothiazide, mean plasma concentrations were similar for 3 h after administration but were higher for the combination tablet than for hydrochlorothiazide alone from 4 through 48 h (p less than 0.05). A significant increase in the extent, but not the rate, of absorption of hydrochlorothiazide was observed for the combination tablet (mean Fr, 120%), which is not considered clinically significant. We propose that this increase may have been due to increased systemic availability of hydrochlorothiazide in the presence of guanabenz, an alpha-adrenergic agonist, which may have delayed intestinal transport of hydrochlorothiazide, resulting in enhanced gastrointestinal absorption.

Adult↗
PubMed1984

Therapeutic and economic controversies in antihypertensive therapy.

Diuretics are recommended for initial antihypertensive therapy because of their low cost and lack of subjective side effects. Unlike alpha- and beta-adrenergic agents, however, diuretics frequently induce metabolic abnormalities that necessitate supplemental therapy and increased monitoring of clinical laboratory tests. These factors increase the total cost of diuretic therapy, making it comparable to that of the alpha- or beta-adrenergic drugs. We show that the total yearly costs of therapy, exclusive of office visits, for patients treated with any of these three classes of agents is approximately $175 to $250, regardless of the drug used. Diuretics are cost effective only in patients who do not require laboratory follow-up or supplemental therapy. Thus, the choice of a drug for initial therapy of hypertension may be based more appropriately on medical (particularly side effects and metabolic abnormalities) rather than financial considerations.

Adrenergic alpha-Agonists↗
PubMed1984

Chronic propranolol treatment decreases pulmonary artery pressure in conscious dogs.

Daily administration of propranolol to 9 chronically instrumented, trained dogs for 2 weeks caused significant (p less than 0.05) decreases in heart rate (70 +/- 8 to 57 +/- 6 beats/min), cardiac output (3.6 +/- 0.3 to 2.9 +/- 0.2 liters/min), pulmonary arterial pressure (15.7 +/- 0.5 to 10.0 +/- 0.5 mm Hg) and total pulmonary vascular resistance (4.6 +/- 0.6 to 3.3 +/- 0.4 units). Nadolol, a structurally dissimilar beta-adrenergic receptor antagonist, caused a similar decrease in total pulmonary resistance. Acute meclofenamate administration did not return to normal pulmonary arterial pressure and resistance in the dogs chronically treated with beta-adrenergic receptor blockers. We therefore conclude that chronic beta-adrenergic receptor blockade lowered pulmonary arterial pressure and resistance by a mechanism independent of cyclooxygenase. In addition, chronic beta-adrenergic receptor blockade did not affect the potential for hypoxic vasoconstriction.

Animals↗
PubMed1983

Suppressed basal antidiuretic hormone release during cyclooxygenase inhibition in conscious dogs.

Both in vitro and in vivo experiments suggest that prostaglandins may affect antidiuretic hormone (ADH) release centrally. In addition, other studies show that prostaglandins administered peripherally may cause ADH release. However, these latter studies have been flawed by hemodynamic alterations and the use of anesthetics, which make interpretation difficult. The present study was designed to test for involvement of prostaglandins produced outside the central nervous system in ADH release in conscious dogs. Administration of meclofenamate (2 mg/kg and 2 mg X kg-1 X h 1, iv) resulted in a consistent fall in plasma ADH levels in five dogs. This diminution of ADH release occurred with no change in systemic hemodynamics, arterial blood gases, or plasma osmolality, suggesting that prostaglandins are important mediators of basal ADH release in the conscious dog. Because meclofenamate does not cross the blood-brain barrier, prostaglandins produced outside the central nervous system appear to be involved in this process. The specific prostaglandin involved or the site of action of prostaglandins on ADH release is not clear at this time.

Animals↗
PubMed1983

Inhibition of hypoxia-induced ADH release by meclofenamate in the conscious dog.

Release of antidiuretic hormone (ADH) due to hypoxic stimuli has been documented in several in vivo models. The current study was performed to determine whether 1) hypoxia causes ADH release in the conscious normovolemic dog and 2) whether endogenous prostaglandins are involved in hypoxic ADH release. Five conscious dogs were made hypoxic by inhalation of 10% O2. Dogs were studied both with and without pretreatment with meclofenamate (2 mg/kg iv and 2 mg . kg-1 . h-1). Hypoxic exposure resulted in elevated plasma ADH; however, meclofenamate totally blocked this response. Hemodynamic responses to hypoxia were unaffected by meclofenamate. In addition, plasma osmolality was unchanged by hypoxia in both groups. Since meclofenamate does not cross the blood-brain barrier, it is concluded that the release of ADH by hypoxia in the conscious dog may be mediated by endogenous prostaglandins produced outside the central nervous system. It appears that elevated renal prostaglandin release, increased ADH, and hemodynamic alterations could all interact to determine the final renal response to hypoxia.

Animals↗
PubMed1983

Antidiuresis and decreased sodium excretion during cyclo-oxygenase inhibition in the conscious dog.

Studies were undertaken to further elucidate the role of endogenous prostaglandins in normal renal function in the awake dog. Meclofenamate (2 mg/kg and 2 mg/kg/h, i.v.) was administered after control measurements. Parallel time control experiments were also performed. Inhibition of renal prostaglandin synthesis was documented by significant reduction in urinary prostaglandin E2 excretion rate. Urine flow and sodium excretion were reduced by meclofenamate infusion. In addition, fractional excretion of sodium was reduced, implying enhanced sodium reabsorption during prostaglandin synthesis inhibition. Renal hemodynamics, glomerular filtration and systemic hemodynamics were unaffected. It is concluded that endogenous prostaglandin release is important in influencing sodium and water excretion in the conscious dog.

Animals↗
PubMed1983

Recent methods for assessing effectiveness of antihypertensive agents.

Clinically relevant graphic approaches to the assessment of patients' blood pressure responses to antihypertensive agents are reviewed and extended to include both statistical components and the effects of treatment-related patient discontinuations. Regression line fits of change in diastolic blood pressure (DBP) versus baseline diastolic blood pressure (BDBP) are used for multicenter comparisons of placebo, guanabenz, methyldopa, clonidine, propranolol, hydrochlorothiazide, and the combination of guanabenz plus hydrochlorothiazide. Orientations of the fitted lines can be contrasted to certain "ideal" response profiles and are particularly useful for comparative purposes. An additional graphic approach was developed to show overall "therapeutic" response rate categories, two of which account for patients discontinuing treatment because of nonresponse or adverse effects. This approach assesses antihypertensive effectiveness, "adjusted" for the effects of treatment-related patient withdrawal, thus addressing criticisms often raised in the evaluation of such agents. Although these methods are generally useful for comparing agents used in chronic disease therapy, further work is needed to extend these procedures to incorporate safety assessments and overall benefit-risk considerations in the selection of treatment modalities.

Antihypertensive Agents↗
PubMed1982

Oxaprozin disposition in renal disease.

Effects of renal disease on the disposition kinetics of oxaprozin, a nonsteroidal antiinflammatory analgesic, were assessed in 15 subjects who were normal, renally impaired, or who had been undergoing hemodialysis. Oral dose clearance (Cloral), volume of distribution at steady-state (V88d), and elimination half-life (t 1/2) did not substantially differ among the three groups. Mean fraction unbound oxaprozin in plasma (fup) increased from 0.08% in the normal group to 0.18% and 0.28% in the two azotemic groups. Consequently, unbound drug kinetic parameters, including intrinsic clearance (Clint) and V88du of unbound drug were reduced from 2.9 l/hr/kg and 193 l/kg in normal subjects to approximately 1.6 l/hr/kg and 91 l/kg in azotemic patients. The smaller volume of distribution is consistent with a decrease in oxaprozin tissue binding in azotemia. The decreased plasma and tissue binding and lower Clint suggest that, in the treatment of azotemic patients with rheumatoid arthritis, the dose of oxaprozin should begin at 600 mg once a day.

Adult↗
PubMed1982

Diuretic response to acute hypoxia in the conscious dog.

Experiments were performed to determine the renal effects of acute hypoxia in conscious normovolemic dogs. Dogs were made hypoxic and also became hypocapnic through increased ventilation. Hypocapnic hypoxia was associated with increased urine flow, arterial blood pressure, cardiac output, PAH and inulin clearance, and electrolyte excretion. Urinary excretion of prostaglandin E2 (PGE2) also increased during hypocapnic hypoxia. To test whether the respiratory alkalosis accompanying hypoxic exposure was important in mediating the observed response, experiments were conducted in which the dogs were hypoxic but remained isocapnic via addition of CO2 to the inspired gas. Urine flow increased and was associated with changes in renal function and hemodynamics similar to those during hypocapnic hypoxia. Experiments were also conducted to determine whether the increased PGE2 release in hypoxia was functionally significant. Dogs were pretreated with meclofenamate and then made hypoxic. Prostaglandin synthesis inhibition did not alter the renal response to hypocapnic hypoxia. Dogs were also treated chronically with propranolol in an attempt to blunt the rise in blood pressure during hypoxia. In dogs with only a small transient increase in blood pressure, the diuresis was blocked. It is concluded that systemic hypoxia results in a mild diuresis in the conscious normovolemic dog. This response occurs independent of changes in arterial pH or renal prostaglandin release. The diuretic effect of hypoxia is probably due to increased renal perfusion pressure and resultant increased filtration.

Animals↗
PubMed1982

Pulmonary pressor response after prostaglandin synthesis inhibition in conscious dogs.

Recent studies have shown that vasodilator prostaglandins are continually produced by the isolated rat lung. We postulated that these vasodilators may contribute to maintenance of normal low pulmonary arterial pressure. Pulmonary pressure and cardiac output were measured in conscious dogs prior to and 30 to 60 min following administration of meclofenamate (2 mg/kg iv, followed by infusion at 2 mg . kg-1 . h-1) or the structurally dissimilar inhibitor RO-20-5720 (1 mg/kg iv, followed by infusion at 1 mg . kg-1 . h-1). The animals were also made hypoxic with inhalation of 10% O2 before and after inhibition. Time-control experiments were conducted in which only the saline vehicle was administered. Meclofenamate or RO-20-5720 caused an increase in mean pulmonary arterial pressure and total pulmonary resistance. Cardiac output and systemic pressure were unaffected. The mild hypoxic pulmonary pressor response observed was not affected by meclofenamate. Animals breathing 30% O2 to offset Denver's altitude also demonstrated increased pulmonary pressure and resistance when given meclofenamate. It is concluded that endogenous vasodilator prostaglandins may contribute to normal, low vascular tone in the pulmonary circulation.

Animals↗
PubMed1982

Evidence for diminished sensitivity of the hamster pulmonary vasculature to hypoxia.

Many mammals exhibit elevated pulmonary arterial pressure when exposed to airway hypoxia. In addition, prolonged hypoxic exposure may result in elevated hematocrit and right ventricular hypertrophy. The current study was designed to test whether the hamster, a fossorial species, may possess naturally selected physiological characteristics advantageous to a chronically hypoxic environment. Hamsters and rats were studied at low altitude (1,520 m) and after 5 wk at high altitude (4,250 m). Hematocrit for low-altitude hamsters was 53 +/- 1 compared with 45 +/- 1 for low-altitude rats. Low-altitude hamsters and rats demonstrated the same right ventricular weight-to-total ventricular weight ratio (RV/T) (0.223 +/- 0.006 vs. 0.222 +/- 0.003). After high-altitude exposure the hematocrit for hamsters and rats was the same (58 +/- 1 vs. 57 +/- 1), but RV/T was less in the hamster (0.251 +/- 0.004 vs. 0.288 +/- 0.005). In addition, the hypoxic pulmonary pressor response of lungs isolated from low- and high-altitude animals was examined. Lungs from hamsters were less responsive than lungs from rats at all levels of hypoxia tested. In addition, exposure to altitude resulted in a diminished pressor response in lungs from both species. It is concluded that the pulmonary vasculature of the hamster is less responsive to hypoxia than that of the rat, and that this relative unresponsiveness may aid the hamster in an hypoxic environment.

Animals↗