Search PubMed⌕ Search

Biomedical subjects

B R Walker

Publications and source records attributed to B R Walker.

At least 145 records · Page 8Linked to original sources
PubMed1992

Role of vasopressin in cardiovascular responses to acute and chronic hyperosmolality.

Experiments were performed in conscious chronically instrumented rats to determine the role of arginine vasopressin (AVP) in the cardiovascular adjustments to acute and chronic increases in plasma osmolality. Animals were implanted with pulsed Doppler flow probes and arterial and venous catheters for the determination of cardiac output, mean arterial blood pressure (MABP), and heart rate and for the calculation of total peripheral resistance and baroreflex sensitivity (BRS). Before and after raising plasma osmolality by either 48-h water deprivation or acute hypertonic saline infusion, specific V1- or V2-vasopressinergic receptor antagonists or vehicle were administered to the animals, and the cardiovascular responses were noted. MABP was significantly elevated in water-deprived animals. These animals also exhibited significantly increased BRS, which was further increased by administration of the V1-receptor antagonist. Animals subjected to acute hypertonic saline infusion also demonstrated increased MABP, although the infusion, unlike water deprivation, did not affect BRS. We observed no significant effects on any other variable measured. We conclude that AVP plays a relatively minor role in the cardiovascular adjustments to acute and chronic hyperosmolality.

Animals↗
PubMed1992

Pulmonary vasodilatory response to neurohypophyseal peptides in the rat.

Experiments were performed on isolated salt-perfused rat lungs to determine the receptor type(s) responsible for the pulmonary vascular effects of the neurohypophyseal peptides arginine vasopressin (AVP) and oxytocin. Bolus administration of AVP to lungs preconstricted with the thromboxane mimetic U-46619 resulted in a dose-dependent vasodilatory response (approximately 65% reversal of U-46619-induced vasoconstriction at the highest dose tested) that was blocked by pretreatment with a selective V1- but not by a selective V2-vasopressinergic receptor antagonist. Administration of a selective V1-agonist to the preconstricted pulmonary vasculature resulted in a vasodilatory response similar to that observed with AVP (approximately 55% reversal of U-46619 vasoconstriction), which was blocked by prior administration of the selective V1-receptor antagonist. Administration of the selective V2-receptor agonist desmopressin to the preconstricted pulmonary vasculature resulted in a small (approximately 8% reversal of U-46619 vasoconstriction) vasodilatory response that was, nevertheless, greater than that produced by addition of vehicle alone and was attenuated by pretreatment with a selective V2-receptor antagonist. Finally, oxytocin also caused vasodilation in the preconstricted pulmonary vasculature; however, the potency of oxytocin was approximately 1% of AVP, and the vasodilation produced by oxytocin was blocked by prior administration of a selective V1-receptor antagonist, suggesting that oxytocin acts via V1-vasopressinergic receptor stimulation. We conclude from these experiments that AVP and oxytocin dilate the preconstricted pulmonary vasculature primarily via stimulation of V1-vasopressinergic receptors. V2-receptor stimulation results in a minor vasodilatory response, although its physiological significance is unclear.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Tissue-specific distribution of the NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase.

11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) converts the active glucocorticoid corticosterone to inactive 11-dehydrocorticosterone in rat (or cortisol to cortisone in man), thereby protecting renal mineralocorticoid receptors from corticosterone or cortisol and allowing preferential access for aldosterone. Recent work suggests that a nicotinamide adenine dinucleotide (NAD+)-dependent 11 beta-OHSD isoform is expressed in distal renal tubule, in contrast with the hepatic isoform which is NAD(+)-phosphate (NADP+)-dependent. To establish the distribution of the NAD(+)-dependent isoform we measured in vitro conversion of [3H]corticosterone to [3H]11-dehydrocorticosterone in homogenized rat tissues in the presence of NADP+ or NAD+. In most tissues (liver, testis, hippocampus, heart, aorta, mesenteric artery) NADP+ increased activity and NAD+ was without effect. However, in whole renal cortex, colon, placenta, and lung both NADP+ and NAD+ increased activity. No difference in cofactor utilization was demonstrated between proximal and distal renal tubules following density gradient separation. This distribution of NAD(+)-dependent activity corresponds with: (i) the distribution of multiple mRNA and/or protein species of 11 beta-OHSD; (ii) the distribution of aldosterone-specific mineralocorticoid receptors; and (iii) the equilibrium between active and inactive glucocorticoids in each tissue. We suggest that the tissue-specific expression of isoforms of 11 beta-OHSD with different kinetic properties confers on them diverse roles in modulating corticosteroid receptor activation.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1992

Clonidine therapy for Shapiro's syndrome.

Shapiro's syndrome comprises agenesis of the corpus callosum in association with episodic hyperhidrosis and hypothermia. We describe a 25-year-old man who is the twentieth case to be reported. There was no evidence of epilepsy, sympathetic nervous system dysfunction or inappropriate vasopressin release. However, investigation demonstrated a central defect in temperature regulation with an abnormally low hypothalamic set-point and normal homeothermic reflexes. Therapy with clonidine, an alpha 2-adrenoceptor agonist, was associated with remission of symptoms: these recurred on four occasions when clonidine was withdrawn. Clonidine therapy was also associated with a return to normal central temperature regulation. We suggest that the efficacy of clonidine reflects an action on hypothalamic thermoregulation rather than on peripheral catecholamine release. These findings have implications for the use of clonidine in other patients with Shapiro's syndrome and in more common disorders of temperature control, including perimenopausal flushing.

Adult↗
PubMed1991

Attentuation of systemic vasoreactivity in chronically hypoxic rats.

Experiments were performed to assess the effects of chronic hypoxia on systemic vasoreactivity in conscious unrestrained rats and in abdominal aortic rings. Two groups of rats were used: normoxic controls and chronically hypoxic rats that were maintained in a hypobaric chamber (380 mmHg) for 4 wk before experimentation. In conscious animals instrumented with pulsed Doppler cardiac output probes and arterial and venous catheters, mean arterial pressure and mean cardiac output were measured before and during graded continuous infusions of phenylephrine (PE), angiotensin II, and arginine vasopressin (AVP). Measurements were made while the animals breathed either room air or 12% O2. Acute exposure to 12% O2 significantly reduced pressor and vasoconstrictor responses for all three agents. These responses were also attenuated in the chronically hypoxic rats in 12% O2; however, acute return to room air conditions did not return pressor or vasoconstrictor responses to normoxic control levels. In abdominal aortic rings from both groups of animals, cumulative dose-response curves to PE and AVP were completed in 21 and 3% O2 conditions. Neither acute nor chronic hypoxia caused a shift in the dose-response curves. In rings from control rats, maximum tension responses to AVP were significantly diminished in 3% O2. Rings from chronically hypoxic rats exhibited less maximum tension to AVP in 21% O2 than did rings from control rats. We conclude that acute hypoxia reversibly attenuates systemic vasoreactivity and that chronic hypoxia induces a more sustained decrease in reactivity. In addition, at least part of the mechanism may reside within the vasculature.

Angiotensin II↗
PubMed1991

Role of vasopressin in acutely altered baroreflex sensitivity during hemorrhage in rats.

Experiments were performed to examine the potential role of circulating arginine vasopressin (AVP) on baroreflex sensitivity during hypotensive and nonhypotensive hemorrhage in the conscious rat. Animals were chronically instrumented for measurement of cardiac output, blood pressure, and heart rate (HR). Three potential stimuli for release of AVP were utilized: 1) rapid 20% arterial hemorrhage that resulted in hypotension, 2) nonhypovolemic hypotension induced by intravenous infusion of nitroprusside, and 3) nonhypotensive hemorrhage (rapid 10% arterial blood withdrawal). Hypotensive hemorrhage was associated with significant reductions in blood pressure, cardiac output, HR, and calculated total peripheral resistance, an increase in baroreflex (BRR) bradycardia in response to pressor infusions of phenylephrine, and a moderate elevation in circulating AVP. Prior intravenous administration of a specific V1-vasopressinergic antagonist augmented the hypotensive response to hemorrhage; however, neither V1- nor V2-blockade affected hemorrhage-induced augmentation of the BRR. Inducement of hypotension by infusion of nitroprusside did not alter subsequent BRR sensitivity. Finally, nonhypotensive hemorrhage was associated with an increase in resting HR and augmented BRR sensitivity. However, in contrast to hypotensive hemorrhage, either V1- or V2-antagonism attenuated the increase in BRR sensitivity seen with 10% hemorrhage. These data suggest that, although AVP may play a role in blood pressure maintenance via its direct vasoconstrictor actions during hypotensive hemorrhage, the observed augmentation of BRR sensitivity associated with severe blood loss is not attributable to a vasopressinergic mechanism activated by circulating AVP. However, blood-borne AVP may contribute to BRR sensitivity alterations in response to mild blood loss.

Animals↗
PubMed1991

Vasopressin-induced bradycardia in barodenervated rats.

Experiments were performed on conscious chronically instrumented rats to determine the contribution of baroreceptor reflex (BRR)-independent mechanisms in the bradycardia associated with intravenous administration of arginine vasopressin (AVP). At least 2 wk prior to experimentation, the aortic and carotid baroreceptors were denervated in six rats. Following recovery, the maximum bradycardic responses to pressor doses of phenylephrine (PE) or AVP were determined on separate days in each animal. Pulse interval (PI) was calculated from heart rate (HR), and the slopes of PI vs. mean arterial blood pressure (MABP) and PI vs. dose were determined for each experiment by linear regression. There was no significant correlation of PI vs. MABP in response to bolus PE in these barodenervated rats. However, there was a significant correlation of PI vs. MABP and PI vs. dose in response to AVP in five of the six barodenervated rats. These data suggest that pressor levels of AVP may elicit bradycardia independent of the BRR. Another group of experiments was performed in the Langendorff-isolated rat heart preparation to assess the direct chronotropic effect of AVP. Hearts were not paced, and the coronary arteries were perfused at a constant flow. HR was determined at various concentrations of AVP (n = 4 at each dose). In addition, because unpaced hearts exhibited low intrinsic rates, the same protocol was performed in hearts receiving isoproterenol to elevate basal HR (n = 4 at each AVP dose). There was no chronotropic effect of AVP in isolated hearts with or without isoproterenol administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

11 beta-hydroxysteroid dehydrogenase in vascular smooth muscle and heart: implications for cardiovascular responses to glucocorticoids.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) converts the active glucocorticoid corticosterone to inactive 11-dehydrocorticosterone in the rat (or cortisol to cortisone in man), thereby protecting renal mineralocorticoid receptors from corticosterone or cortisol and allowing preferential access for aldosterone. We have previously demonstrated that cortisol-induced cutaneous vasoconstriction in man is potentiated by the 11 beta-OHSD inhibitor glycyrrhetinic acid, suggesting that 11 beta-OHSD may protect vascular corticosteroid receptors. In this study we report quantitation of 11 beta-OHSD bioactivity in homogenates of rat aorta, mesenteric artery, caudal artery, and heart, expressed as the percent in vitro conversion of 3H-corticosterone to 3H-11-dehydrocorticosterone. Nicotinamide adenine dinucleotide phosphate (NADP+)-dependent 11 beta-OHSD activity was found in all of these tissues and was significantly higher in resistance vessels than aorta (P less than 0.05) [without NADP+: caudal artery (4.2 +/- 0.2%) greater than mesenteric artery (2.5 +/- 0.7%) = heart (1.67 +/- 0.2%) greater than aorta (0.79 +/- 0.2%); with 200 microM NADP+: caudal artery (43.9 +/- 2.1%) greater than heart (20.6 +/- 1.0%) = mesenteric artery (17.7 +/- 3.1%) = aorta (11.4 +/- 0.4%); heart greater than aorta]. All of these were lower than renal cortex (29.4 +/- 1.8% without NADP+; 82.4 +/- 0.4% with NADP+; P less than 0.001). 3H-11-dehydrocorticosterone was the major metabolite of 3H-corticosterone (greater than 97% of 3H-corticosterone metabolized). Reduction of 3H-11-dehydrocorticosterone to 3H-corticosterone was not detected in these experiments. We also report localization of 11 beta-OHSD-like immunoreactivity by immunohistochemistry using antisera raised against rat liver 11 beta-OHSD, and of 11 beta-OHSD messenger RNA expression by in situ hybridization using complementary RNA probes transcribed from complementary DNA encoding rat liver 11 beta-OHSD. We found 11 beta-OHSD immunoreactivity and messenger RNA expression in vascular and cardiac smooth muscle cytoplasm but not in endothelium. Thus, 11 beta-OHSD is appropriately sited to modulate access of corticosterone to vascular receptors and could influence vascular resistance, cardiac output and thereby blood pressure.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1990

Renal versus hindquarter hemodynamic responses to vasopressin in conscious rats.

Experiments were performed on conscious rats to (a) compare the responsiveness of the renal and hindquarter vascular beds to infusions of exogenous arginine vasopressin (AVP), and (b) determine whether either bed demonstrates V2-vasopressinergic vasodilation when the vasoconstrictor properties of AVP are blocked. Rats were chronically instrumented with pulsed Doppler flow probes on either the left renal artery or the distal abdominal aorta as well as with femoral arterial and venous catheters. One series of experiments examined the vascular responses of these two beds to exogenous AVP infused intravenously (i.v.) at 0.2, 2.0, or 5.0 ng/min. The lowest infusion rate was associated with no detectable changes in mean arterial blood pressure (MAP), heart rate (HR), renal or hindquarter blood flow (RBF or HQBF), or vascular resistance in these beds. In contrast, the higher infusion rates caused a marked increase in MAP, a decrease in HR, and a reduction in HQBF; RBF was unaffected, however. A second series of experiments tested for the presence of a V2-vasodilatory influence during infusion of AVP at 5 ng/min by selectively blocking V1-vasopressinergic receptors or both V1- and V2-receptor types. Little evidence for V2-mediated vasodilation was found in either vascular bed, however. We conclude that although the renal vasculature appears relatively insensitive to exogenous AVP, this insensitivity probably is not due to vasodilation mediated by activation of V2-receptors.

Animals↗
PubMed1990

Serum lipid elevation during isotretinoin therapy for acne in the west of Scotland.

We have studied 116 patients in the West of Scotland receiving isotretinoin for acne vulgaris at a dose of 1 mg/kg per day. No clinical evidence of adverse effects resulting from lipid elevations were seen in the short term. Cholesterol levels rose during the first 6 weeks of therapy, and thereafter stabilized, but triglyceride levels rose after 6 weeks therapy and continued to rise while therapy continued. Pretreatment levels of neither lipid was predictive of the level of elevation observed while on therapy. No other predictors of lipid elevation such as age or sex were identified in this study, which is the largest reported of patients receiving the standard recommended dose of isotretinoin.

Acne Vulgaris↗
PubMed1990

Vasopressinergic augmentation of cardiac baroreceptor reflex in conscious rats.

Experiments were performed on conscious, chronically instrumented rats to determine the contribution of V2-receptor activation in augmentation of cardiac baroreceptor reflex (BRR) sensitivity by arginine vasopressin (AVP). At least 1 wk before experimentation, rats were implanted with arterial and venous catheters, as well as with pulsed Doppler flow probes for measurement of cardiac output (CO). An initial set of experiments was performed to determine whether cardiac BRR sensitivity is enhanced by AVP in conscious rats. A series of pressor doses of either AVP or phenylephrine (PE) were administered on separate days (n = 8). The slope of pulse interval (PI) vs. mean arterial blood pressure (MABP) was determined for each experiment by linear regression and used as an index of cardiac BRR sensitivity. The slope of PI vs. MABP was greater in response to AVP than in response to PE in all animals studied. A separate group of animals (n = 7) received either a 40-min infusion of AVP (5 ng/min iv) or a specific V2-antagonist, d(CH2)5[DIle2,Ile4]AVP (20 micrograms/kg iv), 10 min before infusion of AVP. The responses of MABP, CO, and total peripheral resistance to AVP infusion were similar with and without V2-antagonism; however, the bradycardic response to AVP was less with V2-antagonist pretreatment. Furthermore, administration of V2-antagonist reduced delta PI/delta MABP in response to AVP infusion. Additional experiments were performed to test the effect of infusion of a specific V2-agonist, dVDAVP (5 ng/kg iv), on BRR-induced bradycardia in response to a series of pressor PE bolus doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Cardiovascular responses to hypoxia and hypercapnia in barodenervated rats.

Experiments were performed to examine the role of the arterial baroreceptors in the cardiovascular responses to acute hypoxia and hypercapnia in conscious rats chronically instrumented to monitor systemic hemodynamics. One group of rats remained intact, whereas a second group was barodenervated. Both groups of rats retained arterial chemoreceptive function as demonstrated by augmented ventilation in response to hypoxia. The cardiovascular effects to varying inspired levels of O2 and CO2 were examined and compared between intact and barodenervated rats. No differences between groups were noted in response to mild hypercapnia (5% CO2); however, the bradycardia and reduction in cardiac output observed in intact rats breathing 10% CO2 were eliminated by barodenervation. In addition, hypocapnic hypoxia caused a marked fall in blood pressure and total peripheral resistance (TPR) in barodenervated rats compared with controls. Similar differences in TPR were observed between the groups in response to isocapnic and hypercapnic hypoxia as well. It is concluded that the arterial baroreflex is an important component of the overall cardiovascular responses to both hypercapnic and hypoxic stimuli in the conscious rat.

Animals↗
PubMed1990

Stiffened erythrocytes augment the pulmonary hemodynamic response to hypoxia.

Isolated rat lungs were perfused with suspensions containing normal and stiffened erythrocytes (RBCs) during normoxic and hypoxic ventilation to assess the effect of reduced RBC deformability on the hypoxic pressor response. RBC suspensions were prepared with cells previously incubated in isotonic phosphate-buffered saline with or without 0.0125% glutaraldehyde. The washed RBCs were resuspended in isotonic bicarbonate-buffered saline (with 4% albumin) to hematocrits of approximately 35%. The lungs were perfused with control and experimental cell suspensions in succession while pulmonary arterial pressure was measured during normoxic (21% O2) and hypoxic (3% O2) ventilation. On the attainment of a peak hypoxic pressor response, flow rate was changed so that pressure-flow curves could be constructed for each suspension. RBC deformability was quantified by a filtration technique using 4.7-microns-pore filters. Glutaraldehyde treatment produced a 10% decrease in RBC deformability (P less than 0.05). Over the range of flow rates, Ppa was increased by 15-17% (P less than 0.05) and 26-31% (P less than 0.05) during normoxic and hypoxic ventilation, respectively, when stiffened cells were suspended in the perfusate. The magnitude of the hypoxic pressor response was 50-54% greater with stiffened cells over the three flow rates. In a separate set of experiments, normoxic and hypoxic arterial blood samples from conscious unrestrained rats were used to investigate the effects of acute hypoxia on RBC deformability. Deformability was measured with the same filtration technique. There was no difference in the deformability of hypoxic compared with normoxic RBCs. We conclude that the presence of stiffened RBCs enhances the hemodynamic response to hypoxia but acute hypoxia does not affect RBC deformability.

Animals↗
PubMed1990

Altered baroreflex function after tail suspension in the conscious rat.

Experiments were performed on conscious chronically instrumented rats to determine the contribution of peripheral V2-vasopressinergic receptors in any alteration of baroreceptor reflex (BRR) sensitivity on release from 1 wk of 30 degrees head-down tilt resulting from tail suspension. Initial experiments determined changes in plasma volume (PV) occurring over this period by use of the Evans Blue dye dilution technique. PV was determined immediately before tail suspension and on day 7 of the stimulus. PV, erythrocyte volume, and total blood volume were all significantly diminished on day 7, whereas hematocrit was unchanged. Other rats were instrumented with pulsed Doppler flow probes on the ascending aorta for determination of cardiac output and with arterial and venous catheters 7-10 days before study. Immediately before tail suspension, control cardiac output, mean arterial blood pressure, and heart rate values were determined. In addition, BRR sensitivity was estimated both before and after intravenous administration of a V2-receptor antagonist by assessing the slope of the pulse interval-mean arterial blood pressure relationship in response to a series of pressor doses of phenylephrine. BRR sensitivity was determined on the last day of head-down tilt, 1 min after release from tail suspension, and 10 min after administration of a specific V2-vasopressinergic antagonist. BRR sensitivity tended to fall on day 7 of tail suspension compared with control and was significantly increased after release. However, BRR sensitivity was not altered by intravenous V2 antagonist administration either before tail suspension or after release.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Chronic propranolol attenuates hypoxic pulmonary vasoconstriction in conscious rats.

Experiments were performed on conscious, chronically instrumented rats to assess the effect of chronic propranolol treatment on basal pulmonary hemodynamics and on hypoxic pulmonary vasoconstriction. Rats received either propranolol (4 mg/day) or vehicle for 31 days via implanted osmotic mini-pumps. Animals were then acutely exposed to 8% and 10% O2. Pulmonary arterial pressure (PAP), mean arterial blood pressure (MABP) and heart rate (HR) were monitored via chronically implanted catheters, and cardiac output (CO) was measured by thermodilution. Chronic administration o propranolol was associated with minimal changes in MABP, PAP and total pulmonary resistance (TPuR). However, HR and CO decreased and total systemic resistance (TSR) increased in propranolol treated rats. The acute hypoxic pulmonary vasoconstrictor response of propranolol treated rats was significantly less than that of untreated control animals. Systemic hemodynamic responses to acute hypoxia did not differ between the groups. These data indicate that chronic propranolol administration reduces the acute hypoxic pulmonary vasoconstrictor response in conscious rats, but does not alter basal pulmonary hemodynamics.

Animals↗
PubMed1989

Vasopressin-induced pulmonary vasodilation in rats.

Experiments were performed to determine the pulmonary vascular responses to exogenous or endogenous arginine vasopressin (AVP) in rats. Both in vitro and in vivo approaches were used to examine the direct pulmonary vasoactive properties of AVP and how those properties affect pulmonary hemodynamics in the intact animal. In conscious, unrestrained rats, constant infusion of AVP (4.0 mU.kg-1.min-1 iv) resulted in a fall in mean pulmonary artery pressure (PAP), although systemic pressure was increased. Coincident with the fall in PAP were similar reductions in cardiac output and heart rate. Similarly, bolus administration of AVP reduced PAP, and this effect was augmented during hypoxia. Another series of experiments examined the effect of endogenous AVP released by arterial hypoxemia on pulmonary hemodynamics in conscious rats. Administration of a specific V1-vasopressinergic antagonist had no effect on the PAP response to hypoxia; however, systemic resistance tended to fall following V1-antagonism. To determine the vasoactive properties of AVP independent of these changes in blood flow, a series of experiments were performed on isolated, perfused rat lungs. Injection of 25, 200, or 2,000 mU of AVP into the circulation of the isolated lung was without effect under normoxic conditions. In contrast, 25 mU AVP elicited reproducible pulmonary vasodilation when injected during ongoing hypoxic pulmonary vasoconstriction. This vasodilatory response was unaffected by meclofenamate or by the platelet-activating factor receptor antagonist SRI 63-441, but was blocked by a specific V1-vasopressinergic antagonist. We conclude that although AVP exerts profound systemic vasoconstriction, the pulmonary circulation appears relatively unaffected by exogenous or endogenous AVP in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗