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Biomedical subjects

R D Wright

Publications and source records attributed to R D Wright.

At least 55 records · Page 3Linked to original sources

Calcium antagonists and stimulus-secretion coupling of aldosterone.

Sheep whose left adrenal gland had been autotransplanted to a combined carotid artery-jugular vein skin loop in the neck were used to study the role of calcium in stimulus-secretion coupling for aldosterone biosynthesis. The calcium antagonists nisoldipine and verapamil were infused directly into the adrenal arterial blood supply during Na depletion or in Na replete sheep during concomitant adrenal arterial infusion of angiotensin II or KC1. The stimulation of aldosterone secretion following angiotensin II (1 nmol/l blood flow) or KC1 (delta [K] 1 mmol/l blood flow) was totally blocked by both verapamil (10(-4) mol/l blood flow) and nisoldipine (2.6 X 10(-6) mol/l blood flow). In contrast, neither antagonist had any significant effect on the established hypersecretion of aldosterone caused by 24 h Na depletion as a result of parotid salivary loss. The data suggest an important role for calcium in stimulus-secretion coupling during acute stimulation by K and angiotensin II, but not in the longer-term sodium depletion. The data further suggest that angiotensin may not be the sole sustaining stimulus to aldosterone in sodium depletion or its mechanism switches from a Ca-dependent to a Ca-independent mechanism with Na depletion.

Adrenal Glands↗

Renal handling and acute urinary electrolyte effects of aminoglycoside antibiotics: use of a solitary renal autotransplant in the conscious sheep.

Renal handling of the aminoglycoside antibiotics gentamicin and tobramycin were studied before and after one hour of constant intravenous infusions adjusted to maintain a concentration of 15 micrograms/mL. A solitary renal autotransplant model in four conscious volume replete 40 Kg sheep was used. This unique surgical preparation allows sampling of renal arterial and renal venous blood as well as urine drained through an exteriorized parotid-ureteral fistula. This surgical preparation has considerable potential in renal pharmacology since it uses a conscious, large animal. Baseline studies in this preparation demonstrated normal, 51CrEDTA and 125 I PAH, clearances which were unaffected by the drugs. Aminoglycoside binding to pooled sheep sera was 11% at physiologic PH, calcium and magnesium concentrations. A-V difference was 1.3 +/- .3 micrograms/mL and extraction by the kidney was 9 +/- 3.2% with no differences between gentamicin and tobramycin. Clearance of gentamicin was 84% and tobramycin 86% of GFR. There was no evidence of tubular injury as evidenced by unchanged urinary beta-2 microglobulin excretion. Serum Na, K, Ca and Mg did not change over the course of the study. Both drugs caused a prompt decrease in absolute and fractional sodium excretion while only gentamicin produced a kaliuresis. Early aminoglycoside effects on electrolyte balance may be an eventual determinant of nephrotoxic potential rather than differences in renal drug handling.

Aminoglycosides↗

Morphology of the organum vasculosum of the lamina terminalis (OVLT) of the sheep.

Examination of the ventricular surface of the organum vasculosum of the lamina terminalis (OVLT) of sheep with the scanning electron microscope revealed an elongated protuberance occupying most of the frontal wall of the third ventricle below the level of the anterior commissure. This protuberance lacked ciliated ependymal cells. Examination of horizontal sections with the transmission electron microscope revealed an apparent lack of regularly apposed ependymal cells, suggesting that ependyma is either greatly modified or absent. The surface was composed of numerous intertwining cell processes with some scattered cells situated on this surface. The body of this structure was composed of many cell processes separated by a network of extracellular channels sometimes extending to the ventricular surface. Towards the base of this protuberance, a plexus of blood vessels was observed. Some of these vessels exhibited fenestrated endothelium. Neuronal processes were also apparent in this region. These unusual anatomical features suggest a specific function for this brain region in sheep.

Animals↗

Modifications to the Bruel and Kjaer 2116 Audio Test Station.

The main features of the Bruel and Kjaer Audio Test Station are briefly outlined. A description is given of minor problems experienced in using the equipment for testing hearing aids, together with modifications prompted by users. A modification to the internal memory circuitry is described, which enables test enclosure amplitude correction data to be retained while the test station is switched off. This removes the need to perform a time-consuming daily routine which could result in accidental expensive damage to the measuring microphone and coupler assembly. A simple means is given for rapidly checking the operation of the tester and the integrity of the correction data.

Audiometry, Pure-Tone↗

Osmoregulatory thirst in sheep is disrupted by ablation of the anterior wall of the optic recess.

Ablation of the organum vasculosum of the lamina terminalis (OVLT) and adjacent midline tissue in the anterior wall of the optic recess of the third ventricle resulted in greatly reduced water drinking to intracarotid infusion of hypertonic NaCl in sheep. Daily food and water intake and angiotensin II drinking were not consistently reduced by these lesions. Tissue in or close to the OVLT is probably involved in osmotically induced water-drinking.

Angiotensin II↗

Renal autotransplantation in sheep--preparation and physiology.

A novel procedure for renal autotransplantation in sheep is described. The operative procedure involved two preliminary operations for preparation of carotid artery and jugular vein loops and of a Wright-type parotid fistula. At transplantation the renal artery and vein were anastomosed end-to-end to carotid artery and jugular vein and the ureter was anastomosed end-to-end to the parotid duct. The cranial ends of the carotid artery, jugular vein and parotid duct were ligated and the parotid gland was denervated. The remaining abdominal kidney was removed 2 days after transplantation. Over periods now as long as 36 months, glomerular filtration rate was 24.1 +/- 0.7 ml/min and effective renal plasma flow was 204 +/- 6 ml/min (73 determinations in 7 sheep), compared to values of 48 +/- 4 and 305 +/- 26 ml/min previously reported for sheep with both kidneys in situ. The physiological response of the kidneys to water load and deprivation, arginine-vasopressin injection, intravenous hypertonic sodium load and 24 h sodium depletion have been examined and show the transplanted kidneys responded in the appropriate manner. Maximum urine osmolality of up to 1000 mOsmol/kg was observed after 24 h water deprivation, and minimum osmolality of 108 +/- 25 mOsmol/kg was observed after administration of 75 ml/kg oral water load. Fractional sodium reabsorption was greater than 99.9% after 24 h sodium depletion, whilst it fell to 92.5 +/- 0.5% after intravenous administration of a hypertonic NaCl load. All these values are in the same range as observed for normal sheep following similar treatment. This preparation provides a sole kidney with immediate access to its blood vessels and secretions for physiological and pharmacological research.

Animals↗

Local action of parathyroid hormone (1-34) and (1-84) at the parotid gland of sheep.

Administration of bovine parathyroid hormone (PTH) preparations increased the phosphate concentration in the parotid saliva of sheep. Data on the site of action of PTH (1-84) were obtained by (a) equimolar infusions of PTH (1-84) and (1-34) directly into the arterial blood supply of the vascularly isolated parotid gland in anaesthetized sheep, (b) intravenous infusion of PTH (1-84) at a similar rate and (c) intra-arterial infusion of PTH (1-84) with complete drainage of the venous effluent from the gland during the infusion. Results showed substantial time- and dose-response identity of the two peptides, at 10(-9) to 4 X 10(-9) mol/l in arterial blood, in raising salivary phosphate concentration. The effect of PTH (1-84) was not due to recirculated fragments because the response was obtained when recirculation was prevented by complete venous drainage and little or no response occurred when the same infusion was given i.v.

Animals↗

[Asp1, Val5] angiotensin-(1-8)octapeptide does not stimulate aldosterone secretion in sodium-depleted sheep.

1. To test the hypothesis that [Asp1,Val5]-angiotensin-(1-8)octapeptide ([Asp1,Val5]ANG II) is a more potent agonist to aldosterone secretion in the sodium-depleted animal than is [Asn1,Val5]angiotensin-(1-8)octapeptide ([Asn1,Val5]ANG II), local adrenal arterial infusion of the two peptides has been carried out in sheep with cervical adrenal autotransplants. 2. Neither [Asp1,Val5]ANG II nor [Asn1,Val5]-ANG II further stimulated the increased level of aldosterone secretion in conscious moderately sodium-depleted sheep. Greater sodium deficiency further increased aldosterone secretion. 3. The conclusion of Campbell, Schmitz & Itskovitz [Clinical Science (1979), 56, 325-333] that the free acid form of angiotensin II was a more potent agonist of aldosterone secretion than was the amide form under conditions of reduced sodium status is not supported by studies in sodium-depleted sheep.

Aldosterone↗

Dopaminergic modulation of aldosterone secretion?

Metoclopramide (10 mg i.v. injection followed by 10 mg/h i.v. for 2 h) caused a transient rise in blood concentrations of aldosterone in sodium-replete and sodium-depleted sheep. Infusion of metoclopramide into the adrenal artery of sheep with an autotransplanted adrenal gland, at a rate to give a similar concentration of metoclopramide at the adrenal cell level (calculated from rate of infusion and adrenal blood flow), resulted in no alteration in aldosterone secretion rate in either sodium-replete or sodium-deplete animals, even though intravenous metoclopramide caused transient stimulation of aldosterone secretion in the same sheep when sodium replete. Dopamine administered either into the adrenal arterial blood supply or intravenously had no significant effect on aldosterone secretion and did not reverse the stimulatory effects of angiotensin II on aldosterone secretion in the adrenal transplant. The data do not support the suggestion that direct dopaminergic elements play a tonic inhibitory role in aldosterone secretion. It is possible that the agonist effect of metoclopramide on aldosterone secretion may occur by some non-dopaminergic mechanism and it is tempting to speculate that the effect is centrally mediated.

Adrenal Glands↗

The effect of carbonic anhydrase inhibitors on the anionic composition of sheep's parotid saliva. With an appendix on uncatalysed carbon dioxide-water kinetics by P. T. McTigue.

1. The effects of the carbonic anhydrase inhibitors, acetazolamide, ethoxzolamide and benzolamide on the ionic composition of parotid saliva were studied in anaesthetized sheep with access to the parotid blood vessels. 2. The inhibitors were infused directly into the arterial blood supply to the gland to give blood concentrations in the range 10(-5) to 10(-2) M. 3. Mean anionic concentrations at basal flow rate before inhibitor infusion were, bicarbonate 98 m-mole/l., phosphate 15 m-mole/l. and chloride 26 m-mole/l. In the presence of inhibitors, bicarbonate concentration fell by 11 m-mole/ml. and phosphate and chloride concentrations rose. Secreto-motor nerve stimulation increased bicarbonate concentration by 13 m-mole/l. before infusion of inhibitors and the concentrations of the other anions fell. The bicarbonate rise was abolished by the inhibitors and the fall in phosphate concentration was balanced by a rise in chloride concentration. 4. These effects show that only a small component of the bicarbonate ion transfer system in the sheep parotid gland is sensitive to these inhibitors. 5. The relationship of these findings to a new enzyme with carbonic anhydrase action isolated from the sheep's parotid gland is discussed.

Animals↗

A micropuncture investigation of electrolyte transport in the parotid glands of sodium-replete and sodium-depleted sheep.

1. Parotid secretion has been studied by micropuncture in sodium-replete and sodium-deficient sheep. 2. The osmolality of unstimulated primary saliva was slightly higher than in plasma and fell following cholinergic nerve stimulation. In sodium-depleted animals the osmolality of final saliva was hypotonic and exhibited flow dependency, where as in sodium-replete animals it was always isotonic. 3. In sodium-replete sheep, the primary fluid sodium concentration was about 120-130 mmol l-1 but in final saliva it was about 167 mmol l-1 and showed little or no flow-dependency. In sodium-depleted sheep, the primary sodium concentration averaged only 82.2 mmol l-1 and it was concluded that sodium-depleted primary fluid contained some other unidentified solute that allowed it to remain approximately isotonic; in final saliva the unstimulated sodium concentration was about 40 mmol l-1 and it rose with increasing flow rate to a maximum of 114.9 mmol l-1. 4. The primary fluid potassium concentration in sodium-replete animals did not differ significantly from that seen in sodium-depleted animals and the values were uninfluenced by stimulation; the over-all mean value was 11.2 mmol l-1. In final saliva, in sodium-replete sheep, the potassium concentrations averaged 7.8 mmol l-1 but in sodium-depleted sheep the concentrations were between 5 and 10 times greater than in primary fluid. 5. It was calculated from the equilibrium pH that the primary bicarbonate concentration would have been about 35 mmol l-1. In final saliva, where bicarbonate was measured directly, the concentrations were much greater and increased with stimulation to about 115 mmol l-1. 6. The primary fluid phosphate and chloride concentrations were the same in both sodium-replete and sodium-depleted animals and were unchanged by stimulation; the mean concentration of phosphate was 1.30 mmol l-1 and of chloride, 53.0 mmol l-1. In final saliva the phosphate concentrations were little changed but the chloride concentrations fell to an average value of 20.0 mmol l-1. In final saliva it was found that the summed sodium and potassium concentrations exceeded the summed chloride, bicarbonate and phosphate (in mequiv l-1) concentrations, on average by 13.9 mequiv l-1, regardless of sodium status or flow rate. 7. The results indicate that secretion by the sheep parotid can be accounted for in terms of the standard two-state model. Phosphate seems to enter the saliva only in the primary fluid and potassium and bicarbonate appear to enter at both primary and secondary sites; sodium and chloride enter at the primary level and can be reabsorbed in the ducts. Salt depletion causes the primary fluid concentrations of sodium and chloride to fall and the content of an unidentified solute to rise markedly while, at the ductal level, it causes normally quiescent sodium and potassium transport processes to become activated.

Animals↗

A dose-response comparison of the actions of angiotensin II and angiotensin III in sheep.

Comparisons of aldosterone responses to [des-Asp1]-angiotensin II and angiotensin II, often at single dose levels, have shown a wide range of potency ratios. Therefore four-point dose-response comparisons were performed in sodium-replete sheep, using i.v. infusion rates of angiotension II and angiotensin II amide that reproduced the physiological range of blood concentration of angiotensin II for sheep. Angiotensin III was infused i.v. at the same rates. Effects on arterial blood pressure, cortisol secretion rate, adrenal blood flow and plasma levels of NA+ and K+ were also compared. The potency ratio, angiotensin III : angiotensin II amide, was 0.87 for actual aldosterone secretion rate and 0.90 for the calculated increase in aldosterone secretion. For angiotensin III : angiotensin II the ratios were 0.80 and 0.91 respectively. These ratios were not significantly different from 1.00 but the tendency for angiotensin II to be slightly more potent was probably due to a contribution from derived angiotensin III during infusion of angiotensin II. Angiotensin II or angiotensin II amide was approximately four times as potent as angiotensin III in raising arterial blood pressure. Cortisol secretion rate was slightly but significantly increased by all peptides at the higher infusion rates. Infusions had no effect on adrenal blood flow or plasma levels of Na+ but raised plasma levels of K+ slightly. These results confirm the conclusion from adrenal arterial infusion experiments that angiotensin II and III are almost equipotent in stimulating aldosterone secretion in sheep.

Aldosterone↗

Effect of adrenal arterial infusion of P-113 on aldosterone secretion in Na-deficient sheep.

To examine the role of the renin-angiotensin system in aldosterone regulation, P-113 ([Sar1,Ala8]angiotensin II) was infused into the arterial blood supply of the transplanted adrenal gland in conscious sheep. Effects on the aldosterone response to infused angiotensin II and III in sodium-replete sheep were compared with effects of P-113 on aldosterone secretion in sodium deficiency. P-113 infusion up to 1,000 microgram/h for 1-2 h did not consistently alter aldosterone secretion in sodium-deficient sheep. However, in sodium-replete sheep P-113 infusion for 20 min at 10 microgram/h or more abolished aldosterone responses to high blood levels of angiotensin II and III produced by systemic intravenous or adrenal intra-arterial infusion. P-113 infusions alone had minor agonist activity on aldosterone secretion in sodium-replete sheep. These results indicate that the increased secretion of aldosterone in Na-depleted sheep is not simply and commensurately determined by increase of angiotensin II and III concentration in the arterial blood perfusing the adrenal gland.

Adrenal Glands↗