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D D Smyth

Publications and source records attributed to D D Smyth.

At least 55 records · Page 3Linked to original sources
PubMed1992

Renal alpha 2-adrenoceptors in New Zealand genetically hypertensive rats.

1. Renal alpha 1- and alpha 2-adrenoceptors were characterized in the New Zealand strain of genetically hypertensive (GH) rat and the Otago random-bred albino normotensive (NT) control rat at 4 and 12 weeks of age with [3H]-prazosin and [3H]-rauwolscine. 2. At 4 weeks of age, the density of alpha-adrenoceptors in NT and GH rats was similar to both the alpha 1- (193 +/- 11 vs 163 +/- 14 fmol mg-1 protein) and alpha 2- (347 +/- 34 vs 319 +/- 41 fmol mg-1 protein) adrenoceptor. At 12 weeks of age, GH rats had a greater density of renal alpha 1- (152 +/- 27 vs 238 +/- 17 fmol mg-1 protein) and alpha 2- (175 +/- 42 vs 350 +/- 23 fmol mg-1 protein) adrenoceptors compared to the NT rats. 3. Pre-incubation of kidneys from GH rats (12 weeks of age) with 1 and 10 microM clonidine decreased the density of receptors identified by unlabelled clonidine displacement of [3H]-rauwolscine to 77% and 56% of control. Pre-incubation with adrenaline, 2,6 dimethylclonidine or phenylephrine failed to alter binding. 4. Pre-incubation of kidneys from NT rats (12 weeks) or young GH rats (4 weeks) with 10 microM clonidine failed to alter displacement of [3H]-rauwolscine by unlabelled clonidine. 5. These studies demonstrate that in another strain of hypertensive rat, the GH rat, alpha 2-adrenoceptor density is increased as compared to the normotensive control at 12 but not 4 weeks of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1992

Digitaloid pregnanes promote potassium-sparing diuresis in the guinea pig.

The synthesis of 17 alpha-acetoxy-3 beta-[(beta-D-glucopyranosyl)oxy]- 6 alpha-methylpregn-4-en-20-one, the glucoside of medroxyprogesterone acetate (MPA-glu), is described. MPA-glu and 14-amino-20 beta-hydroxy-3 beta-[(alpha-L-rhamnopyranosyl)oxy]-5 beta, 14 beta-pregnane (LND 623), pregnane glycosides that bind to the digitalis receptor, and digoxin, a cardiac glycoside, were infused intravenously into the anesthetized guinea pig. Each of the three steroids significantly enhanced urinary volume and sodium excretion without affecting blood pressure and creatinine clearance. Potassium excretion was markedly enhanced by digoxin but unaffected by MPA-glu or LND 623. These observations conform to previous work that demonstrated, in the rat, potassium-sparing diuresis by the glucoside of 14 beta-hydroxyprogesterone, a cardiotonic pregnane. There is a dissociation between potency to inhibit [3H]ouabain binding and the extra ATPase actions of the digitaloid pregnanes.

Animals↗
PubMed1992

Opposite rank order of potency for alpha-2 adrenoceptor agonists on water and solute excretion in the rat: two sites and/or receptors?

Preliminary studies determined that, unlike other purported alpha-2 adrenoceptor agonists, 2,6-dimethyl clonidine (2,6-DMC) increased urine flow rate independent of vasopressin. We therefore compared the dose-response curves of three alpha-2 adrenoceptor agonists, clonidine, UK 14,304 and 2,6-DMC. Unilaterally nephrectomized Sprague-Dawley rats were anesthetized and the left kidney was exposed and the ureter cannulated. A 31-gauge needle was advanced into the renal artery to permit direct intrarenal infusion of the study drugs. All three agonists produced a dose-related increase in urine flow rate and sodium excretion. A clear opposite rank order of potency was observed when the urine flow rate was analyzed as free water and osmolar clearance. For free water clearance, clonidine much greater than UK 14,304 much greater than 2,6-DMC, with 2,6-DMC producing little change. The effect on osmolar clearance was opposite with 2,6-DMC much greater than clonidine = UK 14,304. The V2 antagonist [1-(beta-mercapto-beta,beta-pentamethylene-proprionic acid), 2-d-isoleucine,4-isoleucine]arginine-vasopressin blocked the effects of clonidine but not 2,6-DMC. In a water-loaded rat model, 2,6-DMC but not clonidine increased the delivery of filtrate out of the proximal segments of the nephron. These results are consistent with the postulate that lower doses of 2,6-DMC increase solute excretion independent of vasopressin, possibly in proximal segments of the nephron. Clonidine on the other hand increases free water clearance and this effect is mediated through an interaction with the renal actions of vasopressin. Whether these disparate effects represent two distinct receptors or two sites of alpha-2 adrenoceptors in the kidney is not known.

Adrenergic alpha-Agonists↗
PubMed1992

Interference with renal organic cation transport by (-)- and (+)-nicotine at concentrations documented in plasma of habitual tobacco smokers.

Nicotine is the principal psychoactive Nicotiana alkaloid in tobacco. In the present study, we used amantadine as a marker and investigated the potential ability of nicotine and cotinine to interfere with renal organic cation transport in vitro. [3H]Amantadine is concentrated actively by isolated proximal tubules, distal tubules and cortical slices. In proximal tubules, the addition of (-)- or (+)-nicotine (0.1-100 microM) facilitated amantadine (10 microM) accumulation. Apparent Km for amantadine uptake was decreased by a clinically relevant concentration of (-)- and (+)-nicotine (0.4 microM), from 78 +/- 2 to 52 +/- 2 and 61 +/- 5 microM, respectively (mean +/- S.E.M., P less than .05), whereas Vmax was not altered (6.6 +/- 0.1 to 6.3 +/- 0.1 and 6.5 +/- 0.2 nmol/mg/min). The addition of (-)-cotinine (0.4-100 microM) also facilitated amantadine uptake, but with lesser efficacy. Possible mechanisms underlying the present enhancement of uptake include facilitation of amantadine influx and/or attenuation of efflux. Efflux data indicate a prominent hindrance of amantadine egress from preloaded tubules in the presence of 0.4 microM (-)- and (+)-nicotine (51 +/- 4 to 32 +/- 8 and 27 +/- 4 pmol/mg/30 sec, P less than .05) and are supportive of the latter notion. In distal tubules, (-)- or (+)-nicotine produced inhibition only a high concentrations (greater than or equal to 100 microM). Km was increased by 400 microM (-)- and (+)-nicotine from 76 +/- 5 to 124 +/- 9 and 116 +/- 17 microM, and Vmax was moderately decreased from 3.4 +/- 0.5 to 3.0 +/- 0.4 and 3.0 +/- 0.4 nmol/mg/min (P less than .05). The incorporation of (-)-cotinine did not alter amantadine uptake. Enhancement of uptake by (-)- or (+)-nicotine was absent in cortical slices, in which tubular luminal transport has ben proposed to be insignificant, and only low affinity inhibition was apparent. The present data indicate potent interference of renal proximal tubular transport of amantadine by nicotine at concentrations equivalent to those documented in plasma of habitual tobacco smokers and suggest potential alterations in renal organic cationic drug elimination in these subjects.

Amantadine↗
PubMed1991

Differential effects of histamine H2 receptor antagonists on amantadine uptake in the rat renal cortical slice, isolated proximal tubule and distal tubule.

The interaction between amantadine and two histamine receptor antagonists was examined in the rat kidney. Amantadine (10 microM, 30 sec) was actively accumulated by cortical slices (slice/medium ratio = 0.4 +/- 0.3 [3.3 +/- 0.3 at 4 min], mean +/- S.E.M.), isolated proximal tubules (tubule/medium ratio = 35 +/- 1) and distal tubules (tubule/medium ratio = 19 +/- 2). In cortical slices, low cimetidine concentrations facilitated amantadine accumulation, whereas higher concentrations produced inhibition. Uptake in proximal tubules was enhanced by cimetidine and reached a maximum at approximately 100 microM. Cimetidine (20 microM) decreased the apparent Km (88 +/- 5 to 55 +/- 3 microM, P less than .005) without altering Vmax (6.8 +/- 0.5 to 5.8 +/- 0.6 nmol/mg/min). Conversely, cimetidine did not enhance uptake in distal tubules but elicited competitive inhibition at concentrations greater than 1 mM. Although this may partially delineate the differences observed between the cortical slice and proximal tubule data, such a discrepancy may also implicate additional sites of interaction in other segments of the cortical nephron and/or cimetidine inhibition of the relatively more significant luminal amantadine efflux in the proximal tubules. Ranitidine did not enhance amantadine accumulation but produced inhibition at high concentrations. In proximal and distal tubule preparations, ranitidine (10 mM) increased Km from 86 +/- 7 to 121 +/- 8 and 95 +/- 5 to 160 +/- 10 microM, respectively (P less than .05), whereas Vmax was not changed (8.9 +/- 0.7 to 7.9 +/- 0.8 and 4.3 +/- 0.1 to 3.8 +/- 0.2 nmol/mg/min, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Amantadine↗
PubMed1991

Long-term captopril in young and old patients with mild hypertension.

The decrease in renal blood flow (RBF) observed in patients with hypertension can be increased with converting enzyme inhibition (CEI). It is unknown whether the decrease in RBF observed with age can also be increased with CEI. This study compared the short- and long-term effects of captopril monotherapy in young (less than 50 years) and old (greater than 65 years) hypertensive patients. Captopril effectively decreased blood pressure in both groups (diastolic blood pressure less than 90 mm Hg), with the young patients requiring a lower dose (.7 mg/kg) than the elderly patients (1.2 mg/kg). Creatinine and para-aminohippurate clearances were maintained in both groups, with a decrease in renal vascular resistance being observed in the younger patients. Serum aldosterone levels fell significantly after each dose of captopril at all phases of the study, with no change observed in plasma renin levels. Atrial natriuretic peptide (ANP) level was increased in the elderly patients receiving placebo (48.8 +/- 8 pg/mL) when compared with the young subjects (24 +/- 3.8 pg/mL). Captopril did not alter ANP levels in either group.

Adult↗
PubMed1991

Proximal tubular alpha 2-adrenoceptor density in the spontaneously hypertensive rat.

In the kidney of the spontaneously hypertensive rat (SHR), alpha 2-adrenoceptors are increased and may be related to hypertension. We measured alpha 2-adrenoceptor density and characteristics in a proximal tubule suspension with the alpha 2-adrenoceptor antagonist, 3H-rauwolscine. SHR had a significantly greater density of alpha 2-adrenoceptors when compared to their normotensive controls, the Wistar-Kyoto (WKY) rats (146 +/- 13 v 58 +/- 7 fmol/mg protein; P less than .001). Competition experiments determined the alpha 2-adrenoceptor to be an alpha 2B-subtype. Agonist competition curves were shallow and exhibited pseudo-Hill slopes of less than 1, indicating that they bind to both high and low affinity receptor sites. In summary, alpha 2-adrenoceptors are increased in the proximal tubule of SHR and appear to be of the alpha 2B-subtype. An increase in alpha 2-adrenoceptors may be related to abnormalities in hypertension.

Animals↗
PubMed1991

Potentiation of the natriuretic effect of clonidine following indomethacin in the rat.

Previous studies have demonstrated a diuretic effect of clonidine at low intrarenal infusion rates with a natriuretic effect being observed at high infusion rates (greater than or equal to 3 micrograms.kg-1.min-1). The natriuresis at high infusion rates may have been secondary to increased renal prostaglandin production. We therefore evaluated the effects of indomethacin (a cyclooxygenase inhibitor) on the response to clonidine in the anesthetized rat. Intrarenal infusions of saline (vehicle) or clonidine (0.1, 0.3, 1, and 3 micrograms.kg-1.min-1) were examined both in the presence and absence of pretreatment with indomethacin (5 mg/kg, i.p.). Clonidine produced a dose-related increase in urine volume and free water clearance at 0.3, 1, and 3 micrograms.kg-1.min-1 as compared with the vehicle group. Sodium excretion and osmolar excretion were increased only at the highest infusion rate investigated. Following indomethacin pretreatment, clonidine produced a greater increase in urine volume at each infusion rate investigated. The indomethacin pretreatment also resulted in a potentiation of the natriuretic effect of clonidine at all infusion rates. Interestingly, this was associated with an increase in osmolar clearance but not free water clearance. These effects of indomethacin were reversed by infusion of prostaglandin E2. An infusion of prostaglandin E2 attenuated the indomethacin-induced increase in both urine flow rate and sodium excretion, indicating that the effects of indomethacin were mediated by prostaglandin inhibition. These results suggest that endogenous prostaglandin production attenuates the renal effects of clonidine, and as well, that in the presence of alpha 2-adrenoceptor stimulation, prostaglandin E2 mediates an antidiuretic and antinatriuretic effect.

Animals↗
PubMed1991

Differing renal effects of activated and nonactivated isoelectric peaks of human prorenin in rats.

Isoelectric species of renin are physically heterogeneous. Recent evidence suggests that they may differ functionally, with some species producing natriuresis and diuresis, whereas others have no effect. A physiological function of secreted prorenin has not been documented in any species. The present study was designed to confirm and describe for the first time the renal effects of certain isoelectric species of prorenin. Anesthetized Sprague-Dawley rats were injected (0.1 ml) with trypsin-activated or nonactivated prorenin obtained from human ovarian follicular fluid. The dose chosen was calculated as sufficient to produce 2,300 ng angiotensin I.h-1.100 g rat body wt-1 in the presence of excess sheep substrate. Blood pressure, creatinine clearance, urine flow rate, and urine sodium, potassium, and osmolar excretion were measured. Activated prorenin from isoelectric peaks at isoelectric points (pI) 5.1, 5.2, 5.4, and 5.6 produced marked increases in urine volume (sixfold) and sodium excretion (7- to 10-fold) compared with the group receiving the vehicle (1% albumin in 0.9% saline). Activated prorenin from peaks at pI 4.9 and 5.8 produced no significant increase over the vehicle-only experiments. Captopril pretreatment (1 mg/kg iv) completely blocked the effects of peaks at pI 5.4 and 5.6. Interestingly, injection of nonactivated prorenin from peaks at pI 5.4 and 5.6 produced effects similar to the injection of activated prorenin from these peaks. Similarly, this effect was blocked by pretreatment with captopril. In summary, only certain isoelectric peaks of human prorenin whether activated, to active renin, or nonactivated produced a marked natriuresis and diuresis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Characterization of alpha 2-adrenoceptors in the rat: proximal tubule, renal membrane and whole kidney studies.

In the present study, alpha 2-adrenoceptors have been characterized in rat renal proximal tubules which were isolated by a Percoll gradient technique. Competitive binding curves with [3H]rauwolscine (0.5 nM) and alpha 2-adrenoceptor agonists and antagonists were consistent with an alpha 2B-adrenoceptor subtype. However, the rank order of potency (Ki) for clonidine and UK 14,304 was reversed from that reported for other tissues (clonidine, 48 nM greater than UK 14,304, 330 nM). This rank order was confirmed in a crude renal membrane preparation consisting of whole kidney as well as separated medullary and cortical segments. An intrarenal infusion of clonidine at 11 nmol/kg per min resulted in a greater diuresis and natriuresis than an equimolar dose of UK 14,304 suggesting that clonidine also had a greater affinity in the collecting tubules. Further displacement studies in proximal tubules with [3H]rauwolscine and calcium channel blockers demonstrated that verapamil was the most potent (Ki, 2.3 microM), followed by diltiazem (48% displacement at 100 microM) and then nifedipine (no displacement at 100 microM). These studies indicated that alpha 2-adrenoceptor in the rat proximal tubule may be of the alpha 2B-adrenoceptor subtype. Further studies will be required to determine whether the reverse rank order of potency of clonidine and UK 14,304 is consistent with an alpha 2-adrenoceptor subtype which is different from that found in other tissue.

Animals↗
PubMed1990

Atrial-specific granule number and plasma atrial natriuretic peptide in rats: effects of beta-adrenoceptor blockade and sodium intake.

An interrelationship between atrial natriuretic peptide (ANP) and the renin-angiotensin system has been established. Both of these hormonal systems are modulated by sodium balance. The role of the beta-adrenoceptor in the regulation of release of ANP is not clear. We therefore undertook a study to examine changes in atrial-specific granule number and plasma ANP level following beta-adrenoceptor blockade in rats on low and high sodium intakes. A low-sodium diet, as compared with a high-sodium diet, elevated right and left atrial-specific granule number (right atria 54.6 +/- 8.7 vs. 42.3 +/- 5.7; left atria 47.7 +/- 7.7 vs. 30.6 +/- 3.4 granules/unit area) and plasma renin activity (28 +/- 3.7 vs. 5.4 +/- 0.8 ng AI/ml/hr). Plasma ANP levels were lower in the low-sodium animals (98 +/- 34 vs. 345 +/- 38 pg/ml). When treated with the nonspecific beta-adrenoceptor blocker propranolol, the elevated plasma renin activity and atrial-specific granule number in rats on a low sodium intake were significantly less. Neither of these parameters changed in rats on a high sodium intake. Conversely, propranolol treatment resulted in lower plasma ANP levels in rats with high sodium intake. The already-suppressed plasma ANP level in rats on a low-sodium diet was unaltered with beta-adrenoceptor blockade. The results suggest that dietary sodium intake is an important determinant of the response of atrial-specific granule number and plasma ANP levels following beta-adrenoceptor blockade with propranolol.

Adrenergic beta-Antagonists↗
PubMed1990

Drag-reducing polymers: a novel class of diuretic and natriuretic compounds.

Previous studies have demonstrated that Separan AP-30, a drag-reducing polymer, significantly decreased the formation of atherosclerotic plaques in rabbits fed a high-cholesterol diet. Furthermore, Separan AP-273, a polymer similar to but longer than Separan AP-30, markedly increased cardiac output in open-chest rats. Preliminary studies in our laboratory have described diuresis and natriuresis following the intravenous infusion of Separan AP-273. These studies did not determine whether this natriuresis was common to drag-reducing polymers or unique to Separan. In the present study the renal effects of two chemically dissimilar drag-reducing polymers of molecular lengths approaching approximately 100 microns were compared. Sprague-Dawley rats (250-300 g) were anesthetized (Nembutal) and a tracheostomy was performed. A baseline level of sodium and water excretion was established by the infusion of saline (0.097 ml/min, IV). Separan (0.004%), an anionic polyacrylamide; Polyox (0.4%), a poly(ethylene oxide); or mannitol (20%), an osmotic diuretic, was infused into the jugular vein at 0.0034 ml/min. Separan and Polyox both increased the excretion of sodium and water (p less than 0.05). At the doses tested, potassium excretion was unaltered in both groups. Separan, but not Polyox, produced a modest increase in blood pressure. Creatinine clearance was unaltered. At this infusion rate, only hypertonic concentrations of mannitol (20%) induced a similar effect. These results indicate that drag-reducing polymers may represent a novel class of potassium-sparing diuretic and natriuretic compounds. The ability of this class of polymers to decrease the formation of atherosclerotic plaques, increase blood flow, and produce a potassium-sparing natriuresis may be of practical clinical significance.

Acrylic Resins↗
PubMed1990

Role of vasopressin in response to intrarenal infusions of alpha-2 adrenoceptor agonists.

Previous studies have indicated that the effects of renal alpha-2 adrenoceptor stimulation are mediated through the blockade of the renal effects of vasopressin. If this premise is correct then 1) specific antagonists of the antidiuretic effect of vasopressin (V2 antagonists) should mimic alpha-2 adrenoceptor stimulation and 2) in the presence of V2 antagonists, the diuretic and natriuretic effect of clonidine should be attenuated. The renal effects of [d(CH2)5,D-Ile2,Ile4]AVP, a specific V2 antagonist, were studied. On the day of the experiment, uninephrectomized rats were anesthetized, and the carotid artery and jugular vein were cannulated for recording blood pressure and saline infusion, respectively. The left kidney was exposed and the ureter cannulated. A 31-gauge needle was advanced into the renal artery to permit direct i.r. infusion of study drugs. Bolus doses of the V2 antagonist (0, 1, 3, 10, or 30 nmol/kg i.v.) produced a dose-related increase in urine volume and free water clearance at all doses tested. Sodium excretion increased only at the higher doses (10 and 30 nmol/kg). This dose-related dissociation in water and then sodium excretion is similar to that observed after i.r. clonidine infusions. In the presence of the V2 antagonist, clonidine (3 micrograms/kg/min) had no effect on urine volume or free water clearance but significantly decreased the excretion of sodium from control. These results demonstrate that V2 antagonists mimic the effects of i.r. clonidine. As well, in the absence of vasopressin (V2 antagonism), the effects of clonidine are attenuated. Moreover, they are also consistent with not only an antidiuretic role for endogenous vasopressin but also an antinatriuretic one.

Adrenergic alpha-Agonists↗
PubMed1990

Stereoselective inhibition of amantadine accumulation by quinine and quinidine in rat renal proximal tubules and cortical slices.

The renal organic cation transport system was examined. The accumulation of a nonchiral cation, amantadine, by rat renal proximal tubules and cortical slices was investigated, together with the effects of two diastereoisomers, quinine and quinidine. The proximal tubules actively concentrated amantadine with a tissue/medium ratio of 96.3 +/- 1.7 (mean +/- S.E.M., n = 18). Apparent Km was 85 +/- 2 microM and Vmax was 8.0 +/- 0.2 nmol/mg of tubular protein per min. Amantadine accumulation was inhibited competitively by quinine and quinidine with Ki values of 32 +/- 3 and 84 +/- 11 microM, respectively (n = 4). Amantadine was also concentrated by renal cortical slices with tissue/medium ratio of 3.3 +/- 0.3 (n = 4). Apparent Km and Vmax were 94.0 +/- 5.2 microM and 1.27 +/- 0.08 nmol/mg of tubular protein per min, respectively (n = 10). Quinine and quinidine again inhibited amantadine accumulation competitively by the slices, with Ki values of 368 +/- 28 and 780 +/- 84 microM, respectively (n = 4). A similar affinity (Km) for amantadine was observed in both preparations. However, the lower Vmax value in the slice system may be due to additional amantadine transport sites with lower capacity, lesser luminal accumulation and/or limited substrate(s) penetration in the cortical slices. In either preparation, quinine and quinidine functioned as competitive inhibitors and stereoselectivity was observed for the (-)-isomer, quinine, over the (+)-isomer, quinidine. Additional transport sites, reduced luminal substrate accumulation and/or diffusional restraints in the slices are also feasible mechanisms in explaining the differences in Ki values between the two preparations, and their relative contributions await further investigation.

Amantadine↗
PubMed1989

Enhanced natriuretic potency of intravenous clonidine: extrarenal site of action?

We have previously demonstrated that low intrarenal infusion rates of clonidine selectively increased water excretion, whereas higher infusion rates were required to increase solute excretion. This is in contrast to previous experiments where intravenous administration of clonidine resulted in a concomitant increase in water and sodium excretion. We therefore determined the dose response curve for an intravenous infusion of clonidine on water and solute excretion and compared this to the effects of an intrarenal infusion. Uninephrectomized rats were anesthetized and the remaining kidney isolated for the collection of urine. Clonidine (0.1, 0.3, 1 or 3 micrograms/kg per min) or vehicle (saline) was administered either intravenously or intrarenally. Both intravenous and intrarenal administration of clonidine produced a dose selective dissociation of water and solute excretion, that is, at low infusion rates only urine volume was increased. Higher infusion rates were required to increase sodium excretion. In addition, intravenous administration of clonidine was more potent in producing a natriuresis, suggesting that the renal effects may be, in part, secondary to additional peripheral and/or central effects of this agonist following this route of administration.

Animals↗