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Biomedical subjects

D D Smyth

Publications and source records attributed to D D Smyth.

At least 37 records · Page 2Linked to original sources
PubMed1995

The role of the peripheral sympathetic nervous system in the natriuresis following central administration of an I1 imidazoline agonist, moxonidine.

1. Central administration of the I1-imidazoline receptor agonist moxonidine increases sodium excretion without alteration of blood pressure. In the present study we determined whether this natriuretic action was mediated through a decrease in activity of the sympathetic nervous system, as has been reported for the antihypertensive action of this compound. Interruption of the sympathetic nervous system was achieved with prazosin (alpha 1-adrenoceptor antagonist) and renal denervation. 2. In pentobarbitone-anaesthetized Sprague-Dawley rats, intracerebroventricular (i.c.v.) injection of moxonidine alone increased urine volume and sodium excretion. Prazosin (0.15 mg kg-1, i.v.) alone decreased urine flow rate and sodium excretion as compared to the vehicle controls. In the presence of prazosin, i.c.v. injection of moxonidine failed to increase sodium excretion or urine volume as compared to animals which received the prazosin alone. 3. The administration of moxonide (i.c.v.) to sham renal-denervated animals caused an increase in urine flow rate, urine sodium excretion, osmolar clearance and free water clearance. The increase in sodium excretion and osmolar clearance were completely attenuated in renal denervated rats, however, urine flow rate was still increased and this was secondary to the increase in free water clearance which remained intact. 4. These results indicate the importance of an intact sympathetic nervous system in the renal response to i.c.v. moxonidine. Moreover, the differential antagonism of these interventions on solute and water excretion indicate that they may be mediated at two separate sites and/or receptors following i.c.v. moxonidine.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1995

Inhibition of the natriuretic action of the imidazoline receptor agonist moxonidine by indometacin in the rat.

Indometacin pretreatment potentiates the natriuretic action of the mixed alpha 2-adrenoceptor/imidazoline receptor agonist clonidine. In the present study we determined the effects of indometacin pretreatment on natriuretic actions of the selective I1 imidazoline receptor agonist. In anaesthetized rats, an intrarenal infusion of moxonidine (0, 0.3, 1, and 3 nmol/kg/min) increased urine flow rate and sodium excretion without altering blood pressure or creatinine clearance. Indometacin pretreatment abolished the subsequent natriuretic response to an intrarenal infusion of moxonidine (1 nmol/kg/min) without altering blood pressure or creatinine clearance. Administration of prostaglandin E2, at an infusion rate (1 microgram/kg/min) which alone failed to alter urine flow rate, sodium excretion, blood pressure, or creatinine clearance, partially, but not completely, restored the natriuretic response to moxonidine. The ability of indometacin pretreatment to potentiate natriuretic actions of an alpha 2-adrenoceptor agonist and to attenuate those of an imidazoline agonist indicates that these two receptors in the kidney are unique and may serve distinct functions in the regulation of sodium and water excretion.

Adrenergic alpha-Agonists↗
PubMed1995

Efaroxan acts peripherally to block the antisecretory and gastroprotective effects of moxonidine in rats.

I1-imidazoline receptor activation by moxonidine has potent antigastric secretory and gastroprotective effects in rats. We therefore tested whether an imidazoline receptor antagonist, efaroxan, would influence gastric secretion and block the antisecretory and antiulcer effects of moxonidine. When given intracerebroventricularly (i.c.v.), moxonidine inhibited basal acid output in conscious rats to a maximum of 38%. Moxonidine given i.p. also significantly increased gastric adherent mucus levels in rats subjected to cold-restraint stress. Efaroxan alone given i.c.v., did not influence gastric secretion nor did it affect moxonidine's ability to decrease gastric secretion. Similarly, peripherally administered efaroxan did not block the antisecretory effect of moxonidine given i.c.v. However, when both compounds were given i.p., efaroxan pretreatment at all but the lowest doses significantly blocked the antigastric secretory effect of moxonidine. Efaroxan alone (i.p.) did not influence stress-induced gastric mucosal injury or adherent mucus levels. However, pretreatment of rats with efaroxan i.p. significantly blocked the mucus-preserving effect of i.p. moxonidine. These results demonstrate that central (i.c.v.) or peripheral (i.p.) administration of the I1-imidazoline receptor agonist moxonidine is associated with gastroprotection. The ability of i.p. efaroxan to block the effects of i.p. moxonidine but not i.c.v. moxonidine indicates that imidazoline receptors located centrally and peripherally may represent two unique sites associated with gastroprotection.

Animals↗
PubMed1995

Agmatine, an endogenous imidazoline receptor agonist, increases gastric secretion and worsens experimental gastric mucosal injury in rats.

The present experiments tested the actions of a putative endogenous imidazoline receptor agonist, agmatine, on gastric secretion and on experimental gastric mucosal injury in rats. Agmatine, given i.p. (0.5-20.0 mg/kg) or i.c.v. (0.5-2.5 micrograms), augmented basal gastric acid secretion in conscious rats to a maximum of 40% when given i.p. and 44% when given i.c.v. Agmatine also potentiated total secretory volume as well as gastric acid and pepsin output in pylorus-ligated rats. When administered before exposure to stress, agmatine significantly decreased gastric glandular mucus levels and exacerbated stress-induced gastric mucosal injury. These results are in contrast to our data showing that an exogenous agonist of I1-imidazoline receptors, moxonidine, is a potent antisecretory and gastroprotective agent. A precise physiological role for agmatine in blood pressure regulation and in gastrointestinal function awaits clarification. However, it is possible that agmatine functions as an "inverse agonist" at central imidazoline receptors, resulting in hypertension, augmented gastric secretion and exacerbated gastric mucosal injury.

Agmatine↗
PubMed1995

Renal I1-imidazoline receptor-selective compounds mediate natriuresis in the rat.

In the present study, we investigated the renal actions of two compounds reported to interact with the imidazoline receptor: rilmenidine (I1-receptor selective, centrally acting antihypertensive) and agmatine (an endogenous clonidine-displacing substance). Rilmenidine (saline vehicle, 3 or 30 nmol/kg/min) or agmatine (saline vehicle, 3 or 30 nmol/kg/min) was infused directly into the renal artery of anesthetized (pentobarbitone) Sprague-Dawley rats (280-300 g) that had undergone a unilateral nephrectomy 7 to 10 days before the experiment. Rilmenidine produced an increase in urine flow rate at doses that failed to significantly alter blood pressure, creatinine clearance, or heart rate. The increase in urine flow rate was secondary to an increase in osmolar clearance, primarily composed of sodium. Free water clearance was not altered at these infusion rates. Agmatine also increased urine flow rate at doses that failed to alter blood pressure, creatinine clearance, and heart rate. The increase in urine flow rate was secondary to an increase in osmolar clearance, again primarily composed of sodium. The natriuretic action of rilmenidine and agmatine, at doses that do not lower blood pressure acutely, could be beneficial in the antihypertensive actions of these centrally acting agents.

Adrenergic alpha-Agonists↗
PubMed1994

Central and renal I1 imidazoline preferring receptors: two unique sites mediating natriuresis in the rat.

Based on previous studies we postulated that, whereas the natriuresis observed following intracerebroventricular (i.c.v.) moxonidine was mediated by a decrease in renal sympathetic nerve activity, the natriuresis observed following intrarenal (i.r.) infusion of moxonidine was mediated by a direct stimulation of renal I1-imidazoline preferring receptors. Sprague-Dawley rats were unilaterally nephrectomized and i.c.v. cannulated 7 to 10 days and 3 days prior to the day of the experiment, respectively. On the day of the experiment, rats were anesthetized (pentobarbital) and the renal function was isolated. Administration of i.c.v. as well as i.r. moxonidine produced an increase in sodium excretion and urine flow fate. Pretreatment with intravenous prazosin (0.15 mg/kg) completely attenuated the response to i.c.v. moxonidine (1 nmol/5 microliters) but only slightly altered the response to i.r. moxonidine (3 nmol/kg/min). Conversely, intravenous pretreatment with the imidazoline preferring receptor antagonist idazoxan (0.3 mg/kg) completely blocked the response to i.r. moxonidine (3 nmol/kg/min) without altering the response to i.c.v. moxonidine (0.3 nmol/kg). These results would be consistent with the natriuresis observed following i.c.v. moxonidine as being mediated by imidazoline preferring receptors located centrally, whereas that following i.r. moxonidine was mediated directly by renal imidazoline-preferring receptors, with a small component of this response conceivably due to activation of central imidazoline preferring receptors. In summary, the antihypertensive effect of imidazoline preferring receptor agonists may be associated with a natriuresis that is due to stimulation of these receptors, found both peripherally (renal) and centrally.

Adrenergic alpha-Antagonists↗
PubMed1994

Attenuated renal response to moxonidine and rilmenidine in one kidney-one clip hypertensive rats.

1. I1 non-adrenoceptor, imidazoline receptor agonists, such as moxonidine, increase urine flow rate and sodium excretion following infusion into the renal artery. The functions of these agonists in genetic and acquired models of hypertension have not been determined. 2. We therefore studied the renal effects of two known non-adrenoceptor, imidazoline receptor agonists, rilmenidine and moxonidine, in 1K-1C hypertensive and 1K-sham normotensive rats. Rilmenidine (0, 3, 10, 30 nmol kg-1 min-1) or moxonidine (0, 1, 3, 10 nmol kg-1 min-1) was infused directly into the renal artery (30 gauge needle) of 1K-sham normotensive and 1K-1C hypertensive rats. 3. In 1K-sham normotensive rats, rilmenidine and moxonidine produced dose related increases in urine flow rate, sodium excretion and osmolar clearance. Both rilmenidine and moxonidine failed to increase urine flow rate, sodium excretion and osmolar clearance in 1K-1C hypertensive rats to the same extent as in 1K-sham animals. At comparable doses, rilmenidine had no effect, while moxonidine (3 and 10 nmol kg-1 min-1) did result in a small increase in urine volume and osmolar clearance which was less than that observed in the 1K sham control animals. 4. These studies indicate that the renal effects of non-adrenoceptor, imidazoline receptor stimulation are diminished in 1K-1C hypertensive rats compared with 1K-sham normotensive rats. Whether this decrease in activity of the natriuretic non-adrenoceptor, imidazoline receptors contributes to the increase in blood pressure in the 1K-1C acquired model of hypertension remains to be determined.

Animals↗
PubMed1994

Sodium excretion following central administration of an I1 imidazoline receptor agonist, moxonidine.

1. Previously we have shown that an intrarenal infusion of moxonidine, an I1-imidazoline receptor agonist, resulted in a natriuresis which was inhibited by intravenous idazoxan, a selective imidazoline receptor antagonist. Therefore we examined the effects of renal function of intracerebroventricular (i.c.v.) administration of moxonidine with or without i.c.v. idazoxan. 2. Seven days after unilateral nephrectomy, Sprague-Dawley rats had i.c.v. cannulae implanted. Three days later the rats were anaesthetized (pentobarbitone), followed by cannulation of the jugular vein (fluid and drug administration), carotid artery (blood pressure) and the ureter (urine collection). 3. After a 45 min stabilization period, the effect of moxonidine was investigated by the i.c.v. administration of either isotonic saline or moxonidine (0.1, 0.3 or 1 nmol in isotonic saline) administered in 5 microliters over 1 min. All doses of moxonidine resulted in an increase in urine flow with a concomitant increase in sodium excretion without affecting blood pressure. The highest dose of moxonidine (1 nmol) also increased free water clearance. 4. In a second series of experiments, the effects of idazoxan on the natriuretic response to i.c.v. moxonidine were determined. Moxonidine (0.3 nmol) again increased sodium and water excretion as compared to the i.c.v. saline control animals. Pretreatment with i.c.v. idazoxan (0.3 nmol), at a dose which alone failed to alter sodium and water excretion, completely attenuated the renal response to moxonidine. These results are consistent with central I1-imidazoline receptors mediating a moxonidine-induced increase in sodium and water excretion at doses that do not alter blood pressure.

Animals↗
PubMed1994

Chlorotyrosine exerts renal effects and antagonizes renal and gastric responses to atrial natriuretic peptide.

3-Chloro-L-tyrosine (3CT) is an inhibitor of tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis. In vivo inhibition of tyrosine hydroxylase results in lower catecholamine levels. 3CT (0.5 mg/kg), administered as a bolus i.v. to anesthetized uninephrectomized rats, elicited increases of 72% and 44% in urinary sodium concentration and volume, respectively, whereas a dose of 1 mg/kg caused increases of 27% and 29%. 3CT, 1 mg/kg, resulted in a 2-fold increase in plasma aldosterone (ALD); 0.5 mg/kg was without significant effect. At a dose of 1 mg/kg 3CT significantly antagonized the renal effects of atrial natriuretic peptide (ANP) (1.5 micrograms kg-1 min-1 by intrarenal infusion), expressed as an enhanced excretion of urine volume (102 +/- 14 vs. 70 +/- 11 microliters/min) and sodium (16.1 +/- 1.8 vs. 11.5 +/- 1.7 microEq/min) and increased osmolar clearance (171 +/- 12 vs. 144 +/- 13 microliters/min). A dose of 0.5 mg/kg of 3CT did not produce these same responses to ANP. The increased urine flow caused by 3CT may reflect reduced norepinephrine synthesis. The inverse dose-effect relationship of 3CT on urine flow rate may result from concomitant depletion of dopamine (DA) and elevated circulating ALD. The antagonism of 3CT on responses to ANP is not at the receptor level, because 3CT did not compete for [125I] ANP binding or inhibit ANP-stimulated guanylate cyclase in kidney cell membranes. It was proposed that the reduced basal sympathetic and renal DA tone, together with the elevated ALD level, account for this antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Selective alpha-1 adrenoceptor blockade and renal sodium handling in humans.

In animal studies, acute interruption of the activity of renal alpha-1 adrenoceptors by renal denervation results in an increase in sodium and water excretion. Chronic selective blockade of alpha-1 adrenoceptors by prazosin in clinical practice has been associated with sodium retention, however. Previous studies in the authors' laboratory using chronic alpha-1 blockade in the rat have demonstrated a decreased ability to excrete a saline load. Therefore, the authors determined the effect of chronic selective alpha-1 adrenoceptor blockade with prazosin in eight healthy volunteers. Volunteers underwent a water load to establish a water diuresis, followed by a modest saline load using intravenous saline (0.9% NaCl). This experimental protocol was repeated after four weeks of prazosin therapy (5 mg twice daily). Prazosin failed to alter body weight (73.6 +/- 4.2 versus 74.5 +/- 4.1 kg, expressed as mean +/- standard error), mean blood pressure (86.7 +/- 2.7 versus 84.7 +/- 2.3 mm Hg), creatinine clearance (127.0 +/- 8.5 versus 133.4 +/- 12.0 mL/min), renal blood flow as measured by para-aminohippurate clearance (1202 +/- 88 versus 1175 +/- 69 mL/min) and the 24-hour sodium excretion (115 +/- 11 versus 128 +/- 19 mmol). In the presence of the experimentally induced saline load, chronic prazosin treatment was associated with a decreased free water clearance (e.g., hour 3, 7.8 +/- .7 versus 6.3 +/- 2.0 mL/min; P < or = .05) and fractional excretion of sodium (e.g., hour 3, 1.48 +/- .10 versus 1.15 +/- .13; P < or = .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Gender and age as factors in the inhibition of renal clearance of amantadine by quinine and quinidine.

We studied the short-term effect of oral doses of quinine and quinidine on the renal clearance of amantadine in healthy young (age range, 27 to 39 years) and older (age range, 60 to 72 years) adults of both genders in a three-limbed randomized crossover study. Renal clearance of amantadine (13.2 +/- 5.8 L/hr) was significantly inhibited by quinine (9.7 +/- 4.8 L/hr) and quinidine (8.9 +/- 4.0 L/hr) only in male subjects and was not associated with age. The chiral selectivity for the renal clearance of quinidine over quinine was confirmed and extended with the suggestion of both age- and gender-associated changes on the renal clearance ratio for these two diastereomeric drugs. These data support the continued use of amantadine for studies on the renal elimination of organic cationic drugs.

Adult↗
PubMed1993

Decreased renal activity of vasopressin in spontaneously hypertensive rats.

OBJECTIVE: Recent studies have found vasopressin to be antinatriuretic as well as antidiuretic. We therefore wished to determine the endogenous renal activity of vasopressin in spontaneously hypertensive rats (SHR) and one-kidney, one clip hypertensive (1K1C) rats. METHODS: The renal effects of a vasopressin (V2) antagonist, [d(CH2)5,D-Ile2,Ile4]-arginine vasopressin (0, 10 or 30 nmol/kg), were compared in SHR and 1K1C rats and their respective controls, the Wistar-Kyoto (WKY) rat and the Sprague-Dawley rat. RESULTS: The V2 antagonist produced a dose-related increase in urine flow rate and free water clearance in all groups studied (WKY rats, SHR, Sprague-Dawley rats and 1K1C rats). Sodium excretion and osmolar clearance were increased only in the WKY rats and 1K1C rats. The response in the SHR was significantly less than that observed in the WKY rats. At both doses of V2 antagonist investigated, the urine flow rate was two- to threefold greater in the WKY rats than in SHR, in spite of similar control levels. Conversely, the response observed in the acquired model of hypertension (1K1C rats) at the one dose of V2 antagonist investigated (30 nmol/kg) was similar to that found in the control Sprague-Dawley rats, suggesting that the decreased response observed in SHR was not secondary to the increased blood pressure. CONCLUSIONS: These data demonstrate that the endogenous level of renal activity of vasopressin in SHR is suppressed compared with control WKY rats.

Animals↗
PubMed1993

Renal imidazoline preferring sites and solute excretion in the rat.

1. Moxonidine has been found to have an approximately 600 fold greater affinity for I1 imidazoline preferring sites as compared to alpha 2-adrenoceptors in the rat kidney. The effects of an intrarenal infusion of moxonidine in an anaesthetized rat preparation were investigated and contrasted with the effects previously reported for alpha 2-adrenoceptor stimulation. 2. An intrarenal infusion of moxonidine (1, 3 and 10 nmol kg-1 min-1) produced an increase in urine flow rate and sodium excretion. Moxonidine increased urine volume through an increase in osmolar clearance rather than an increase in free water clearance as previously reported for alpha 2-adrenoceptor stimulation. 3. The effects of moxonidine also appeared to be unique from the effects of alpha 2-adrenoceptor stimulation. An imidazoline preferring site specific blocking dose of idazoxan (0.3 mg kg-1), but not an alpha 2-adrenoceptor specific blocking dose of rauwolscine (0.3 mg kg-1) attenuated the renal effects of moxonidine (3 nmol kg-1 min-1). Moreover, unlike alpha 2-adrenoceptor agonists, the effects of moxonidine were not altered by prior treatment with a V2 vasopressin receptor antagonist. 4. These results indicate differences between stimulation of alpha 2-adrenoceptors and I1 imidazoline preferring sites in the rat kidney and suggest a direct physiological function of renal imidazoline preferring sites.

Adrenergic alpha-Agonists↗
PubMed1993

Suppressed renal response to 2,6-dimethyl clonidine but not clonidine in one kidney-one clip hypertensive rats.

The disparate renal actions of clonidine and 2,6-dimethyl clonidine (2,6-DMC), recently reported by the authors, may be the result of stimulation of alpha-2 adrenoceptors and imidazoline-preferring sites, respectively. Studies found that in one kidney-one clip (1K-1C) hypertension, the density of renal binding sites labeled by [3H] idazoxan (imidazoline-preferring sites) but not [3H] rauwolscine (alpha-2 adrenoceptors) was decreased compared with the 1K control rats. The renal response to 2,6-DMC in 1K-1C hypertensive rats and 1K control rats was compared. In 1K control rats, 2,6-DMC infusion directly into the renal artery (0, 1 and 3 micrograms kg-1 min-1) produced a dose-related increase in the percent fractional excretion of water and sodium and osmolar clearance. This effect was similar to that reported for the imidazoline-preferring site agonist moxonidine. Conversely, in 1K-1C hypertensive rats, these infusion rates of 2,6-DMC failed to alter renal water and solute excretion. By contrast, clonidine (3 micrograms kg-1 min-1) produced a similar increase in the percent fractional excretion of water and sodium, free water clearance and osmolar clearance in 1K-1C hypertensive rats and 1K normotensive rats. In renal membranes from 1K-1C hypertensive rats, [3H] idazoxan binding (imidazoline-preferring site antagonist) was decreased, whereas the binding of [3H] rauwolscine (alpha-2 adrenoceptor antagonist) was unaltered. As proposed in a previous study, the decreased response to 2,6-DMC but not clonidine in 1K-1C hypertensive rats indicates that these two agonists, although structurally similar, are functioning at two unique sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1993

Effects of neuropeptide Y and [Leu31,Pro34] neuropeptide Y on experimental gastric lesion formation and gastric secretion in the rat.

The present study examined the effects of neuropeptide Y (NPY) and a selective NPY1 receptor agonist, leucine31 proline34 neuropeptide Y ([leu31,pro34]NPY) on gastric lesion formation and gastric secretion in three preparations: Basal gastric acid secretion in conscious rats, restraint-induced gastric lesion formation and acid and pepsin output and gastric mucosal damage in pylorus-ligated rats. The hypothesis that benextramine, a non-selective NPY receptor antagonist, could attenuate responses to NPY or [leu31,pro34]NPY was also tested. Both NPY and [leu31,pro34]NPY (i.p. and i.c.v.) decreased basal gastric acid output, restraint-induced gastric lesion formation, and acid and pepsin secretion and gastric mucosal damage in pylorus-ligated rats. The magnitude of inhibition of secretion and of ulcer reduction was significantly greater for [leu31,pro34]NPY than for NPY at comparable doses. Benextramine blocked the protective effect of NPY and [leu31,pro34]NPY against restraint-induced gastric mucosal injury. Both central and peripheral treatment with benextramine blocked the antisecretory effects of centrally administered NPY and [leu31,pro34]NPY. These data were consistent with both a central and a peripheral action of NPY on the gut, possibly through Y1 receptors.

Adrenergic alpha-Antagonists↗
PubMed1993

Gender-associated differences in rat renal tubular amantadine transport and absence of stereoselective transport inhibition by quinine and quinidine in distal tubules.

The present studies compared male and female rat renal proximal and distal tubular uptake of amantadine, in relation to their transport kinetics and enantioselective inhibition by two diastereoisomers, 8S,9R-(-)-quinine and 8R,9S-(+)-quinidine. Under control conditions, amantadine was concentrated by both tubule fractions with a gender difference for distal tubules (tissue:medium ratio, 18.0 +/- 1.4 for males and 11.0 +/- 0.6 for females; mean +/- S.E.M., P < .05). This was reflected by a higher Km value only in female distal vs. proximal tubular tissue (153 +/- 8 vs. 108 +/- 9 microM; P < .01) but decrease in Vmax values in distal compared to proximal tubules (P < .01) showed no gender-related difference. In proximal tubules, 8S,9R-(-)-quinine and 8R,9S-(+)-quinidine competitively inhibited amantadine transport with apparent inhibitory potency of 2- to 3-fold in favor of 8S,9R-(-)-quinine (P < .01) and without gender preference. Conversely in distal tubules, competitive inhibition of amantadine transport was also elicited by either 8S,9R-(-)-quinine or 8R,9S-(+)-quinidine at a similar concentration range (10-1000 microM), with absence of chiral or gender preference. The present transport data have demonstrated an apparent absence of stereoselectivity in distal tubular uptake inhibition of amantadine, and are suggestive of disparate pathways and/or rate limiting steps involved between renal proximal and distal tubular handling of chiral organic cations for both genders, and between genders for distal tubular transport of amantadine.

Amantadine↗
PubMed1992

Stereoselective inhibition of renal organic cation transport in human kidney.

Amantadine was found to be concentrated by human cortical slices, with apparent Km and Vmax values of 187 +/- 11 microM and 1.37 +/- 0.28 nmol mg-1 min-1 respectively (mean +/- s.e. mean, n = 4). Addition of quinine (8S, 9R-(-)-isomer) or quinidine (8R, 9S-(+)-isomer) competitively inhibited this accumulation (apparent Ki values of 261 +/- 44 (n = 4) and 586 +/- 68 microM (n = 3), respectively). The stereoselectivity of this inhibition is the reverse of that seen with respect to the renal clearances of the diastereoisomers.

Adult↗