Biomedical subjects

S T Kau

Publications and source records attributed to S T Kau.

At least 37 records · Page 2Linked to original sources

PubMed1992

Renal and antihypertensive effects of a novel eukalemic diuretic, ICI 207,828.

ICI 207,828, an aminomethylphenol pyrazine derivative, produces water diuretic effects with only minimal alterations in kaliuresis in dogs and rats after oral and parenteral administration. In the dog, ICI 207,828 reached maximum activity at a dose of 10 mg/kg, p.o. This was comparable to that of hydrochlorothiazide (HCTZ) at a dose of 5 mg/kg, p.o. or higher. In the rat, a dose of 30 mg/kg, p.o. of ICI 207,828 was comparable to the maximum of water diuretic and saluretic response obtained with HCTZ at a dose of 10 mg/kg, p.o. Based upon studies using in vitro amphibian models of the mammalian nephron, ICI 207,828 appeared to act on both the thick ascending limb of the loop of Henle and the late distal nephron. In the toad bladder preparation, ICI 207,828 inhibited Na+ transport when placed on either the mucosal (amiloride-like) or serosal (thiazide-like or loop diuretic-like) sides. This compound also inhibited Cl- transport in the toad cornea preparation (loop diuretic-like). ICI 207,828 did not change plasma K+ significantly in dogs dosed for 14 days at doses having diuretic effects (5 and 10 mg/kg, p.o., daily). In contrast, HCTZ consistently decreased plasma K+, whereas amiloride increased it significantly. ICI 207,828 demonstrated antihypertensive effects in spontaneously hypertensive rats. At 30 mg/kg, p.o., b.i.d., ICI 207,828 and HCTZ produced approximately equal antihypertensive activities during a 3 1/2-day treatment period. The pharmacological profile of ICI 207,828 indicates that this compound is a potent eukalemic diuretic and antihypertensive agent in animals.

Amiloride↗

PubMed1992

Evaluation of the renal site of action of a novel, eukalemic diuretic, ICI 207,828.

ICI 207,828 is a novel eukalemic diuretic in animals that is comparable in effect to hydrochlorothiazide. We used micropuncture and microperfusion techniques to determine the site(s) of action of this compound in the rat nephron. Either furosemide (FUR) or ICI 207,828 were perfused through the loop of Henle in situ. Both compounds caused significant reduction in water and electrolyte reabsorption by the loop. The effect of ICI 207,828 was significantly less than that of FUR. Both amiloride and ICI 207,828 were perfused, in situ, through the superficial distal tubule. ICI 207,828 had an effect similar to amiloride. Sodium and water reabsorption and potassium secretion were inhibited. In free-flow micropuncture studies, ICI 207,828, infused continuously i.v., had little effect on electrolyte and water reabsorption by the superficial proximal tubule. This compound significantly inhibited water and electrolyte reabsorption by the loop of Henle. Distal tubule secretion of potassium was inhibited. In addition, fractional potassium reabsorption beyond the superficial, late distal tubule was inhibited by ICI 207,828. From these results, we conclude that ICI 207,828 significantly inhibits electrolyte and water transport by the loop of Henle and distal tubule, and at sites beyond the superficial distal tubule such as either the collecting duct system or juxtamedullary nephrons. The reduction in distal potassium secretion, in concert with reduced loop of Henle and postdistal reabsorption, results in no net potassium loss in the urine, thus rendering this compound eukalemic.

Amiloride↗

PubMed1991

Experimental hyperreflexia: effect of intravesical administration of various agents.

In anesthetized rabbits, we can induce a significant degree of spontaneous activity in the urinary bladder by placing a ligature around the proximal portion of the external urethra. Previous studies characterized the activity as primarily reflex in nature, since intravesical hexamethonium selectively inhibited the hyperreflexia. In this current study we determined the effect of intravesical administration of a variety of compounds to inhibit the induced hyperreflexia. The following agents were tested at concentrations of 1, 10, 100 and 500 mumol/l (intravesically): verapamil, cromakalim, nifedipine, diltiazem, and atropine; lidocaine was tested in 0.05, 0.5 and 5% solutions. The results are summarized as follows: (1) Lidocaine was the most effective agent tested, virtually eliminating both the amplitude and frequency of the spontaneous activity at the lowest concentration (0.5%). (2) Verapamil and nifedipine were somewhat more potent than cromakalim and diltiazem. Atropine sulfate was the least potent, inhibiting both the amplitude and frequency of the hyperreflexia by less than 50% at 500 mumol/l. (3) In all cases, the amplitude of the spontaneous activity was inhibited to a significantly greater degree than the frequency of the spontaneous activity. (4) In general, there was no effect of any of the agents on mean arterial pressure at 1 or 10 mumol/l. At 100 and 500 mumol/l, all agents except for lidocaine and cromakalim decreased arterial pressure. These two agents produced no consistent fall in blood pressure at any concentration. In conclusion, the acute hyperreflexic (rabbit) preparation provides a highly reproducible and consistent model for the study of the effect of drugs on hyperreflexia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Micropuncture evaluation of the site of action of 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (MK447) in the rat kidney.

Free-flow micropuncture and in situ microperfusion techniques were used to define the site of action and relative effect of MK447 [2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride] vs. furosemide in the rat kidney. MK447 was administered i.v. at 5 mg/kg/hr. Infusion of this drug had little effect on proximal tubule reabsorption of water, Na+ and K+. In contrast, reabsorption of these constituents by the loop of Henle was significantly reduced. There was a tendency for water and Na+ reabsorption to rise and for K+ secretion to fall along the distal tubule. These latter effects can be explained by the contributions of an increased distal flow rate and increased tubule fluid K+ concentration. Net addition of K+ beyond the distal tubule was observed. This may be due to effect of the drug on the collecting duct system or juxtamedullary nephrons. The effects of MK447 and furosemide on loop of Henle reabsorption were compared in microperfusion experiments. Furosemide reduced Na+, K+ and water reabsorption by the loop, whereas MK447 had no effect. A 6-bromophenol sulfate ester of MK447 significantly reduced loop reabsorption. From these observations, we conclude that MK447 affects water and electrolyte reabsorption by the loop of Henle and beyond the superficial late distal tubule. The fact that a potential metabolite, but not MK447, significantly reduced reabsorption by the in situ, perfused loop of Henle supports the hypothesis that the p.o. and i.v. effects of MK447 are dependent on metabolism.

Absorption↗

PubMed1990

Effect of route of administration on the relative efficacy and potency of 2-aminoethyl-4-(1,1-dimethylethyl)-6-iodophenol HCl (MK447) and furosemide.

2-Aminoethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (MK447) is a chemically novel diuretic that has oral efficacy and potency greater than furosemide (FUR). In this study, the relative efficacy and potency of MK447 and FUR were assessed following oral, i.v. bolus and i.v. infusion administration in rats and dogs. MK447 was more potent than furosemide but the two were equally efficacious when administered orally to rats and dogs. The relative potency remained unchanged when administered as an i.v. bolus to rats (1 mg/kg). However, when infused continuously there was no difference in potency or efficacy between the two compounds. These observations lead to the conclusion that pharmacokinetic differences between the two compounds play a major role in determining their relative oral potency. Comparative studies of the effects of compounds given by different routes of administration are useful in providing insight into the role of pharmacokinetics in overall response to different compounds.

Administration, Oral↗

PubMed1990

Use of renal artery infusion in dogs for evaluation of diuretics.

In this paper we report on a series of experiments evaluating a model of renal artery infusion (RAI) as a screening technique for comparison of new diuretics, and test some assumptions underlying its use. The femoral artery and vein of Beagle dogs were catheterized for the infusion of solutions, measurement of arterial blood pressure and the sampling of arterial blood. The left kidney was isolated through a flank incision, and a 27 ga. needle, connected to PE10 tubing, was inserted into the renal artery for administration of test diuretics. Both ureters were catheterized for collection of urine. Effects on renal function were assessed during control, drug infusion, and recovery periods. At low doses, the loop diuretics, furosemide (FUR) and MK447, increased urinary excretion within the first 15 min of infusion. The effect of muzolimine, another loop diuretic, was delayed until about 45 min after initiation of infusion. Renal function returned to baseline after cessation of drug infusion. At high doses, excretion was increased by all the loop diuretics within the first 15 min of infusion. The response to muzolimine and MK447 was prolonged well into the recovery period, while that to furosemide returned promptly to baseline. Two distal diuretics, hydrochlorothiazide and amiloride, caused a significant increase in urinary excretion at both low and high doses. The magnitude of the response was significantly less than for the loop diuretics. Low doses of the loop diuretics had very little effect on the contralateral kidney; however, at high doses the excretion rate of the contralateral kidney was significantly increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

On the topically effective ocular hypotensive properties of ICI 147,798, a natriuretic beta-adrenoceptor antagonist, in rabbits.

The ocular antihypertensive effects of ICI 147,798, a natriuretic, non-selective beta-blocker lacking local anaesthetic and intrinsic sympathomimetic activities, were evaluated in unanaesthetized rabbits with water-load-induced ocular hypertension. The racemate was approximately 20 times more potent as a beta-blocker than its d-isomer. The magnitude of reductions in intraocular pressure (IOP) elicited by both compounds was equal following topical administration of an equal dose-concentration (100-300 microliters, 0.5% or 0.75%) to one or both eyes, and the activities were similar to those obtained with timolol. A five-hour duration of the IOP lowering effect was achieved by ICI 147,798 and timolol in this rabbit model. ICI d-147,798 exhibited a shorter duration, which could be prolonged by increasing the concentration of the ophthalmic solution. Timolol caused a pronounced reduction of isoproterenol-induced tachycardia after a single dose (200 microliters, 0.5%) or by repeating the dose twice a day for four consecutive days. Following the same dose regimen, neither ICI 147,798 nor its d-isomer significantly altered the heart rate response produced by isoproterenol. These findings indicate that ICI 147,798, while effective as a potential antiglaucoma agent, does not display the characteristics of beta-blockers on heart rate effects noted with timolol. The results also cast some doubt on the contention that the IOP lowering effect of certain beta-blockers is predominantly determined by specific blockade of beta-adrenoceptors.

Administration, Topical↗

PubMed1989

ICI 147,798: a slowly dissociable beta adrenoceptor antagonist that causes insurmountable beta-1 and surmountable beta-2 adrenoceptor antagonism in isolated tissues.

ICI 147,798 has been shown to exhibit both diuretic and beta-antagonist properties in vivo. The present study investigated the nature and selectivity of the beta-antagonism in a variety of isolated tissues. ICI 147,798 produced a concentration-dependent suppression of the maximum chronotropic response of norepinephrine in guinea pig right atria (beta-1 adrenoceptor). ICI 147,798 caused a concentration-dependent shift to the right of the salbutamol concentration-response curve in the guinea pig trachea (beta-2 adrenoceptor), and Schild analysis suggested competitive inhibition. Propranolol produced parallel shifts to the right of the norepinephrine concentration-response curve in guinea pig right atria, except at relatively high concentrations. The inhibitory effects of propranolol in guinea pig right atria were reversed by greater than 95%, whereas the effects of ICI 147,798 were only slightly reversed after a 6-hr washout period. Preincubation of propranolol with ICI 147,798 in guinea pig right atria prevented completely the suppression of the norepinephrine maximum chronotropic response. Postincubation of propranolol with ICI 147,798 partially reversed the suppression of the maximum chronotropic response. ICI 147,798 had no effect on the maximum chronotropic responses of either histamine (H2-receptor) or forskolin (adenylate cyclase activation) in guinea pig right atria and had no effect on agonist responses in a variety of other receptor systems. The insurmountable beta-1 adrenoceptor antagonism was evaluated based on the assumptions of irreversible competitive antagonism, mixed competitive and noncompetitive antagonism and slowly dissociating competitive antagonism ("hemi-equilibrium" conditions). Concentration-dependent changes in norepinephrine KA values suggested the first three possibilities were unlikely.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMed1989

Insurmountable beta receptor blockade by ICI 147,798 in rabbits.

In rabbits, the characteristics of cardiac beta-1 receptor blockade produced by ICI 147,798, a novel beta receptor blocking agent with diuretic properties, were evaluated and compared with those of propranolol. In conscious rabbits, i.v. injections of 0.31, 1.0 and 3.1 mg/kg of ICI 147,798 and 1.0 mg/kg of propranolol caused significant bradycardia. ICI 147,798 produced a dose-dependent shift to the right of the dose-response (chronotropic) curve of isoproterenol with suppression of the maximal tachycardia, an effect characteristic of insurmountable beta receptor blockade. Propranolol also produced a shift to the right of the dose-response curve of isoproterenol without affecting the maximal tachycardia. ICI 147,798-induced antagonism was specific for beta adrenoceptors as it failed to modify the effects of acetylcholine, angiotensin II, phenylephrine, adenosine, histamine and prostaglandin E2 on mean arterial pressure and heart rate. In rabbits with prior autonomic blockade, ICI 147,798, like propranolol, failed to inhibit the positive chronotropic effects of theophylline which are mediated by postreceptor mechanisms. In reserpinized rabbits, ICI 147,798 was found to have no intrinsic sympathomimetic activity. Unlike the effects of propranolol, which were attenuated by first-pass through the hepatic vascular bed, the effects of ICI 147,798 were unaffected suggesting an absence of first-pass metabolism. The effects of propranolol (1.0 mg/kg i.v.) were not detectable at 24 hr after injection, whereas significant beta receptor blocking activity was still present at 24 hr after ICI 147,798 (1.0 mg/kg i.v.). The results suggest that ICI 147,798 is a specific, long-acting, insurmountable beta-1 receptor blocking agent without intrinsic sympathomimetic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMed1988

Bumetanide stimulation of sodium permeability of the apical membrane of toad urinary bladder.

The effects of bumetanide on Na transport in the isolated toad urinary bladder were investigated. When applied to the serosal side, this loop diuretic inhibited Na transport. By contrast, when applied to the mucosal side, it stimulated Na transport by increasing the apical Na permeability. These dual effects of bumetanide were also observed with the loop diuretic furosemide. The mucosal action of bumetanide was attributable to release of Na self-inhibition, as evidenced by its dependency on mucosal Na concentration and its interaction with another apical Na permeability stimulator, p-chloromercuriphenyl sulfonate. The stimulatory action of bumetanide was not reduced by the natriferic effect of antidiuretic hormone, but it was totally blockable by the epithelial Na channel blocker amiloride. Bumetanide, however, caused a leftward shift of the concentration-response curve of amiloride on Na current as predicted from its effect on Na self-inhibition. This stimulatory activity of bumetanide and furosemide as demonstrated in the in vitro isolated amphibian epithelia suggests that these loop diuretics also have the potential to stimulate Na transport at the distal portion of the mammalian nephron. Thus, this property of these diuretics might be one of the factors contributing to the observation of increased Na reabsorption along the distal tubule after in vivo administration of furosemide and piretanide as reported in some micropuncture studies.

4-Chloromercuribenzenesulfonate↗

PubMed1987

Amphibian cornea as a model for studying intrinsic activities of loop diuretics.

The inhibitory activity of various standard diuretics and compounds on Cl- transport in the toad cornea has been investigated. The relative potency of these diuretics shows a pattern and follows a sequence similar to their inhibitory potency on salt reabsorption in the isolated mammalian cortical thick ascending limb of Henle's loop. The suitability and convenience of using toad cornea as an in vitro model for that segment of the mammalian nephron is well demonstrated.

Animals↗

PubMed1987

ICI 147,798: a novel diuretic agent with beta adrenoceptor blocking activity.

ICI 147,798 is a novel compound which has both diuretic and beta adrenoceptor blocking properties in a single molecule. The natriuretic activity at 30 mg/kg p.o. was about 65% of the hydrochlorothiazide value at 10 mg/kg p.o. in saline-loaded rats; the corresponding kaliuretic activity was 42%. The natriuretic and the kaliuretic activity of ICI 147,798 in dogs were similar to that of hydrochlorothiazide over the doses 1 to 20 mg/kg p.o., although significantly less kaliuresis was obtained with ICI 147,798 at 1 mg/kg p.o. In the toad bladder preparation (analogous to the distal mammalian nephron), ICI 147,798 inhibited Na+ transport with mucosal and serosal IC50 values of 56 and 120 microM, respectively. ICI 147,798 inhibited isoproterenol-induced tachycardia in rats, cats, guinea pigs and dogs; these effects were associated with antagonism of isoproterenol vasodepressor responses. The pKB values of ICI 147,798 were 9.1 and 8.8 in isolated right atria and trachea of guinea pigs, respectively. ICI 147,798 did not exhibit local anesthetic activity in rabbit cornea and intrinsic sympathomimetic activity in catecholamine-depleted dogs and rats. Duration of beta blockade after a p.o. dose of 1 mg/kg in dogs followed the sequence: nadolol greater than ICI 147,798 greater than atenolol greater than timolol greater than propranolol. It is concluded that ICI 147,798 is a novel diuretic agent with nonselective beta blockade, and it appears to have the potential of a direct tubular action.

Adrenergic beta-Agonists↗

PubMed1987

Comparative cardiovascular effects of loop-acting, thiazide-type and potassium-sparing diuretics in spontaneously hypertensive rats.

Studies were carried out in conscious, chronically-cannulated, spontaneously hypertensive (SH) rats to determine the comparative cardiovascular actions of a series of diuretic compounds. The effects of three oral doses of hydrochlorothiazide, trichlormethiazide, chlorthalidone, metolazone, spironolactone, triamterene, amiloride, furosemide, ethacrynic acid, MK-447, hydrochlorothiazide + amiloride, and MK-447 + amiloride on blood pressure and heart rate were monitored continuously for four hr and again 24 hr post-dose. Thiazides, thiazide derivatives and antikaliuretic diuretics exerted little or no antihypertensive effects, while the loop-acting diuretics (except ethacrynic acid) and combinations markedly reduced blood pressure. Antihypertensive responses to furosemide, MK-447 and the diuretic combinations were associated with either stable heart rate or paradoxical bradycardia, but not compensatory tachycardia. Heart rate remained relatively unaltered by individual doses of the remaining compounds.

Animals↗

PubMed1986

Effects of detergents on sodium transport in toad urinary bladder.

The effects of ionic, nonionic and zwitterionic detergents (zwittergents) on apical sodium permeability of toad urinary bladder were investigated. Applied to the mucosal side at concentrations less than 1/100 of their respective critical micellar concentration (CMC), sodium lauryl sulfate, Triton X-100 and a series of sulfobetaine zwittergents reversibly increased amiloride-sensitive sodium current. These detergents decreased the current at concentrations higher than 1/100 of the CMC and caused large, irreversible increases of tissue electrical conductance at a concentration close to the CMC. Nonionic detergent Tween 80, however, stimulated the current at concentrations from 1/100 to 10,000 of its CMC. The maximum stimulation of current by each zwittergent occurred at 1/100 of its CMC, and the larger the CMC, the greater the stimulation attainable. Analysis of the dependence of current on mucosal sodium concentration in the presence of stimulating doses of a zwittergent and Tween 80 showed that the increase in current was not the result of increased apical maximum sodium permeability, but the consequence of removal of sodium self-inhibition. The amiloride dose-response curve in the presence of stimulating dose of zwittergent was shown to shift to the left and yield a smaller apparent inhibition constant as predicted on the basis of such a removal and an unaltered intrinsic amiloride blocking kinetic.

Amiloride↗

PubMed1986

Myocardial and vascular actions of amiloride in spontaneously hypertensive rats.

Experiments were conducted to characterize the cardiovascular actions of the potassium-sparing diuretic amiloride in spontaneously hypertensive and normotensive Wistar-Kyoto rats. Amiloride produced dose-dependent and sustained reductions in blood pressure in spontaneously hypertensive, but not Wistar-Kyoto rats. In intact spontaneously hypertensive rats, amiloride reduced blood pressure, heart rate and myocardial oxygen consumption, and increased simultaneously myocardial contractility. The antihypertensive response was unaltered by bilateral nephrectomy, atropine, cimetidine plus mepyramine, sulpiride and ouabain, but was prevented by phentolamine, hexamethonium and reserpine. Pressor responses to norepinephrine, tyramine, phenylephrine and clonidine were depressed significantly after amiloride, suggesting that amiloride interfered with alpha adrenoceptor-mediated vasoconstriction; vascular reactivity to arginine vasopressin, isoproterenol, histamine and acetylcholine was unaltered. The bradycardic response to amiloride persisted in all groups of animals in spite of surgical or pharmacological pretreatments; positive chronotropic responses to isoproterenol were unaltered by amiloride. The positive inotropic responses to amiloride were evident in the presence of bradycardia, and under conditions in which afterload remained constant or was allowed to decrease. The negative chronotropic and positive inotropic actions of amiloride were due to a direct action of the drug on myocardial tissues, and occurred independently of the antihypertensive effect.

Amiloride↗

PubMed1986

Mechanism of tubular uptake on human growth hormone in perfused rat kidneys.

The mechanism of tubular uptake of labeled human growth hormone ([125I]hGH), a low molecular weight protein (approximate 21,5000 daltons), was studied in isolated perfused rat kidneys. Fractional reabsorption (FR) of [125I]hGH was decreased from 94 to 77% over a period of 80 min as perfusate oncotic pressure was lowered by reducing the albumin concentration from 7.5 to 2.5 g/100ml, whereas greater reductions in fractional sodium (delta 35%) and fluid reabsorption (delta 42%) occurred, indicating that tubular [125I]hGH uptake is likely a specific process not directly dependent upon net fluid and sodium reabsorption. Absolute absorption rates of [125I]hGH filtered loads were inhibited by cytochalasin B, a microfilament disrupter when kidneys were perfused with either albumin concentration. Cytochalasin B inhibited [125I]hGH absorption in both a dose-and time-related manner. The low dose of cytochalasin B (2.5 micrograms/ml) decreased [125I]hGH absorption without significantly altering sodium, fluid or glucose reabsorption. With high doses (5 and 10 micrograms/ml), cytochalasin B affected tubular absorption of [125I]hGH to an extent much greater than sodium, fluid and glucose reabsorption. Inhibition of cytochalasin B on FR[125I]hGH was poorly correlated with the concurrent inhibition of FRNa and FRH2O. Accordingly, tubular reabsorption of [125I]hGH is not directly linked to that of sodium, fluid and glucose. The present studies are consistent with the hypothesis that renal absorption of low molecular-weight proteins is via an endocytotic process involving microfilaments.

Absorption↗

PubMed1985

Lack of renal tubular and hemodynamic effects of non-selective and delta-opioid receptor antagonism.

The renal pharmacological actions of the non-selective opioid receptor antagonist naloxone and the selective delta (delta)-opioid receptor antagonist ICI 154,129 were examined in conscious dogs. Neither naloxone nor ICI 154,129 altered glomerular filtration rate, renal blood flow, blood pressure, heart rate, or renal excretion of water, Na+, K+, or Cl-. In addition, urine and plasma osmolality and electrolyte concentrations and hematocrit were unchanged, suggesting that neither agent produced physiologically significant alteration in plasma vasopressin levels. These data suggest that (a) naloxone and ICI 154,129 exert no renal pharmacological effects in dogs and (b) under resting physiological conditions, delta-opioid receptors, as well as other opioid receptor subtypes, probably are not involved in the tonic regulation of renal hemodynamics or tubular function.

Animals↗

PubMed1984

A method for screening diuretic agents in the rat.

A reproducible screening method for diuretic agents has been developed based upon the selection of a group of homogenous rats with a similar excretory pattern of water and electrolytes. Normal saline (4% body weight) was used as a hydrating fluid to select appropriate rats and to validate the diuretic activity of standard diuretics. The method required only a small number of rats for screening compounds and produced consistent responses in increasing water and electrolyte excretion.

Animals↗