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PubMedDate not supplied

Effects of antihypertensive therapy on blood pressure and renal function in rats with hypertension due to chronic blockade of nitric oxide synthesis.

Different antihypertensive treatment regimes were studied in rats during long-term inhibition of nitric oxide synthesis. Male Munich Wistar rats (weight 150-200 g) were put on oral L-nitro-arginine methyl ester (L-NAME, 50 mg/l drinking water) for 12 weeks. The control group (n = 16) received only tap water. Six weeks after starting L-NAME administration rats were divided into 7 groups (n = 13 in each group: group 1, no treatment; group 2, l-arginine 1 g/l drinking water; group 3, doxazosin 30 mg/kg/day; group 4, felodipine 25-30 mg/kg/day; group 5, losartan 40 mg/kg/day; group 6, metoprolol 300-350 mg/kg/day, and group 7, ramipril 1 mg/kg/day. Systolic blood pressure (sBP) was measured in the conscious rat 1, 6, and 12 weeks after study begin. After a treatment period of 6 weeks albuminuria, glomerular filtration rate (GFR) and renal plasma flow (RPF; inulin and p-aminohippuric acid clearance) were analyzed. All rats showed a significant increase in sBP under 6 weeks of L-NAME administration. Control rats remained normotensive during the whole study period. Rats receiving L-NAME without antihypertensive treatment showed a further increase in sBP after 12 weeks. Blood pressure was lowered in all treated animals, except in rats receiving l-arginine. Values for GFR were lowest in the placebo group, the l-arginine group and in rats receiving felodipine (p < 0.05 compared to the control group). RPF was lowest in the placebo group, the l-arginine group, the felodipine group and the ramipril group (p < 0.05 compared to the control group).(ABSTRACT TRUNCATED AT 250 WORDS)

Albuminuria↗
PubMed1995

Renal hemodynamic effects of chronic ketorolac tromethamine treatment in aged lean and obese Zucker rats.

Ketorolac tromethamine is a relatively new non-steroidal anti-inflammatory drug (NSAID), with potent analgesic activity. Similar to other NSAIDs, ketorolac has the potential to impair renal function. To assess the renal hemodynamic impact of the ketorolac in aged lean and obese rats, ketorolac was orally administered to 46-week-old lean and obese Zucker rats for two weeks. Ketorolac was mixed with rat chow in a manner to provide a dose equivalent to 15 mg/kg body weight/day. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured under anesthesia by standard inulin and p-aminohippuric acid clearance method, respectively. Urinary prostaglandin (PG) E2 excretion was measured before and after ketorolac treatment. Ketorolac treatment significantly reduced obese rat GFR (0.47 +/- 0.08 vs 0.78 +/- 0.03 ml/min/g, p < 0.002) and ERPF (1.12 +/- 0.14 vs 2.36 +/- 0.26 ml/min/g, p < 0.001) relative to obese control rats. In comparison, ketorolac did not significantly alter lean rats GFR (0.77 +/- 0.04 vs 0.91 +/- 0.06 ml/min/g) or ERPF (1.92 +/- 0.20 vs 2.48 +/- 0.15 ml/min/g) relative to lean control rats. Chronic ketorolac treatment significantly reduced hematocrit by 20 and 30 percent in lean and obese rats relative to controls, respectively. The renal vascular resistance was significantly increased with ketorolac treatment in obese rats (36 +/- 4 vs 79 +/- 14 mmHg/ml/min, p < 0.001) but not lean rats (28 +/- 3 vs 38 +/- 5 mmHg/ml/min, NS) relative to corresponding controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1995

[Cardiovascular effects of a calcium channel blocker in hypoxia caused by altitude].

OBJECTIVE: High altitude pulmonary oedema can be successfully treated and prevented by calcium channel blockers. Moreover, calcium entering in the cells could explain the congestive phenomena of acute mountain sickness (AMS). These findings led us to study the action of a calcium channel blocker, isradipine, in the prevention of non-complicated AMS. METHODS: In a double blind randomized study, 20 healthy volunteers received 5 mg of isradipine (n = 6) or placebo (n = 6) for 8 days. After 5 days of treatment in normoxia, the subjects were rapidly transported to an altitude of 4350 m. The efficiency of the treatment was then estimated by the AMS symptom score, haemodynamic parameters and renal function. RESULTS: The administration of isradipine did not significantly modify AMS symptom score nor most of other parameters measured in high altitude hypoxia. Heart rate was an average of 15 b/min lower in the isradipine group, probably because of a direct action of isradipine on the sinus node. Otherwise, the effects of hypoxia were similar in both groups and were in accordance with the literature. There was no clear explanation for the increase in cardiac output and stroke volume when the subjects moved from supine to standing position. Renal blood flow, measured by Doppler or para-aminohippuric acid clearance was not modified by hypoxia. Cerebral blood flow was elevated, due to the direct vasodilator effect of hypoxia. However this increase did not seem to be the main mechanism responsible for the congestive phenomena. On the other hand, the increase in capillary permeability (demonstrated by the increased transcapillary escape rate of albumin, and albuminuria) appeared to play a major role in the pathogenesis of AMS and high altitude cerebral oedema. Isradipine had no protective effect on these phenomena and its use should be restricted to the treatment of high altitude pulmonary oedema.

Adult↗
PubMed1995

Sustained vasoconstriction associated with daily cyclosporine dose in heart and lung transplant recipients: potential pathophysiologic role of endothelin.

Transient decreases in glomerular filtration rate (GFR) and renal plasma flow (RPF) have been associated with each daily dose of cyclosporine (CYA) in patients with renal allografts. We examined the differential dose effects of CYA on native renal function in 24 recipients of heart or lung transplants (treated with 7.3 +/- 0.5 mg/kg/day [mean +/- SEM]) and in seven patients with psoriasis (treated with 4.2 +/- 0.7 mg/kg/day). GFR and RPF were measured by urinary inulin and para-aminohippuric acid clearances 2 hours before the morning CYA dose and for 6 hours after. The age of heart and lung transplant recipients at renal study (2 months after transplantation) was 47 +/- 2.0 years. Their serum creatinine levels rose from 80 +/- 4.0 mumol/L during the first week after transplantation to 120 +/- 4.0 mumol/L at renal study (p < 0.0001). Their GFR and RPF were decreased before the CYA dose at 64 +/- 2.4 and 340 +/- 16 ml/min per 1.73 m2 and did not vary during the study. In comparison, the age of patients with psoriasis was 51 +/- 4.6 years at renal study (24 +/- 4.0 months after CYA treatment). Their serum creatinine levels rose from 80 +/- 4.0 mumol/L before treatment to 100 +/- 10 mumol/L at renal study (p = 0.07). Transient decreases of their baseline GFR and RPF (85 +/- 7.4 and 380 ml/min per 1.73 m2) with a nadir occurring during the first 2 hours of CYA ingestion were observed together with the recovery of these parameters toward baseline by the end of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine↗
PubMed1994

Renal hemodynamic response to stress is influenced by ACE-inhibitors.

Cardiovascular responses to new antihypertensive agents have been studied extensively under resting and stress conditions. However, the effects of antihypertensive agents on renal hemodynamics have only been investigated at rest. To test whether antihypertensive therapy leads to disparate renal hemodynamic effects during exposure to mental stress as opposed to resting conditions, we performed a double-blind, placebo-controlled crossover study. In 17 normotensive healthy men, glomerular filtration rate (GFR; inulin clearance) and renal plasma flow (RPF; para-aminohippuric acid clearance) were measured at rest and after a standardized mental stress test, with or without one week's treatment with a new, long-acting ACE-inhibitor cilazapril 2.5 mg/day. ACE-inhibition did not change resting blood pressure, RPF, GFR, or derived parameters, such as filtration fraction, renal vascular resistance and renal fraction of cardiac output. Mental stress caused an acute increase in GFR (p < 0.001) and filtration fraction with both treatments (0.001). However, the increase in GFR and filtration with mental stress was greater (p < 0.05) with cilazapril treatment than with placebo. Thus, renal hemodynamic responses to mental stress were influenced by ACE inhibitors. We conclude that the impact of antihypertensive agents on renal hemodynamics during stress cannot a priori be delineated from measurements at rest.

Adult↗
PubMed1994

Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis.

To determine the role of indoxyl sulfate in the progression of glomerular sclerosis, the serum level of indoxyl sulfate was measured in patients with uremia, and the effect of oral administration of indoxyl sulfate on renal function and renal histology was studied in subtotally nephrectomized uremic rats. Further, the effects of a low-protein diet and oral sorbent (AST-120) administration on the serum and urine levels of indoxyl sulfate were studied in different groups of subtotally nephrectomized uremic rats. We noted a marked elevation of serum level of indoxyl sulfate in the patients with uremia. The oral administration of indoxyl sulfate to the uremic rats increased the serum creatinine and blood urea nitrogen levels and decreased creatinine clearance, inulin clearance, and p-aminohippuric acid clearance. The glomerular sclerosis index in the indoxyl sulfate-administered uremic rats was higher than in the control uremic rats. A low-protein diet and AST-120 administration decreased the serum and urine levels of indoxyl sulfate, the blood urea nitrogen level, the urinary protein level, and the glomerular sclerosis index in the uremic rats as compared with those on a high-protein diet. Thus, indoxyl sulfate, a circulating uremic toxin, stimulated the progression of glomerular sclerosis in the uremic model. A low-protein diet and AST-120 reduced the serum and urine levels of indoxyl sulfate and suppressed the progression of glomerular sclerosis.

Aged↗
PubMed1993

Mechanism of ochratoxin A-induced reduction of glomerular filtration rate in rats.

The nephrotoxin ochratoxin A (OTA) causes a reduction of glomerular filtration rate (GFR) and of para-aminohippuric acid (PAH) clearance. We determined renal plasma flow (RPF), filtration fraction (FF) and total renal vascular resistance (TRVR). Using furosemide, we investigated the role of tubuloglomerular feedback (TGF) for GFR reduction. Using enalapril and the angiotensin II antagonist DUP 753 we investigated the role of angiotensin II for GFR reduction. Six days' application of 0.5 mg/kg b.wt. of OTA i.p. to male Wistar rats leads to RPF reduction from 3.98 +/- 0.18 to 1.97 +/- 0.18 ml/(min.g kidney wet weight) and GFR reduction from 1.08 +/- 0.06 to 0.69 +/- 0.04 ml/(min.g kidney wet weight) (n = 6, P < .05 for both). FF increased to 130% of control and TRVR to 202% of control (n = 6, P < .05 for both). The application of furosemide (30 mg/(h.kg b.wt.) after pretreatment with OTA had no effect on the reduction of GFR indicating that TGF is not involved. Pretreatment with OTA and enalapril [0.5 mg/(d.kg) b.wt.] blunted the effect of OTA alone significantly (GFR only dropped to 88% of control). Pretreatment with OTA and DUP 753 [20 mg/(d.kg) b.wt.] blunted the effect of OTA alone significantly: GFR and RPF only dropped to 89 and 91% of control, respectively. FF and TRVR were no longer different from control. Acute application of DUP 753 (2 mg/kg b.wt. i.v.) after pretreatment with OTA blunted the effect of OTA to a lesser extend. Our conclusions are: 1) Reduction of PAH clearance and of GFR is in part due to reduced RPF. 2) The increase in TRVR is at least in part caused by an increase of the efferent resistance. 3) Activation of the TGF is not involved in GFR reduction. 4) The increase in TRVR and the decrease of GFR are mainly mediated by angiotensin II.

Angiotensin II↗
PubMed1993

Role of calcium in plasma protein binding and renal handling of alendronate in hypo- and hypercalcemic rats.

Alendronate (4-amino-1-hydroxybutylidine-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation for the treatment of osteoporosis. Earlier studies in animals from this laboratory disclosed that systemically administered alendronate is rapidly taken up by bone tissues to the extent of 60% to 70% of the dose and excreted by the kidney, 30% to 40% in 24 hr, and that renal excretion is the only route of elimination. This study was designed to explore the effect of calcium on plasma protein binding and the renal handling of alendronate. The binding of alendronate to rat plasma was concentration, pH and calcium dependent. The fraction of unbound drug in rat plasma increased from about 3% to 9% over a drug concentration range of 0.2 to 10 micrograms/ml. Supplementation of calcium strongly augmented the binding to serum albumin. The binding of alendronate in plasma increased with increasing pH from about 50% at pH 6.6 to 98% at pH 8.6. The effects of pH on the binding of calcium and of alendronate to serum albumin were qualitatively similar. Under steady-state conditions, the binding of alendronate was substantially lower in hypocalcemic rats but unchanged in hypercalcemic rats. Although hypocalcemia caused a significant decrease in the renal secretion of alendronate, there was no effect on the renal secretion of tetraethylammonium bromide and p-aminohippuric acid. The differential effect of hypocalcemia suggests that calcium may play an important role in the renal handling of alendronate. However, hypercalcemia resulted in a substantial decrease of renal secretion of all three compounds and the decreased renal secretion was associated with a marked decrease in the glomerular filtration rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Alendronate↗
PubMed1993

Effect of selective inhibition of thromboxane synthesis on renal function in diabetic nephropathy.

Studies of nondiabetic renal disease suggest that thromboxane may be an important mediator of abnormal renal function. The role of thromboxane in diabetic nephropathy is not fully understood. We measured in a double-blind, randomized, placebo-controlled crossover study the effect of a thromboxane synthase inhibitor (FCE 22178, 400 mg two or three times per day) on urinary excretion of thromboxane B2 and 6-keto-prostaglandin F1 alpha, glomerular filtration rate (measured as clearance of polyfructosan), effective renal plasma flow (clearance of para-aminohippuric acid), fractional clearances of albumin and immunoglobin G and the reabsorption rate of beta 2-microglobulin in 15 patients with type 1 (insulin-dependent) diabetic nephropathy. In seven additional patients, the effect of the thromboxane synthase inhibitor given as 400 mg twice per day was compared with that of the thromboxane synthase inhibitor given as 400 mg three times per day. FCE 22178 administration caused a significant inhibition in the excretion of urinary thromboxane B2 and 2,3-dinor-thromboxane B2 compared with placebo (12.3 +/- 2.1 vs 24.6 +/- 5.1 ng/gm creatinine, p = 0.006, and 78.5 +/- 20.3 vs 335.5 +/- 84.1 ng/gm creatinine, p = 0.004, respectively) without any compensatory increase of 6-keto- prostaglandin F1 alpha or 2,3-dinor-6-keto-prostaglandin F1 alpha that reflect prostacyclin I2 biosynthesis. Glomerular filtration rate, effective renal plasma flow, renal vascular resistance, and filtration fraction were not significantly different after placebo or thromboxane synthase inhibitor treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1997

In vivo evidence for carrier-mediated efflux transport of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine across the blood-brain barrier via a probenecid-sensitive transport system.

By analyzing the amount of ligand remaining in the brain after microinjection into the brain cortex, the apparent efflux rate constants (Keff) of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (DDI) across the blood-brain barrier at low concentrations were determined to be 0.0317 +/- 0.0068 min(-1) and 0.0253 +/- 0.0037 min(-1), respectively. At higher concentrations, efflux exhibited saturation. The concentration of unlabeled DDI to inhibit 50% of the saturable efflux of [3H]DDI was found to be 11.3 +/- 5.7 microM, assuming that DDI diffused into the same volume of brain as that of trypan blue after intracerebral administration. The efflux rate of [3H]AZT from the brain was significantly inhibited by DDI, probenecid, p-aminohippuric acid, benzylpenicillin and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, but not by thymidine. Moreover, the efflux rate of [3H]DDI was significantly inhibited by AZT and probenecid, but not by deoxyinosine and inosine. After intracerebroventricular injection, the apparent efflux clearances of [3H]AZT and [3H]DDI from the cerebrospinal fluid were significantly inhibited by the coadministration of probenecid. However, intracerebroventricularly administered probenecid had no effect on the efflux of [3H]AZT and [3H]DDI from the brain after intracerebral microinjection, which suggested that the efflux transport system of the blood-cerebrospinal fluid barrier is not responsible for the elimination of AZT and DDI from the cerebral cortex. These results provide kinetic evidence that AZT and DDI are transported from brain into circulating blood across the blood-brain barrier via a probenecid-sensitive carrier-mediated efflux transport system.

Animals↗
PubMed1998

Functional characterization of an organic cation transporter (hOCT1) in a transiently transfected human cell line (HeLa).

Recently, a polyspecific organic cation transporter, hOCT1, was cloned from human liver. To date, limited studies examining the functional characteristics of the transporter have been performed. The purpose of the present study was to develop a mammalian expression system for hOCT1 and to characterize the interactions of various compounds with the cloned transporter. Lipofection was used to transiently transfect the hOCT1 plasmid DNA in a human cell line, HeLa. We tested the interaction of an array of organic cations and other compounds with hOCT1 by determining Ki values in inhibiting 14C-tetraethylammonium (TEA) transport in the transfected cells. Transient expression of hOCT1 activity was observed between 24 and 72 hr post-transfection, with maximal expression at approximately 40 hr. TEA transport was temperature dependent and saturable with Vmax and K(m) values of 2.89 +/- 0.448 nmol/mg protein/30 min and 229 +/- 78.4 microM, respectively. 14C-TEA uptake in hOCT1 plasmid DNA-transfected HeLa cells was trans-stimulated by unlabeled TEA and 1-methyl-4-phenyl-pyridinium. Organic cations, including clonidine, quinine, quinidine and verapamil (0.1 mM), significantly inhibited 14C-TEA uptake, whereas the organic anion, p-aminohippuric acid (5 mM), did not. The neutral compounds, corticosterone (Ki, 7.0 microM) and midazolam (Ki, 3.7 microM) potently inhibited 14C-TEA uptake. The Ki values of several compounds in interacting with hOCT1 differed substantially from the corresponding values for the rat organic cation transporter, rOCT1, and the human kidney-specific organic cation transporter, hOCT2, determined in previous studies. Transiently transfected HeLa cells represent a useful tool in studying the interactions and kinetics of organic cations and other xenobiotics with hOCT1 and in understanding the molecular events involved in organic cation transport.

Carrier Proteins↗
PubMed1997

Kidney function changes in rats after single-dose administration of borocaptate sodium.

Kidney function changes after single-dose administration of borocaptate sodium (mercaptoundecahydro-closododecaborate, B12H11SH, BSH) were studied in rats. Changes of glomerular filtration rate (GFR) measured as 14C-inulin clearance, renal plasma flow rate (3H-p-aminohippuric acid clearance) and urine flow rate (UFR) after a slow intravenous injection of BSH (25 mg/kg b.w.) were investigated in rats under pentobarbital anaesthesia. It was found that a slow BSH injection induces a gradual decrease of renal plasma flow and glomerular filtration rate resulting in an almost constant reduction of the filtration fraction. These alterations were accompanied by a temporary increase of urine flow rate. Although a direct effect of BSH on the nephron cannot be excluded, it is suggested that the observed changes in kidney function might at least partly be mediated by disturbances in the function of the cardiovascular system following BSH injection. The role of the dianionic sulfhydryl group present in the borocaptate molecule in inducing these renal functional changes is discussed.

Animals↗
PubMed1975

Nalidixic acid: intrarenal distribution and its effect upon para-aminohippurate excretion.

Studies performed on the intrarenal distribution of nalidixic acid in dogs show that this weak organic acid is indeed accumulated in the kidney, the highest concentration being attained in the cortex and followed in order by the outer medulla, papillae, and inner cortex. Our results also show that nalidixic acid produces significant changes in the para-aminohippuric concentration and on the filtered load, secretion and clearance of para-aminohippuric acid. Stop-flow experiments confirmed the inhibitory effect of nalidixic acid upon para-aminohippuric acid secretion. It is plausible that nalidixic acid may inhibit the secreted moiety of creatinine. This inhibitory effect is localized in the proximal tubule, where para-aminohippuric acid is known to be secreted. Based on our data it is suggested that nalidixic acid competes with para-aminohippuric acid for the same transport system or that the decreased secretory para-aminohippuric acid activity after nalidixic acid may be caused by a direct inhibition produced by the latter.

Aminohippuric Acids↗
PubMed1992

Uptake of uric acid and p-aminohippurate (PAH) by renal cortical slices of various mammals.

1. Accumulation of uric acid and PAH was measured in renal cortical slices of various mammalian species. 2. The slice to medium ratio of uric acid was above unity in the rabbit, guinea pig, pig and cow, suggesting an active accumulation of uric acid, while it was near or below unity in the rat and mongrel dog. 3. Uric acid uptake in the rabbit, guinea pig and cow was significantly inhibited by PAH. 4. Uric acid was a potent inhibitor of PAH uptake in the rabbit, guinea pig, dog and pig, but much less potent in the rat and cow. 5. Kinetic analysis showed that uric acid inhibited PAH uptake in a competitive manner in all species studied except for the cow showing a noncompetitive type. 6. These results indicate that uric acid and PAH share a common transport mechanism at the basolateral membrane of the rabbit, guinea pig and pig.

Animals↗