Effect of prostaglandin endoperoxide analogue on canine renal function, hemodynamics and renin release

We studied the effect of a stable, cyclic ether analogue of prostaglandin endoperoxide (EPA) on canine renal function, hemodynamics, and renin release. Infusion of EPA into one renal artery decreased renal blood flow in a dose dependent manner. At a dose of 10(-7) g/kg/min the renal blood flow decreased from a baseline of 384 to 267 ml/min/100 g. This flow decrease was unaltered by phentolamine and saralasin, but was potentiated by prior treatment with indomethacin. Urine flow, glomerular filtration rate, sodium, and potassium excretion all decreased in a dose dependent manner; however, neigher fractional excretion of sodium nor free water clearance showed any significant change, making direct tubular effects of EPA unlikely. EPA caused a significant increase in renin release that was completely blocked by prior treatment with indomethacin. We conclude that EPA is a potent renal vasoconstrictor and that this vasoconstriction is responsible for the renal functional changes observed. Renin release is not a direct effect of EPA but probably is secondary to an endogenously generated prostaglandin. Since EPA mimics the effects of natural prostaglandin endoperoxides on smooth muscle in vitro, it is possible that prostaglandin endoperoxide-induced vasoconstriction in vivo modulates the effects of their vasodilatory products, prostaglandin E2 and I2.     

Renal responses of Australian lungfish to vasotocin, angiotensin II, and NaCl infusion

The Australian lungfish (Neoceratodus forsteri) responds to intravenous injections of 0.63 ng/kg or more of arginine vasotocin with increased dorsal aortic blood pressure, inulin clearance, urine flow, and tubular rejection of Na+. Single injections of 1 ng/kg or more of angiotensin II or norepinephrine also increase dorsal aortic pressure but do not cause consistent diuresis and natriuresis, Continuous infusions of angiotensin II or repeated injections of norepinephrine produce sustained hypertension and more modest diuresis and natriuresis than are seen after injections of arginine vasotocin that cause less hypertension. Infusions of isosmolar or hyposmolar NaCl solutions increase blood pressure, inulin clearance, urine flow, and tubular Na+ rejection in a manner resembling the response to argininge vasotocoin injections. These data are consistent with the hypothesis that arginine vasotocin is released in response to volume expansion in lungfishes and that it may act on the kidney as a diuretic and natriuretic hormone. They do not rule out a more direct action of expansion on renal functions.     

Trends in siting strategies

Renal function was measured by clearance technique before and after acute myocardial infarction (MI) induced by left coronary artery ligation in male Sprague-Dawley rats. The animals were anaesthetized with halothane-nitrous oxide, paralysed with pancuronium and artificially ventilated. All parameters were stable throughout the experiment in sham-operated time control animals (n = 8). After MI, rats developed left ventricular dysfunction with increased left ventricular end-diastolic pressure and decreased mean arterial pressure. MI produced antidiuresis and antinatriuresis without changes in glomerular filtration rate (GFR), lithium clearance or renal albumin excretion (n = 8). The antidiuretic and antinatriuretic responses to MI were similar in rats with chronic bilateral renal denervation (n = 5). Three additional rats with chronic bilateral renal denervation had cardiac arrest and were resuscitated with cardiac massage, i.v. lidocaine and intracardiac adrenaline administration. These animals showed a transient increase in urine flow rate, sodium and albumin excretion with maximum 30-60 min after resuscitation, while GFR and lithium clearance were normal. Since cardiac ischaemia and sympathetic stimulation are strong stimuli for the release of atrial natriuretic peptide (ANP), we examined if ANP (0.25, 0.50, and 1.00 microg kg(-1) min(-1), n = 8 per dose) affects urinary albumin excretion. ANP increased dose-dependently the urine/plasma concentration ratio of albumin relative to inulin, which suggests that ANP increases the glomerular permeability for albumin. We conclude that MI causes stimulation of renal tubular sodium and water reabsorption by a mechanism which is independent of intact renal innervation. MI does not produce any change in renal albumin excretion in rats, but transient albuminuria may be observed in rats following cardiac arrest and/or manoeuvres used in cardiac resuscitation. Since ANP produces albuminuria, we speculate that ANP may be an important mediator of albuminuria in states with elevated plasma concentrations of ANP.     

Improved kidney function with intravenous prostaglandin E1 in patients with terminal heart failure

In end stage congestive heart failure activation of a series of compensatory mechanisms increase renal vascular resistance and impair renal function. Prostaglandin E1 is increasingly used in the treatment of severe heart failure for its vasodilating actions. In various experimental settings prostaglandin E analogues are known to improve renal function by modulating renal filtration pressure and redistribution of renal blood flow. However, prostaglandin E1 decreases systemic blood pressure and thus, also renal perfusion pressure, a fact by which renal function might be further compromized in heart failure patients. The aim of the study was to evaluate the effects of prostaglandin E1 on excretory renal function in patients with end stage heart failure and to prove the hypothesis, that the well known local actions of prostaglandins on renal microcirculation might outweigh the negative impact of an expected decrease in perfusion pressure. 25 patients with terminal congestive heart failure were investigated. 13 patients received prostaglandin E1 at a dose of 13.5 +/- 1.9 ng/kg/min in combination with constant rates of dopamine and dobutamine (group A), 12 patients received prostaglandin E1 at a dose of 10.3 +/- 1.7 ng/kg/min without catecholamines (group B). There was no significant difference in prostaglandin dosages between groups. Kidney function was assessed by measuring plasma creatinine and urea nitrogen, urinary output, creatinine clearance, osmotic and free water clearance at baseline and after 72 h of infusion therapy. Hemodynamic parameters were measured by using a balloon tipped pulmonary arterial catheter. Hemodynamic measurements during infusion showed a significant improvement in all patients. At the same time as expected mean arterial pressure decreased in both groups (p < 0.001). Nevertheless, in both groups a significant increase of creatinine clearance during infusion was observed (in group A from 45 ml/min to 78 ml/min., p < 0.05, in group B from 59 ml/min to 105 ml/min., p < 0.001). Creatinine clearance in group B (without catecholamines) reached higher levels than group A (p < 0.05). Urinary volumes did not change during infusion therapy, whereas free water clearance significantly decreased, as an indication of an improvement of renal concentrations ability. We conclude, that in patients with end stage heart failure continuous infusion of prostaglandin E1 improves excretory kidney function. These findings suggest that the local effects of prostaglandin E1 on renal microcirculation can counterregulate the negative impact of prostaglandins on renal perfusion pressure.     

The effects of an angiotensin blocker (saralasin) on kidney function in dehydrated sheep

Saralasin, an angiotensin II analogue and receptor blocker, was infused at 7 and 15 micrograms . min-1 into dehydrated conscious Merino ewes. This caused mean arterial blood pressure, cardiac output, heart rate and renal vascular resistance to fall, and central venous pressure to rise. Renal plasma flow was unaffected but there were significant reductions in glomerular filtration rate, filtration fraction, urine flow, sodium and potassium excretion, solute clearance and solute-free water reabsorption. It is suggested that saralasin produced these effects by inhibiting endogenous angiotensin II activity, and in particular by causing a reduction in renal post-glomerular resistance. This in turn caused a fall in glomerular filtration rate and filtration fraction. While saralasin might have had effects on renal tubular function and perhaps on vasopressin secretion, the observed effects on renal function can be explained by the decrease in glomerular filtration rate and filtration fraction.     

Acromesomelic dwarfism: description of a patient and comparison with previously reported cases

SPF-male rats were treated intraperitoneally with phenobarbital (30 mg/kg/day) or 0.9% sodium chloride for 4 days. Endogenous creatinine clearance in conscious rats and inulin clearance in nondiuretic rats under inactin anesthesia were measured 24 hr following the last injection. In an additional group of treated rats diuresis was induced by sodium chloride and mannitol and then inulin- and PAH clearance were measured simultaneously. Following 4 days treatment with phenobarbital, endogenous creatinine clearance and inulin clearance were not significantly different in control and phenobarbital-treated animals. In contrast significant changes were found in urine volume and PAH clearance in the phenobarbital-treated animals. These results do not reflect any change in glomerular filtration rate, but might be attributed to an increase in renal plasma flow or an activated tubular transport system following phenobarbital administration.     

Renal nerves are not involved in sodium and water retention during mechanical ventilation in awake dogs

BACKGROUND: The role of renal nerves during positive end-expiratory pressure ventilation (PEEP) has only been investigated in surgically stressed, anesthetized, unilaterally denervated dogs. Anesthesia, sedation, and surgical stress, however, decrease urine volume and sodium excretion and increase renal sympathetic nerve activity independent of PEEP. This study investigated in awake dogs the participation of renal nerves in mediating volume and water retention during PEEP. METHODS: Eight tracheotomized, trained, awake dogs were used. The protocol consisted of 60 min of spontaneous breathing at a continuous positive airway pressure of 4 cm H2O, followed by 120 min of controlled mechanical ventilation with a mean PEEP of 15-17 cm H2O (PEEP), and 60 min of continuous positive airway pressure. Two protocols were performed on intact dogs, in which volume expansion had (hypervolemic; electrolyte solution, 0.5 ml x kg(-1) x min(-1)) and had not (normovolemic) been instituted. This was repeated on the same dogs 2 or 3 weeks after bilateral renal denervation. RESULTS: Hypervolemic dogs excreted more sodium and water than did normovolemic dogs. There was no difference between intact and renal-denervated dogs. Arterial pressure did not decrease when continuous positive airway pressure was switched to PEEP. Plasma renin activity, aldosterone, and antidiuretic hormone concentrations were greater in normovolemic dogs. The PEEP increased aldosterone and antidiuretic hormone concentrations only in normovolemic dogs. CONCLUSIONS: In conscious dogs, renal nerves have no appreciable contribution to sodium and water retention during PEEP. Retention in normovolemic dogs seems to be primarily caused by an activation of the renin-angiotensin system and an increase in the antidiuretic hormone. Excretion rates depended on the volume status of the dogs.     

Prognostic factors in differentiated thyroid carcinoma: a multivariate analysis of 234 consecutive patients

The role of prostaglandin E2 (PGE2) and prostaglandin F2alpha (PGF2alpha) in the pathogenesis of hypertension and altered renal functions, which are the main symptoms of preeclampsia, has gained importance. Serum and urine samples of 59 women (24 preeclamptic pregnant (PEP), 20 normotensive pregnant (NTP) and 15 nonpregnant) were investigated by means of prostaglandin levels and urea, creatinine and creatinine clearance values. PEP patients, when compared with NTP patients, show a significant decrease in PGE2 and PGF2alpha levels (p < 0.01 and p < 0.05, respectively) accompanied by changes in some parameters of renal function such as serum urea, creatinine and creatinine clearance. Although disorders in prostaglandin levels may be responsible for some renal pathologic changes, renal functional and morphologic alterations may also result in abnormal prostaglandin activity.     

Subthreshold concentration of endothelin-1-enhanced, capsaicin-induced bronchoconstriction in anaesthetized guinea-pigs

OBJECTIVES: Preeclampsia is characterized by an increase in vascular tone associated with reduced uteroplacental flow. The nature of hypertension arising in pregnancy suggests that the abnormal increase in blood pressure is dependent on some humoral factor that mediates vasospasm. There is evidence that preeclampsia results from a breakdown in the balance between vasodilators such as prostacyclin and prostaglandin E2 and nitric oxide and the vasoconstrictors angiotensin II, thromboxane A2, serotonin, and endothelin. Furthermore, vascular reactivity to angiotensin II is greatly enhanced in preeclampsia as opposed to normal pregnancies. The increased vascular tone and the enhanced thromboxane production noted in preeclampsia may be mediated by the increased sensitivity to angiotensin II because angiotensin II coupled to an AT1 receptor is a potent vasoconstrictor and stimulates the accumulation of free arachidonic acid, the precursor of thromboxane and the prostaglandins. STUDY DESIGN: We used a rat model that has been shown to express the relevant clinical features of human preeclampsia to investigate the involvement of the AT1 angiotensin receptor in this pathologic condition. Pregnant rats were divided into three groups that were either infused with saline or endotoxin on the 14th day of pregnancy. One of the endotoxin-infused groups was further treated with the AT1-selective antagonist losartan from day 11 until day 19 of pregnancy. RESULTS: Perinatal outcome, blood pressure, and urine protein were monitored for each group. We observed that endotoxin infusion resulted in a decrease in pup weight and number of pups and caused an increase in mean arterial pressure as well as increased proteinuria when compared with saline solution-infused animals. In contrast, endotoxin-infused rats receiving losartan exhibited no change in number or weight of pups when compared with control, and losartan tended to diminish the rise in mean arterial pressure. In addition, the increase in urinary protein excretion was completely blocked by losartan. CONCLUSIONS: Endotoxin infusion in pregnant rats appears to be a suitable model for the study of preeclampsia. Moreover, the angiotensin II-dependent activation of an AT1 receptor appears to mediate a portion of the pathophysiologic features associated with preeclampsia.     

Histamine H1-receptors in HL-60 monocytes are coupled to Gi-proteins and pertussis toxin-insensitive G-proteins and mediate activation of Ca2+ influx without concomitant Ca2+ mobilization from intracellular stores

The responses of renal haemodynamic and natriuretic indices to the oral prostaglandin synthetase inhibitor indomethacin (200 mg), to infused angiotensin II (1 ng min-1 kg-1) and to the combination of the two were studies in placebo-controlled fashion in eight normal male subjects both prior to and following administration of intravenous frusemide (20 mg). As compared with placebo, angiotensin II infusion alone caused significant reductions in absolute rate of sodium excretion, fractional sodium excretion, urine flow rate and effective renal plasma flow (all P < 0.001 vs placebo) but had no effect on glomerular filtration rate. The only change observed in these parameters with indomethacin alone was a small but significant reduction in urine flow rate (P < 0.005 vs placebo). As compared with the effects of angiotensin II alone, indomethacin pre-treatment followed by angiotensin II infusion led to much greater falls in absolute rate of sodium excretion, fractional sodium excretion, urine flow rate and effective renal plasma flow (all P < 0.0001 vs placebo) associated with a significant reduction in glomerular filtration rate (P < 0.0001) not observed with angiotensin II alone. Frusemide administration at the midpoint of each study limb resulted in each case in a prompt 15 to 20 fold increase in natriuresis. The renal haemodynamic and natriuretic effects of angiotensin II, indomethacin and their combination were not qualitatively different from those observed in the pre-frusemide phase. Our findings provide a clear demonstration in man of the important homeostatic role of renal prostaglandins in preserving renal function, particularly glomerular filtration, under conditions of elevated circulating angiotensin II.     

Ethacrynic acid induced release of prostaglandin E to increase renal blood flow

Ethacrynic acid administered to anesthetized dogs was found to increase the level of prostaglandin E as determined by radioimmunoassay in renal venous blood at the time when renal blood flow was increased by this agent. No change was found in the renal venous level of prostaglandin F. When ethacrynic acid was administered after treatment with indomethacin, which blocks the increase in renal blood flow induced by the natriuretic agent, no increase in the renal venous level of prostaglandin E was seen. Thus, the dilation of the renal vasculature would appear to be caused by a stimulation of synthesis and release of prostaglandin E by ethacrynic acid.     

Prospective study of atherosclerotic disease progression in the renal artery

BACKGROUND: The aim of this study was to determine the incidence of and the risk factors associated with progression of renal artery disease in individuals with atherosclerotic renal artery stenosis (ARAS). METHODS AND RESULTS: Subjects with >/=1 ARAS were monitored with serial renal artery duplex scans. A total of 295 kidneys in 170 patients were monitored for a mean of 33 months. Overall, the cumulative incidence of ARAS progression was 35% at 3 years and 51% at 5 years. The 3-year cumulative incidence of renal artery disease progression stratified by baseline disease classification was 18%, 28%, and 49% for renal arteries initially classified as normal, <60% stenosis, and >/=60% stenosis, respectively (P=0.03, log-rank test). There were only 9 renal artery occlusions during the study, all of which occurred in renal arteries having >/=60% stenosis at the examination before the detection of occlusion. A stepwise Cox proportional hazards model included 4 baseline factors that were significantly associated with the risk of renal artery disease progression during follow-up: systolic blood pressure >/=160 mm Hg (relative risk [RR]=2.1; 95% CI, 1.2 to 3.5), diabetes mellitus (RR=2.0; 95% CI, 1.2 to 3.3), and high-grade (>60% stenosis or occlusion) disease in either the ipsilateral (RR=1.9; 95% CI, 1.2 to 3.0) or contralateral (RR=1.7; 95% CI, 1.0 to 2.8) renal artery. CONCLUSIONS: Although renal artery disease progression is a frequent occurrence, progression to total renal artery occlusion is not. The risk of renal artery disease progression is highest among individuals with preexisting high-grade stenosis in either renal artery, elevated systolic blood pressure, and diabetes mellitus.     

The effects of large doses of fentanyl and fentanyl with nitrous oxide on renal function in the dog

Renal effects of large doses of fentanyl (1 mg/kg) were determined in 14 mongrel dogs before and after addition of 50 per cent nitrous oxide. Fentanyl significantly increased urine osmolarity and decreased urine output and free water clearance but did not change inulin or PAH clearances. The arterial blood pressure and cardiac output were significantly decreased after 0.1 mg/kg fentanyl and these changes were then maintained during the remainder of the study period. Addition of nitrous oxide produced no further changes in cardiac output and arterial blood pressure but did increase urine output, PAH, inulin and free water clearances and decreased urine osmolarity. These data demonstrate that high doses of fentanyl have significant antidiuretic properties in the dog and these probably are related to the release of antidiuretic hormone. Our results also indicate that addition of nitrous oxide reverses fentanyl induced antidiuresis.     

Measurement of glomerular filtration rate (GFR) after administration of iodine contrast medium with the Renalyzer PRX90 in healthy cats and cats with kidney diseases

In the present study, the measurement of the glomerular filtration rate (GFR) in the cat with the aid of an iodine contrast medium clearance with the renalyzer PRX90 is introduced. Investigations on the accuracy of measurement showed that even repeated measurement of plasma samples after two days of storage at room temperature yielded reproducible clearance results. Also, partial dilution of the plasma sample (2 ml with 1 ml Aqua bidest.) to reduce the volume of blood withdrawn still produced reliable results. Further dilution of the plasma volume (1 ml with 2 ml Aqua bidest.) however did not allow for accurate measurements. A total of 59 cats of different age and sex were included in the study. 31 cats had healthy kidneys with urea and creatinine values within the reference range, unchanged urine findings and physiologic urine protein patterns (SDS-PAGE). These cats served as reference group. The GFR reference value ascertained for these animals was 2.1 ml/min/kg BW (mean = 3.45 ml/min/kg with s = +/- 1.0 ml/min/kg). 28 cats had elevated values of urea and creatinine in the blood, as well as partially changed urine findings. For further diagnosis of renal disease, separation of urine proteins was done with the SDS-PAGE in the PhastSystem, which in all cases yielded a pathologic urine protein pattern. In 11 cases the renal disease could be further confirmed by histological investigation. GFR in these patients was clearly lowered compared with healthy cats, with measured values between 0 and 1.8 ml/min/kg. It can be concluded that the renalyzer allows reliable determination of the GFR also in the cat. To what extent measurement of the GFR is also helpful to diagnose nephropathies in the stage of compensation needs to be further investigated. In cats with high grade uremia and a GFR below 1 ml/min however, an exact calculation is not possible, since the accuracy of measurement within this range is inadequate. Thus, in severe disease no correct assessment is possible, and no statement concerning prognosis can be made.     

Effect of administration and subsequent cessation of buserelin on cancellous bone of female rats

OBJECTIVE: Low-dose dopamine has been used in critically ill patients to minimize renal dysfunction without sufficient data to support its use. The aim of this study was to determine whether low-dose dopamine improves renal function, and whether dobutamine, a nondopaminergic inotrope, improves renal function. DESIGN: Prospective, randomized, double-blind trial. PATIENTS: Twenty-three patients at risk for renal dysfunction were entered into the study. Five patients were later withdrawn. Study data for the remaining 18 patients were: mean age 55 yrs; mean Acute Physiology and Chronic Health Evaluation (APACHE) II score of 18; mean weight 71 kg). The following conditions were present: mechanical ventilation (n = 17 [inverse-ratio ventilation, n = 6]); inotrope administration (n = 11); sepsis (n = 13); and adult respiratory distress syndrome or multiple organ failure syndrome (n = 9). INTERVENTIONS: The study patients were administered dopamine (200 micrograms/min), dobutamine (175 micrograms/min), and placebo (5% dextrose) over 5 hrs each in a randomized order. Ventilator settings, fluid management, and preexisting inotropic support were not altered during the study. MEASUREMENTS AND MAIN RESULTS: Systemic hemodynamic values and indices of renal function (4-hr urine volume, fractional excretion of sodium, and creatinine clearance) were measured during the last 4 hrs of each infusion. Dopamine produced a diuresis (145 +/- 148 mL/hr) compared with placebo (90 +/- 44 mL/hr; p < .01) without a change in creatinine clearance. Conversely, dobutamine caused a significant increase in creatinine clearance (97 +/- 54 mL/min) compared with placebo (79 +/- 38 mL/min; p < .01), without an increase in urine output. CONCLUSIONS: In stable critically ill patients, dopamine acted primarily as a diuretic and did not improve creatinine clearance. Dobutamine improved creatinine clearance without a significant change in urine output.     

The effect of indomethacin on renal function in pentobarbital-anesthetized dogs

The effects of indomethacin, an inhibitor of prostaglandin synthesis, on renal blood flow, glomerular filtration rate, urine flow and excretion of sodium and potassium were studied in the anesthetized dog. Indomethacin, 2.5 mg/kg i.v., decreased renal blood flow but increased aortic pressure and calculated renal vascular resistance. Glomerular filtration rate was not influenced by the synthetase inhibitor. Sodium excretion was decreased and para-aminohippurate extraction was increased after administration of indomethacin. Transient decreases in urine flow and potassium excretion were observed; however, both parameters returned to control value 75 minutes after administration of indomethacin. The early decrease in urine flow rate correlated closely with the decrease in sodium excretion. These data suggest that in the anesthetized dog, endogenous prostaglandins may serve to maintain renal blood flow but not glomerular filtration rate. Under the conditions of the present experiments, sodium excretion and to a lesser extent potassium excretion have been suggested as being dependent on prostaglandin synthesis.     

The effect of indomethacin and other anti-inflammatory drugs on the renin-angiotensin system

The administration of two different doses of indomethacin, 9 and 18 mg/kg, to two different groups of rabbits was followed 6 h later by a significant decrease in plasma renin activity, and these levels were not increased by hemorrhage. The administration of 2 mg/kg of indomethacin did not alter the basal levels of plasma renin activity, but it was effective in diminishing the peripheral increase of renin produced by hemorrhage. Similar effects were obtained in other groups of rabbits treated with 9 mg/kg of meclofenamate or 18 mg or aspirin. The lowering effect of indomethacin on plasma renin activity is not specifically related to hemorrhage because it also prevented the increase in plasma renin activity elicited by 5 mg/kg of furosemide. Further studies showed that indomethacin did not exert any significant effect in vivo on the plasma level of renin substrate or on the generation of angiotensin from normal plasma by exogenous renin. And indomethacin did not interfere with the binding capacity of anti-angiotensin I for angiotensin I in the radioimmunoassay reaction or with the in vitro formation of angiotensin from hog renin-nephrectomized rabbit plasma reaction. The results thus indicate that the lowering effect of indomethacin on plasma renin activity is due to the interference with renal renin release. That this effect may be related to the blockade of prostaglandin synthesis is suggested by the similar effect exhibited by other blockers of prostaglandin synthesis.     

Captopril renal scintigraphy in renovascular hypertension

Renovascular disease is a common cause of secondary hypertension. Renal artery stenosis is present in up to one third of patients with clinical markers suggestive of renovascular hypertension, such as hypertension refractory to medical management, severe hypertension in a young patient and worsening of renal function after the use of an angiotensin-converting enzyme inhibitor. Early discovery of renal artery stenosis may allow amelioration or cure of the hypertension and halt progressive loss of renal function. Although renal arteriography remains the gold-standard aid to diagnosis and to planning surgical intervention, it is an invasive procedure that may cause deterioration of renal function. In the presence of renal artery stenosis, glomerular filtration is maintained by angiotensin. Administration of captopril in renal scintigraphy removes this compensatory mechanism and causes a temporary impairment of renal function in the affected kidney. Nuclear tracers can visualize this impairment, thus allowing assessment of the physiologic significance of a renal artery stenosis. The test can be done as a outpatient procedure.     

Renal clearance of domoic acid in the rat

The renal clearance (Clr) of the seafood toxin domoic acid (DA) was investigated in the rat. Following cannulation of the right femoral artery, the left femoral vein and the bladder of anaesthetized rats, a single bolus injection of either [3H]DA, [14C]p-aminohippuric acid (PAH) or [3H]inulin was administered through the venous cannula. Blood samples were taken from the arterial cannula at 1, 2, 10, 30, 50, 70, 90, 110 and 130 min following injection, and urine samples were collected at 20-min intervals starting from the time of bolus injection. Based on plasma concentration-time profiles, the total clearances (Clt) for DA, PAH and inulin were 9.12, 33.17 and 7.50 ml/min/kg body weight, respectively. The Clr calculated from urinary excretion rates were not significantly different from the Clt. Probenecid significantly reduced the Clr of PAH but did not affect that of DA. When DA was given at doses of 0.5 ng, 0.5 mg and 2.0 mg/kg body weight, the pharmacokinetic parameters Clt, Clr, elimination-rate constant and apparent volume of distribution at steady state were not statistically different between doses. The entire dose of 3H was recovered in the urine by 160 min after dosing, and analysis of urine samples by HPLC confirmed that the radiolabel (3H) was associated predominantly with the parent form of DA. The results of the present study demonstrate that DA is cleared from plasma primarily through the kidneys. DA clearance occurs primarily by renal glomerular filtration since its Clt is comparable with that of inulin, is less than that of PAH and is not affected by probenecid.     

Effect of caffeine treatment on plasma renin activity and angiotensin I concentrations in rats on a low sodium diet

Animals treated acutely with an adenosine receptor antagonist have elevated plasma renin activity. This observation suggests that endogenous adenosine plays a physiologically significant role in restraining renin release. However, it is unclear whether chronic blockade of adenosine receptors would cause a rise of renin activity since tolerance to adenosine blockade is known to develop quickly. An earlier study partially addressed this question by showing that chronic blockade of adenosine receptors with caffeine exacerbated both the rise of plasma renin activity and the decline of renal function in 2-kidney-1-clip (2K1C) renovascular hypertensive rats. However, that study did not determine whether the difference in renin activity occurred solely as a secondary result of the difference in renal function. The purpose of this study was to reexamine the effect of chronic caffeine consumption on plasma renin activity and angiotensin I levels in animals in another high-renin model, i.e., the low sodium diet. The low sodium diet is devoid of the potential confounding effect of deteriorating renal function associated with the 2K1C renovascular hypertension model. In this study, animals received normal rat chow and drank either 0.1% caffeine water or vehicle for ten days. After ten days, all rats were switched to a low sodium diet for three weeks. Plasma renin activity and plasma angiotensin I levels were measured before, and at 1 and 3 weeks after initiating the low sodium diet. The results of this study show that chronic blockade of adenosine receptors with 0.1% caffeine water increases plasma renin activity and angiotensin I concentration before and throughout the three weeks when animals were on the low sodium diet. The results of this study suggest that the inhibitory role of adenosine on renin release is a general physiological process, rather than a special situation applicable only to the 2K1C model.