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Biomedical subjects

J P Kokko

Publications and source records attributed to J P Kokko.

At least 19 recordsLinked to original sources
PubMed1997

Bartter's syndrome, supraventricular tachycardia, mitral valve prolapse, and asthma: a therapeutic challenge.

A 25-year-old man with acquired Bartter's syndrome, mitral valve prolapse, and supraventricular tachycardia secondary to a low atrial focus was diagnosed with asthma. The unique aspects of managing these coexisting diseases are evaluated. Calculation of free-water clearance in the diagnosis of Bartter's syndrome and the etiology and characteristics of the syndrome are discussed.

Adult↗
PubMed1996

Current concepts of the countercurrent multiplication system.

The production of a concentrated urine is achieved by countercurrent multiplication in the renal medulla. While the single effect in the outer medulla is known to be active NaCl reabsorption in the thick ascending limb, the single effect in the inner medulla is not definitively established. However, the passive model of Kokko and Rector [1] and Stephenson [2] remains the most widely accepted mechanism for the single effect in the inner medulla. Continued experimental studies of transport in perfused inner medullary nephron segments and mathematical simulations that incorporate these new experimental values and anatomic complexity will be needed to fully elucidate the process of urinary concentration. In addition, the availability of molecular reagents will permit investigation into the molecular mechanisms that regulate transport proteins which play crucial roles in the urinary concentrating mechanism.

Amphibian Proteins↗
PubMed1992

Urinary concentrating ability in patients with Jk(a-b-) blood type who lack carrier-mediated urea transport.

Water homeostasis is regulated in large part by the proper operation of the urinary concentrating mechanism. In the renal inner medulla, urea recycling from the inner medullary collecting duct to the inner medullary interstitium is thought to be essential for the production of a concentrated urine; however, it has not been possible to test this hypothesis in humans. Recently, a unique combination of genetic abnormalities has been described: absence of Kidd blood group antigens and absence of carrier-mediated urea transport in erythrocytes. Because animal studies indicate a similarity between urea transport in red blood cells and the nephron, it was postulated that patients without the Kidd antigen might lack facilitated urea transport in their kidneys. Hence, their ability to concentrate urine maximally was measured. Current models of nephron function would predict that in the complete absence of urea transport, the maximal concentrating ability would be around 800 to 900 mosM/kg H2O. Two homozygous patients had a moderate decrease in maximal concentrating ability (UosM,max = 819 mosM/kg H2O); a heterozygote also had some limitation. These studies raise the possibility that the erythrocyte urea transporter and the kidney urea transporter are encoded by a single gene (detected by the mutational loss of the Kidd antigen) and that a lack of facilitated urea transport impairs urea recycling in the kidney and, hence, maximal urinary concentrating ability.

Adolescent↗
PubMed1990

Countercurrent system.

Urinary concentration is achieved by countercurrent multiplication in the inner medulla. The single effect in the outer medulla is active NaCl absorption from the thick ascending limb. While the single effect in the inner medulla is not definitively established, the majority of experimental data favors passive NaCl absorption from the thin ascending limb. Continued experimental studies in inner medullary nephron segments will be needed to elucidate fully the process of urinary concentration.

Animals↗
PubMed1989

Chronic indomethacin increases rabbit cortical collecting tubule Na+-K+-ATPase activity.

To help determine whether prostaglandin-mediated inhibition of transport in the isolated rabbit cortical collecting tubule (CCT) is related to a suppression of sodium pump activity, adrenalectomized rabbits on replacement dexamethasone were treated for 3 days with vehicle or the prostaglandin inhibitor, indomethacin. On the day of death, rabbits treated with indomethacin had a significantly reduced urinary prostaglandin E2 (PGE2) excretion rate compared with vehicle-treated animals (107 +/- 7 vs. 415 +/- 129 ng.kg body wt-1.day-1, indomethacin vs. vehicle, P less than 0.05). In addition, CCTs obtained from indomethacin-treated rabbits had a significantly higher Na+-K+-ATPase activity than controls (2.66 +/- 0.33 vs. 1.17 +/- 0.33 mol Pi.kg dry wt-1.h-1, 37 degrees C, P less than 0.005); Mg-ATPase activity was invariant. Despite the elevated CCT Na+-K+-ATPase activity, there was no evidence of a sustained increase in Na reabsorption and/or K excretion by the kidney. Thus at death, the fractional excretions of Na and K, urinary Na/K ratios and plasma K values in rabbits given indomethacin were not significantly different from control values. There was also no evidence for a direct effect of either indomethacin or PGE2 on Na+-K+-ATPase activity when added directly to CCT broken-cell assays. Therefore in vivo chronic indomethacin administration leads to a rise in CCT Na+-K+-ATPase activity, which is coincident with a fall in urinary PGE2, suggesting that endogenous PGE2 may suppress the activity of this enzyme by a cell-mediated process.

Adrenal Glands↗
PubMed1987

Comparison of loop diuretics in patients with chronic renal insufficiency.

Furosemide and bumetanide share a number of characteristics including reduced natriuretic effects in azotemic patients. It has been presumed that this condition affects each drug equally. Previous studies, however, suggest dissimilar pathways of delivery to their sites of action. Though not rigorously tested, this potential disparity might cause them to differ when used in azotemia. We, therefore, assessed the pharmacokinetic and pharmacodynamic characteristics of intravenously administered furosemide and bumetanide in ten adult patients with stable, chronic renal insufficiency (mean creatinine clearance = 14.1 +/- 2.0 ml/min/1.73 m2) in a randomized, cross-over study during controlled sodium intake. Our goals were to assess differences in diuretic effectiveness and in so doing to determine the dose required to produce a maximal response. The mean diuretic doses of 172 and 4.3 mg for furosemide and bumetanide, respectively (ratio = 40:1) were sufficient to produce a maximum response. Despite similarities in maximal fractional excretion of sodium (18.2 +/- 2.6% with furosemide vs. 19.4 +/- 4.5% with bumetanide, P = 0.687) demonstrating an equal tubular responsiveness to both drugs, overall response as quantified by cumulative natriuresis in the initial eight hour period was 52% greater with furosemide (108 +/- 17 vs. 71 +/- 7 mEq; P = 0.042). The difference in total excreted sodium was accounted for by a preserved nonrenal clearance of bumetanide (113 +/- 12 compared to 53 +/- 5 ml/min for furosemide, P = 0.001) which resulted in relatively less bumetanide in serum available to be delivered into the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

The role of the collecting duct in urinary concentration.

In summary, the three major segments of the collecting duct subserve three different functions in the urinary concentrating mechanism. The main function of the cortical collecting tubule is to raise the fractional solute contribution and absolute concentration of urea in fluid that it delivers to the outer medullary collecting duct. The function of the outer medullary collecting duct is to raise further the absolute intraluminal urea concentration. Finally, the inner medullary collecting duct has two major functions in urinary concentration: first, it adds net urea to the papillary interstitium, and second, it allows the generation of maximally concentrated urine due to osmotic water equilibration. Indeed, the urine osmolality can rise to levels higher than the papillary interstitial osmolality as a consequence of inequalities of the reflection coefficients of urea and sodium chloride.

Animals↗
PubMed1987

Effects of protein kinase C activation on sodium, potassium, chloride, and total CO2 transport in the rabbit cortical collecting tubule.

Several hormones induce phosphatidylinositol turnover in cell membranes and thus activate protein kinase C. Activation of protein kinase C can, in turn, have effects on epithelial transport. These experiments were designed to investigate the effects of two activators of protein kinase C, phorbol 12-myristate,13-acetate (PMA) and L-alpha-1,2-dioctanoylglycerol (L-alpha-1,2-DOG), and two inactive analogues, 4 alpha-phorbol and 4-O-methyl phorbol 12-myristate,13-acetate, on sodium, potassium, chloride, and total CO2 transport in the rabbit cortical collecting tubule. Utilizing in vitro microperfusion techniques, we found that activation of protein kinase C with either PMA or L-alpha-1,2-DOG significantly inhibited net sodium absorption, net potassium secretion and transepithelial voltage in a dose-dependent manner. There was no effect on net chloride or total CO2 transport. In contrast, the inactive phorbol analogues did not alter either sodium or potassium transport. These studies demonstrate that in the rabbit cortical collecting tubule sodium and potassium transport can be inhibited by compounds known to activate proteins kinase C. Thus, hormones that induce phosphatidylinositol turnover in the rabbit cortical collecting tubule may lead to inhibition of sodium transport by activation of protein kinase C.

Animals↗
PubMed1986

Effects of acute and chronic dosing of NSAIDs in patients with renal insufficiency.

Administration of nonsteroidal anti-inflammatory drugs (NSAIDs) to patients with chronically impaired renal function has been reported to cause abrupt and sustained reductions in renal plasma flow (RPF), glomerular filtration rate (GFR), and solute and water excretion in association with decreased renal prostanoid production. However, the time course of these acute effects and whether they are sustained during chronic exposure to the NSAIDs are unknown. Accordingly, using standard clearance and balance techniques, we investigated the effects of acute (zero to four hours) and chronic (five days) oral administration of two different NSAIDs on renal function in patients with stable, mild to moderate chronic renal insufficiency (CRI) and in normal subjects. In patients, acute oral administration of ketoprofen (K) and indomethacin (I) resulted in significant decreases in GFR (K: from 36 +/- 3 to 20 +/- 4 ml/min, P = 0.001; I: from 37 +/- 6 to 30 +/- 7 ml/min, P = 0.032; in RPF (K: from 194 +/- 21 to 146 +/- 21 ml/min, P = 0.002; I: from 222 +/- 33 to 147 +/- 18 ml/min, P = 0.016); and in urinary PGE2 excretion (K: from 0.60 +/- 0.25 to 0.08 +/- 0.02 ng/min, P = 0.05; I: from 0.34 +/- 0.06 to 0.18 +/- 0.06 ng/min, P = 0.042). Fractional excretion of sodium chloride and fractional free water clearance (CH2O/CIn) also decreased significantly after both agents. In normal subjects, GFR and RPF were not significantly decreased after acute dosing, whereas urinary PGE2 and fractional excretions of NaCl and free water decreased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Regulation of net bicarbonate transport in rabbit cortical collecting tubule by peritubular pH, carbon dioxide tension, and bicarbonate concentration.

The effects of changes in peritubular pH, carbon dioxide tension (PCO2), and HCO3- concentration on net HCO3- transport was examined in in vitro perfused cortical collecting tubules (CCTs) from unpretreated New Zealand white rabbits. Lowering peritubular HCO3- concentration and pH by reciprocal replacement of HCO3- with Cl-, significantly stimulated net HCO3- absorption. Lowering peritubular HCO3- concentration and pH, by substitution of HCO3- with gluconate, while keeping Cl- concentration constant, also stimulated net HCO3- absorption. Raising peritubular HCO3- concentration and pH, by reciprocal replacement of Cl- with HCO3-, inhibited net HCO3- absorption (or stimulated net HCO3- secretion). When the tubule was cooled, raising peritubular HCO3- concentration had no effect on net HCO3- transport, suggesting these results are not due to the passive flux of HCO3- down its concentration gradient. The effect of changes in ambient PCO2 on net HCO3- transport were also studied. Increasing the ambient PCO2 from 40 mmHg to either 80 or 120 mmHg, allowing pH to fall, had no effect on net HCO3- transport. Similarly, lowering ambient PCO2 to 14 mmHg had no effect on net HCO3- transport. Simultaneously increasing peritubular HCO3- concentration and PCO2, without accompanying changes in peritubular pH, i.e., isohydric changes, stimulated net HCO3- secretion to the same degree as nonisohydric increases in peritubular HCO3- concentration. Likewise, isohydric lowering of peritubular HCO3- concentration and PCO2 stimulated net HCO3- absorption. We conclude that: acute changes in peritubular HCO3- concentration regulate acidification in the CCT and these effects are mediated by a transcellular process; acute changes in ambient PCO2 within the physiologic range have no effect on HCO3- transport in the in vitro perfused CCT; and acute in vitro regulation of CCT acidification is independent of peritubular pH.

Absorption↗
PubMed1986

Hormonal regulation of proton secretion in rabbit medullary collecting duct.

With the exception of aldosterone, little is known about the hormonal regulation of distal nephron acidification. These experiments investigated the effects of prostaglandin E2, indomethacin, lysyl-bradykinin, 8-bromo-cyclic AMP, and forskolin on proton secretion in the major acidifying segment of the distal nephron, the medullary collecting duct from inner stripe of outer medulla. Using in vitro microperfusion and microcalorimetry, net bicarbonate reabsorption (proton secretion) was measured in rabbit medullary collecting ducts before, during, and after exposure to each test substance. PGE2 reduced proton secretion 12.2%, while the following substances stimulated proton secretion: indomethacin 14.2%; 8-bromo-cyclic AMP 34.5%; forskolin 39%. Lysyl-bradykinin was without effect. These studies demonstrate that distal nephron acidification, in addition to being stimulated by aldosterone, is significantly inhibited by the hormone PGE2. The stimulation of proton secretion by cAMP suggests that other hormones known to activate adenylate cyclase may also influence distal nephron acidification.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1985

Effects of in vitro aldosterone on the rabbit cortical collecting tubule.

Considerable evidence indicates that the cortical collecting tubule is a target epithelium for aldosterone. Isolated perfused cortical collecting tubules from rabbits given large doses of deoxycorticosterone acetate (DOCA) for several days, or whose endogenous production of aldosterone is increased by dietary means, exhibit large lumen-negative transepithelial voltages, increased sodium (Na) absorption, and increased potassium (K) secretion compared with tubules from normal animals. However, controversy exists regarding the response of this nephron segment to acute in vitro administration of aldosterone. To address this issue we performed three groups of experiments: 1) clearance experiments on adrenalectomized rabbits to determine the minimum time required after in vivo aldosterone administration before significant changes in sodium excretion are observed; 2) microperfusion experiments on cortical collecting tubules from normal and adrenalectomized rabbits in which transepithelial voltage was measured before and after adding aldosterone to the bath; 3) microperfusion experiments on cortical collecting tubules from adrenalectomized rabbits in which transepithelial voltage, sodium and potassium flux were measured before and after in vitro exposure to aldosterone or dexamethasone. The clearance studies demonstrate that after a 2 hr latent period aldosterone produces significant antinatriuresis without change in K excretion. In vitro studies failed to reveal a steroid-induced change in the transepithelial voltage of cortical collecting tubules from either normal or adrenalectomized rabbits. However, aldosterone added in vitro to collecting tubules from adrenalectomized rabbits produced an increase in net Na absorption without a significant change in voltage or K secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1985

Effects of aldosterone on potassium recycling in the kidney of adrenalectomized rats.

Recent studies have suggested that potassium, like urea, undergoes medullary recycling. The present cortical and papillary micropuncture studies were designed to confirm the existence of medullary potassium recycling and to determine whether acute infusions of aldosterone affected this phenomenon. Thus, nephron segmental analysis of potassium and sodium transport was conducted in adrenalectomized Munich-Wistar rats and similarly prepared rats that received aldosterone acutely to achieve physiological blood levels. The clearance results demonstrated that aldosterone has an acute antinatriuretic and a kaliuretic effect, whereas the micropuncture studies demonstrated that 1) aldosterone increases potassium secretion between early and late distal tubule punctures; 2) aldosterone causes an increase in delivery of potassium to the papillary collecting duct; 3) aldosterone does not increase potassium secretion across the papillary collecting duct; and 4) aldosterone significantly increases medullary potassium recycling as evidenced by increased quantities of potassium present at the bend of the loop of Henle in response to aldosterone infusions. Thus, the studies confirm the existence of potassium recycling and suggest that this phenomenon is a feedback system that, in part, regulates urinary potassium excretion.

Adrenalectomy↗