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Biomedical subjects

M G Cogan

Publications and source records attributed to M G Cogan.

At least 37 records · Page 2Linked to original sources
PubMed1989

Angiotensin II stimulates early proximal bicarbonate absorption in the rat by decreasing cyclic adenosine monophosphate.

These studies explored the hypothesis that angiotensin II increases bicarbonate absorption in the proximal convoluted tubule (PCT) by decreasing intracellular cAMP. In vivo microperfusion was performed in rat PCT with measurements of bicarbonate absorption and of tubular fluid cAMP delivery, as a reflection of intracellular cAMP. Intravenous angiotensin II potently increased S1 PCT bicarbonate absorption (348 +/- 11 to 588 +/- 8 peq/min.min, P less than 0.001) and decreased tubular fluid cAMP (18 +/- 2 to 12 +/- 2 fmol/mm.min, P less than 0.05). Parathyroid hormone had the expected opposite effects, which were additive to those of angiotensin II. Over a wide range of hormonal activities, there was an excellent inverse relationship between hormonally modulated bicarbonate absorption and cAMP delivery. Pertussis toxin pretreatment significantly attenuated (by 35-45%) the angiotensin-induced increase in bicarbonate absorption and decrease in cAMP delivery, indicating Gi-protein intermediation. Luminal dibutyryl cAMP abolished the transport response to angiotensin II. In conclusion, these in vivo results suggest angiotensin II stimulates bicarbonate absorption in the S1 PCT by a G1-mediated depression in intracellular cAMP.

Adenylyl Cyclases↗
PubMed1988

Flow dependence of bicarbonate transport in the early (S1) proximal convoluted tubule.

We previously found, using an in vivo microperfusion pump rate of 30 nl/min, that proton secretion in the early (S1) proximal convoluted tubule (PCT) of the Munich-Wistar rat exhibited saturation kinetics. The maximal transport capacity was very high, approximately 500-600 peq.mm-1.min-1. The present studies assessed the change in early PCT acidification kinetics in response to an increase in microperfusion rate to 45 nl/min. First, bicarbonate permeability in the early PCT was measured and was found to be flow dependent. Proton secretion was then calculated using perfusate bicarbonate concentrations from 8 to 100 mM. Saturation of early proximal acidification (Vmax) still occurred at approximately 500-600 peq.mm-1.min-1, but the bicarbonate concentration effecting half-maximal acidification (apparent Km) decreased (from approximately 11 mM at 30 nl/min perfusion rate to less than 6 mM at 45 nl/min). By increasing luminal perfusion rate further to 60 nl/min at constant luminal bicarbonate concentration (25 mM), we confirmed that luminal flow rate did not affect the maximal level of acidification. Similar flow-dependent changes in acidification kinetics in the late PCT were also found, as has been previously shown. In conclusion, although an increase in luminal flow increased bicarbonate permeability and apparent affinity for substrate transport, there was no effect on maximal acidification rate in the early PCT.

Animals↗
PubMed1988

Atrial natriuretic factor does not inhibit basal or angiotensin II-stimulated proximal transport.

Atrial natriuretic factor (ANF) can functionally overcome the effects of angiotensin II in several tissues. Since ANF and angiotensin II in physiological concentrations have opposite effects on renal sodium excretion, we evaluated whether functional antagonism of the two hormones occurs in the proximal convoluted tubule, as has been recently reported with use of the shrinking split-droplet technique. We used the more conventional technique of in vivo microperfusion to measure the response to systemic ANF (0.5 micrograms.kg-1.min-1) when the endogenous angiotensin II level and proximal transport were normal or when transport was first stimulated by systemic angiotensin II administration (20 ng.kg-1.min-1). In both cases, ANF did not significantly alter bicarbonate, chloride, or water transport in either the early or late proximal convoluted tubule. This inability by ANF to directly affect proximal transport is consonant with the known lack of high-affinity receptors and appropriate second messenger system for ANF in the proximal convoluted tubule.

Angiotensin II↗
PubMed1988

Urinary cGMP as biological marker of the renal activity of atrial natriuretic factor.

Current evidence suggests guanosine 3',5'-cyclic monophosphate (cGMP) serves as the second messenger for atrial natriuretic factor (ANF) in the kidney in vivo. We examined whether extracellular cGMP accumulation quantitatively reflected the concentration of cGMP within renal cells and whether urinary excretion of cGMP correlated with the physiological action of ANF. cGMP egression was examined in renal epithelial LLC-PK1 cells. ANF augmented intracellular cGMP concentration and extracellular cGMP appearance. Extracellular cGMP was an excellent function of the time-integrated intracellular cGMP concentration. In clearance studies in awake rats, urinary cGMP was primarily of renal cellular origin and correlated with the natriuresis induced by ANF in a time-dependent and concentration-dependent fashion. Urinary cGMP excretion may be useful as a biological marker for the renal activity of ANF in vivo.

Animals↗
PubMed1988

Angiotensin II stimulation of hydrogen ion secretion in the rat early proximal tubule. Modes of action, mechanism, and kinetics.

Physiologic concentrations of angiotensin II stimulate sodium transport by intestinal and renal early (S1) and late (S2) proximal tubule epithelial cells. We recently found that hydrogen ion secretion, which effects sodium bicarbonate absorption, was a transport function preferentially and potently increased by angiotensin II in S1 cells. S1 cells are normally responsible for half of the total renal hydrogen ion secretion. The mechanism by which angiotensin II regulates intestinal sodium transport is by potentiating sympathetic nerve activity and norepinephrine release. Direct control of hydrogen ion secretion by angiotensin II via receptors on epithelial cells has not been previously demonstrated. We now report that stimulation of in vivo hydrogen ion secretion in the rat early proximal tubule by angiotensin II was not mediated via change in nerve activity. Rather, enhanced hydrogen ion secretion by angiotensin II correlated with increased angiotensin II receptor density on epithelial cells in the early compared to late microdissected proximal tubule. Basolateral as well as luminal angiotensin II stimulated bicarbonate absorption. Angiotensin II reduced bicarbonate permeability and caused alteration in the apparent substrate affinity, but not maximal capacity, of the proximal hydrogen ion secretory system involving the Na+/H+ antiporter.

Angiotensin II↗
PubMed1987

Thrombin activation of the Na+/H+ exchanger in vascular smooth muscle cells. Evidence for a kinase C-independent pathway which is Ca2+-dependent and pertussis toxin-sensitive.

The mechanism by which human alpha-thrombin activates the Na+/H+ exchanger was studied in cultured neonatal rat aortic smooth muscle cells. Thrombin (0.4 unit/ml) caused a rapid cell acidification followed by a slow, amiloride-inhibitable alkalinization (0.10-0.14 delta pHi above base line). In protein kinase C down-regulated cells (exposed to phorbol 12-myristate 13-acetate for 24 or 72 h), the delta pHi induced by thrombin was only partially attenuated. This protein kinase C-independent activation of the Na+/H+ exchanger was blocked by pertussis toxin (islet activating protein (IAP)), reducing delta pHi by 50%. IAP did not directly inhibit Na+/H+ exchange activity as assessed by the response to intracellular acid loading. Thrombin also stimulated arachidonic acid release by 2.5 fold and inositol trisphosphate release by 6.2 fold. IAP inhibited both of these activities by 50-60%. Intracellular Ca2+ chelation with 120 microM quin2 prevented the thrombin-induced Ca2+ spike, inhibited thrombin-induced arachidonic acid release by 75%, and inhibited thrombin-induced activation of the Na+/H+ exchanger in protein kinase C-deficient cells by 65%. Increased intracellular [Ca2+] alone was not sufficient to activate the Na+/H+ exchanger, since ionomycin (0.3-1.5 microM) failed to elevate cell pH significantly. 10 microM indomethacin inhibited thrombin-induced delta pHi in both control and protein kinase C down-regulated cells by 30-50%. Thus, thrombin can activate the Na+/H+ exchanger in vascular smooth muscle cells by a Ca2+-dependent, pertussis toxin-sensitive pathway which does not involve protein kinase C.

Animals↗
PubMed1987

Comparison of the natriuresis and chloruresis associated with glomerular hyperfiltration induced by atrial natriuretic factor or glucagon.

The impact on renal sodium chloride reabsorption of an acute increase in glomerular filtration rate (GFR) induced by atrial natriuretic factor (ANF) or glucagon was examined in the conscious rat. These hormones have no direct effect on proximal solute transport and have opposite effects on distal transport. ANF and glucagon increased GFR to a comparable extent (2.0 +/- 0.2 to 3.5 +/- 0.4 ml/min, p less than 0.01, and 1.9 +/- 0.1 to 3.3 +/- 0.1 ml/min, p less than 0.001, respectively). While most (95-97%) of the increment in filtered sodium chloride was reabsorbed, a small portion (3-5%) escaped tubular reabsorption. Absolute sodium and chloride urinary excretion rates increased similarly in response to each hormone, by two- to three-fold. Slightly imperfect load-dependent sodium chloride reabsorptive response by the nephron, despite opposite direct effects on distal nephron transport, may account for the observed natriuresis and chloruresis associated with the acute glomerular hyperfiltration induced by ANF or glucagon administration.

Absorption↗
PubMed1987

Dietary NaCl determines severity of potassium depletion-induced metabolic alkalosis.

It is uncertain whether, in humans, potassium depletion can cause or sustain metabolic alkalosis of clinically important degree in the absence of coexisting known alkalosis-producing conditions. Previously we found, in normal humans ingesting abundant NaCl, that dietary K+ depletion alone can induce and sustain a small decrease in blood acidity and increase in plasma bicarbonate concentration; we hypothesized that more severe alkalosis was prevented by mitigating mechanisms initiated by renal retention of dietary NaCl that was induced by K+ depletion. To ascertain the acid-base response to dietary K+ depletion under conditions in which the availability of NaCl for retention is greatly limited, in the present study of six normal men we restricted dietary K+ as in the previous study except that intake of NaCl was maintained low (2 to 7 mEq/day, Low NaCl Group) instead of high (126 mEq/day, High NaCl Group). Plasma acid-base composition and renal net-acid excretion (NAE) did not differ significantly between groups during the control period. In the steady state of K+ depletion (days 11 to 15 of K+ restriction), neither plasma K+ concentration (2.9 +/- 0.9 mEq/liter vs. 3.0 +/- 0.1 mEq/liter) nor cumulative K+ deficit (399 +/- 59 mEq vs. 466 +/- 48 mEq) differed significantly between groups. During K+ restriction, persisting metabolic alkalosis developed in both groups, which was more severe in the Low NaCl Group: increment in [HCO3-]p, 7.5 +/- 1.0 mEq/liter versus 2.0 +/- 0.3 mEq/liter, P less than 0.001; decrement in [H+]p, 5.5 +/- 0.6 nEq/liter versus 2.9 +/- 0.4 nEq/liter, P less than 0.003. A significantly more severe alkalosis in the Low NaCl Group was evident at all degrees of K+ deficiency achieved during the course of the 15 days of K+ restriction, and the severity of alkalosis in the Low NaCl Group correlated with the degree of K+ deficiency. During the generation of alkalosis (days 1 to 7 of K+ restriction), NAE increased in the Low NaCl Group whereas it decreased in the High NaCl Group. During the maintenance of alkalosis (days 11 to 15), NAE stabilized in both groups after it returned to values approximating the control values. In both groups, urine Cl- excretion decreased during K+ restriction even though Cl- intake had not been changed, with the result that body Cl- content increased negligibly in the Low NaCl Group (28 +/- 6 mEq) and substantially in the High NaCl Group (355 +/- 64 mEq).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1987

Atrial natriuretic factor inhibits maximal tubuloglomerular feedback response.

The effect of atrial natriuretic factor (ANF) on maximal tubuloglomerular feedback was assessed in 16 Munich-Wistar rats. When the loop of Henle was not perfused, ANF increased single nephron glomerular filtration rate (SNGFR) and stop-flow pressure (SFP) from 32 +/- 2 nl/min and 32 +/- 2 mmHg in the control period to 37 +/- 2 nl/min (P less than 0.05) and 40 +/- 2 mmHg (P less than 0.025) after ANF administration, respectively. Because ANF caused SFP to rise but did not significantly alter plasma protein concentration, the estimated glomerular capillary hydraulic pressure increased. Maximal tubuloglomerular feedback response (examined by increasing orthograde microperfusion of the loop from 0 to 50 nl/min) was significantly inhibited by ANF; changes in SNGFR and SFP during the control state, -9 +/- 2 nl/min and -9 +/- 1 mmHg, were reduced to -4 +/- 2 nl/min (P less than 0.05) and -5 +/- 1 mmHg (P less than 0.05), respectively, after ANF administration. In conclusion, the increase in SNGFR caused by ANF is associated with an increase in glomerular capillary hydraulic pressure and with a blunted maximal tubuloglomerular feedback response.

Animals↗
PubMed1987

Acidification is inhibited in late proximal convoluted tubule during chronic metabolic alkalosis.

In vivo microperfusion was used to assess the changes in the active and passive components of bicarbonate absorption in the rat late proximal tubule during chronic metabolic alkalosis. In tubules perfused with 40 mM bicarbonate, net bicarbonate absorption was inhibited and normal flow dependence was attenuated during alkalosis, compared with values in normal tubules perfused with 40 or even 25 mM bicarbonate concentrations. Under all conditions, bicarbonate back leak was small and contributed little to alterations in net bicarbonate transport, even though bicarbonate permeability was reduced by approximately 75% during chronic metabolic alkalosis and was flow dependent. Suppression of net bicarbonate absorption during chronic metabolic alkalosis was instead attributable to inhibition of proton secretion as a function of both luminal bicarbonate concentration and flow rate. At the highest level of bicarbonate delivery to yield maximal acidification rates, proton secretion during alkalosis was diminished by 38% (from 216 +/- 15 to 133 +/- 10 peq X mm-1 X min-1, P less than 0.001). In conclusion, despite extracellular volume contraction, potassium deficiency, and reduction in bicarbonate permeability during chronic metabolic alkalosis, net bicarbonate absorption in the late proximal convoluted tubule is depressed as a function of luminal bicarbonate concentration and flow rate because acidification is inhibited by hyperbicarbonatemia/alkalemia.

Absorption↗
PubMed1987

Kinetics of bicarbonate transport in the early proximal convoluted tubule.

Bicarbonate permeability and bicarbonate transport kinetics in the S1 segment of the proximal convoluted tubule (PCT) have not been previously studied. In vivo microperfusion at a rate of 30 nl/min was performed in early and late PCT of Munich-Wistar rats. Bicarbonate permeability was first defined, using a bicarbonate-free, acetazolamide-containing perfusate, and was over fourfold higher in the early compared with the late PCT (20.4 +/- 1.8 vs. 4.6 +/- 0.4 X 10(-7) cm2/s, P less than 0.001). Net bicarbonate absorption was then measured using perfusate bicarbonate concentrations of 15, 25, 40, and 100 mM at 30 nl/min perfusion rate. Proton secretory rate was calculated for each group by subtracting the passive bicarbonate transport component from the net flux. Saturation kinetics of acidification were observed in both the early and late PCT. The maximal proton secretory rate at the highest luminal bicarbonate concentration (Vmax) in the early PCT was about twice that in the late PCT (504 +/- 37 vs. 265 +/- 15 peq.mm-1.min-1, P less than 0.001). However, the luminal bicarbonate concentration eliciting half-maximal proton secretion (apparent Km) was approximately the same (11 mM) in the early and late PCT. In conclusion, the early PCT has a higher bicarbonate permeability and proton secretory capacity than the late PCT. Increased Vmax but axial constancy of Km suggests that there is amplification of similar transport mechanism(s) affecting bicarbonate absorption in S1 compared with S2 cells.

Absorption↗
PubMed1987

Reduced glomerular filtration rate can maintain a rise in plasma bicarbonate concentration in humans.

In humans, deficiency of chloride and potassium were found to perpetuate the hyperbicarbonatemia that attends metabolic alkalosis induced by gastric aspiration partly by increasing renal bicarbonate reabsorption, commensurate with the attendant increase in filtered bicarbonate load, and partly by decreasing glomerular filtration rate (GFR), which minimizes the degree of which the filtered bicarbonate load increases and thereby minimizes the requisite increase in bicarbonate reabsorption. The relative contribution of stimulated renal bicarbonate reabsorption might increase, however, if the supply of extrarenal bicarbonate is increased, in which case a greater degree of hyperbicarbonatemia would be sustained. To investigate that possibility, we reexamined the mechanism of perpetuation of gastric alkalosis in normal subjects eating a low NaCl diet supplemented with bicarbonate salts. Prior to gastric aspiration, plasma bicarbonate concentration ([HCO3]p) and pH were higher than in similarly studied subjects not receiving bicarbonate: 29.9 +/- 0.6 vs. 25.3 +/- 0.1 and 7.43 +/- 0.008 vs. 7.41 +/- 0.002 mEq/l, respectively. With continued bicarbonate supplementation, gastric aspiration induced a further significant increase (p less than 0.05) in [HCO3]p of 10.8%, to values not significantly different from those in nonbicarbonate-loaded subjects with gastric alkalosis: 33.2 +/- 1.2 mEq/l. GFR decreased significantly by 8.4% (from 98 +/- 4 to 90 +/- 3 ml/min, p less than 0.025), offsetting nearly commensurately the increase in [HCO3]p so that total bicarbonate reabsorption was not significantly increased (2.90 +/- 0.12 vs. 2.97 +/- 0.19 mEq/min, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Angiotensin II: a potent regulator of acidification in the rat early proximal convoluted tubule.

The early proximal convoluted tubule (PCT) is the site of 50% of bicarbonate reabsorption in the nephron, but its control by angiotensin II has not been previously studied. In vivo microperfusion was used in both the early and late PCT in Munich-Wistar rats. Systemic angiotensin II administration (20 ng/kg X min) or inhibition of endogenous angiotensin II activity with saralasin (1 microgram/kg X min) caused profound changes in bicarbonate absorption in the early PCT (169 +/- 25 and -187 +/- 15 peq/mm X min, respectively). Because the bicarbonate absorptive capacity of the early PCT under free-flow conditions is 500 peq/mm X min, angiotensin II administration or inhibition affected greater than 60% of proton secretion in this segment. Both agents less markedly affected bicarbonate absorption in the late PCT (+/- 28 peq/mm X min) or chloride absorption (+/- 68-99 peq/mm X min) in both the early and late PCT. Because of its potential for controlling the majority of bicarbonate absorption in the early PCT (hence greater than or equal to 30% of bicarbonate absorption in the entire nephron), angiotensin II may be a powerful physiologic regulator of renal acidification.

Absorption↗
PubMed1986

In vivo evidence that cGMP is the second messenger for atrial natriuretic factor.

cGMP generation has been associated with many of the vascular and endocrine actions of atrial natriuretic factor (ANF) in vitro. To examine the role of cGMP as a second messenger for the renal hemodynamic action of ANF in vivo, we measured glomerular filtration rate (GFR) and cGMP concentration in systemic artery, renal vein, and urine as well as in Bowman's space and end-proximal tubule (by free-flow micropuncture) after administration of ANF. ANF increased GFR by 45% and simultaneously induced a greater than 5-fold increase of cGMP concentration in glomerular ultrafiltrate (Bowman's space) when compared to controls. There was no significant increase in either systemic artery or renal vein cGMP concentration. Thus, the source of increased Bowman's space cGMP is not from the blood via filtration but rather from either glomerular mesangial or epithelial cells, which are not in direct contact with the circulation. Although a small amount of tubular handling of cGMP occurred along the length of the nephron, the augmented cGMP production from the glomerulus accounted for most of the 10- to 12-fold higher urinary cGMP excretion observed after ANF administration. Intrarenal arterial infusion of dibutyryl cGMP, but not dibutyryl cAMP, increased GFR in a dose-dependent fashion (from 10 to 1000 microM) by a mechanism similar to that of ANF--an increase in glomerular hydraulic pressure. Thus, ANF markedly stimulated glomerular production of cGMP, which coincided with a marked increase in GFR. Since dibutyryl cGMP itself was capable of increasing GFR, cGMP is the likely second messenger for ANF in vivo.

Animals↗
PubMed1986

Neurogenic regulation of proximal bicarbonate and chloride reabsorption.

Although a change in renal nerve activity is known to alter proximal reabsorption, it is unclear whether reabsorption of NaHCO3 or NaCl or both are affected. Sprague-Dawley rats (n = 10) were studied using free-flow micropuncture techniques during euvolemia and following acute ipsilateral denervation. Glomerular filtration rate and single nephron glomerular filtration rate were stable. Absolute proximal bicarbonate reabsorption fell following denervation (933 +/- 40 to 817 +/- 30 pmol/min) with a parallel reduction in chloride reabsorption (1,643 +/- 116 to 1,341 +/- 129 peq/min). Urinary sodium, potassium, bicarbonate, and chloride excretion all increased significantly. To further assess the physiological significance of neurogenic modulation of proximal transport, other rats (n = 6) were subjected to acute unilateral nephrectomy (AUN). There is evidence that AUN induces a contralateral natriuresis (renorenal reflex) at least partially by causing inhibition of efferent renal nerve traffic. AUN caused significant changes in proximal NaHCO3 and NaCl reabsorption as well as in whole kidney electrolyte excretion in the same pattern as had denervation. Prior denervation of the remaining kidney prevented the proximal and whole kidney response to AUN (n = 6). In conclusion, depression of renal nerve activity inhibits both NaHCO3 and NaCl reabsorption in the rat superficial proximal convoluted tubule. The data are consistent with the hypothesis that changes in renal nerve activity modify whole kidney electrolyte excretion under physiological conditions at least partially by regulating proximal transport.

Absorption↗
PubMed1986

Atrial natriuretic factor can increase renal solute excretion primarily by raising glomerular filtration.

Controversy persists on whether atrial natriuretic factor (ANF) raises renal solute excretion simply by increasing glomerular filtration rate (GFR) or whether it directly inhibits tubular transport (independent of changes in flow rate). Free-flow micropuncture techniques were used in 10 Munich-Wistar rats. ANF caused a significant increase in single-nephron and whole-kidney GFR (41.6 +/- 1.4 to 52.7 +/- 2.3 nl/min and 0.95 +/- 0.05 to 1.24 +/- 0.09 ml/min, respectively). Although absolute proximal sodium, bicarbonate, and chloride reabsorption increased, the increment in reabsorption was less than the increase in load; therefore solute delivery out of the proximal tubule increased by approximately 30-35%. Whole-kidney electrolyte excretion also rose markedly. When single-nephron and whole-kidney GFR were reduced back to a control level by aortic constriction (40.2 +/- 1.8 nl/min and 0.93 +/- 0.05 ml/min, respectively), proximal transport reverted to normal values despite persistent ANF administration. Ninety percent of the ANF-induced natriuresis and chloruresis were simultaneously abolished when GFR was normalized. In conclusion, ANF has no direct effect on reabsorption in the superficial proximal convoluted tubule independent of changes in filtration rate. Although direct effects on more distal or deeper nephron segments are not precluded, the present data suggest that ANF can increase renal solute excretion predominantly by acutely augmenting GFR.

Animals↗
PubMed1986

Axial heterogeneity of bicarbonate, chloride, and water transport in the rat proximal convoluted tubule. Effects of change in luminal flow rate and of alkalemia.

These studies examined regulation of superficial proximal convoluted tubule (PCT) transport as a function of length. When single nephron glomerular filtration rate (SNGFR) increased from 28.7 +/- 0.7 nl/min in hydropenia to 41.5 +/- 0.4 nl/min in euvolemia, bicarbonate, chloride, and water reabsorption in the early (1st mm) PCT increased proportionally: from 354 +/- 21 peq/mm X min, 206 +/- 55 peq/mm X min, and 5.9 +/- 0.4 nl/mm X min to 520 +/- 12 peq/mm X min, 585 +/- 21 peq/mm X min, and 10.1 +/- 0.4 nl/mm X min, respectively. These high transport rates did not increase further, however, when SNGFR went to 51.2 +/- 0.7 or 50.7 +/- 0.6 nl/min after atrial natriuretic factor or glucagon administration. Anion and water transport rates in the late PCT were lower and exhibited less flow dependence. During chronic metabolic alkalosis, acidification was inhibited in the late but not early PCT. In conclusion, the early PCT is distinguished from the late PCT by having high-capacity, flow-responsive but saturable, anion- and water-reabsorptive processes relatively unaffected by alkalemia.

Absorption↗