The Experts below are selected from a list of 56910 Experts worldwide ranked by ideXlab platform
Robert M Rapoport - One of the best experts on this subject based on the ideXlab platform.
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pco2 and Ph Regulation of cerebral blood flow
Frontiers in Physiology, 2012Co-Authors: Seonghun Yoon, Mario Zuccarello, Robert M RapoportAbstract:CO2 Serves as one of the fundamental regulators of cerebral blood flow. It is widely considered that this Regulation occurs through pCO2-driven changes in Ph of the cerebral spinal fluid, with elevated and lowered Ph causing direct relaxation and contraction of the smooth muscle, respectively. However, some findings also suggest that pCO2 acts independently of and/or in conjunction with altered Ph. This action may be due to a direct effect of cerebral spinal fluid pCO2 on the smooth muscle as well as on the endothelium, nerves, and astrocytes. Findings may also point to an action of arterial pCO2 on the endothelium to regulate smooth muscle contractility. Thus, the effects of Ph and pCO2 may be influenced by the absence/presence of different cell types in the various experimental preparations. Results may also be influenced by experimental parameters including myogenic tone as well as solutions containing significantly altered HCO3- concentrations, i.e., solutions routinely employed to differentiate the effects of Ph from pCO2. In sum, it appears that pCO2, independently and in conjunction with Ph, may regulate cerebral blood flow.
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pco 2 and Ph Regulation of cerebral blood flow
Frontiers in Physiology, 2012Co-Authors: Seonghun Yoon, Mario Zuccarello, Robert M RapoportAbstract:CO(2) serves as one of the fundamental regulators of cerebral blood flow (CBF). It is widely considered that this Regulation occurs through pCO(2)-driven changes in Ph of the cerebral spinal fluid (CSF), with elevated and lowered Ph causing direct relaxation and contraction of the smooth muscle, respectively. However, some findings also suggest that pCO(2) acts independently of and/or in conjunction with altered Ph. This action may be due to a direct effect of CSF pCO(2) on the smooth muscle as well as on the endothelium, nerves, and astrocytes. Findings may also point to an action of arterial pCO(2) on the endothelium to regulate smooth muscle contractility. Thus, the effects of Ph and pCO(2) may be influenced by the absence/presence of different cell types in the various experimental preparations. Results may also be influenced by experimental parameters including myogenic tone as well as solutions containing significantly altered HCO(3) (-) concentrations, i.e., solutions routinely employed to differentiate the effects of Ph from pCO(2). In sum, it appears that pCO(2), independently and in conjunction with Ph, may regulate CBF.
R D Vaughanjones - One of the best experts on this subject based on the ideXlab platform.
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intracellular Ph Regulation in heart
Journal of Molecular and Cellular Cardiology, 2009Co-Authors: R D Vaughanjones, Kenneth W Spitzer, Pawel SwietachAbstract:Intracellular Ph (Phi) is an important modulator of cardiac excitation and contraction, and a potent trigger of electrical arrhythmia. This review outlines the intracellular and membrane mechanisms that control Phi in the cardiac myocyte. We consider the kinetic Regulation of sarcolemmal H+, OH- and HCO3- transporters by Ph, and by receptor-coupled intracellular signalling systems. We also consider how activity of these Phi effector proteins is coordinated spatially in the myocardium by intracellular mobile buffer shuttles, gap junctional channels and carbonic anhydrase enzymes. Finally, we review the impact of Phi regulatory proteins on intracellular Ca2+ signalling, and their participation in clinical disorders such as myocardial ischaemia, maladaptive hypertroPhy and heart failure. Such multiple effects emPhasise the fundamental role that Phi Regulation plays in the heart.
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characterization of intracellular Ph Regulation in the guinea pig ventricular myocyte
The Journal of Physiology, 1999Co-Authors: Chae Hun Leem, Dominique Lagadicgossmann, R D VaughanjonesAbstract:Intracellular Ph was recorded fluorimetrically by using carboxy-SNARF-1, AM-loaded into superfused ventricular myocytes isolated from guinea-pig heart. Intracellular acid and base loads were induced experimentally and the changes of Phi used to estimate intracellular buffering power (β). The rate of Phi recovery from acid or base loads was used, in conjunction with the measurements of β, to estimate sarcolemmal transporter fluxes of acid equivalents. A combination of ion substitution and Pharmacological inhibitors was used to dissect acid effluxes carried on Na+-H+ exchange (NHE) and Na+-HCO3− cotransport (NBC), and acid influxes carried on Cl−-HCO3− exchange (AE) and Cl−-OH− exchange (CHE). The intracellular intrinsic buffering power (βi), estimated under CO2/HCO3−-free conditions, varied inversely with Phi in a manner consistent with two principal intracellular buffers of differing concentration and pK. In CO2/HCO3−-buffered conditions, intracellular buffering was roughly doubled. The size of the CO2-dependent component (βCO2) was consistent with buffering in a cell fully open to CO2. Because the full value of βCO2 develops slowly (2·5 min), it had to be measured under equilibrium conditions. The value of βCO2 increased monotonically with Phi. In 5 % CO2/HCO3−-buffered conditions (Pho 7·40), acid extrusion on NHE and NBC increased as Phi was reduced, with the greater increase occurring through NHE at Phi 7·15. At resting Phi (7·04-7·07), all four carriers were activated equally, albeit at a low rate (about 0·15 mM min−1). The Phi dependence of flux through the transporters, in combination with the Phi and time dependence of intracellular buffering (βi+βCO2), was used to predict mathematically the recovery of Phi following an intracellular acid or base load. Under several conditions the mathematical predictions compared well with experimental recordings, suggesting that the model of dual acid influx and acid efflux transporters is sufficient to account for Phi Regulation in the cardiac cell. Key properties of the Phi control system are discussed. Intracellular Ph in mammalian myocardial cells is governed by the balance among four sarcolemmal acid-equivalent ion transporters (Sun et al. 1996). Two of these, Na+-H+ exchange (NHE) and Na+-HCO3− cotransport (NBC), mediate acid-equivalent efflux (acid extrusion; Dart & Vaughan-Jones, 1992; Lagadic-Gossmann et al. 1992a) while the other two, Cl−-HCO3− exchange (anion exchange; AE) and Cl−-OH− exchange (CHE) mediate acid-equivalent influx (acid loading; Vaughan-Jones, 1979; Sun et al. 1996; Leem & Vaughan-Jones, 1998b). Activity of the transporters is modulated by Ph. In the present work, we attempt to characterize the overall kinetics of cardiac Phi Regulation in terms of the activity of these acid/base transporters. In order to do this, we have determined experimentally the Phi sensitivity of acid-equivalent flux through each type of transporter. Provided that all relevant transporters have been identified it should then be possible, by summing their fluxes, to reconstruct the time course of Phi Regulation following acute, intracellular acid or base loads. By inspecting the Phi sensitivity of the four transporters, it should also be possible to deduce the relative importance of each to the control of intracellular Ph, and to the maintenance of resting Phi. In order to investigate the kinetic properties of a transporter, we have used recordings of Phi in isolated ventricular myocytes to estimate sarcolemmal fluxes of acid equivalents. Fluxes are calculated as the product of dPhi/dt (the rate of change of Phi), caused by a transporter's activity, and βtot, which represents total intracellular buffering power. The value assumed for βtot therefore affects the estimate of acid/base flux. Buffering comprises two components that can be summed algebraically (Roos & Boron, 1981). These are intrinsic, non-CO2-dependent buffering (βi) and CO2-dependent buffering (βCO2). The values of intrinsic and CO2-dependent buffering power vary differently as Phi varies. Two further points are relevant. (i) In some cell types, such as smooth muscle myocytes (Baro et al. 1989; Aickin, 1994) and CNS neurones (Amos et al. 1996), βCO2 is reported to be essentially zero, even in the presence of Physiological concentrations of CO2, although the reason for this is far from clear and such reports remain controversial. To date, systematic measurements of βCO2 have not been made in the cardiac ventricular cell, although clear effects of CO2-dependent buffering on Phi are evident (Leem & Vaughan-Jones, 1998a). (ii) In the cardiac cell, intracellular CO2-dependent buffering equilibrates slowly, most notably following acute intracellular alkali loads (Leem & Vaughan-Jones, 1998a). This is in contrast to intracellular intrinsic buffering which, on the time scale of the experiments shown in the present work, equilibrates essentially instantaneously (Leem & Vaughan-Jones, 1998a). The slow equilibration of CO2-dependent buffering produces Phi transients that may be mistaken for acid transport. Estimates of transporter flux from recordings of Phi must therefore be made when the intracellular CO2/HCO3− buffer system is at equilibrium. In view of the complexities and uncertainties concerning intracellular buffering in cardiac cells, we have designed experiments to measure both βi and βCO2. By using data from the experiments outlined above, we have formulated a mathematical model of Phi Regulation that takes into account not only Phi-controlled acid efflux and influx through multiple types of transporter, but also intrinsic buffering and slow, intracellular CO2-dependent buffering. A preliminary account of some of this work has been published (Leem & Vaughan-Jones, 1996).
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characterization of intracellular Ph Regulation in the guinea pig ventricular myocyte
The Journal of Physiology, 1999Co-Authors: Chae Hun Leem, Dominique Lagadicgossmann, R D VaughanjonesAbstract:1. Intracellular Ph was recorded fluorimetrically by using carboxy-SNARF-1, AM-loaded into superfused ventricular myocytes isolated from guinea-pig heart. Intracellular acid and base loads were induced experimentally and the changes of Phi used to estimate intracellular buffering power (beta). The rate of Phi recovery from acid or base loads was used, in conjunction with the measurements of beta, to estimate sarcolemmal transporter fluxes of acid equivalents. A combination of ion substitution and Pharmacological inhibitors was used to dissect acid effluxes carried on Na+-H+ exchange (NHE) and Na+-HCO3- cotransport (NBC), and acid influxes carried on Cl--HCO3- exchange (AE) and Cl--OH- exchange (CHE). 2. The intracellular intrinsic buffering power (betai), estimated under CO2/HCO3--free conditions, varied inversely with Phi in a manner consistent with two principal intracellular buffers of differing concentration and pK. In CO2/HCO3--buffered conditions, intracellular buffering was roughly doubled. The size of the CO2-dependent component (betaCO2) was consistent with buffering in a cell fully open to CO2. Because the full value of betaCO2 develops slowly (2.5 min), it had to be measured under equilibrium conditions. The value of betaCO2 increased monotonically with Phi. 3. In 5 % CO2/HCO3--buffered conditions (Pho 7.40), acid extrusion on NHE and NBC increased as Phi was reduced, with the greater increase occurring through NHE at Phi 7.15. At resting Phi (7.04-7.07), all four carriers were activated equally, albeit at a low rate (about 0.15 mM min-1). 4. The Phi dependence of flux through the transporters, in combination with the Phi and time dependence of intracellular buffering (betai + betaCO2), was used to predict mathematically the recovery of Phi following an intracellular acid or base load. Under several conditions the mathematical predictions compared well with experimental recordings, suggesting that the model of dual acid influx and acid efflux transporters is sufficient to account for Phi Regulation in the cardiac cell. Key properties of the Phi control system are discussed.
Claudiu T Supuran - One of the best experts on this subject based on the ideXlab platform.
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novel approaches for designing drugs that interfere with Ph Regulation
Expert Opinion on Drug Discovery, 2019Co-Authors: Emanuela Berrino, Claudiu T SupuranAbstract:Introduction: In all living species, Ph Regulation is a tightly controlled process, with a plethora of proteins involved in its Regulation. These include sodium-proton exchangers, carbonic anhydras...
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interfering with Ph Regulation in tumours as a therapeutic strategy
Nature Reviews Drug Discovery, 2011Co-Authors: Dario Neri, Claudiu T SupuranAbstract:The ability of tumour cells to maintain a slightly alkaline intracellular Ph and an acidic extracellular Ph aids the growth of primary tumours and the formation of metastases. Inhibiting Ph-regulating proteins in tumours represents a novel therapeutic strategy that is not exploited by the classical anticancer drugs.
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Interfering with Ph Regulation in tumours as a therapeutic strategy
Nature Reviews Drug Discovery, 2011Co-Authors: Dario Neri, Claudiu T SupuranAbstract:The high metabolic rate of tumours often leads to acidosis and hypoxia in poorly perfused regions. Tumour cells have thus evolved the ability to function in a more acidic environment than normal cells. Key Ph regulators in tumour cells include: isoforms 2, 9 and 12 of carbonic anhydrase, isoforms of anion exchangers, Na+/HCO3- co-transporters, Na+/H+ exchangers, monocarboxylate transporters and the vacuolar ATPase. Both small molecules and antibodies targeting these Ph regulators are currently at various stages of clinical development. These antitumour mechanisms are not exploited by the classical cancer drugs and therefore represent a new anticancer drug discovery strategy.
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epithelial carbonic anhydrases facilitate pco2 and Ph Regulation in rat duodenal mucosa
The Journal of Physiology, 2006Co-Authors: Misa Mizumori, Claudiu T Supuran, Justin G Meyerowitz, Tetsu Takeuchi, Shu Lim, Paul W N Lee, Paul H Guth, Eli Engel, Jonathan D Kaunitz, Yasutada AkibaAbstract:The duodenum must absorb ∼450 mmol of H+ per 24 h in order to decrease [H+] of the luminal content by 6 log orders over its 15 cm length (Feldman & Colturi, 1984). HCl in the duodenal lumen is neutralized by HCO3− secreted by the pancreas and duodenal epithelium, generating extremely high luminal CO2 pressures (PCO2 > 30 kPa) which dissipate by the proximal jejunum (Rune & Henriksen, 1969; Winship & Robinson, 1974). Gastric mucosal CO2 and H+ permeability is low, since pyloric obstruction leads to severe metabolic alkalosis due to the inability of the stomach to absorb substantial quantities of H+ or CO2 (Gamble & Ross, 1925; Javaheri & Nardell 1981). Thus, the duodenum is the major site for intestinal H+ and CO2 absorption. Transmucosal bulk absorption of CO2 and H+ is likely to follow the sequence of transport across the apical cell membrane into the cytosol, transport across the basolateral membrane of the epithelium into the subepithelial interstitium, followed by transport into the portal vein. The mechanism for CO2 and H+ transport across cell membranes remains incompletely understood. In terms of transapical CO2 and H+ transport, one accepted model involves conversion of luminal H+ and HCO3− to CO2 and H2O, diffusion of CO2 across the apical plasma membrane, and hydration of CO2 to HCO3− and H+ in the cytoplasm. This process, sometimes termed the Jacobs-Stewart cycle after its original description in red blood cells (Jacobs & Stewart, 1942), requires the presence of intracellular and extracellular carbonic anhydrases (CAs) and a plasma membrane anion exchanger. Since the duodenal epithelium has abundant cytoplasmic and membrane-associated CA activity (Sugai et al. 1994; Lonnerholm et al. 1989; Parkkila et al. 1994; Saarnio et al. 1998; Purkerson & Schwartz, 2005; Leppilampi et al. 2005) and apical anion exchangers (Wang et al. 2002; Spiegel et al. 2003), we hypothesized that most of the excess duodenal luminal H+ was absorbed through neutralization of secreted HCO3−, yielding luminal CO2. CO2 is the molecular species that then traverses the apical membrane, which enters the cytoplasm, and is hydrated to H2CO3, which then dissociates in the cytoplasm to H+ and HCO3−. HCO3− is transported into the lumen whereas H+ is transported into the submucosal space by membrane transport proteins. In essence, luminal H+ is transported through the apical membrane as CO2, but HCO3− is simultaneously secreted in its anionic form. Several observations support this hypothesis. We, and others have found that luminal acidification or elevation of luminal PCO2 provokes several epithelial responses, such as acidification of the cytoplasm and subepithelial interstitial fluid, increased mucosal blood flow, increased HCO3− secretion, and increased mucus secretion (Flemstrom & Kivilaakso, 1983; Flemstrom, 1994; Seno et al. 1998; Paimela et al. 1990, 1992; Akiba & Kaunitz, 1999; Akiba et al. 2000, 2001a,b, 2006). Since these responses appear to be dependent on acidification of the subepithelial space, and since elevated luminal CO2 or H+ provoke similar responses, it appears that luminal CO2 must be converted to subepithelial H+, which then signals these protective mechanisms (Allen & Flemstrom, 2005). The further characterization of transmucosal H+ and CO2 movement thus has larger implications for the understanding of mucosal protective mechanisms and the signalling pathways coordinating mucosal responses to acid perfusion. In order to further test our hypothesis, we devised a system in which the movement of CO2 and H+ between lumen, mucosa and the portal vein was measured. In order to determine the contribution of cytoplasmic and extracellular CAs towards H+ and CO2 movement, we used cell-permeant and -impermeant CA inhibitors. Finally, transmucosal tracer carbon movement was measured using 13C. Our results support our hypothesis that luminal H+, neutralized by secreted HCO3−, is converted to CO2 prior to entry into the cytoplasm of the epithelial cells, and that cellular CO2 is reconverted to H+, which then is transported into the portal vein.
Etana Padan - One of the best experts on this subject based on the ideXlab platform.
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functional and structural dynamics of nhaa a prototype for na and h antiporters which are responsible for na and h homeostasis in cells
Biochimica et Biophysica Acta, 2014Co-Authors: Etana PadanAbstract:The crystal structure of down-regulated NhaA crystallized at acidic Ph4 [21] has provided the first structural insights into the antiport mechanism and Ph Regulation of a Na(+)/H(+) antiporter [22]. On the basis of the NhaA crystal structure [21] and experimental data (reviewed in [2,22,38] we have suggested that NhaA is organized into two functional regions: (i) a cluster of amino acids responsible for Ph Regulation (ii) a catalytic region at the middle of the TM IV/XI assembly, with its unique antiparallel unfolded regions that cross each other forming a delicate electrostatic balance in the middle of the membrane. This unique structure contributes to the cation binding site and allows the rapid conformational changes expected for NhaA. Extended chains interrupting helices appear now a common feature for ion binding in transporters. However the NhaA fold is unique and shared by ASBTNM [30] and NapA [29]. Computation [13], electroPhysiology [69] combined with biochemistry [33,47] have provided intriguing models for the mechanism of NhaA. However, the conformational changes and the residues involved have not yet been fully identified. Another issue which is still enigma is how energy is transduced "in this 'nano-machine.'" We expect that an integrative approach will reveal the residues that are crucial for NhaA activity and Regulation, as well as elucidate the Phand ligand-induced conformational changes and their dynamics. Ultimately, integrative results will shed light on the mechanism of activity and Ph Regulation of NhaA, a prototype of the CPA2 family of transporters. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.
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revealing the ligand binding site of nhaa na h antiporter and its Ph dependence
Journal of Biological Chemistry, 2012Co-Authors: Michal Maes, Abraham Rimon, Lena Kozachkovmagrisso, Assaf Friedler, Etana PadanAbstract:Ph and Na(+) homeostasis in all cells requires Na(+)/H(+) antiporters. In most cases, their activity is tightly Ph-regulated. NhaA, the main antiporter of Escherichia coli, has homologues in all biological kingdoms. The crystal structure of NhaA provided insights into the mechanism of action and Ph Regulation of an antiporter. However, the active site of NhaA remained elusive because neither Na(+) nor Li(+), the NhaA ligands, were observed in the structure. Using isothermal titration calorimetry, we show that purified NhaA binds Li(+) in detergent micelles. This interaction is driven by an increase in enthalpy (ΔH of -8000 ± 300 cal/mol and ΔS of -15.2 cal/mol/degree at 283 K), involves a single binding site per NhaA molecule, and is highly specific and drastically dependent on Ph; Li(+) binding was observed only at Ph 8.5. Combining mutational analysis with the isothermal titration calorimetry measurements revealed that Asp-163, Asp-164, Thr-132, and Asp-133 form the Li(+) binding site, whereas Lys-300 plays an important role in Ph Regulation of the antiporter.
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transport mechanism and Ph Regulation of the na h antiporter nhaa from escherichia coli an electroPhysiological study
Journal of Biological Chemistry, 2011Co-Authors: Thomas Mager, Etana Padan, Abraham Rimon, Klaus FendlerAbstract:Using an electroPhysiological assay the activity of NhaA was tested in a wide Ph range from Ph 5.0 to 9.5. Forward and reverse transport directions were investigated at zero membrane potential using preparations with inside-out and right side-out-oriented transporters with Na+ or H+ gradients as the driving force. Under symmetrical Ph conditions with a Na+ gradient for activation, both the wt and the Ph-shifted G338S variant exhibit highly symmetrical transport activity with bell-shaped Ph dependences, but the optimal Ph was shifted 1.8 Ph units to the acidic range in the variant. In both strains the Ph dependence was associated with a systematic increase of the Km for Na+ at acidic Ph. Under symmetrical Na+ concentration with a Ph gradient for NhaA activation, an unexpected novel characteristic of the antiporter was revealed; rather than being down-regulated, it remained active even at Ph as low as 5. These data allowed a transport mechanism to advance based on competing Na+ and H+ binding to a common transport site and a kinetic model to develop quantitatively explaining the experimental results. In support of these results, both alkaline Ph and Na+ induced the conformational change of NhaA associated with NhaA cation translocation as demonstrated here by trypsin digestion. Furthermore, Na+ translocation was found to be associated with the displacement of a negative charge. In conclusion, the electroPhysiological assay allows the revelation of the mechanism of NhaA antiport and sheds new light on the concept of NhaA Ph Regulation.
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trans membrane domain iv is involved in ion transport activity and Ph Regulation of the nhaa na h antiporter of escherichia coli
Biochemistry, 2002Co-Authors: Livnat Galili, Andrea Rothman, Lena Kozachkov, And Abraham Rimon, Etana PadanAbstract:We have previously shown that the activity of NhaA is regulated by Ph and found mutations that affect dramatically the Ph dependence of the rate but not the K(m) (for Na(+) and Li(+)) of NhaA. In the present work, we found that helix IV is involved both in ion translocation as well as in Ph Regulation of NhaA. Two novel types of NhaA mutants were found clustered in trans membrane segment (TMS) IV: One type (D133C, T132C, and P129L) affects the apparent K(m) of NhaA to the cations with no significant effect on the Ph profile of the antiporter; no shift of the Ph profile was found when the activity of these mutants was measured at saturating Na(+) concentration. In contrast, the other type of mutations (A127V and A127T) was found to affect both the K(m) and the Ph dependence of the rate of NhaA whether tested at saturating Na(+) concentration or not. These results imply that residues involved in the ion translocation of NhaA may (A127) or may not (D133, T132, and P129) overlap with those affecting the Ph response of the antiporter. All mutants cluster in the N-terminal half of the putative alPha-helix IV, one type on one face, the other on the opposite. Cys accessibility test demonstrated that although D133C is located in the middle of TMS IV, it is inhibited by N-ethylmaleimide and is exposed to the cytoplasm.
Seonghun Yoon - One of the best experts on this subject based on the ideXlab platform.
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pco2 and Ph Regulation of cerebral blood flow
Frontiers in Physiology, 2012Co-Authors: Seonghun Yoon, Mario Zuccarello, Robert M RapoportAbstract:CO2 Serves as one of the fundamental regulators of cerebral blood flow. It is widely considered that this Regulation occurs through pCO2-driven changes in Ph of the cerebral spinal fluid, with elevated and lowered Ph causing direct relaxation and contraction of the smooth muscle, respectively. However, some findings also suggest that pCO2 acts independently of and/or in conjunction with altered Ph. This action may be due to a direct effect of cerebral spinal fluid pCO2 on the smooth muscle as well as on the endothelium, nerves, and astrocytes. Findings may also point to an action of arterial pCO2 on the endothelium to regulate smooth muscle contractility. Thus, the effects of Ph and pCO2 may be influenced by the absence/presence of different cell types in the various experimental preparations. Results may also be influenced by experimental parameters including myogenic tone as well as solutions containing significantly altered HCO3- concentrations, i.e., solutions routinely employed to differentiate the effects of Ph from pCO2. In sum, it appears that pCO2, independently and in conjunction with Ph, may regulate cerebral blood flow.
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pco 2 and Ph Regulation of cerebral blood flow
Frontiers in Physiology, 2012Co-Authors: Seonghun Yoon, Mario Zuccarello, Robert M RapoportAbstract:CO(2) serves as one of the fundamental regulators of cerebral blood flow (CBF). It is widely considered that this Regulation occurs through pCO(2)-driven changes in Ph of the cerebral spinal fluid (CSF), with elevated and lowered Ph causing direct relaxation and contraction of the smooth muscle, respectively. However, some findings also suggest that pCO(2) acts independently of and/or in conjunction with altered Ph. This action may be due to a direct effect of CSF pCO(2) on the smooth muscle as well as on the endothelium, nerves, and astrocytes. Findings may also point to an action of arterial pCO(2) on the endothelium to regulate smooth muscle contractility. Thus, the effects of Ph and pCO(2) may be influenced by the absence/presence of different cell types in the various experimental preparations. Results may also be influenced by experimental parameters including myogenic tone as well as solutions containing significantly altered HCO(3) (-) concentrations, i.e., solutions routinely employed to differentiate the effects of Ph from pCO(2). In sum, it appears that pCO(2), independently and in conjunction with Ph, may regulate CBF.