JOURN4L
Vol.
OF
APPLIED
bYSIOLOGY
39, No. 3, September
fitters
1975.
in U.S.A.
to the Editor Letters should address a group of readers, not just the author of the article; they should offer a di$erent interpretation, a correction, or point out an error or oversight; they should stimulate intellectual, if not experimental, activity; and they should be capable of provoking a rewarding response the authors.
from
To the Editor: I read with interest the paper by Dain and Gold (J. Appl. Physiol. 38: 96-l 00, 1975) on experimental asthma in conscious allergic dogs. Although they only studied very few animals, they were able to show changes in lung mechanics due to histamine and to antigen similar to those seen in man. However, I fear their enthusiasm for their parasympathetic hypothesis for the mechanism of asthma has allowed their interpretation of their data to run ahead of the facts as presented in the paper. They claim that asthma induced by both histamine and antigen was largely reversed by isoproterenol and atropine, but they only give results in terms of the maximum increase in resistance after control tests and the lowest level of resistance measured after treatment with isoproterenol or atropine. They do not give all the intermediate points, but from the illustrations provided it is clear that much of the histamine effect has worn off by 9 min after the challenge, and similarly much of the effect of antigen has worn off by 13 min or so after challenge. In the experiments when isoproterenol or atropine were used, these drugs were given 2 or 3 min after the challenge, and the minimum airways resistance was measured within another 5 min for isoproterenol and another 10 min for atropine. The minimum values recorded should be compared with the minimum values recorded in the control experiments. Rough calculations show that pulmonary resistance was still increased by 2 or 3 times in the control experiments after 9-13 min, and was also increased by about 3070 in both the isoproterenol and atropine experiments. Unfortunately the authors do not provide adequate data to enable the reader to assess the true magnitude of the effect of isoproterenol or the massive dose of atropine used in these studies, and it is a little optimistic for them to state that “aerosols of isoproterenol or atropine sulfate inhibited the increased resistance.” S. Godfrey Institute of Child
Health,
University
pine treatment, airflow resistance was only 20-30% above control, clearly indicating an inhibition of the bronchoconstrictor response. Apparently, Dr. Godfrey is unfamiliar with the dose of atropine required to block vagally mediated bronchoconstriction. At least 0.5 mg/kg is required in dogs; as much as 2 mg/kg are required in smaller mammals. By delivering the atropine as an aerosol, we increased the selectivity of the effect on airway tissues with minimal extrapulmonary side effects. Thus, we delivered the dose of atropine required to achieve the desired pharmacological effect, i.e., postganglionic parasympathetic efferent blockade. Finally, we believe that these experiments indicate that the conscious, allergic dog is a suitable subject for a long-term study of asthma. Our results are consistent with our earlier findings in in anesthetized dogs that a vagal reflex is involved in the bronchoconstrictor response to inhaled histamine and specific antigen. D. Dain University
of London
REPLY
To the Editor: Dr. Godfrey’s analysis of our article has missed a number of critical points. Our study clearly demonstrates that it is possible to measure the mechanical properties of the lungs reproducibly over long periods of time in awake, conscious dogs. The changes in the mechanical properties of the lungs induced by both histamine and antigen aerosols in these dogs are similar to those described in human subjects. The figures and th e t ex t indicate that during the control experiments the airflow resistance after histamine aerosol was still 240280y0 above control at 8-9 min and more than 100% above control at 13 min when the effects of treatment with isoproterenol and atropine, respectively, were reported. Similarly, airflow resistance after antigen aerosol was at its peak value of 307 y0 above control at 1 l-l 2 min and still exceeded 200 y0 above control at 20-21 min when the effects on the airway response of isoproterenol and atropine, respectively, were reported. After isoproterenol or atro-
and W. M. Gold of California, San Francisco
To the Editor: In a recent paper entitled “Splanchnic hemodynamic response to passive hyperventilation” (J. AppZ. Physiol. 38: 156-162, 1975) the author, Dr. E. Johnson, discusses some apparent variances with the observations of Greenway and Lautt (Circulation Res. 26: 697-703, 1970). We had reported, as Dr. Johnson “that transsinusoidal fluid filtration in the liver is correctly noted, dependent on the sinusoidal hydrostatic pressure and that no protective mechanisms are available to prevent filtration when hepatic venous pressure is raised for long periods.” She feels that this prolonged filtration of fluids is inconsistent with observations by herself as well as Hanson and P. C. Johnson (Am. J. Physiol. 211: 712-720, 1966). Dr. Johnson assumes that a prolonged increase in filtration rate should result in “a uniform increase in transhepatic portal venous resistance consonant with notably increased tissue pressure.” It is this assumption rather than her results which is at variance with our observations. No consistent increase in portal resistance was seen by her or Hanson and Johnson and unpublished observations of my own would tend to agree with this. However, the fact that they did not see an increase in portal resistance is not relevant to the case of whether prolonged filtration occurs since in our paper the point was made that increased fluid filtration in the liver does not appear to significantly elevate tissue pressure. One therefore should not expect an increased portal resistance in the presence of prolonged filtration in the liver. We pointed out that this situation is “in marked contrast to the results observed in the intestinal vascular bed where the filtration ceased after 5-8 min . . . principally due to an increase in tissue hydrostatic pressure.” Filtered fluids pass across the liver into the peritoneal spaces with a protein content nearly equal to that of plasma and the rate of filtration continues undiminished over a period of up to 5 h, an observation that would be unlikely if tissue pressure were to be notably increased due to filtration. Further, the rate of filtration
511
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LETTERS
512 per mmHg elevation in hepatic venous pressure was the same for small pressure elevations (2 mmHg) as for large elevations (14 mmHg) indicating a lack of notable changes of tissue pressure in spite of widely varying total rates of filtration. The livers in these experiments and those of Hanson and Johnson did not show signs of hepatic congestion of the type reported by Brauer, Holloway, and Leong (Am.J. Physiol. 197: 681-692, 1959) using the isolated, perfused rat liver, but it should be noted that considerable objections to the use of isolated liver preparations for hemodynamic studies have been raised (Greenway and Stark, Physiol. Rev. 51: 23-65, 197 1; Lautt and Plaa, Can. J. Physiol. Pharmacol. 52: 727, 1974). In conclusion, our observation of prolonged filtration of fluids as a result of elevated hepatic venous pressure does not imply that tissue pressure would be notably elevated and would not therefore predict changes in portal resistance resulting from tissue pressure changes. Our results also do not preclude an active myogenic effect of elevated venous pressure on presinusoidal resistance vessels; in fact we have concluded (Greenway and Lautt, &it. J. Pharmacol. 44: 177, 1972) that activity of the presinusoidal resistance vessels does not significantly affect sinusoidal pressure or the filtration induced by elevated hepatic venous pressure. W. W. Lautt Dept. of Physiology,
University
of Saskatchewan
REPLY
To the Editor: In their paper entitled “Effects of hepatic venous pressure on transsinusoidal fluid transfer in the liver-of the anesthetized cat” (Circulation Res. 26: 697-703, 1970), Greenway and Lautt ligated and cut the ligaments connecting the central and
TO THE EDITOR
left lobes of the liver to the diaphragm. The liver, with the exception of the right posterior lobe was then lifted and inserted into a Plexiglas plethysmograph. Hepatic venous pressure was elevated by raising the outlet of the hepatic venous cannula and the ensuing increase in hepatic volume was measured by plethysmography. Hepatic blood volume (51Cr-tagged red blood cells) increased rapidly (approx twofold by 20 min, Fig. 3) and then remained essentially constant. Total hepatic volume continued to increase at a steady rate so that at 60 min it was greater than threefold (Fig. 3). This steady rate of increase was reported by them to continue for at least 4 h. “On restoration of hepatic venous pressure to zero, the hepatic blood volume returned toward the control level and 80% of the increase during the period of raised venous pressure drained from the liver. The filtered fluid remained in the plethysmograph.” Thus excess fluid was almost certainly present in the interstitium
01 the liver. In my study entitled “Splanchnic hemodynamic response to passive hyperventilation” (J. Appl. Physiol. 38: 156-162, 1975), the liver was in situ with ligaments intact. The abdomen was closed. Hepatic venous pressure was elevated as a result of increased intrathoracic pressure during intermittent positive-pressure hyperventilation (a procedure which raises intra-abdominal pressure as well). The period of hyperventilation lasted 180 min. Had interstial fluid been accumulating to the extent noted by Greenway and Lautt, during my study, where the liver was less free to expand, I would have expected to see some transhepatic impedance to the low pressure portal venous system. Elsie Ernest Johnson Dept. of Anaesthesia and Harvard Medical School
Respiratory
Therapy
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 10, 2019.
Vol.
OF
APPLIED
bYSIOLOGY
39, No. 3, September
fitters
1975.
in U.S.A.
to the Editor Letters should address a group of readers, not just the author of the article; they should offer a di$erent interpretation, a correction, or point out an error or oversight; they should stimulate intellectual, if not experimental, activity; and they should be capable of provoking a rewarding response the authors.
from
To the Editor: I read with interest the paper by Dain and Gold (J. Appl. Physiol. 38: 96-l 00, 1975) on experimental asthma in conscious allergic dogs. Although they only studied very few animals, they were able to show changes in lung mechanics due to histamine and to antigen similar to those seen in man. However, I fear their enthusiasm for their parasympathetic hypothesis for the mechanism of asthma has allowed their interpretation of their data to run ahead of the facts as presented in the paper. They claim that asthma induced by both histamine and antigen was largely reversed by isoproterenol and atropine, but they only give results in terms of the maximum increase in resistance after control tests and the lowest level of resistance measured after treatment with isoproterenol or atropine. They do not give all the intermediate points, but from the illustrations provided it is clear that much of the histamine effect has worn off by 9 min after the challenge, and similarly much of the effect of antigen has worn off by 13 min or so after challenge. In the experiments when isoproterenol or atropine were used, these drugs were given 2 or 3 min after the challenge, and the minimum airways resistance was measured within another 5 min for isoproterenol and another 10 min for atropine. The minimum values recorded should be compared with the minimum values recorded in the control experiments. Rough calculations show that pulmonary resistance was still increased by 2 or 3 times in the control experiments after 9-13 min, and was also increased by about 3070 in both the isoproterenol and atropine experiments. Unfortunately the authors do not provide adequate data to enable the reader to assess the true magnitude of the effect of isoproterenol or the massive dose of atropine used in these studies, and it is a little optimistic for them to state that “aerosols of isoproterenol or atropine sulfate inhibited the increased resistance.” S. Godfrey Institute of Child
Health,
University
pine treatment, airflow resistance was only 20-30% above control, clearly indicating an inhibition of the bronchoconstrictor response. Apparently, Dr. Godfrey is unfamiliar with the dose of atropine required to block vagally mediated bronchoconstriction. At least 0.5 mg/kg is required in dogs; as much as 2 mg/kg are required in smaller mammals. By delivering the atropine as an aerosol, we increased the selectivity of the effect on airway tissues with minimal extrapulmonary side effects. Thus, we delivered the dose of atropine required to achieve the desired pharmacological effect, i.e., postganglionic parasympathetic efferent blockade. Finally, we believe that these experiments indicate that the conscious, allergic dog is a suitable subject for a long-term study of asthma. Our results are consistent with our earlier findings in in anesthetized dogs that a vagal reflex is involved in the bronchoconstrictor response to inhaled histamine and specific antigen. D. Dain University
of London
REPLY
To the Editor: Dr. Godfrey’s analysis of our article has missed a number of critical points. Our study clearly demonstrates that it is possible to measure the mechanical properties of the lungs reproducibly over long periods of time in awake, conscious dogs. The changes in the mechanical properties of the lungs induced by both histamine and antigen aerosols in these dogs are similar to those described in human subjects. The figures and th e t ex t indicate that during the control experiments the airflow resistance after histamine aerosol was still 240280y0 above control at 8-9 min and more than 100% above control at 13 min when the effects of treatment with isoproterenol and atropine, respectively, were reported. Similarly, airflow resistance after antigen aerosol was at its peak value of 307 y0 above control at 1 l-l 2 min and still exceeded 200 y0 above control at 20-21 min when the effects on the airway response of isoproterenol and atropine, respectively, were reported. After isoproterenol or atro-
and W. M. Gold of California, San Francisco
To the Editor: In a recent paper entitled “Splanchnic hemodynamic response to passive hyperventilation” (J. AppZ. Physiol. 38: 156-162, 1975) the author, Dr. E. Johnson, discusses some apparent variances with the observations of Greenway and Lautt (Circulation Res. 26: 697-703, 1970). We had reported, as Dr. Johnson “that transsinusoidal fluid filtration in the liver is correctly noted, dependent on the sinusoidal hydrostatic pressure and that no protective mechanisms are available to prevent filtration when hepatic venous pressure is raised for long periods.” She feels that this prolonged filtration of fluids is inconsistent with observations by herself as well as Hanson and P. C. Johnson (Am. J. Physiol. 211: 712-720, 1966). Dr. Johnson assumes that a prolonged increase in filtration rate should result in “a uniform increase in transhepatic portal venous resistance consonant with notably increased tissue pressure.” It is this assumption rather than her results which is at variance with our observations. No consistent increase in portal resistance was seen by her or Hanson and Johnson and unpublished observations of my own would tend to agree with this. However, the fact that they did not see an increase in portal resistance is not relevant to the case of whether prolonged filtration occurs since in our paper the point was made that increased fluid filtration in the liver does not appear to significantly elevate tissue pressure. One therefore should not expect an increased portal resistance in the presence of prolonged filtration in the liver. We pointed out that this situation is “in marked contrast to the results observed in the intestinal vascular bed where the filtration ceased after 5-8 min . . . principally due to an increase in tissue hydrostatic pressure.” Filtered fluids pass across the liver into the peritoneal spaces with a protein content nearly equal to that of plasma and the rate of filtration continues undiminished over a period of up to 5 h, an observation that would be unlikely if tissue pressure were to be notably increased due to filtration. Further, the rate of filtration
511
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 10, 2019.
LETTERS
512 per mmHg elevation in hepatic venous pressure was the same for small pressure elevations (2 mmHg) as for large elevations (14 mmHg) indicating a lack of notable changes of tissue pressure in spite of widely varying total rates of filtration. The livers in these experiments and those of Hanson and Johnson did not show signs of hepatic congestion of the type reported by Brauer, Holloway, and Leong (Am.J. Physiol. 197: 681-692, 1959) using the isolated, perfused rat liver, but it should be noted that considerable objections to the use of isolated liver preparations for hemodynamic studies have been raised (Greenway and Stark, Physiol. Rev. 51: 23-65, 197 1; Lautt and Plaa, Can. J. Physiol. Pharmacol. 52: 727, 1974). In conclusion, our observation of prolonged filtration of fluids as a result of elevated hepatic venous pressure does not imply that tissue pressure would be notably elevated and would not therefore predict changes in portal resistance resulting from tissue pressure changes. Our results also do not preclude an active myogenic effect of elevated venous pressure on presinusoidal resistance vessels; in fact we have concluded (Greenway and Lautt, &it. J. Pharmacol. 44: 177, 1972) that activity of the presinusoidal resistance vessels does not significantly affect sinusoidal pressure or the filtration induced by elevated hepatic venous pressure. W. W. Lautt Dept. of Physiology,
University
of Saskatchewan
REPLY
To the Editor: In their paper entitled “Effects of hepatic venous pressure on transsinusoidal fluid transfer in the liver-of the anesthetized cat” (Circulation Res. 26: 697-703, 1970), Greenway and Lautt ligated and cut the ligaments connecting the central and
TO THE EDITOR
left lobes of the liver to the diaphragm. The liver, with the exception of the right posterior lobe was then lifted and inserted into a Plexiglas plethysmograph. Hepatic venous pressure was elevated by raising the outlet of the hepatic venous cannula and the ensuing increase in hepatic volume was measured by plethysmography. Hepatic blood volume (51Cr-tagged red blood cells) increased rapidly (approx twofold by 20 min, Fig. 3) and then remained essentially constant. Total hepatic volume continued to increase at a steady rate so that at 60 min it was greater than threefold (Fig. 3). This steady rate of increase was reported by them to continue for at least 4 h. “On restoration of hepatic venous pressure to zero, the hepatic blood volume returned toward the control level and 80% of the increase during the period of raised venous pressure drained from the liver. The filtered fluid remained in the plethysmograph.” Thus excess fluid was almost certainly present in the interstitium
01 the liver. In my study entitled “Splanchnic hemodynamic response to passive hyperventilation” (J. Appl. Physiol. 38: 156-162, 1975), the liver was in situ with ligaments intact. The abdomen was closed. Hepatic venous pressure was elevated as a result of increased intrathoracic pressure during intermittent positive-pressure hyperventilation (a procedure which raises intra-abdominal pressure as well). The period of hyperventilation lasted 180 min. Had interstial fluid been accumulating to the extent noted by Greenway and Lautt, during my study, where the liver was less free to expand, I would have expected to see some transhepatic impedance to the low pressure portal venous system. Elsie Ernest Johnson Dept. of Anaesthesia and Harvard Medical School
Respiratory
Therapy
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 10, 2019.
