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J Appl Physiol 85: 2040-2046, 1998;
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Vol. 85, Issue 6, 2040-2046, December 1998

Effects of changes in pH and CO2 on pulmonary arterial wall tension are not endothelium dependent

Michèle Sweeney, David Beddy, Valerie Honner, Bridget Sinnott, Ronan G. O'Regan, and Paul McLoughlin

Department of Human Anatomy and Physiology, University College, Dublin 2, Ireland

    ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References

We examined the changes in isolated pulmonary artery (PA) wall tension on switching from control conditions (pH 7.38 ± 0.01, PCO2 32.9 ± 0.4 Torr) to isohydric hypercapnia (pH change 0.00 ± 0.01, PCO2 change 24.9 ± 1.1 Torr) or normocapnic acidosis (pH change -0.28 ± 0.01, PCO2 change -0.3 ± 0.04 Torr) and the role of the endothelium in these responses. In rat PA, submaximally contracted with phenylephrine, isohydric hypercapnia did not cause a significant change in mean (± SE) tension [3.0 ± 1.8% maximal phenylephrine-induced tension (Po)]. Endothelial removal did not alter this response. In aortic preparations, isohydric hypercapnia caused significant (P < 0.01) relaxation (-27.4 ± 3.2% Po), which was largely endothelium dependent. Normocapnic acidosis caused relaxation of PA (-20.2 ± 2.6% Po), which was less (P < 0.01) than that observed in aortic preparations (-35.7 ± 3.4% Po). Endothelial removal left the pulmonary response unchanged while increasing (P < 0.01) the aortic relaxation (-53.1 ± 4.4% Po). These data show that isohydric hypercapnia does not alter PA tone. Reduction of PA tone in normocapnic acidosis is endothelium independent and substantially less than that of systemic vessels.

acidosis; vascular smooth muscle; nitric oxide; carbon dioxide

    INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References

NORMAL GAS EXCHANGE in the lung depends on the appropriate regulation of pulmonary blood flow to ensure matching of regional perfusion to ventilation. Hypoxic pulmonary vasoconstriction is one mechanism that contributes to this matching. It is frequently suggested that hypercapnia causes pulmonary vasoconstriction, a response that would also divert blood flow away from poorly ventilated alveoli. This postulated vasoconstrictor effect of hypercapnia is in marked contrast to its well-known systemic vasodilator action. However, the reported data on this issue are in direct conflict. In previous investigations carried out in vivo or in isolated lung preparations, hypercapnic acidosis and normocapnic acidosis have been reported to increase (7, 12, 25, 28), decrease (8, 27), or leave unchanged (12, 14, 18) pulmonary vascular resistance. Similarly, the pH-independent action of elevated CO2 has been variously reported as vasodilator (7, 8, 12, 27), vasoconstrictor (22), or without effect (7, 14). In isolated pulmonary arteries, Lloyd (20) reported that both hypercapnic and normocapnic acidosis reduced the contractile response to most stimuli, although the role of the endothelium was not considered. We have previously found that, in isolated preconstricted pulmonary arteries with intact endothelium, hypercapnic acidosis caused relaxation (26). Furthermore, normocapnic acidosis, which caused an identical fall in extracellular pH, led to a similar relaxation, suggesting that the action of hypercapnic acidosis is mediated entirely through its effect on extracellular pH (26). Thus there is a controversy as to the effects of changes in pH and PCO2 on pulmonary vascular tone. Indeed, it is not clear that the responses of pulmonary vessels to these conditions are fundamentally different from those of systemic vessels, and no direct comparisons of isolated vessels from the two circulations have been made.

It is now well recognized that the endothelium has a central role in modulating vascular resistance through its release of both vasoconstrictor and vasodilator mediators. The vasodilator effect of hypercapnia on systemic vessels has been reported to be at least partly due to increased production of the endothelium-dependent relaxant factor nitric oxide (13, 17). There is also evidence that, at least in some systemic vessels, hypercapnic acidosis causes relaxation by stimulating endothelial production of prostacyclin (29). The question of whether the endothelium modulates the pulmonary vascular response to hypercapnia and alterations in extracellular pH has not been directly examined previously.

The present study was undertaken to compare the direct effects of elevated PCO2 at constant, normal extracellular pH (isohydric hypercapnia) and reduced extracellular pH at normal PCO2 (normocapnic acidosis) on vascular smooth muscle tension in pulmonary and systemic arteries by examining both vessel types by using an identical isolated preparation. We wished to test the hypothesis that the effects of these two conditions on pulmonary arterial wall tension were modulated by altered vasodilator production by the pulmonary endothelium.

    METHODS
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Abstract
Introduction
Methods
Results
Discussion
References

Preparation of Tissues

The first-order branches of the main pulmonary artery were isolated postmortem from adult male Sprague-Dawley rats; cleaned of adherent connective tissue; and cut into ring segments, 2-3 mm in length. Each vessel segment was mounted in a tissue bath by gently threading the arterial ring onto a horizontally oriented, fixed-position, surgical steel wire. A second similar wire, connected to a force transducer (model F30, Hugo-Sachs Electronik, March, Germany, or model FTO3C, Grass Instruments, Quincy, MA), was introduced into the lumen above the first wire. The rings were then placed in organ baths (50 ml) maintained at 37°C in control physiological saline solution (PSS; see Experimental Conditions and Solutions) equilibrated with a gas mixture of 5% CO2-95% air. Where paired protocols are described, rings from the same arterial branch were compared. Isometric tension was recorded as a function of time by using an analog-to-digital system (Biopac MP100 WS, Linton Instrumentation, Norfolk, UK) connected to a desktop computer (Apple Macintosh Performa 475) or a Grass model 7 polygraph. Ring segments of thoracic aorta were prepared and mounted in exactly the same manner. In some experiments, the endothelium was deliberately removed by rubbing the intimal surface with a fine-bore, roughened plastic tube (Kit Clot Removal M168, Ciba Corning, Medfield, MA).

The rings were left to equilibrate for 1 h in control PSS. After equilibration, the rings were set at a mean optimal pretension of 2.6 ± 0.2 N/m on the basis of ring weight and left to stabilize for a further 30 min. Optimal pretension had been determined in a series of preliminary experiments. All rings underwent a similar "run-up" procedure before an experimental protocol. Each ring was maximally contracted and subsequently relaxed by three successive exposures to 80 mM KCl (isosmotically substituted for NaCl) followed by rinsing with control PSS. A first cumulative concentration-response curve (CCRC) to the alpha 1-agonist phenylephrine (10-9 to 10-5 M) was then recorded. On the basis of this CCRC, the concentration of phenylephrine required to produce a submaximal contraction [50% of maximum response (EC50) or 70% of maximum response (EC70)] of the ring segment was determined and added to the bath. The presence of an intact endothelium was confirmed by demonstrating a relaxation of this submaximal contraction in response to ACh (bath concentration 10-5 M) of >20% of the maximal tension developed by that ring. Scanning-electron microscopy confirmed that, when this criterion was fulfilled, the endothelium was >90% intact (data not shown). In those rings in which the endothelium had been deliberately removed, its absence was confirmed by demonstrating a failure to relax on exposure to ACh (10-5 M). Scanning-electron microscopy confirmed that in those rings the endothelium had been removed (data not shown).

After the run-up procedure, rings were entered into an experimental protocol (see Experimental Protocols). On completion of the experimental protocol, a second CCRC to phenylephrine was recorded, and the response to ACh (10-5 M) was again examined. Finally, the response to 80 mM KCl was determined. If the maximal contraction of a ring after the experimental protocol was <90% of the initial maximal phenylephrine-induced tension (Po), the results from that ring were discarded. Isolated aortic rings were treated in exactly the same manner, except that the optimal pretension was 5.1 ± 0.3 N/m.

Experimental Conditions and Solutions

Control conditions consisted of PSS (122.6 mM NaCl, 5.4 mM KCl, 20 mM NaHCO3, 0.9 mM Na2HPO4, 0.8 mM MgSO4, 2.4 mM CaCl2, and 5.5 mM D-glucose, thermostatically maintained at 37°C and equilibrated with 5% CO2-95% air. Tension development by the vascular rings was examined in two different experimental conditions: 1) isohydric hypercapnia produced by equilibration of modified PSS (NaHCO3 isosmotically substituted for NaCl) with 10% CO2-90% air so that extracellular pH was maintained at control values and 2) normocapnic acidosis produced by switching to a modified PSS (NaHCO3 isosmotically replaced by NaCl) equilibrated with 5% CO2-95% air so that PCO2 was maintained at control values while pH fell. The reduction in pH was equal to that observed when control PSS was equilibrated with 10% CO2-90% air, i.e., hypercapnic acidosis.

In some experiments, calcium-selective electrodes were used to produce solutions in which the pH and PCO2 were altered as described above while calcium activity (ionized calcium) was maintained constant at the control value (16). Syringe samples of the bathing fluid were taken intermittently throughout all experiments for analysis of PO2, PCO2, and pH by using an automated blood-gas analyzer (model 278, Ciba Corning).

Experimental Protocols

Effects of isohydric hypercapnia on tension. Initially, each ring was submaximally contracted with phenylephrine (EC50 or EC70). Once a steady contraction was observed, the bath solution was switched to the test conditions in the continuing presence of the same concentration of phenylephrine. Twenty minutes later, the bath solution was returned to control conditions. The response of a preparation to the intervention in these experiments was quantified as the difference between the average tension during minutes 15-20 after the switch to experimental conditions and the average steady-state control tension during the last 5 min before the switch. Pulmonary arterial and aortic rings were examined, both in the presence of an intact endothelium and after its mechanical removal.

Effects of isohydric hypercapnia at constant calcium activity. Isohydric hypercapnia at constant calcium concentration caused a reduction in calcium activity (16). To exclude the possibility that the observed effects were mediated by such an alteration of calcium activity, solutions of constant calcium activity were prepared for test and control conditions by using ion-selective electrodes. A further series of experiments was undertaken, as described in Effects of isohydric hypercapnia on tension, with use of these solutions.

Inhibition of nitric oxide synthase (NOS) in isohydric hypercapnia. Pulmonary arterial rings were allowed to equilibrate in isohydric hypercapnic or control conditions for 15 min. A "priming concentration" of phenylephrine (3.30 × 10-9 M) was added to the bath, eliciting a small increase in tension. When a steady tension was achieved, a CCRC (10-7 to 10-3 M) for Nomega -nitro-L-arginine methyl ester (L-NAME), a specific NOS inhibitor, was examined. Rings were exposed to increasing concentrations of L-NAME at 15-min intervals.

Inhibition of cyclooxygenase in isohydric hypercapnia. A similar protocol to that described in Inhibition of nitric oxide synthase (NOS) in isohydric hypercapnia was carried out. After the addition of a priming concentration of phenylephrine, indomethacin was added incrementally to the tissue baths (10-9 to 10-6 M) in a paired protocol.

Acetylcholine-stimulated endothelium-dependent relaxation in isohydric hypercapnia. Pulmonary arterial rings were allowed to equilibrate in isohydric hypercapnic or control conditions for 15 min. Submaximal contractions (~70% Po) were then elicited with phenylephrine, and the concentration-dependent relaxations to ACh (10-9 to 10-5 M) were determined.

Effects of sodium pyruvate on tension. Salts of weak organic acids in the extracellular fluid lead to sustained reductions of intracellular pH in vascular smooth muscle in the absence of changes in extracellular pH or PCO2 (23). Rings were submaximally contracted with phenylephrine [as described in Effects of isohydric hypercapnia on tension], and the bath solution was switched to one containing 25 mM sodium pyruvate isosmotically substituted for NaCl and equilibrated with 5% CO2-95% air. At the end of a 20-min period, the bath solution was returned to control conditions.

Effects of normocapnic acidosis. A further series of experiments was undertaken in which the protocols outlined above were repeated except that the test condition was normocapnic acidosis.

Reagents

All salts and drugs were supplied by Sigma Chemical (Poole, Dorset, UK). Phenylephrine, ACh, and L-NAME were made up as stock (10-1 M) solutions in distilled water and subsequently diluted in PSS to achieve the desired bath concentration. Indomethacin was dissolved in 0.1 M Na2CO3 to give a stock solution of 10-1 M. This stock was then diluted in PSS to give the desired bath concentrations. All solutions except stock phenylephrine were made up fresh daily and stored on ice.

Data Analysis

All tensions and changes in tension are expressed as a percentage of the Po developed in an individual ring (%Po). All values shown are means ± SE. Paired or unpaired t-tests were used as appropriate. For multiple comparison of means across experimental groups, analysis of variance was carried out, and where a significant F-value was found a Student-Newman-Keuls post hoc test was used to assess the significance of the differences between means. A value of P < 0.05 was accepted as statistically significant.

    RESULTS
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Abstract
Introduction
Methods
Results
Discussion
References

Mean Po developed in the pulmonary artery preparations (phenylephrine 10-5 M) was 2.2 ± 0.2 N/m. In endothelium-intact rings, the mean relaxation observed in response to ACh (10-5 M) during submaximal phenylephrine-induced contractions was 45.2 ± 1.8% Po. Mean Po in aortic rings (phenylephrine 10-5 M) was 3.7 ± 0.2 N/m, whereas, in submaximally contracted, endothelium-intact rings, ACh caused a relaxation of 37.4 ± 2.4% Po.

Figure 1 shows reproductions of original experimental records of the responses of a pulmonary arterial and aortic ring to a switch to isohydric hypercapnia. Isohydric hypercapnia usually, although not always, caused an initial transient relaxation in pulmonary arteries. This was followed by recovery to control values within 5 min. In the majority of experiments, tension had achieved a steady state within 10 min after the switch to test conditions, and, in all cases, a steady state had been achieved within 15 min. Return of bath solutions to control conditions in the continuing presence of phenylephrine led to a recovery of tension to a value similar to initial. In contrast, in aortic rings the switch to isohydric hypercapnia led to a transient contraction followed by a sustained relaxation.


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  		Fig. 1.   Typical original recordings of tension development over time during isohydric hypercapnia in a pulmonary arterial ring (A) and an aortic ring (B). PHEN, phenylephrine added to obtain a submaximal contraction. ACh, ACh (10-5 M) added to bath.

Table 1 summarizes the responses of pulmonary and aortic rings to isohydric hypercapnia in the presence and in the absence of a functional endothelium. In pulmonary vessels this intervention did not lead to a significant change in steady-state wall tension, and this behavior was unchanged after endothelial removal. In contrast, isohydric hypercapnia caused a significant relaxation of aortic rings, and this relaxation was attenuated but not completely abolished by endothelial removal.

                              
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  		Table 1.   Effects of isohydric hypercapnia on steady-state tension development in isolated pulmonary arterial and thoracic aortic rings in the presence of an intact endothelium and in endothelium-denuded rings

Similarly, in a further series of pulmonary arterial rings (n = 6) in which calcium activity was maintained equal to that in control PSS, isohydric hypercapnia did not cause a significant change in tension (-0.4 ± 1.9% Po).

To examine the effects of NOS inhibition on tension development in isohydric hypercapnia, pulmonary arterial rings were set at optimal pretension in control PSS, as described in Preparation of Tissues. After a switch to isohydric hypercapnic conditions, no significant change in basal tension was observed over the subsequent 20 min. A priming concentration of phenylephrine was then added, and the mean increases in tension in response to cumulative increases in L-NAME concentration are shown in Fig. 2. The response in isohydric hypercapnia was not significantly different from that in control conditions. After the addition of a priming concentration of phenylephrine, cumulative increases in indomethacin concentration (10-9 to 10-6 M) caused a mean maximum tension (n = 6) under control conditions of 4.8 ± 2.7% Po, a value not significantly different (paired t-test) from that under test conditions (6.5 ± 4.0% Po). Figure 3 shows that the mean response curves for ACh in isohydric hypercapnia were not significantly different from those elicited in control conditions.


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  		Fig. 2.   Increase in tension in pulmonary arterial rings in response to increasing concentrations of nitric oxide synthase inhibitor Nomega -nitro-L-arginine methyl ester (L-NAME) in control and isohydric hypercapnic (IH) conditions. Values are means ± SE; n, no. of preparations. %Po, percentage of initial maximal phenylephrine-induced tension. There were no significant differences between response curves elicited in these 2 conditions (P = 0.62; ANOVA).


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  		Fig. 3.   Reduction in tension in pulmonary arterial rings in response to different concentrations of acetylcholine in control and isohydric hypercapnic conditions. Values are means ± SE; n, no. of preparations. There were no significant differences between response curves elicited in these 2 conditions (P = 0.62; ANOVA).

In a group of endothelium-intact, pulmonary arterial rings (n = 3), the switch to PSS containing 25 mM sodium pyruvate did not cause a significant change in mean extracellular pH (0.00 ± 0.00) or PCO2 (0.4 ± 0.4 Torr), nor did it alter tension significantly (6.2 ± 5.3% Po).

Table 2 summarizes the changes in steady-state tension development of pulmonary and aortic rings during normocapnic acidosis in the presence and in the absence of a functional endothelium. In endothelium-intact pulmonary vessels, this intervention led to a significant reduction in wall tension, and this response was unchanged after endothelial removal. In a further series of experiments in which calcium activity during normocapnic acidosis was maintained equal to that in control PSS (n = 6), the mean change in tension (-16.7 ± 3.0% Po) was not significantly different from that observed at constant calcium concentration (Table 2). In aortic preparations, normocapnic acidosis caused a reduction that was significantly greater than that in either intact or denuded pulmonary rings. Endothelial removal enhanced the aortic relaxation significantly.

                              
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  		Table 2.   Effects of normocapnic acidosis on steady-state tension development in isolated pulmonary arterial and thoracic aortic rings in the presence of an intact endothelium and in endothelium-denuded rings

To examine the effects of NOS inhibition on tension development in normocapnic acidosis, pulmonary arterial rings were initially set at optimal pretension in control PSS, as described in Preparation of Tissues. After a switch to normocapnic acidotic conditions, no significant change in basal tension was observed over the subsequent 20 min. A priming concentration of phenylephrine was then added, and the mean increases in tension in response to cumulative increases in L-NAME concentration are shown in Fig. 4. The response in normocapnic acidosis was not significantly different from that under control conditions. After the addition of a priming concentration of phenylephrine, cumulative increases in indomethacin concentration (10-9 to 10-6 M) in a paired protocol (n = 3) caused a mean Po under control conditions of 4.6 ± 1.0 %Po, which was not significantly different (paired t-test) from that under normocapnic acidotic conditions (6.3 ± 5.8% Po). Figure 5 shows that the relaxation in response to ACh in normocapnic acidosis and control conditions was not significantly different.


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  		Fig. 4.   Increase in tension in pulmonary arterial rings in response to increasing concentrations of nitric oxide synthase inhibitor L-NAME in control and normocapnic acidotic conditions. Values are means ± SE; n, no. of preparations. There were no significant differences between the response curves elicited in these 2 conditions (P = 0.49; ANOVA).


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  		Fig. 5.   Reduction in tension in pulmonary arterial rings in response to different concentrations of acetylcholine in control and normocapnic acidotic (NA) conditions. Values are means ± SE; n, no. of preparations. There were no significant differences between response curves elicited in these 2 conditions (P = 0.49; ANOVA).

    DISCUSSION
Top
Abstract
Introduction
Methods
Results
Discussion
References

These results demonstrate that isohydric hypercapnia, a condition that causes intracellular acidosis (2, 3), had no effect on steady-state tension development in submaximally contracted, conduit pulmonary arteries (Table 1) and that the endothelium did not modulate the responses of the pulmonary vessels to this stimulus. In contrast, in aortic preparations isohydric hypercapnia caused a substantial relaxation that was, in large part, endothelium dependent. In support of this observation, our data indicate that both basal and stimulated production of the endothelial vasodilators nitric oxide and prostacyclin were unchanged in isohydric hypercapnia.

Normocapnic acidosis led to relaxation of isolated pulmonary arteries that was significantly less that that seen in systemic vessels (Table 2). Removal of the endothelium did not alter the pulmonary response but significantly augmented the relaxation of aortic preparations. These data indicate that tension development in pulmonary vascular smooth muscle is substantially less sensitive to extracellular acidosis than in systemic vascular smooth muscle. The pulmonary endothelium did not modulate this response, whereas in the aorta the endothelium attenuated it. In keeping with this observation, our data indicate that both basal and stimulated production of the endothelial vasodilators nitric oxide and prostacyclin were unchanged in normocapnic acidosis.

Isolated arterial rings were used to allow us to address the question of whether there is a fundamental difference in the direct effects of isohydric hypercapnia and normocapnic acidosis on pulmonary and systemic arteries. To our knowledge, no such direct comparison of pulmonary and systemic arteries from a single species has been made. Our results agree with those of Lloyd (20), who reported that both hypercapnic and normocapnic acidosis reduced the contractile response to most stimuli in isolated strips of pulmonary arterial smooth muscle. However, our findings extend those of Lloyd by examining the effects of high CO2 and reductions in pH in the presence and in the absence of a functional endothelium.

We have previously demonstrated that the changes in wall tension in response to these conditions stabilized within 5-10 min and then remain stable for up to 90 min (26). Thus we used the mean wall tension between 15 and 20 min after switch to experimental conditions as an index of the steady-state response. We examined the effects of isohydric hypercapnia and normocapnic acidosis because we have previously reported that in isolated pulmonary vessels the relaxant effect of normocapnic acidosis was not significantly different from that of hypercapnic acidosis (26). This observation is similar to that reported in other vessels (3) and suggests that the effect of hypercapnic acidosis is mediated through its effect on extracellular pH alone or, in other words, that alteration of intracellular pH alone does not affect tension in vasular smooth muscle. This interpretation is supported by our finding that exposure to sodium pyruvate at normal extracellular pH and PCO2, an intervention that leads to sustained reduction of intracellular pH (23), did not alter tension significantly in endothelium-intact pulmonary artery rings.

It was our purpose to exclude effects due to reflex mechanisms, hormonal influences, anesthesia, release of vasoactive mediators from the formed elements of blood (24), and other influences not originating in the vessel wall. In particular, we wished to avoid influences from the pulmonary parenchyma. To achieve this, we used first-order branches of the pulmonary artery, i.e., conduit vessels. It has previously been demonstrated that these conduit vessels display the phenomenon of hypoxic vasoconstriction (9), a finding reproduced in our preparation (results not shown). The fact that these vessels demonstrate hypoxic vasoconstriction, a property that distinguishes pulmonary resistance vessels from those of the systemic circulation, suggests that they can serve as a useful model to examine other differences in behavior between the two circulations. We compared the pulmonary arteries with isolated rings of aorta because both are conduit vessels. It has previously been shown that such isolated aortic preparations dilate in hypercapnia and acidosis, responses that parallel the vasodilator responses observed in isolated small systemic arteries and the reductions in resistance in isolated systemic vascular beds and intact animals (2-4, 13, 19, 29). Although our results demonstrate a clear quantitative difference between pulmonary and systemic vessels, direct confirmation that similar behavior occurs in the resistance vessels is required.

We had initially hypothesized that the effects of isohydric hypercapnia and normocapnic acidosis on the pulmonary artery were modulated by the pulmonary endothelium. Our findings that the responses of the pulmonary vessels in these conditions were unaltered by endothelial removal, NOS inhibition, and cyclooxygenase inhibition refute this hypothesis. Endothelial production of vasodilators in vivo is continuously stimulated by endogenous mediators such as catecholamines, endothelins, and shear stress (15); therefore, we examined ACh-stimulated, endothelium-dependent relaxation and found that it was unaltered in the pulmonary artery rings in isohydric hypercapnia and normocapnic acidosis. In contrast, the aortic endothelium largely mediated the relaxation observed in isohydric hypercapnia and significantly attenuated the relaxation due to normocapnic acidosis. Taken together, our findings demonstrate an important functional difference between pulmonary and systemic endothelium. Although it was not the primary object of our study, the observation that endothelial removal enhanced the relaxant response to normocapnic acidosis in aortic rings is worthy of comment. In a similar preparation, Loutzenhiser et al. (21) have previously reported that cyclooxygenase inhibition increases the steady-state relaxation observed in norepinephrine-preconstricted, isolated aortic rings in response to a reduction in extracellular pH. Taken together, these data may suggest that relaxation of wall tension in response to normocapnic acidosis in aortic vessels is attenuated by altered prostaglandin production, although more direct experimental confirmation is required.

It is important to note that differences in responses of the pulmonary and systemic vessels to changes in PCO2 and pH were not entirely due to the differences in their endothelial responses. In the absence of the endothelium, normocapnic acidosis caused pulmonary vascular smooth muscle to relax to a significantly lesser degree than systemic vascular smooth muscle (Table 2). Isohydric hypercapnia did not have a relaxing effect on pulmonary vascular smooth muscle but caused significant relaxation of systemic vascular smooth muscle in the absence of an endothelium (Table 1). This indicates that there is a fundamental difference between the responses of pulmonary and systemic arterial smooth muscle to both normocapnic acidosis and isohydric hypercapnia. The effects and mechanisms of action of these interventions in the systemic circulation have been extensively investigated (1, 2, 4-6, 10, 11), but little information is available regarding pulmonary vessels.

In summary, we have observed important differences in the tension responses of isolated pulmonary and systemic vessels to changes in extracellular pH and PCO2. Pulmonary arteries do not relax in response to isohydric hypercapnia, whether or not the endothelium is intact. Aortic preparations relax under these conditions, and this relaxation is largely endothelium dependent. Normocapnic acidosis leads to an endothelial-independent relaxation of pulmonary arteries, which is significantly less than that observed in the aorta. Taken together, these observations suggest that, in conduit vessels, the pulmonary endothelium does not mediate or modulate the vascular smooth muscle responses to changes in pH or PCO2, in marked contrast to the central role of the endothelium in the systemic vascular responses to these stimuli. Furthermore, the direct relaxant effect of normocapnic acidosis in the pulmonary artery is substantially less than that in the aorta, suggesting that pulmonary vascular smooth muscle tension development is relatively resistant to reductions in extracellular pH.

    ACKNOWLEDGEMENTS

This work was supported by Forbairt, the Health Research Board of Ireland, and the Irish Lung Foundation.

    FOOTNOTES

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Address for reprint requests: P. McLoughlin, Dept. of Human Anatomy and Physiology, University College, Earlsfort Terrace, Dublin 2, Ireland (E-mail: Paul.McLoughlin{at}ucd.ie).

Received 3 March 1998; accepted in final form 4 August 1998.

    REFERENCES
Top
Abstract
Introduction
Methods
Results
Discussion
References

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