(Received 13 February 1958)

Transcription

1 226 J. Physiol. (I958) I43, TH MCHANISM OF TH CHANGS IN FORARM VASCULAR RSISTANC DURING HYPOXIA By J.. BLACK AND I. C. RODDI From the Department of Physiology, The Queen's University of Belfast (Received 13 February 1958) Though both hypoxia and hypercapnia stimulate respiration, their effects on the circulation are quite distinct in many ways. In the present paper experiments are described which contrast the effects of these two stimuli on some aspects of the circulation. It was found that hypercapnia caused a rise in forearm vascular resistance whereas hypoxia caused a fall. vidence was obtained that the fall in resistance with hypoxia was mediated through a humoral rather than a nervous mechanism and resulted from the washing out of CO2 from the lungs during the hypoxic hyperpnoea. MTHODS The experiments were carried out on healthy young adults. They lay recumbent in a room at 2-22o C, breathed through a valved mouth-piece and wore a nose clip. By a suitable arrangement of taps and connecting tubing the subject, when required to do so, breathed various gas mixtures from a Douglas bag, instead of room air. The gas mixtures were made up as required by passing calculated proportions of 2, C2 and N2 through a gas-meter into a Douglas bag. The proportions of the gases in the mixture were then checked by analysing a sample of the mixed gas in a Haldane gas analysis apparatus. Respiratory movements were recorded by two stethographs, one round the chest and the other round the abdomen, connected to a single volume recorder. Arterial pressure was measured from a needle in the brachial artery by capacitance manometry and venous pressure from a needle in an antecubital vein by saline manometry. Forearm blood flow was estimated by venous occlusion plethysmography. In two experiments the radial, median and ulnar nerves to the left forearm were blocked with 2% lignocaine. RSULTS Comparison of the effects of hypoxia and hyperecapnia on forearm vascular resistance Four subjects breathed 5-1% 2 in N2 for 2-6 min. Then after a period of some minutes of breathing room air, a mixture of 4-1% CO2 + 2% 2 in N2 was substituted. The results of a typical experiment are shown in Fig. 1. The

2 FORARM VASCULAR RSISTANC DURING HYPOXIA 227 hypoxia and the hypercapnia caused a comparable degree of respiratory stimulation. The hypoxic hyperpnoea, however, was followed by a phase of periodic breathing. Hypoxia caused a large increase in forearm blood flow with little change in mean arterial or venous pressure so that the vascular resistance in the forearm (calculated by dividing mean perfusion pressure by mean flow) was considerably reduced; in the experiment shown in Fig. 1 it was about halved. The heart rate increased from about 8 to 15 beats/min. L. c,v U I.415 a 5 4' L 4i I. _ " %a co X._ I.., O: e =- U- r_ - O3,,2u v U2- L. U. 2,, Sec Fig. 1. A comparison of the effects of acute hypoxia and hypercapnia on respiratory movements (inspiration downwards), heart rate, arterial blood pressure, forearm blood flow and forearm vascular resistance. The clear rectangle represents the period of hypoxia (6 2 in N2) and the black rectangle the period of hypercapnia (7% CO2 + 2% 2 in N2). When carbon dioxide excess was breathed the effects were quite different. The systolic, diastolic and mean arterial pressures increased and there was a slight fall in blood flow. Vascular resistance in the forearm was about doubled. The heart rate showed only a slight increase. Figs. 2 and 3 show forearm blood flow plethysmograms and arterial blood pressure records made during this type of experiment and the results of all such experiments are summarized in Table 1. In each subject hypoxia caused a fall in forearm vascular resistance whereas hypercapnia caused a rise. 15 PHYSIO. CXLIII

3 228 J.. BLACK AND I. C. RODDI Comparison of hypoxia and voluntary hyperventilation on forearm vascular resistance It is well known that the hyperpnoea during acute hypoxia causes increased elimination of carbon dioxide from the lungs with a resultant fall in alveolar pco2. A fall in alveolar pco2 is also seen during voluntary hyperventilation. Forearrmi blood flow 67' C2 in N2,~~~~~~~~~~~~~~~~~~ Fig. 2. ~~~~~~~~~~9 sec Plethysmographic recordings of forearm blood flow made during acute hypoxia (above) and acute hypercapnia (below). Hypoxia g...1 Hypercapnla,-, -f 15.I ~ eta ~~'L.IlIItIihhIkIfl _ ~~~~1 Before During After Fig 3. Recordings of arterial blood pressure made before, during and after acute hypoxia (6 % 2 in N2) shown above, and acute hypercapnia (7 % CO2 + 2% 2 in N2) shown below. TABL 1. A comparison of the changes in heart rate, forearm blood flow, arterial pressure and forearm vascular resistance during hypoxia and hypercapnia in four subjects. The changes are the maximum changes observed and are expressed as a percentage of the levels observed during the control periods Gas mixture (%) Forearm Forearm r-'^ ~ Heart blood Arterial vascular Subject 2 CO2 N2 rate flow pressure resistance.l P.A S.C H.McK B.B

4 FORARM VASCULAR RSISTANC DURING HYPOXIA 229 It is of interest, therefore, that.the circulatory changes which accompany hypoxia and voluntary hyperventilation have many features in common. Fig. 4 shows the result of an experiment in which some of these circulatory changes have been compared. Both stimuli caused a large increase in heart rate and blood flow, both in the normally innervated and the nerve-blocked forearms. The vascular resistance in the normally innervated and the nerveblocked forearms was reduced. It was clear, therefore, that the active dilatation of the forearm blood vessels with both these stimuli was mediated through humoral rather than nervous mechanisms. Z Lm, 4'-&r 1 - z 5 I 15 : _ 11 m~~~~l4fff 15 U< ' <~~~~~ 8 1~~~~~~~~~~~~~~~ 5 -~~~~~~~~~~~~~~~~~~~U Minutes Fig. 4. A comparison of the effects of acute hypoxia and voluntary hyperventilation on heart rate, arterial pressure, blood flow in the normal and nerve-blocked forearms and vascular resistance in the normal and nerve-blocked forearms. *, Normal forearm;, nerve-blocked forearm. The open rectangle represents the period of hypoxria (8% 2 in N2) and the black rectangle the period of hyperventilation. The effiect of hypoxia on forearmn vascular resistance when al>veolar pco2 is kept constant The humoral vasodilatation in the forearm during voluntary hyperventilation results from the increased washing out of 2 from the lungs and the consequent hypocapnia (Clarke, 1952; Roddie, Shepherd & Whelan, 1957). The dilatation does not occur if similar hyperventilation is performed when sufficient carbon dioxide is added to the inspired gas mixrture to minimize or prevent increased carbon dioxide elimination (Fig. 5). Since the hyperpnoea with hypoxia causes increased washing out of 2 it was thought possible that 15-2

5 23 J. B. BLACK AND I. C. RODDI the resultant hypocapnia might contribute to the vascular changes. To test this hypothesis subjects were made to breathe oxygen-poor mixtures on two occasions. On the first occasion the gas mixture contained no C2 so that inoreased C2 elimination occurred. On the second occasion about 4 % C2 was added to the gas mixture in an attempt to minimize or prevent increased washing out of C2 during the hyperpnoea. Fig. 6 shows the result of one such o% Mc v w c S- Vbo v cl7: 1! V ~-a I~ L. v C'Is V a- a- 4u 2U L. a- U_ 6 75 sec Fig. 5. The effect of voluntary hyperventilation with air and with 5% C2 in 3 on heart rate, arterial pressure, forearm blood flow and forearm vascular resistance. Stethographic recordings of respiratory movements (inspiration downwards) are shown. The hatched rectangle represents the period of hyperventilation with air and the cross-hatched rectangle the period of hyperventilation with 5% CO2 in 2- experiment. The subject breathed 8% 2 in N2 on two occasions. On the second occasion 4 % C2 was added to the inspired gas. When this was done the increase in ventilation during the hypoxia was much greater. On the other hand the increases in forearm blood flow and heart rate were smaller. Instead of a slight fall in arterial pressure there was a definite increase. Instead of decreasing, the forearm vascular resistance remained unchanged and it was possible to account for the small rise in forearm blood flow by the increase in

6 FORARM VASCULAR RSISTANC DURING HYPOXIA 231 the perfusion pressure. The result of a similar experiment on another subject is shown in Fig. 7 and the results of all such experiments are summarized in Table 2. It was concluded that many of the vascular effects of acute hypoxia were due more to hypocapnia than to lack of oxygen. Lack of oxygen appeared to cause no important reflex changes in the calibre of the forearm blood vessels in the presence of a nearly normal alveolar C2 level. us ~~ ~ ~ ~ ~ ~ ~ ~ 8 4) ~~~~~~~~~~~~~~~~~~~~~~~~~~~1. 4J CL 1 4 t~5-3 6 o~ ~ ~~~~~~~~~~~~~o +8%3 n ~4 < 5 1 4) fl s2 b t 1 min~~~~~~~~~~~~~~~~~. Fig wa6aioprsno rete. theeffesofauen hypxiaonresiaoymvments whesp5-1at 2on downwareahdsforsheartraepreriods presaverae,iceaei forearm blood anwaclrrssanc flow (a)bout therethisnocincreae inspiredwas mixureto vasoilaain NO ince tbhenrufceno waslitl cadded toatherisiaore venos blodxpesure tmanaind alveoa flow incearlyions C2dno theramson,bexlainedt Bnanmincreas by 943 pefoundion3ressureasteinfrarmdilattoon Nwas breathed.ted theog presomotoexerimenssicwimlrchnehere 5-% nnwsee in the normal and the nerve-blocked limb. Nor was it due to the mechanical

7 232 J.. BLACK AND I. C. RODDI effects of the hyperpnoea, since when 4 % carbon dioxide was added to the hypoxic gas mixture the vasodilatation did not occur even though the respiratory excursions were greater. The vasodilatation must, therefore, have been due to a humoral mechanism. One possibility was that the vasodilatation was brought about by the fall in arterial blood oxygen acting directly on the Z. C 2- Lm -i =-. 15,,,. 4, bo 1 ' -a 4,1, Ē D a Lo _ 4, (4C v 2 1- l n_ co _- min Fig. 7. A comparison of the effects of acute hypoxia on heart rate, arterial pressure, normal and nerve-blocked forearm blood flow and normal and nerve-blocked forearm vascular resistance (a) when there was no C2 in the inspired gas mixture (8% O2 in N2) and (b) when sufficient C2 was added to the inspired gas mixture to maintain the alveolar pc2 nearly constant (4% C2 + 8% 2 in N2)., Nerve-blocked forearm;, normal forearm. TABL 2. A comparison of the changes in heart rate, forearm blood flow, arterial pressure and forearm vascular resistance during hypoxia when the alveolar PCO2 is allowed to fall and hypoxia when a fall in alveolar PCO2 is prevented. The changes are expressed as a percentage of the levels observed during the control periods Gas mixture (%) Subject 2 C2 N2 S.C H.McK. 8*2-91*8 8* B.B W.B Heart rate Forearm blood flow Arterial pressure Forearm vascular resistance Nerve- Normal blocked Nerve- Normal blocked

8 FORARM VASCULAR RSISTANC DURING HYPOXIA 233 resistance blood vessels. However, there was no evidence for this, since hypoxia did not cause vasodilatation in the nerve-blocked forearm when sufficient CO2 was added to the inspired gas to prevent excessive C2 elimination from the lungs. The humoral vasodilatation with hypoxia seemed to be related in some way to the increased elimination of C2 which normally accompanies hypoxic hyperpnoea, but the exact mechanism was not clear. If carbon dioxide had a direct vasoconstrictor effect on forearm blood vessels the results might be explained by the fall in arterial blood pco2 causing vasodilatation. This would be most unlikely, since the main body of evidence indicates that C2 has a direct vasodilator action both in animals (Dale & vans, 1922) and in human cerebral vessels (Kety & Schmidt, 1948) and skin vessels (Diji & Greenfield, 1958; Glover & Greenfield, 1958). It would be more probable that the rapid fall in arterial PCO2 led to some biochemical change in the blood, or to the release of some agent such as adrenaline which causes vasodilatation in skeletal muscle (Whelan, 1952). Of course this is only one of several humoral vasodilator mechanisms which might be evoked and the present experiments did not provide conclusive evidence in support of any of them. The increase in forearm blood flow with hypoxia was very similar to that seen during voluntary hyperventilation in man (Roddie et al. 1957). In both cases the increase was due to vasodilatation mediated by a humoral mechanism and was related to an increased rate of elimination of carbon dioxide from the body. It could be prevented if C2 elimination was impeded. During voluntary hyperventilation in man though nerve-blocked muscle vessels dilate, nerveblocked skin vessels constrict and this result would be consistent with release of adrenaline into the general circulation (Swan, 1951; Whelan, 1952). It would certainly be of interest to study the effects of hypoxia and voluntary hyperventilation on peripheral blood flow in adrenalectomized patients. The results also confirm that C2 loss normally modifies the respiratory response to lack of oxygen, but the respiratory measurements were so crude that they provided no evidence for or against the hypothesis that C2 excess and oxygen lack interact as respiratory stimulants (Gray, 195; Nielson & Smith, 1951; Cormack, Cunningham & Gee, 1957). The large increase in heart rate with hypoxia was not seen when carbon dioxide elimination was impeded. It may be, therefore, that the tachycardia normally seen with hypoxia is partly due to CO2 loss. C2 loss similarly modified the arterial pressure response to hypoxia. When increased C2 elimination was allowed to occur freely the arterial pressure was little changed or fell slightly. However, when C2 elimination was impeded hypoxia invariably caused an increase in pressure. 'Pure hypoxia', i.e. hypoxia when sufficient C2 was added to the inspired gas mixture to impede excessive C2 elimination, caused only a slight increase

9 234 J.. BLACK AND I. C. RODDI in forearm blood flow. The arterial pressure was also increased and the increase in flow could be accounted for by the increase in perfusion pressure indicating that resistance to blood flow in the forearm was practically unchanged. The effects of pure hypoxia on the peripheral circulation in man therefore seem different from those of carbon dioxide excess. ven small degrees of hypercapnia cause an increase in resistance to blood flow in the forearm. Though the mechanism of this increase is not known with certainty it is likely that vasomotor nervous activity plays a part since sympathetic nerves are largely responsible for the intense vasoconstriction in muscle when 3 % CO2 is breathed (McArdle, Roddie, Shepherd & Whelan, 1957). Pure hypoxia, on the other hand, did not increase resistance to blood flow in the forearm even when it was very severe (5 % 2) and the present experiments did not provide any evidence that this stimulus can cause reflex vasoconstriction in the limbs. This conclusion was supported by the fact that the responses of the nerve-blocked and normally innervated forearms to pure hypoxia were essentially similar. However, though the results provided no evidence for reflex vasoconstriction with hypoxia, they did not of course completely exclude it. Both hypercapnia and pure hypoxia caused a rise in arterial pressure and the present experiments indicated that the mechanisms of these pressor responses were not identical. The pressor response to hypercapnia was due in part to increased vascular resistance in the limbs. With pure hypoxia on the other hand the pressor response was due either to increased resistance in vascular beds other than those in the limbs, or to increased cardiac output or to both. However, the vascular effects of pure hypoxia are very similar to those seen when the common carotid arteries are compressed in man (Roddie & Shepherd, 1957). Both stimuli cause an increase in arterial pressure but this is not accompanied by increased vascular resistance in limbs. SUMMARY 1. Normal subjects breathed 5-1 %2 in N2 for 2-6 min and forearm blood flow was measured by venous occlusion plethysmography. 2. Hypoxia brought about in this way resulted in a large increase in ventilation, heart rate and forearm blood flow. There was relatively little change in either arterial or venous pressure so that vascular resistance in the forearm was considerably reduced. 3. Since vascular resistance in the nerve-blocked forearm also fell it was clear that the forearm vasodilatation with hypoxia was due to a humoral rather than a nervous mechanism. 4. When increased elimination of CO2 from the lungs during hypoxia was prevented by adding sufficient CO2 to the oxygen-poor gas mixture to maintain the alveolar pco2 nearly constant, the increases in forearm blood flow and

10 FORARM VASCULAR RSISTANC DURING HYPOXIA 235 heart rate were much smaller and vascular resistance in the forearm was not appreciably altered. 5. It is concluded that the fall in vascular resistance in the forearm during hypoxia is due more to the hypocapnia resulting from the hyperpnoea than directly to the lack of oxygen. RFRNCS ABRAMSON, D. I., LANDT, H. & BNJAMIN, J.. (1943). Peripheral vascular responses to acute anoxia. Arch. int. Med. 71, ANDRSON, D. P., ALLN, W. J., BARCROFT, H., DHOLM,. G. & MANNING, G. W. (1946). Circulatory changes during fainting and coma caused by oxygen lack. J. Physiol. 14, CLARK, R. S. J. (1952). The effect of voluntary overbreathing on the blood flow through the human forearm. J. Physiol. 118, CORMACK, R. S., CUNNINGHAM, D. J. C. & G, J. B. L. (1957). The effect of carbon dioxide on the respiratory response to want of oxygen in man. J. exp. Physiol. 42, DAL, H. H. & VANS, C. L. (1922). ffects on the circulation of changes in the carbon dioxide content of the blood. J. Physiol. 56, DIJI, A. & GRNFILD, A. D. M. (1958). The local effect of carbon dioxide on the blood vessels of human skin. J. Physiol. 14, 42P. GLOVR, W.. & GRNFILD, A. D. M. (1958). The blood flow through the human hand immersed in a saturated solution of carbon dioxide. J. Physiol. 143, 67P. GRAY, J. S. (195). Pulmonary Ventilation and its Physiological Regulation. First ed. Springfield: Thomas. KTY, S.. & SCHMIDT, C. F. (1948). The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J. clin. Invest. 27, McARDL, L., RODDI, I. C., SHPHRD, J. T. & WHLAN, R. F. (1957). The effect of inhalation of 3% carbon dioxide on the peripheral circulation of the human subject. Brit. J. Pharmacol. 12, NILSON, M. & SMITH, H. (1951). Studies on the regulation of respiration in acute hypoxia. Acta physiol. scand. 24, RODDI, I. C. & SHPHRD, J. T. (1957). The effects of carotid artery compression in man with special reference to changes in vascular resistance in the limbs. J. Physiol. 139, RODDI, I. C., SHPHRD, J. T. & WHLAN, R. F. (1957). Humoral vasodilatation in the forearm during voluntary hyperventilation. J. Physiol. 137, SWAN, H. J. C. (1951). Observations on a central dilator action of adrenaline in man. J. Physiol 112, WHLAN, R. F. (1952). Vasodilatation in human skeletal muscle during adrenaline infusions. J. Physiol. 118,