(Received 17 March 1967)

Transcription

1 J. Phy8iol. (1967), 192, pp With 4 text-ftgures Printed in Great Britain THE EFFECTS OF ALTERATION OF C02 AND ph ON INTESTINAL BLOOD FLOW IN THE CAT BY F. P. McGINN, D. MENDEL AND P. M. PERRY From the Department of Physiology, King's College, Strand, London, W.C. 2 (Received 17 March 1967) SUMMARY 1. The effect of alteration of arterial blood ph on intestinal blood flow in the cat has been determined under conditions of constant perfusion pressure. 2. Arterial blood ph was altered over the range by infusion of acid and alkali. When end-tidal CO2 was held constant, there was no change in intestinal blood flow. 3. When arterial blood ph was altered over the range 7' by the administration of CO2 at constant respiratory volume and rate, flow increased with increasing CO2. 4. The intestinal vascular bed was less responsive to noradrenaline at ph 7-2 than at ph 7-6. The change in sensitivity was evident when endtidal CO2 was controlled and depended therefore on a change in hydrogenion concentration. 5. The dilator effect of CO2 did not depend upon alteration of sensitivity to noradrenaline since it was seen after adrenergic blockade. INTRODUCTION The effect of alteration of blood ph upon the circulation has been of interest since Gaskell (1880) showed that lactic acid was dilator to frog blood vessels and Bayliss (1901) found that an increase in CO2 had a similar effect. There is evidence that a decrease in blood ph, induced either by infusion of acid or by inhalation of CO2, is dilator to the cerebral circulation (Sokoloff, 1960), coronorary circulation (Gollwitzer-Meier, Haussler & Kruger, 1938) and skin (Deal & Green, 1954). With muscle beds the position is confficting in that both constriction (Lennox & Gibbs, 1932; Steck & Gellhorn, 1939) and dilatation (Deal & Green, 1954; Fleishman, Scott & Haddy, 1957) have been seen. It is uncertain whether the dilator effect of CO2 is due to a direct effect upon blood vessels (Mc- Dowall, 1930) or is the result of a change in ph (Gollwitzer-Meier et al. 1938).

2 670 F. P. McGINN, D. MENDEL AND P. M. PERRY Apart from any effect that change of ph and CO2 may have directly on blood vessels, investigation of the effect of alteration of these variables is complicated by their effects on the vasomotor centre, on cardiac performance, and also by the possibility that the sensitivity of blood vessels to catechol amines can be changed (Page & Olmsted, 1951; Bygdeman, 1963). The intestinal circulation has received little attention in connexion with these problems. Bernthal (1930), Mohamed & Bean (1951) and Brickner, Dowds, Willitts & Selkurt (1956) have all reported some degree of dilatation of the mesenteric vascular bed when the CO2 in the inspired air was increased. There is little information, however, on the effect of alteration of ph independently of CO2 or on the sensitivity of this vascular bed to catechol amines with altered ph. These problems were the subject of the present investigation. METHODS Experimental animals. Cats of average weight 2-4 kg (range kg) were anaesthetized with intraperitoneal sodium pentobarbitone 42 mg/kg ('Nembutal', Abbott Laboratories Ltd.) and maintained by further injections of sodium pentobarbitone 6 mg I.v. if spontaneous movements occurred. Operative procedure. The trachea was cannulated and the left common carotid artery was dissected clear of surrounding tissue. A mid line incision was made in the abdomen and haemostatis secured. The superior mesenteric artery was cleaned to its first division, which was usually into a large central vessel and two smaller vessels at right angles to this. Care was taken to avoid injury to the surrounding sympathetic nerves. A femoral artery and splenic and cephalic veins were prepared for cannulation. At the end of the operative procedure the animals were heparinized ('Pularin', Evans Medical Ltd., 500 u./kg body wt.). Blood flow. Blood flow was measured by means of a density flowmeter (Dawes, Mott & Vane, 1953). In this method, which is based on the stromuhr principle, the time taken for a certain known quantity of fluid to travel between two electrodes is determined. The basic design of the chamber was unchanged but the circuit was altered by using two double triode valves controlling two multi-contact relays instead of the larger number of relays used in the original apparatus. The time taken for the fluid to travel between two electrodes was recorded on a millisecond stop-clock (Venner Electronics, Ltd., Type TSA 3314) which was activated when the fluid reached the first electrode and stopped when it reached the second electrode. When the apparatus was calibrated against known flow rates, it was accurate to within + 3 % over the range 1-40 ml./min. The pressure drop across the flowmeter was 1 mm Hg at the highest rates of flow. Intestinal blood flow was measured by inserting the flowmeter between the carotid and mesenteric arteries. The carotid connexion to the flowmeter was first made by a polythene cannula (internal diameter 1-5 mm) and the large central branch of the mesenteric artery was then cannulated. To prevent total bowel ischaemia during this' procedure the main mesenteric artery was left unoccluded and a ligature tied immediately distal to the two small arteries. Sufficient blood was carried by these small arteries to cause a retrograde flow of blood from the larger branch. After cannulation, the main artery was occluded, care being taken not to involve the sympathetic nerves. The area of intestinal perfusion in this preparation, as determined by an injection of dye into the superior mesenteric artery at the end of the experiment, was the whole of the small intestine but not including the duodenum.

3 INTESTINAL BLOOD FLOW 671 Pressure measurement. Perfusion pressure was determined by means of a manometer (S.E. Laboratories Ltd., 75/8) attached to the side arm of the arterial inflow. Portal venous pressure was recorded by means of another manometer (Statham Laboratories, Inc., P 23Gb) from a catheter in the splenic vein. Blood pressure compensation was obtained by allowing the animal to bleed into or receive blood from a reservoir maintained at a known pressure. Arterial ph measurement. The ph of femoral artery blood samples (0.2 ml.) was measured with a capillary electrode system (Electronic Instruments, Ltd., Model SHH 33) and a ph meter (Electronic Instruments, Ltd., Model 48A) with an accuracy of 0-01 ph units at a temperature of 370 C. End-tidal C02. Carbon dioxide concentration in the expired air was analysed continuously by means of a Beckman Infra-red Analyser (Model LB-1) and Microcatheter Sample Pump. Air for analysis was withdrawn at a rate of 200 ml./min from a polythene cannula inserted into the endotracheal tube with its tip just proximal to the carina. The highest recorded concentration of C02 in each respiratory movement was taken as the end-tidal C02. In some experiments respiration was controlled with a Starling 'Ideal' Pump, and the sampling catheter was led into the endotracheal tube through an air-tight side arm. When varying CO2 and 02 mixtures were given a period of at least 5 min was allowed for an equilibrium to be reached before the end-tidal C02 levels were taken. Infusins. Intravenous infusions of M-NaHCO2 or M-HCI (Analar, B.D.H.) were given into a cephalic vein at a rate of 0-44 ml./min. (-)-Noradrenaline bitartrate ('Levophed', Bayer Products Company) was given at a constant rate of 0-24 ml./min through a side arm with very small dead space into the superior mesenteric artery cannula. Recording. Systemic blood pressure, portal venous pressure, end-tidal C02 and arterial blood ph were recorded by means of a U.V. multi-channel recorder (S.E. Laboratories, Ltd., No. 2100). RESULTS Arterial ph and intestinal blood flow The effect on intestinal blood flow of alteration of arterial blood ph by intravenous infusion of acid and alkali was investigated in eight cats. In each experiment, blood flows were recorded at 5 min intervals with a stabilized arterial blood pressure of 100 mm Hg. Arterial blood ph was determined when steady blood flow conditions were obtained, and an infusion of sodium bicarbonate or hydrochloric acid was given into a cephalic vein at a rate of 0-44 ml./min. Blood flow and arterial blood ph were determined at 20 min intervals, the blood pressure being held constant. The infusions were discontinued, usually after 45 min, when an arterial blood ph of about 7-7 with alkali, and a ph of about 7-1 with acid, was achieved. End-tidal C02 was recorded continuously in each experiment and in some experiments was controlled to within 5 % of the desired level by controlling the extent of respiration by means of the Starling pump at a rate of 20 c/min. Alkaline infusion. The effect of increasing the blood ph by means of an alkaline infusion was investigated in six cats. In three of these experiments end-tidal C02 was controlled at a Pco. of 24 mm Hg. In the three 43 Physiol. 192

4 672 F. P. McGINN, D. MENDEL AND P. M. PERRY experiments with spontaneous respirations the average respiratory rate before infusion of NaHCO3 was 29/min (range 24-33) and the average end-tidal Pco, was 21 mm Hg (range mm Hg). The infusion of alkali resulted in a decrease in respiratory rate and an increase in end-tidal CO2 in each experiment, the average respiratory rate at the end of the infusion being 23/min (range 18-27) and the average end-tidal PCO2 being 25 mm Hg (range mm Hg). The relation of intestinal blood flow and arterial blood ph is shown in Fig. 1A. Each blood flow is the average of six successive determinations. It can be seen that although there was an average ph change of from 7.41 to 7 70 there was no consistent change in flow. 20 A _OO- 0 B 0 0,,: A_-AW^ 5 _ -~ --i- _* Arterial blood ph Fig. 1A. The effect' of an increase in arterial blood ph on intestinal blood flow. B. The effect of a decrease in arterial blood ph on intestinal blood flow. Continuous lines and filled symbols: controlled respirations with end-tidal PC,o2 constant. Interrupted lines and open symbols: spontaneous respirationls. Acid infusion. The effect of decreasing arterial blood ph by infusion of hydrochloric acid was investigated in five cats. In three of these experiments the effect of an infusion of alkali had previously been determined and the animals were allowed to return spontaneously to near normal arterial blood ph levels before the acid infusion was given. With three infusions end-tidal CO2 was held constant at a PCO, of 25 mm Hg. The results are shown in Fig. 1 B. It can be seen that in the experiments

5 INTESTINAL BLOOD FLOW 673 with controlled end-tidal CO2 there was little change in flow even with ph values of below 7 1. In the two experiments with uncontrolled respiration there was no change in flow in one experiment in which the respiratory rate increased from 28 to 35/min and the end-tidal Pco. fell from 20 to 18 mm Hg. In the other experiment flow increased on infusion of acid from 9 4 to 11-3 ml./min. This increase in flow was associated with an increase in respiratory rate from 30 to 34/min and a rise in end-tidal PCo2 from 20 to 25 mm Hg. As the infusion continued, flow increased to 12*2 ml./min, the respiratory rate increased to 36/min, but end-tidal Pco2 fell to 22 mm Hg. The effect of carbon dioxide The effect on intestinal blood flow of alteration of arterial blood ph by alteration of the inspired C02 was determined in seven cats. It is known that alteration of the degree of pulmonary inflation can affect systemic peripheral resistance (Salisbury, Galletti, Lewin & Rieben, 1959; Daly & Scott, 1963), and in order to prevent the respiratory effects of C02 from affecting peripheral resistance, ventilation was controlled by means of the Starling pump at a respiratory rate of 20 c/min. The tidal volume was adjusted at the beginning of the experiment, with the animal breathing air, so as to reduce the end-tidal Pco0 to the region of 10 mm Hg and to increase the arterial blood ph. This tidal volume and respiratory rate were then kept constant. At least 15 min were allowed with this procedure to ensure stable conditions of blood flow, end-tidal C02 and arterial blood ph. End-tidal C02 was then altered by allowing the animal to receive 1-8 % C02 in 02 from Douglas bags attached to the Starling pump. In all experiments, end-tidal C02 was progressively increased by allowing the animal to breathe from bags with increasing concentrations of C02, without return to air between each bag. When the maximal desired end-tidal C02 was achieved the procedure was varied. In two experiments, the animal was returned to air after breathing gradually decreasing concentrations of C02. In five experiments the animal was returned directly to air, and in one of these experiments, the animal after its return to air was given different concentrations of C02 without any particular order. Determinations of arterial blood ph and blood flow were made 5 min after the end-tidal C02 had reached a constant value on each gas mixture. The effect of the over-ventilation required to reduce the end-tidal C02 was to cause a fall in blood pressure in some of these experiments and it was necessary to stabilize the blood pressure at lower levels than previously (mean blood pressure 85 mm Hg). In some experiments blood flow with the reduced perfusion pressure was initially low. There was a small rise in 43-2

6 674 F. P. McGINN, D. MENDEL AND P. M. PERRY portal pressure on increasing the C02 in the inspired air, the maximum change being only 3 mm Hg, so that the net perfusion pressure remained relatively constant. The changes in intestinal flow with alteration of inspired C02 are shown in Fig. 2. Each value for flow is the average of six determinations. The v 12 _ 0 'g ' *A,0 Ca 66 i4 _ End-tidal PCO2 (mm Hg) Fig. 2. The relation between end-tidal PCO2 and intestinal blood flow. Controlled respirations. Symbols indicate different cats. The two experiments in which the effect of both increasing and decreasing concentrations of CO2 were examined are indicated by the filled circles and diamonds. Regression line shown. points plotted are all those obtained with increasing concentrations of C02 (seven experiments) and the points obtained in the two experiments with decreasing C02. In two preliminary experiments the effect of increasing the end-tidal PCO2 up to 40 mm Hg by means of 1-5 % C02 was examined. In these there was an increase in intestinal blood flow associated with each increase in end-tidal C02. In the other five experiments the end-tidal Pco2 was increased up to 60 mm Hg by increasing the inspired C02 to 8 %. In four of these experiments there was an increase in intestinal blood flow with each increase in end-tidal C02, although in one experiment the change in flow between end-tidal PCO0 of 49 and 58 mm Hg was only 0 3 ml./min ( ml./min). In the other experiment flow increased when the end-

7 INTESTINAL BLOOD FLOW 675 tidal Pco0 was changed from 6 to 30 mm Hg, but fell on further increasing the end-tidal Pco,. In all these experiments when the animal was returned to air after breathing increased C02, flow decreased to near normal levels. In the experiment in which CO2 was given in a random order the flow increased with increased CO2 and was decreased with decreased CO2. The average arterial blood ph was changed from 7*55 to The regression equation for the observed data was y = 0 11x+2 89, with intestinal blood flow as the dependent variable, and the regression line is shown in Fig. 2. From this line it was apparent that a 10 mm Hg rise in end-tidal Pco, resulted in about 1 ml./min increase in intestinal blood flow. Arterial ph and noradrenaline It seemed from the above experiments that intestinal blood flow changed in relation to CO2 rather than to arterial blood ph. The possibility was investigated that the apparent dilator effect of CO2 may have been due to a reduced sensitivity to adrenergic transmitter with decrease in arterial blood ph (Bygdeman, 1963) rather than to a direct effect of CO2 on the vessel wall. The effects ofalteration of arterial blood ph on the sensitivity ofintestinal blood flow to noradrenaline was investigated in four cats. Changes in arterial blood ph were produced by infusion of acid and alkali in three experiments, in two of which end-tidal Pco2 was controlled. In the fourth experiment, the arterial blood ph was altered by changing the concentration of inspired CO2 as described above. In each experiment, blood pressure was kept constant throughout. Blood flow was recorded for 5 min at the desired ph level and an infusion of noradrenaline (2,tg/ml. at 0x25 ml./min) was then given for 2 min. Successive readings of blood flow were made until the blood flow returned to control values. In the experiments in which arterial blood ph was altered by infusion of acid or alkali determinations of the sensitivity to noradrenaline were made in the ph ranges 7*15-7*25, 7*35-7*45 and One determination was made in each of the extreme ph ranges and at least two in the control range ( ), one at the start of the experiment and one after the determination with altered ph. Sixteen noradrenaline infusions were examined in the three cats. In the experiment in which arterial blood ph was altered by changing the inspired C02, five infusions of noradrenaline were given both with increasing and decreasing CO2 concentrations. In all these experiments noradrenaline was less effective in reducing intestinal blood flow when the arterial blood ph was decreased than when it was increased. The results were similar when the end-tidal PCO2 was held constant. Figure 3 shows the average percentage flow reduction over three ph ranges in the four experiments, and the standard errors of the mean.

8 676 F. P. McGINN, D. MENDEL AND P. M. PERRY The difference between the flow reduction over the ph range (29 %) and that over the ph range 7*55-7*65 (52.6 %) was significant (P < 0.01) Arterial blood ph Fig. 3. The percentage decreases in intestinal blood flow caused by noradrenaline infusion at different arterial blood ph ranges. Vertical lines indicate standard errors of the mean. The effect of C02 after adrenergic blockage These experiments suggested that since variations in transmitter sensitivity could be demonstrated when end-tidal CO2 was held constant, the response was related to a change in blood ph. In the experiments in which the concentration of inspired CO2 was altered, there was also a change in arterial blood ph. It was therefore still uncertain whether CO2 affected intestinal blood vessels directly or by alteration of their sensitivity to transmitter. In order to examine further the possibility that C02 may have been directly dilator to these vessels, the effect of variation of transmitter sensitivity was eliminated by adrenergic blockade with 2-(N-p-tolyl-N-m-hydroxyphenyl-amino-methyl)-imidazoline, 1 mg/kg I.v. ('Rogitine', Ciba Laboratories Ltd.). Experiments were performed in six cats. In five of these animals the effect of CO2 on intestinal blood flow had previously been determined. At the end of this procedure the animals were allowed to breathe spontaneously for 30 min before blockade with Rogitine, and after a further 30 min the respiration was again controlled at a rate of 20 c/min. The blood pressure was stabilized at a suitable level which was lower than before (average 70 mm Hg). The end-tidal PCO2 was first lowered to about 10 mm Hg by

9 INTESTINAL BLOOD FLOW 677 over-ventilation and then altered as described previously, using concentrations of 1-8% C02 in 02 with the same ventilation. In all these experiments the end-tidal C02 was increased in steps, the animals then being returned to air. The results are shown in Fig. 4, where intestinal blood flows obtained with increasing end-tidal PCO2 up to 70 mm Hg are shown. Each flow g 10 / 0 0~~~~~~~~ o "= 6 _.< A4 H 4 A End-tidal PCO2 (mm Hg) Fig. 4. The relation between end-tidal PCO2 and intestinal blood flow after adrenergic blockade with Rogitine 1 mg/kg i.v. Controlled respirations. Symbols indicate different cats and correspond to those in Fig. 2. Regression line shown. value is the average of six determinations. The average arterial blood ph after over-ventilation was 7-48 and the average after administration of C02 was In each experiment an increase in C02 was associated with an increase in flow. On returning the animals to air the flow always decreased, but in three experiments remained about 25 % above initial values after 30 min. The regression equation for the results may be expressed as y = 0 08x+4*37 with intestinal blood flow as the dependent variable, and the regression line is shown. There was no significant difference between the slope of this regression line and that before adrenergic blockade (P > 0 3).

10 678 F. P. McGINN, D. MENDEL AND P. M. PERRY DISCUSSION In the present experiments the effect of alteration of arterial blood ph and C02 on intestinal blood flow has been determined. The separation of the effects of hydrogen-ion from those of C02 has been achieved in experiments with infusion of acid or alkali by maintaining the end-tidal C02 constant. It has been shown by Gerst, Rattenborg & Holaday (1959) that there is a close relation in the dog between end-tidal Pco. and arterial blood PCO2 and that this relation has been assumed here. The use of a controlled perfusion pressure in any particular experiment has eliminated the effects that possible changes in cardiac output might have on flow. It is clear from these experiments that alteration of ph as such had remarkably little effect on intestinal blood flow. The results in Fig. 1 show clearly that wide variations of hydrogen-ion concentration caused small and inconsistent changes in flow when end-tidal PCO1 was controlled. Rogers, Atkinson & Long (1965) using a perfused dog intestine preparation altered the ph of the perfusing fluid by the addition of acid and alkali. It is clear from their results that alteration of the ph of the medium did not alter the perfusion pressure with constant flow. In contrast to this result, when the amount of C02 in the inspired air was varied from 1 to 8 %, the rate and depth of respiration being held constant, there was generally an increase in flow with an increase in C02. This is in agreement with Bernthal (1930) and Mohamed & Bean (1951) who found that high concentrations of C02 in the inspired air increased intestinal blood flow in the dog. The latter authors also showed that the cha nge in flow could not be explained in terms of altered intestinal motility or t onus. It was expected that the effect of carbon dioxide would prove to b e complex, the effect on flow being a resultant of a constrictor effect acting through the vasomotor centre and a local dilator effect. We found no evidence of the central action of C02 leading to a diminished intestinal blood flow, although in one of our experiments an increase in flow with Pco, above 30 mm Hg was not seen and in another experiment only small flow changes were found between Pco0 of 49 and 58 mm Hg. Brickner et al. (1956), on the other hand, observed this effect of C02 in the dog when the amount of C02 added to the inspired air was from 1 to 4 %. With higher percentages, the dilator effect of C02 was observed. Miohamed & Bean (1951) reported that the central constrictor effect of C02 on the dog intestine vessels was small compared with its direct vasodilator action. The finding that the sensitivity of intestinal blood vessels to C02 was similar before and after adrenergic blockade would support this view. The possibility was investigated that the dilator effect of C02 locally

11 INTESTINAL BLOOD FLOW 679 may have been related to an alteration of transmitter sensitivity, so that any noradrenaline released at the sympathetic nerve endings would be relatively ineffective with increased CO2. Although it was found that noradrenaline was less effective in reducing flow when the arterial blood ph was decreased and while it was possible that part of the dilator effect of CO2 may have been due to a concomitant change in ph, it was also clear that when the effect of carbon dioxide was examined after adrenergic blockage, a dilator effect was still evident. In the experiments in which the effectiveness of injected noradrenaline was examined it was clear that the intestinal blood vessels were less responsive when ph was decreased and when end-tidal Pco. was held constant, so that the effect could be related to hydrogen-ion rather than to CO2. This result was in agreement with that of Bygdeman (1963) on a perfused muscle bed of the cat and with Tobian, Martin & Eilers (1959) on aortic strips of the rat. In view of the finding that alteration of ph was associated with variation in the vascular response to noradrenaline, it was somewhat surprising that alterations of ph without change in CO2 did not produce any changes in flow, since it would be expected that there should be an altered sensitivity to spontaneously liberated transmitter. One explanation may be related to the observation of Bygdeman (1963) that the vasoconstriction produced by sympathetic stimulation in a perfused limb was less impaired by a decrease in ph than was the response to injected noradrenaline. He suggested that noradrenaline produced by nerve stimulation was liberated close to receptor sites while injected noradrenaline had a longer pathway to reach these sites. An alteration of ph may have changed the amount of noradrenaline reaching the receptor or the number of receptors reached. REFERENCES BAYLISS, W. M. (1901). Action of carbon dioxide on blood vessels. J. Physiol. 26, P. BERNTHAL, T. G. (1930). Some observations upon changes in volume flow of blood accompanying changing respiratory conditions. Am. J. Phy8iol. 95, BRICKNER, E. W., DOWDS, E. G., WILLITTS, B. & SELKURT, E. E. (1956). Mesenteric blood flow as influenced by progressive hypercapnia. Am. J. Phy8iol. 184, BYGDEMAN, S. (1963). Vascular reactivity in cats during induced changes in the acid-base balance of the blood. Acta phy8iol. 8cand. 61, suppl. 222, DALY, M. DE B. & SCOTT, M. J. (1963). The cardiovascular responses to stimulation of the carotid body chemoreceptors in the dog. J. Physiol. 165, DAWES, G. S., MOTT, J. C. & VANE, J. R. (1953). The density flowmeter, a direct method for the measurement of the rate of blood flow. J. Physiol. 121, DEAL, C. P. & GREEN, H. D. (1954). Effects of ph on blood flow and peripheral resistance in muscular and cutaneous vascular beds in the hind limb of the pentobarbitalized dog. Circulation Res. 2, FLEISHMAN, M., SCOTT, J. & HADDY, F. J. (1957). Effect of ph change upon systemic large and small vessel resistance. Circulation Res. 5, GASKELL, W. H. (1880). On the tonicity of the heart and blood vessels. J. Physiol. 3,

12 680 F. P. McGINN, D. MENDEL AND P. M. PERRY GERST, P. H., RATTENBORG, C. & HOLADAY, D. A. (1959). The effects of haemorrhage on pulmonary circulation and respiratory gas exchange. J. clin. Inve8t. 38, GOLLWITZER-MEIER, K., HAUSSLER, H. & KRUGER, E. (1938). tyber den Einfluss der Wasserstoffionenkonzentration des Blutes auf den Gaswechsel des Herzens. Pfluger8 Arch. ge8. Physiol. 239, LENNOX, W. G. & GIBBS, E. L. (1932). The blood flow in the brain and the leg of man and the changes induced by alteration of blood gases. J. clin. Inveat. 11, McDowALL, R. J. S. (1930). The effect of carbon dioxide on the circulation. J. Phy8iol. 70, MOHAMED, M. S. & BEAN, J. W. (1951). Local and general alterations of blood CO2 and influence of intestinal motility in regulation of intestinal blood flow. Am. J. Phy8iol. 167, PAGE, I. H. & OLMSTED, 0. F. (1951). The influence of respiratory gas mixtures on arterial pressure and vascular reactivity in normal and in hypertensive dogs. Circulation 3, ROGERS, L. A., ATKINSON, R. A. & LONG, J. P. (1965). Responses of isolated perfused arteries to catecholamines and nerve stimulation. Am. J. Phy8siol. 209, SALIsBuRY, P. F., GALLETTI, P. M., LEwIN, R. J. & RIEBEN, P. A. (1959). Stretch reflexes from the dog's lungs to the systemic circulation. Circulation Res. 7, SOKOLOFF, L. (1960). The effects of carbon dioxide on cerebral circulation. Anesthe8iology 21, STECK, I. E. & GELLHORN, E. (1939). The effects of carbon dioxide inhalation on the peripheral blood flow in the normal and in the sympathectomised patient. Am. Heart J. 18, TOBiAN, L., MARTIN, S. & EILERs, W. (1959). Effect of ph on norepinephrine-induced contractions of isolated arterial smooth muscles. Am. J. Phy8iol. 196,