Birmingham B15 2TT. (Received 25 November 1992) hypoxia (breathing 8 or 6% 02 for 5 min).

Transcription

1 Journal of Physiology (1993), 47, pp With 4 figures Printed in Great Britain THE ROLE OF VASOPRESSIN IN THE REGIONAL VASCULAR RESPONSES EVOKED IN THE SPONTANEOUSLY BREATHING RAT BY SYSTEMIC HYPOXIA BY ANNE-MARIE M. LOUWERSE AND JANICE M. MARSHALL From the Department of Physiology, the Medical School, Vincent Drive, Birmingham B15 2TT (Received 25 November 1992) SUMMARY 1. In spontaneously breathing rats anaesthetized with Saffan, we have investigated the role of vasopressin in the cardiovascular responses evoked by systemic hypoxia (breathing 8 or 6% 2 for 5 min). 2. Breathing 8% 2 evoked an increase in respiratory frequency and tidal volume; arterial 2 pressure (Pa, 2) fell to 37 mmhg and arterial CO2 pressure (Pa C2) fell to 3 mmhg. Concomitantly, there was a fall in arterial pressure, tachycardia and increases in femoral and renal vascular conductances indicating net vasodilatation in skeletal muscle and kidney. The vasopressin Vl-receptor antagonist, d(ch2)5tyr(me)-arginine vasopressin (2 jug kg-' i.v.), had no significant effect on the baseline values of any recorded variables, nor on the respiratory or blood gas changes evoked by 8 % 2. However, it accentuated the fall in arterial pressure and the increase in femoral vascular conductance (+22 vs. +77 % at the 5th minute) produced by 8% 2, but had no significant effect on the increase in renal vascular conductance. 3. Breathing 6% 2 evoked qualitatively similar responses as 8% 2 but Pal 2 fell to 33 mmhg and Pa co2 fell to 28 mmhg and the respiratory and cardiovascular changes tended to be larger than those evoked by 8% 2. Again the Vl-receptor antagonist accentuated the hypoxia-induced fall in arterial pressure and increase in femoral vascular conductance (+ 5 vs. + 76% at the 5th minute). 4. Infusion of vasopressin (1-5 ng min-' kg-' i.v.) for 5 min with the aim of producing a plasma concentration comparable to that reached during 8% 2 induced a rise in arterial pressure (9%), bradyeardia (-5%) and a decrease in femoral (-11 %) and renal vascular conductance (-4 %). 5. These results suggest that vasopressin released during hypocapnic hypoxia helps to limit the evoked fall in arterial pressure by exerting a vasoconstrictor influence on skeletal muscle. INTRODUCTION In recent studies we have analysed the cardiovascular responses evoked by systemic hypoxia in the spontaneously breathing rat and have deduced the role in these responses of the sympathetic nervous system, of circulating adrenaline, of MS 1933

2 464 A.-M. M. LOUWERSE AND J. M. MARSHALL locally released metabolites and of factors secondary to the hyperventilation (Marshall & Metcalfe, 1988a, b, 1989, 199; Mian, Marshall & Kumar, 199; Neylon & Marshall, 1991). There is evidence in the rat and other species that systemic hypoxia also causes an increase in plasma vasopressin levels (Anderson, Pluss, Berns, Jackson, Arnold Schreier & McDonald, 1978; Forsling & Aziz, 1983; Raff, Shinsako, Keil & Dallman, 1983; Walker, 1986). However, very little is known about the role of vasopressin in the control of the cardiovascular system during systemic hypoxia. In experiments on conscious rats, Walker (1986) deduced from the effect of the selective vasopressin V1-receptor antagonist, d(ch2)5tyr(me)-arginine vasopressin, upon arterial pressure, cardiac output and calculated total peripheral resistance, that vasopressin had no significant effect during hypocapnic hypoxia, i.e. when arterial C2 pressure (Pa c2) was allowed to fall during the hyperventilation induced by breathing 8 % 2, but that it did exert a significant vasoconstrictor influence during normocapnic hypoxia, i.e. when Pa, co2was prevented from falling by addition of CO2 to the inspirate. In some contrast, in experiments on spontaneously breathing rats anaesthetized with Saffan, in which hypocapnia was allowed to develop during systemic hypoxia (breathing 8% 2), we found that the same vasopressin Vlreceptor antagonist significantly reduced constrictor responses evoked in individual arterioles of the spinotrapezius muscle (see Marshall, Lloyd & Mian, 1993), suggesting that vasopressin does exert a significant vasoconstrictor influence during hypocapnic hypoxia, at least on skeletal muscle. Thus, the aim of the present study was to test the effect of the V1-receptor antagonist upon the cardiac and regional vascular responses induced in the spontaneously breathing rat by hypocapnic hypoxia. Two different levels of hypoxia were used: that imposed by administering 8% 2 the same as Walker (1986), and a more severe level, imposed by administering 6% 2, at which we hoped the influences of vasopressin would be more evident. To complement these experiments, we examined the cardiovascular responses evoked by vasopressin infused intravenously at a rate chosen to achieve plasma levels comparable to those measured in rats during systemic hypoxia (Forsling & Aziz, 1983) assuming a metabolic clearance rate of vasopressin from plasma of 5 ml min-' kg-' (Crofton, Ratliff, Brooks & Share, 1986). The anaesthetic used for these studies was the steroid mixture Saffan (Pittman-Moore, Uxbridge, UK) which in previous studies has shown contrasts with commonly used anaesthetics in that it allows the cardiovascular components of the alerting or defence response to be evoked by stimulation of a peripheral input (see Marshall & Metcalfe, 1988a). Since this pattern of respond depends on synaptic transmission through the hypothalamus, it might be expected to provide suitable conditions for investigating the physiological role of vasopressin released by peripheral inputs. Some of these results have been presented to the Physiology Society (Louwerse & Marshall, 1991). METHODS Experiments were performed on seventeen male Wistar rats prepared as described previously (Marshall & Metcalfe, 1988a, b). Briefly, anaesthesia was induced with a mixture of N2/2/halothane and maintained by a continuous infusion of Saffan at 7-12 mg kg-' h-1 (i.v.). The trachea was cannulated with a T-shaped cannula, the side-arm of which was connected via a

3 V'ASOPRESSIN AND SYSTEMIC HYPOXIA flow head to an electrospirometer. Air, or an hypoxic mixture, was delivered across the open end of the flow head throughout the experiment. Arterial pressure was recorded from a femoral artery and heart rate was derived from the pressure recording via a rate meter. Blood flow was recorded from a femoral artery with the paw ligated by a stout ligature, and from the left renal artery, via electromagnetic flow probes. The flow probes were calibrated in vitro by constant flow infusion through a freshly excised artery. Regional vascular conductances were computed on-line by electronic division of blood flow by arterial pressure. All variables were recorded on an 8-channel pen recorder (Lectromed, Jersey, UK). A femoral vein was cannulated to allow administration of drugs, while a brachial artery was cannulated to allow removal of blood samples for analysis of PaJ', P and arterial ph. These samples and the hypoxic mixtures, which were made up on the day of the experiment from air and N2 (BOC Ltd, UK) in a PVC Douglas bas, were analysed by a Nova Stat Profile 3 (V. A. Howe & Co. Ltd, MA, USA. After surgery had been completed and all recording devices had been attached an equilibration period of at least 3 min was allowed. Each animal was then given two 5 min hypoxic periods of breathing 8 and 6% 2, separated by an interval that was sufficiently long to allow all variables to return to a steady state (at least 1 min). These periods were followed by a 5 min infusion of vasopressin ([Arg8]vasopressin, Sigma Chemical Co., UK) delivered by a pump (Sage Instruments, MA, USA) at 1-5 ng min-' kg-1 i.v. in a total volume of 1 ml. The vasopressin V,-receptor antagonist, d(ch2)5tyr(me)-arginine vasopressin (Sigma), was given (2 jug kg-' I.v.) and the protocol just described was repeated. Arterial samples (14 1ll) for analysis of blood gas status were taken during air breathing after the initial equilibrium period, at the 2nd minute of each period of hypoxia and during air breathing at the end of the experiment. Each sample was replaced with an equal volume of physiological saline. Statistical analyses. All results are expressed as means+ S.E.M. Baseline levels of each variable were compared before and after the V -receptor antagonist using Student's paired t test. The differences between responses evoked by hypoxia and by vasopressin before and after the V1- receptor antagonist were tested using the paired t test. For the cardiovascular and respiratory responses we compared the logarithm of the difference between the baseline value and the peak value attained during the stimulus before and after the antagonist; logarithmic transformation was performed because the variance of the data increased proportionately with the mean (Dixon & Massey, 1969). RESULTS The pattern of respiratory and cardiovascular response induced by 8 and 6% 2 before the V -receptor antagonist was comparable to that described previously (Marshall & Metcalfe, 1988b; Neylon & Marshall, 1991) (see Fig. 1). There was hyperventilation; respiratory frequency increased progressively from a control value of breaths min-', while tidal volume increased from the control value of ml by the end of the 2nd minute, but tended to wane towards the control value by the end of the 5th minute. Similarly, heart rate increased from the control value of beats min-' by the 2nd minute, but tended to wane thereafter (Figs 1, 2 and 3). Meanwhile, mean arterial pressure fell progressively during each period of hypoxia from a control value of mmhg, and femoral and renal vascular conductance increased, indicating vasodilatation in both vascular beds; femoral and renal blood flow tended to remain constant. Blood gas analyses made during air breathing and at the 2nd minute of hypoxia showed that Pa, and Pa co 2 2 fell significantly, the changes being greater during 6 % 2: Pa was mmhg during air breathing and fell to 37+3 and to 33+3 mmhg during 8 and 6% 2 respectively (P < 1 in each case) while Pa co was mmhg during air breathing and fell to 3 and 28 mmhg during 8 and 6 % 2 respectively (P < 1 in each case). 465

4 466 A. -M. M. LOUWERSE AND J. M. MARSHALL The V1-receptor antagonist had no significant effect on the baseline level of arterial pressure during air breathing ( mmhg), nor on the baseline level of any other recorded variable. The antagonist also had no effect on the changes induced by hypoxia in ventilation, except the respiratory frequency at the 5th minute of 6% 2 RF (breaths min1) VT (ml) RVC (ml min-1 mmhg-) RBF (ml min-) 1'c5 r.14: 2 FVC.5 (ml min-' mmhg-) FBF 5 (ml min1) HR 5 (beats min1) ABP (mmhg) -*A"-... I., III IIlTrM",, -,- 6 - J] %-la waffmowp M. vv1-antagonisst ommom 8% 2 8% 2 T-T= -T min Fig. 1. The effect of the Vl-receptor antagonist on respiratory and cardiovascular responses evoked by 8% 2. Traces from above down: respiratory frequency (RF) in breaths min-1; tidal volume (VT) in ml; renal vascular conductance (RVC) in ml min-' mmhg-'; renal blood flow (RBF) in ml min-'; femoral vascular conductance (FVC) in ml min-' mmhg-'; femoral blood flow (FBF) in ml min-'; heart rate (HR) in beats min-' and arterial pressure (ABP) in mmhg. The bar beneath each set of traces indicates the period of hypoxia. (Figs 2 and 3), nor on the Pa, 2and Pa CO2values; Pa 2 fell to and mmhg during 8 and 6% 2 respectively, while Pa, co2 fell to and mmhg during 8 and 8% 2 respectively. However, there were effects on the cardiovascular responses evoked by hypoxia (Figs 2 and 3). The heart rate changes were comparable to those recorded before the antagonist, but the fall in arterial pressure was greater at the 2nd minute of 8% 2 and at the 5th minute of 6% 2. Furthermore, the increase in femoral vasodilatation was greater at the 5th minute of both 8 and 6 % 2 indicating potentiation of the muscle vasodilatation. The increases in renal r, l

5 VASOPRESSIN AND SYSTEMIC HYPOXIA vascular conductance tended to be greater during both levels of hypoxia, but this did not reach significance. Effects of vasopressin infusion Vasopressin infusion had no effect on respiratory frequency, but produced a significant fall in tidal volume. There was also a highly significant fall in heart rate 467 8% RF VT lnxxx1fnx ABP -1 - HR 5 I X L] kj,'t. 1-5 FVC FIlrLi FBF RVC 1 2 Tre A RBF nl Time (min) n Time (min) Fig. 2. Effect of the Vl-receptor antagonist on mean respiratory and cardiovascular changes evoked by 8% 2. All abbreviations as indicated in Fig. 1. Each column represents mean percentage change from the baseline +s.e.m. at the end of the 2nd minute and 5th minute of hypoxia. Open and hatched columns indicate before and after the Vlreceptor antagonist respectively. **, * indicate significant differences between changes evoked before and after the antagonist at P <.1 and P < 5 respectively. and increase in arterial pressure. Femoral and renal vascular conductance fell significantly indicating vasoconstriction; there was no change in blood flow in either vascular bed (Fig. 4). At the end of the experiments, after the Vl-receptor antagonist had been given, vasopressin infusion had no significant effect on any of the recorded variables (Fig. 4).

6 468 A. -M. M. LOUWERSE AND J. M. MARSHALL DISCUSSION In the present study on Saffan-anaesthetized rats, systemic hypoxia induced by spontaneous breathing of 8 and 6% 2 for 5 min produced comparable respiratory and cardiovascular changes to those described previously (Marshall & Metcalfe, 6% RF vil VT - L 5- ABP uii-t w HR -1.' 1 5 FVC FBF -2 I~~~~~~~~~~~~~~~~~~~~~~~~~ I T RVC Fig. 4T RBF F~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Time (min) Time (min) 3. Effects of the Vl-receptor antagonist on mean respiratory and cardiovascular changes evoked by 6% 2. All abbreviations and symbols as in Fig b; Neylon & Marshall, 1991). These comprised hyperventilation and tachyeardia which tended to wane after the first 2 min of hypoxia, together with a fall in arterial pressure and vasodilatation in skeletal muscle and kidney, the magnitude of the changes tending to be larger during 6 2 than during 8% 2. Judging from the blood gas measurements made at the 2nd minute of the hypoxia, Pa 2fell to 38 and 33 mmhg during 8 and 6% 2 respectively, and as a consequence of the

7 VASOPRESSIN AND SYSTEMIC HYPOXIA hyperventilation Pa co2fell to 3 and 28 mmhg respectively. 469 Thus, the systemic hypoxia was accompanied by substantial hypocapnia. Assuming the metabolic clearance rate of vasopressin from plasma in the rat is 5 ml min-' kg-' (Crofton et al. 1986), then infusion of vasopressin at RF 1-1 I1 r VT 1 -o ABP -15 **m HR -15 1J * FVC FBF L.J ** RVC [**L** RBF Fig. 4. Changes evoked in respiratory and cardiovascular variables by vasopressin infusion before and after the V1-receptor antagonist. All abbreviations and symbols as in Fig. 2. I~ 1-5 ng min-1 kg-1 would have produced a rise in plasma vasopressin concentration of approximately 3 pg ml-'. Forsling & Aziz (1983) measured increases in plasma vasopressin of 25 pg ml-' and 8 pg ml-' at the end of 1 min periods of - spontaneously breathing 1 and 8% 2 respectively, in rats anaesthetized with pentobarbitone and in conscious rats. The 6 % 2 mixture used in the present study may well have produced a rather larger increase than 8% 2. Thus, the plasma vasopressin concentration we achieved by vasopressin infusion was probably of the same order, but somewhat lower than the concentrations reached in the periods of hypocapnic hypoxia. Indeed, our recent assays of plasma vasopressin during longer, 16 PHY 47

8 47 A. -M. M. LOUWERSE AND J. M. MARSHALL 2 min periods of breathing 1 or 8%2 in Saffan-anaesthetized rats showed concentrations of 74 and 117 pg ml-' respectively (Louwerse, Marshall & Forsling, 1992). The vasopressin concentration reached during infusion was certainly in the vasoactive range for it produced a small, but significant increase in arterial pressure and vasoconstriction in skeletal muscle and kidney. The magnitude of the increase in arterial pressure was comparable to that recorded in conscious rats in response to vasopressin infusion at similar rates (Crofton et al. 1986). The decrease in vascular conductance evoked in the kidney was not as pronounced as in skeletal muscle, whether considered as a percentage of the control value, or in absolute terms. This accords with previous evidence that vasopressin has a weak vasoconstrictor influence on the kidney, relative to its influence on other vascular beds (Gardner, Bennett & Compton, 1988). Vasopressin infusion also produced a substantial decrease in heart rate. It has been argued by some, that the bradyeardia evoked by vasopressin is larger than would be expected as a baroreceptor reflex response to the rise in arterial pressure: it may be partly attributable to an effect of vasopressin upon the central nervous system, possibly by a direct action in the cardiac vagal neurones (see Liard, 1984; Johnston, 1985; Bennett & Gardner,1986). The fact that vasopressin infusion caused a decrease in respiratory tidal volume could not be explained as a reflex change evoked by peripheral chemoreceptors since vasopressin evokes an increase in their activity (McQueen, 1981). However, if vasopressin exerted a vasoconstrictor influence upon cerebral circulation, this may have caused a reduction in cerebral perfusion, a decrease in oxygen delivery to the brain and a consequent central depressive effect on respiration (Martin-Body, 1988). Accordingly, the secondary decrease in respiration seen in the rat during systemic hypoxia, which is attributable to a central depressive effect of hypoxia, is manifest mainly as a decrease in tidal volume (Neylon & Marshall, 1991). Judging from the lack of effect of vasopressin infusion at the end of the experiment after the V1-receptor antagonist had been administered, there was effective blockade of V1-receptors for the duration of the experiment. Blockade of V1-receptors had no effect on the baseline arterial pressure or regional vascular conductance suggesting that circulating levels of vasopressin exert little tonic vasoconstriction influence in normoxia. Moreover, blockade of the V1-receptors had no effect on the values of Pa, 2 or Pa, co2recorded during air breathing, or at the 2nd minute of hypoxia. This is important for the interpretation of our findings since the magnitude of the cardiovascular changes induced by hypoxia is closely related to the fall in Pa 2 (Marshall & Metcalfe, 1988 b). Furthermore, in the absence of systemic administration of a pharmacological antagonist, the cardiovascular changes induced by two successive periods of systemic hypoxia are fully comparable (Mian & Marshall, 1991). Thus, it is reasonable to attribute differences between the responses evoked by hypoxia before and after the Vl-antagonist to the effect of the antagonist per se. In fact, the hypoxia-induced fall in arterial pressure was accentuated after V1- receptor blockade, particularly that induced by 6% 2. Furthermore, the vasodilatation evoked in muscle was substantially increased both during 8 and 6% 2 We have previously deduced that the fall in arterial pressure during hypocapnic hypoxia is mainly due to muscle vasodilatation (Marshall & Metcalfe, 1988b). Thus,

9 VASOPRESSIN AND SYSTEMIC HYPOXIA taken together with the effects of vasopressin infusion, these findings indicate that vasopressin released during hypocapnic hypoxia exerts a significant vasoconstrictor influence on skeletal muscle which helps to limit the muscle vasodilatation evoked by influences such as adenosine, K+ and adrenaline (Mian et al. 1991; Neylon & Marshall, 1991) and thereby to limit the fall in arterial pressure. This conclusion accords with our direct observations that V1-receptor blockade limits the constriction induced in individual arterioles of the spinotrapezius muscle during hypocapnic hypoxia (Marshall et al. 1993). The fact that V1-receptor blockade did not significantly affect the renal vasodilator response to hypoxia is consistent with the relatively weak influence of exogenous vasopressin on renal vasculature (see above). In accordance with the lack of effect of V1-receptor blockade on the blood gas values recorded during 8 and 6 % 2 there was no effect on the respiratory changes. The significant reduction in the increase in respiratory frequency recorded at the 5th minute of breathing 6% 2 could be explained by blockade of the effect of an hypoxia-induced rise in plasma vasopressin levels on the peripheral chemoreceptors (McQueen, 1981). Thus the present findings seem to contrast with those obtained by Walker (1986) in that he reported no significant vasoconstrictor influence of vasopressin during hypocapnic hypoxia (see Introduction). This may be because it is easier to identify a vasoconstrictor influence on individual vascular beds than on total peripheral resistance calculated from cardiac output and arterial pressure. However, the disparity may also be attributed to the magnitude of the evoked fall in arterial pressure. The fall induced by 8% 2 in Saffan-anaesthetized rats was greater than that induced in conscious rats by the same level of hypoxia (Walker, 1986) and our recent studies indicated that during hypocapnic hypoxia, baroreceptor unloading is the dominant stimulus for vasopressin release (Louwerse et al. 1992). Similar reasoning may account for the fact that the Vl-receptor antagonist did not have a markedly greater effect on the vascular responses evoked by 6 % 2 than on those evoked by 8% 2. Although the stimulus to vasopressin release caused by peripheral chemoreceptor activation (Harris, 1979) may have been substantially greater with 6%2 than with 8% 2 given the slope of the Pa 2-chemoreceptor discharge relationship, the falls in arterial pressure evoked by these stimuli and therefore the extent of baroreceptor unloading must have been very similar. This work was supported by the Wellcome Trust. 471 REFERENCES ANDERSON, R. J., PLUSS, R. G., BERNS, A. S., JACKSON, J. T., ARNOLD, P. E., SCHREIER, R. W. & McDONALD, K. M. (1978). Mechanism of effect of hypoxia on renal water excretion. Journal of Clinical Investigation 62, BENNETT, T. & GARDINER, S. M. (1986). Influence of exogenous vasopressin on baroreflex mechanisms. Clinical Science 7, CROFTON, J. T., RATLIFF, D. L., BRoOKS, D. P. & SHARE, L. (1986). The metabolic clearance rate of the pressor responses to vasopressin in male and female rats. Endocrinology 118, DIXON, W. J. & MASSEY, F. J. (1969). Introduction to Statistical Analysis. McGraw-Hill, New York. FORSLING, M. L. & Aziz, L. A. (1983). Release of vasopressin in response to hypoxia and the effect of aminergic and opioid antagonists. Journal of Endocrinology 99,

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