SUMMARY1. In rats anaesthetized with Saffan we have studied the effects of the adenosine receptor antagonists, theophylline and 8-phenyltheophylline, upon the respiratory and cardiovascular responses evoked by 5 min periods of systemic hypoxia.2. In the group of animals that were to receive theophylline (15 mg kg-' i.v.), arterial 02 pressure (Pal 02) fell from 83 + 2 mmHg during air breathing to 38 + 3 or 34 + 3 mmHg during the 5th minute of two different control periods of hypoxia, while in the group that were to receive 8-phenyltheophylline (10 mg kg-' i.v.), Pa 02 fell from 83 + 1 to 53 + 2 mmHg. Neither drug significantly altered the levels of Pa, 2 reached during hypoxia. 3. During the control periods of hypoxia respiration increased, but the increase evoked at the 5th minute was significantly less than that evoked at the 2nd minute of hypoxia. This secondary waning of the hyperventilation was abolished by both drugs.4. Similarly, both drugs attenuated the tendency for the hypoxia-induced tachyeardia to wane between the 2nd and 5th minute.5. Further, both drugs substantially reduced both the hypoxia-induced fall-in arterial pressure and the increases in vascular conductance in hindlimb muscle, carotid vasculature and kidney.6. Thus, we propose that in the rat the release of adenosine by hypoxic tissues makes a major contribution to the secondary decrease in respiration and heart rate that occurs during systemic hypoxia and to the accompanying vasodilatation in muscle and fall in arterial pressure. The effects of the adenosine antagonists on the carotid and renal vasculature are more equivocal and may be partly explained as a smaller autoregulatory dilatation to a smaller fall in systemic arterial pressure.7. These results and proposals are discussed in relation to the conditions that are known to cause release of adenosine and in relation to its known effects upon the respiratory and cardiovascular systems.

1. In two groups of Saffan-anaesthetized rats, we studied the role of the renin-angiotensin system in mediating the antidiuresis and antinatriuresis induced by moderate systemic hypoxia. 2. In both groups, a first period of hypoxia (breathing 12% 02 for 20 min) induced a fall in arterial partial pressure of 02 (Pa°2; to 42 mmHg), a fall in mean arterial pressure (MABP), no change in renal blood flow (RBF) due to an increase in renal vascular conductance (RVC = RBF/MABP) and falls in urine flow and absolute sodium excretion (UNa V). Concomitantly, plasma renin activity increased from 3-08 + 0-68 (mean + S.E.M.) to 8 36 + 18 ng ml-hrF. 3. In group 1 (n = 11), Losartan (10 mg kg-, i.v.), the angiotensin (AII) AT1 receptor antagonist, induced a fall in MABP (115 + 3 to 90 + 3 mmHg), an increase in RVC such that RBF was unchanged, and falls in glomerular filtration rate (GFR), urine flow and UNa V. However, hypoxia induced qualitatively similar changes to those seen before Losartan treatment. 4. In group 2 (n = 9), we occluded the aorta distal to the renal artery to prevent basal MABP and renal perfusion pressure (RPP) from falling after addition of Losartan and to keep the hypoxia-induced fall in MABP the same as before Losartan treatment. Nevertheless, Losartan induced an increase in basal RVC, RBF, urine flow and UNa V whilst hypoxia induced falls in urine flow and UN. V that were proportionately similar to those seen prior to addition of Losartan. 5. These results indicate that in the Saffan-anaesthetized rat, AII exerts tonic, renal vasoconstrictor and consequent antidiuretic and antinatriuretic influences in normoxia, but does not contribute to the hypoxia-induced antidiuresis and antinatriuresis. We propose that renin secretion is increased by the hypoxia-induced fall in RPP rather than by an increase in renal sympathetic activity. Thus, the AII generated cannot produce antidiuresis and antinatriuresis by its known facilitatory influence on the actions of an increase in sympathetic activity on the renal tubules and is insufficient to produce these effects by direct actions. Rather, these results support the view that the antidiuresis and antinatriuresis of moderate hypoxia is predominantly due to the fall in RPP.Some individuals who climb to high altitude show diuresis and natriuresis and tolerate the hypoxia well. Others show antidiuresis and antinatriuresis and commonly succumb to mountain sickness (Milledge & Catley, 1984;Honig, 1989). The antidiuresis and antinatriuresis has been attributed to the actions of angiotensin II (AII) upon the kidney, the AII being generated by hypoxia-induced stimulation of the renin-angiotensin system (Milledge & Catley, 1984.Although an increase in renin secretion might be explained as a reflex response to an increase in renal sympathetic activity caused by hypoxic stimulation of peripheral chemoreceptors (Marshall, 1994), this conclusion cannot be firmly drawn from high altitude studies, because those who climb to high altitude not only experience systemic hypoxia, but also ...

1. In rats anaesthetized with Saffan, renal function was monitored from the left kidney from the 5th minute of spontaneous breathing of 12% 02 for two 20 min periods and during air breathing before, between and after the hypoxic periods. Two groups of animals (I and II) were used, each group comprising two subgroups in which the left kidney was innervated or denervated, respectively; in Group II, renal perfusion pressure (RPP) was maintained during the 2nd hypoxic period by occl97uding the distal aorta.2. In both subgroups of Group I, both hypoxic periods produced hyperventilation, arterial P02falling to -50 mmHg. Concomitantly, mean arterial pressure (MABP) fell by similar extents (-23 %, from a baseline level of 140 mmHg during the 2nd hypoxic period). In the innervated subgroup, renal vascular conductance (RVC) increased, but glomerular filtration rate (GFR) fell (by 48 and 6%, respectively, during the 2nd hypoxic period), while urine flow, absolute sodium excretion (UNa V) and fractional sodium excretion (FENa) fell (by 52, 63 and 61 %, respectively). Baseline urine flow, UN. V and FENa were higher in the denervated subgroup, but hypoxia produced similar percentage changes from baseline in all variables. 3. In Group II, both subgroups showed similar changes during the 1st hypoxic period as the corresponding subgroups of Group I. However, during the 2nd hypoxic period when the fall in MABP was reduced to 7%, the increase in RVC persisted only in the denervated subgroup; there was no significant change in GFR, urine flow, UNaV or FENa in either subgroup. 4. These results indicate that, in the rat, moderate hypoxia produces antidiuresis and antinatriuresis that are not dependent on the renal nerves, but are dependent on the hypoxiainduced fall in MABP. The fall in renal perfusion pressure (RPP) may directly determine renal function, but reflex influences upon the kidney initiated by, for example, arterial baroreceptor unloading, may play a role. The fall in GFR and increase in RVC, which persisted after denervation or when renal perfusion was controlled, implies a local dilatatory influence acting preferentially on the efferent arterioles.It is recognized that systemic hypoxia can have pronounced effects on renal function. However, these effects are controversial. For example, systemic hypoxia has been reported to induce antidiuresis and antinatriuresis in anaesthetized dogs (Anderson et at.

Studies were performed on rats that had been made chronically hypoxic (CH rats) in a normoxic chamber at 12% O2 for 3–5 weeks. Under Saffan anaesthesia, respiratory and cardiovascular variables, renal haemodynamics and renal function were recorded while the rats spontaneously breathed 12% O2 followed by a switch to air breathing for 20 min. Plasma renin activity was assessed by radioimmunoassay of angiotensin I. Plasma atrial natiruetic peptide (ANP) was indirectly assessed by measurement of cyclic GMP in urine. When breathing 12% O2, CH rats showed hyperventilation and raised haematocrit (52%) relative to normoxic (N) rats. But arterial pressure (ABP), renal blood flow (RBF), renal vascular conductance (RVC), mean right atrial pressure (mRAtP), urine flow, glomerular filtration rate (GFR) and absolute sodium excretion (UNaV) were comparable to those recorded in N rats breathing air. Urinary cGMP was 40% greater than in N rats, but plasma renin activity was not significantly greater in CH than in N rats. Air breathing in CH rats induced hypoventilation, a 12% increase in ABP, no change in mRAtP, RBF or GFR, but increases of 75 and 100% in urine flow and UNaV, respectively. Neither urinary cGMP nor plasma renin activity changed. Such increases in urine flow and UNaV were absent when renal perfusion pressure (RPP) was prevented from rising during air breathing by using an occluder on the dorsal aorta. We propose that by 3–5 weeks of chronic hypoxia renal function was normalized, principally because arterial O2 content was normalized by the increase in haematocrit and because ABP and renal haemodynamics were normalized: acute hypoxia in N rats produces a fall in ABP. We suggest that plasma ANP was raised by the actions of hypoxia or erythropoietin on the atrium, rather than by atrial distension, but suggest that ANP had little direct influence on renal function and tended to limit the influence of the renin–angotensin system. We further propose that the diuresis and natriuresis seen during air breathing were mediated by the increase in RPP; neither plasma ANP nor renin activity change in the immediate short term.