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A comparison has been made of intestinal fluid absorption between male Okamoto spontaneously hypertensive rats (s.h.r.) and normotensive male Wistar controls. S.h.r. show enhanced fluid absorption both in hypertensive adults and in young s.h.r. before hypertension has developed. Several potential causes for increased fluid transport in s.h.r. were tested using pharmacological antagonists. It is unlikely that enhanced fluid absorption is due to high sympathetic nervous activity, the renin-angiotensin system or is secondary to hypertension. Intestine from s.h.r. have a high short-circuit current indicating a change in ion pump activity. These results are discussed in relation to the possible causes of increased fluid (ion) transport by the intestine of s.h.r.

1. Dietary sodium depletion and subsequent repletion was studied in rabbits. Potassium intake was maintained constant. 2. during sodium depletion and repletion blood pressure, packed cell volume, food consumption and body weight remained at control values. 3. Decreased sodium excretion was observed in both urine and faeces during sodium depletion and the physiological control of these changes is discussed in relation to the renin-angiotensin-aldosterone system. 4. Potassium excretion during sodium depletion initially fell as a result of reduced urine volume and gradually returned to normal. Urine potassium concentration remained constant. 5. Faecal excretion of potassium rose by 63% during sodium depletion and there was a rise from a control value of 17-25% in the proportion of total potassium excretion accounted for by the faecal component. 6. Water consumption and urine volume both decreased in the initial phase of sodium depletion and then returned to control levels. 7. It is important to consider both urinary and faecal excretion of sodium and potassium when calculating balance status for either ion. Faecal excretion, as well as kidney function, shows important physiological adaptations.

The election of blood from the heart produces changes in transthoracic impedance. It has been proposed that the cardiac output may be determined from these changes. The cardiac output was measured by impedance cardiography and by the thermal dilution method before and after full thickness burn injury to the skin of the anaesthetized rat. The values obtained by the impedance method showed a good correlation with simultaneous thermal dilution cardiac output measurements (r=+0.67 pre-burn, and +0.76 post-burn). Impedance cardiography confirmed the early post-burn reduction in cardiac output reported by other workers using invasive techniques. Good agreement between the two methods was also obtained when the cardiac output of burn injured animals was altered by fluid infusion. This non-invasive technique of cardiac output monitoring may therefore have an important place in the investigation of cardiac function after trauma and burn injury.

At low doses, angiotensin II (AII) stimulates jejunal sodium and water absorption in the pentobarbital sodium-anesthetized rat. This response to the hormone can be blocked by cycloheximide and has a rapid onset and decay, indicating that any protein involved must have a short half-life and/or fast turnover. At high doses, AII inhibits jejunal absorption by a process that does not involve protein synthesis and has a rapid onset but slow decay. The AII-induced inhibition of water absorption can be abolished, and a net stimulation ensues after pretreatment of the animals with meclofenamate or indomethacin, suggesting that at high doses AII stimulates intestinal prostaglandin biosynthesis. The AII analogue, [Sar1,Leu8]AII, significantly stimulated jejunal water absorption and was devoid of any inhibitory response at any dose administered. Simultaneous infusion of low doses of [Sar1,Leu8]AII and AII resulted in a stimulation of water transport, while simultaneous infusion of high dose [Sar1,Leu8]AII and AII also stimulated water absorption. It is suggested that the AII analogue is a full agonist with regard to stimulation of jejunal transfer but antagonizes the inhibitory response to high doses of AII. A model consistent with these data is discussed.

The half-life (T 1/2) of angiotensin II was measured in rats with chronic indwelling catheters. In conscious animals T 1/2 was 14.8 +/- 2.5 s; during anaesthesia T 1/2 increased by 60%. Anaesthesia decreased the control arterial pressure, but did not alter the sensitivity to injected angiotensin II. The causes and consequences of this change in angiotensin catabolism are discussed.

Excitation-secretion coupling for active and inactive renin was investigated by manipulating the ionic composition of media in which rabbit kidney cortex slices were incubated. Alterations in [Ca++] and [K+] produced qualitatively similar, but quantitatively distinct, changes in the release of the two forms of renin. Under control conditions, the slices secreted 15-20% of total renin in the inactive form and exposure to Ca++-free or low [K+] media increased this to 30-40%, a similar proportion to that stored within the kidney. Decreasing [Na+] stimulated release of active renin but reduced inactive renin. There appeared to be antagonism between the effects of Na+ and Ca++ ions in respect of active renin but synergism for release of the inactive form. It is suggested that the characteristics of a single renin release mechanism in the rat kidney resemble those for secretion of inactive, rather than active, renin in other species.

Rats were prepared with chronic cannulae in the carotid artery, jugular vein and urinary bladder; they were then kept 2 days to allow recovery from surgery. A steady-state continuous saline diuresis was established, then various anaesthetic agents were injected and changes in the urine flow, sodium and potassium excretion rates, GFR, ERPF, ERBF and blood pressure were measured. Five groups of rats were studied: (1) control animals given saline in place of any anaesthetic agent, all parameters measured remained constant; (2) althesin (1.2 mg/kg), all parameters remained constant except for the blood pressure which decreased slightly for 5 min; (3) althesin (12 mg/kg); (4) ketamine (50 mg/kg); (5) pentothal (50 mg/kg). The above anaesthetics altered all of the measured parameters except urine output. Various mechanisms for these anaesthetic agents are discussed. In althesin anaesthetized rats, all the retarded renal parameters recovered within 30 min. It is concluded that for the study of renal function, if a brief anaesthesia is needed, althesin is a more suitable anaesthetic agent.

Dopamine and isoprenaline have been examined for their effects on guinea-pig renal blood flow in vivo and on cAMP production in a mainly isolated glomeruli/blood vessel preparation in vitro. The renal vasodilatation caused by both of these drugs can be differentiated by the use of specific antagonists, sulpiride blocking the effects of dopamine, and propranolol the vasodilatation produced by isoprenaline. Similarly, both drugs stimulated cAMP production, isoprenaline being much more active than dopamine (1000X) in this respect. Again, the dopamine antagonist fluphenazine specifically inhibited the dopamine-induced cAMP increases whilst the beta blocker atenolol blocked the rise in cAMP due to isoprenaline but not that due to dopamine. Sulpiride although potently inhibiting dopamine-induced renal vasodilatation was without effect on dopamine-stimulated cAMP levels. This result is similar to that reported in the CNS where sulpiride blocks dopamine activity in a variety of tests but is without effect on the dopamine-stimulated adenylate cyclase. Two dopamine agonists, ADTN and SKF 38393 were tested, and in both preparations had potent dopaminergic activity although SKF 38393 exhibited characteristics of a partial agonist on the adenylate cyclase model.

1. Blood flow was measured in the renal cortex and medulla of anaesthetized rats by the hydrogen washout method. The effects of dopamine infusion were measured. 2. Low doses of dopamine (20 and 65 n-mole.kg-1.min-1) caused only small increases in renal blood flow, and a higher dose (200 n-mole.kg-1.min-1) caused vasoconstriction. After alpha-blockade with phenoxybenzamine (9 mumole.kg-1), all doses of dopamine caused vasodilatation in the cortex and medulla of the kidney. 3. This dopamine-induced renal vasodilatation was almost abolished by sulpiride (0.7 mumole.kg-1.min-1), but was only slightly attenuated by propranolol (10 mumole.kg-1). 4. Sulpiride did not significantly alter the renal blood flow responses to noradrenaline or isoprenaline, or the blood pressure responses to histamine, acetylcholine, 5HT, noradrenaline and isoprenaline. 5. In normal rats, infusion of sulpiride generally caused a reduction in renal cortical blood flow. This response showed a positive correlation with the initial blood pressure. 6. It is concluded that there are specific dopamine receptors in the renal vasculature of the rat, and that dopamine may play a role in the normal control of renal blood flow.

1. Evidence is presented that cyclic AMP inhibits the incorporation of l-[4,5-(3)H]leucine into protein in a cell-free system from rat liver. This inhibition occurs after aminoacyl-tRNA formation. 2. Microsomal fractions, isolated after the incubation of postmitochondrial supernatant with cyclic AMP and ATP, show a diminished ability to synthesize protein. Both cyclic AMP and ATP are required for this effect. 3. A possible physiological role for the anti-anabolic action of cyclic AMP is discussed in terms of the control of gluconeogenesis.

Grass carp bile, sometimes eaten by Chinese people, has previously been shown to induce acute renal failure in man and to result in the death of experimental mice and rats. A toxic extract from the bile acid fraction of grass carp bile (LD50 109 mg/kg) was injected into pentobarbitone anesthetized rats and an increase in urinary excretion of water and salts was produced. The bile extract also caused a prompt fall in systemic arterial blood pressure and cardiac output. It was also found, in vitro, that the bile salts caused a potent hemolysis. The hypothesis that hemoglobin is released from hemolysed red blood corpuscles and might be responsible for the long term renal functional damage is considered. Another alternative hypothesis is that the hypotension induced by the bile toxin may result in renal underperfusion and thus make the kidney more susceptible to the nephrotoxic action of the grass carp bile.

1. Pyruvate kinase purified from the hepatopancrease of Carcinus maenas exhibited sigmoidal saturation kinetics with respect to the substrate phosphoenolpyruvate in the absence of the allosteric activator fructose 1,6-bisphosphate, but normal hyperbolic saturation was seen in the presence of this activator. The activation appears to be the result of a decrease in the s0.5 (phosphoenolpyruvate) and not to a change in Vmax. 2. In the presence of ADP and ATP at a constant nucleotide-pool size the results indicate that phosphoenolpyruvate co-operativity is lost on increasing the [ATP]/[ADP] ratio. 3. Paralleling this change is the observation that the fructose 1,6-bisphosphate activation became less at the [ATP]/[ATP] ratio was increased. This was due to the enzyme exhibiting a near-maximal activity in the absence of activator. 4. L-Alanine inhibited the enzyme, but homotropic co-operative interactions were only seen with a cruder (1000000g supernatant) enzyme preparation. The inhibition by alanine could be overcome by increasing the concentration of either phosphoenolpyruvate or fructose 1,6-bisphosphate, although increasing the L-alanine concentration did not appear to be able to reverse the activation by fructose 1,6-bisphosphate. 5. In the presence of a low concentration of phosphoenolpyruvate, increasing the concentration of the product, ATP, caused an initial increase in enzyme activity, followed by an inhibitory phase. In the presence of either fructose 1,6-bisphosphate or L-alanine only inhibition was seen. 6. The inhibition by ATP could not be completely reversed by fructose 1,6-bisphosphate.

Specific [125I]-angiotensin binding to crude basolateral/brush border membranes of rat kidney cortex was influenced by guanine nucleotides. The order of potency of nucleotides in their ability to decrease specific binding, was Gpp(NH)p greater than GTP greater than or equal to ITP greater than GDP greater than ATP greater than GMP greater than IDP. The kinetic alterations induced by a maximally effective concentration of Gpp(NH)p were: (a) a reduced steady state level of binding and (b) a markedly slower rate of ligand dissociation. The presence of Gpp(NH)p was found to increase the affinity of [125I]-angiotensin binding sites in rat renal cortex membranes. This contrasts with the decreases in affinity of [125I]-angiotensin binding reported in adrenal and mesenteric artery membranes.

The effect of tachyphylaxis to angiotensin II amide on the pressor potency of angiotensin I, II and III and noradrenaline was investigated in conscious rabbits with indwelling cannulae. No significant difference was observed between the reduction in responses to angiotensin II (58 +/- 4%) and angiotensin III (42 +/- 6%) but angiotensin I (15 +/- 5 %) and noradernaline (17 +/- 10%) responses were less markedly inhibited. If all angiotensin I pressor activity was mediated through its conversion to angiotensin II one would expect an equivalent degree of cross-tachyphylaxis to occur with the two peptides. Our results suggest that angiotensin I may have significant inherent pressor activity of its own, independent of conversion. This compound is already known to have activity at other target tissues. The absence of a significant difference in the degree of tachyphylaxis with angiotensin II and III may indicate they have substantially common pathways as pressor agents.

An enzymic synthesis utilising arginine kinase for preparing arginine phosphate in a high state of purity is described. The dissociation constant of magnesium arginine phosphate, determined by gel filtration, was 30.0 +/- 0.9 mM. That for potassium arginine phosphate was calculated to be 63.0 +/- 4.0 mM measured by the effect of potassium on the apparent magnesium dissociation constant. The effect of KCl on the reaction catalysed by the type-M pyruvate kinase from Carcinus maenas (the common shore crab) pincer and leg muscle was investigated. No effect was seen on the C. maenas pyruvate kinase activity, apart from that due to alteration of the K+ concentration, on adding up to 70 mM potassium arginine phosphate to the reaction medium. The less pure form of arginine phosphate was found to give an apparent noncompetitive inhibition of the enzyme when phosphoenolpyruvate was the varied substrate. This apparent inhibition can be accounted for by the removal of ADP from the assay medium in a side reaction involving arginine kinase and arginine phosphate. These results are discussed in terms of the possible physiological control of the type-M pyruvate kinase from C. maenas.

1. Renal function was measured in seven normo thermic (38 degrees C) and seven hypothermic (27 degrees C) dogs. 2. The glomerular filtration rate was 60 per cent lower in the hypothermic animals, and the renal blood flow as 51 per cent lower. The intrarenal distribution of blood flow was measured by the uptake of 86Rb from the blood into different regions of the kidney. Hypothermia reduced flow by 34 per cent in the outer cortex, 72 per cent in the inner cortex, 61 per cent in the outer medulla and 69 per cent in the inner medulla. 3. Radioautography indicated a high blood flow to an area of the outer medulla of hypothermic kidneys, which may indicate medullary blood flow "shunting". 4. The results have been discussed in relation to a number of clinical and experimental observations.

The presence of calcium in the fluid in which intestinal or kidney tissue is incubated is required for the tissue to respond to angiotensin. Everted sacs of rat colonic mucosa exhibited an increased rate of fluid transport in the presence of angiotensin; this response was lost when the serosal fluid, but not the mucosal fluid, was calcium-free. Angiotensin-stimulated transport was maintained when calcium was replaced with strontium or barium, but was lost when calcium was exchanged for magnesium. Similarly, calcium ions were required in the incubation fluid of rat kidney cortex slices to demonstrate angiotensin-enhanced sodium transport. These observations are discussed in relation to the possible roles of divalent cations in the mechanism of action of angiotensin.

Angiotensin I is known to have direct agonist activity at some target tissues, independent of its conversion to angiotensin II. Aspects of its possible direct role as a pressor agent were investigated in conscious rabbits. Phentolamine (3 mg/kg i.v.), a dose which did not affect baseline blood pressure, reduced the pressor response to angiotensin II by 17% (P less than 0.05) but did not alter the sensitivity to angiotensin I. Noradrenaline activity was reduced by 56%. Propranolol (2 mg/kg i.v.), a dose which did not affect baseline blood pressure but which substantially reduced the depressor response to isoprenaline, had no effect on the pressor activity of either angiotensin I or II. Noradrenaline potency was reduced by 32%. Hexamethonium (20 mg/kg i.v.), caused a potentiation of the response to angiotensin I and II and noradrenaline. This was probably a non-specific action associated with the decrease in baseline blood pressure. No differential effect of ganglion blockade on the two angiotensins was noted. The dissociation of the effects of phentolamine on angiotensins I and II provides further evidence that pressor actions of these two compounds act through partially different mechanisms.

1. Active and inactive renin release by rabbit kidney cortex slices was investigated. Inactive renin was estimated as the increase in renin activity after acidification (pH 2 . 8) of slice supernatant solutions. 2. Active renin release was increased when incubation medium [Na+] was reduced. This relationship was linear (r2 = 0 . 96) over the range [Na+] = 23-133 mM. 3. For the same range of [Na+] inactive renin secretion decreased when medium [Na+] was reduced (r2 = 0 . 92). Therefore, the proportion of total renin which was in the inactive form decreased linearly as [Na+] was reduced (r2 = 0 . 97). 4. Chloride ions did not appear to be important in altering the secretion of either active or inactive renin. 5. Adding furosemide to the incubation medium in concentrations up to 40 micrograms/ml. did not change secretion of either form of renin. The action of furosemide on secretion of active and inactive renin in vivo is therefore secondary to altered renal function. 6. Regulation of the relative amount of active and inactive renin in plasma could be entirely an intrarenal event. It is not essential to invoke a plasma activating enzyme for inactive renin in order to explain changes in plasma levels of the two forms of renin. 7. This paper supports the hypothesis that release of inactive renin by the kidney is controlled by a sodium-sensitive mechanism.

A study has been made of the effects of protein synthesis inhibitors on the responses of rat jejunum in vivo to intravenous infusions of angiotensin. Actinomycin D, an inhibitor of the transcription stage of protein synthesis, was without effect on the stimulation of fluid transport which follows the infusion of low doses of angiotensin. Cycloheximide, an inhibitor of the translation stage of protein synthesis, blocked the stimulatory response to angiotensin, but was without effect on the inhibitory response to high doses of the hormone. It is concluded that low (physiological) doses of angiotensin stimulate fluid transport by a mechanism involving protein synthesis at a stage later than transcription whereas high doses of the hormone inhibit fluid transport by a process which does not require protein synthesis.