D. T. Fei

Angiotensin I, II, and III in sheep. A model of angiotensin production and metabolism.

SUMMARY The arterial and centra] venous concentrations of angiotensin I (AI), Val5-anglotensln II ([Val5]AII), and Val5-anglotensin III ([Val5]AIII(2-8)) were quantitatively determined in conscious sheep before and after sodium depletion. All three anglotenslns were elevated in blood with progressive sodium loss. During sodium deficiency the arteriovenous concentration ratios (A:V) of AI, [Val5]AII, and [Val5]AIII(2-8) were found to be 0.48 ± 0.03 (n - 9), 130 ± 0.05 (n - 16), and 1.52 ± 0.05 (n = 11) respectively. Intravenous infusion of [Val5]AII or [Val5]AIII(2-8) significantly elevated the A: V of respective angiotenslns, being 2.09 ± 0.28 (n - 5) for [Val5]AII and 2.2 ± 031 (n - 6) for [Val5]AIII(2-8). The blood clearance rates of exogenous [Val5]AII and [Vall]AIII(2-8) in sodium-depleted sheep were calculated to be 135 ± 15 liter/hr (n = 10) and 140 ± 13 liter/hr (n = 10) respectively. Based on these experimental data, a steady-state model of angiotensin metabolism was constructed.If it is assumed that endogenous arterial blood [Val5]AII and [Val5]AIII(2-8) cleared metabollcally at a similar rate as exogenous arterial blood angiotensins, it can be calculated that at steady-state 55% of the arterial [Val5]AII concentration was derived from the peripheral vascular bed. For [Val5]AIII(2-8), 63% of the arterial concentration was derived from the pulmonary circulation. The concentration of [Val5]AIII(2-8) in arterial blood was 42% of [Val5]AII.

Stress, ACTH, salt intake and high blood pressure.

Epidemiological evidence supports the thesis that high salt intake is involved in the aetiology of hypertension. If sodium intake is not causal, it appears other factors do not cause high blood pressure in unacculturated societies with low sodium intake. In this context, it is potentially important that stress causing ACTH release, as well as other neurohumoral effects, causes increased salt appetite and can impair renal sodium excretion.

Onset and dose relationships of ACTH effects on blood pressure in sheep.

The threshold and dose-response relationships for the blood pressure and metabolic effects of adrenocorticotropic hormone (corticotropin, ACTH) were examined in conscious sheep. Corticotropin was infused at five rates (0.5 micrograms/kg/day, n = 4; 1 micrograms/kg/day, n = 4;2 micrograms/kg/day, n = 6; 5 micrograms/kg/day, n = 5; and 10 micrograms/kg/day, n = 5) for 3 days, and the time of onset of the rise in blood pressure was assessed with a computer-based system. The effects of equimolar infusion of beta-endorphin and ACTH at 5 micrograms/kg/hour also were examined. Corticotropin infusion at 0.5 microgram/kg/day had no effect on mean arterial pressure. An ACTH infusion of 1.0 microgram/kg/day significantly increased mean arterial pressure (p less than 0.001), but the rise was less than that at the three higher doses, all of which produced similar effects. Changes in heart rate were significant at the 10 micrograms/kg/day level only (p less than 0.01). Initial urinary sodium retention was present at the three higher but not the two lower rates of infusion. Corticotropin infusion had no effect on urinary potassium excretion at any rate but produced hypokalemia at rates of 1.0 microgram/kg/day and above, which appeared to be dose related. Plasma sodium concentration was increased significantly only at the three higher rates (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Angiotensin Converting Enzyme Inhibition with SQ 14 225 on Blood Pressure in Sheep

The effect of intravenous injection of the angiotensin converting enzyme inhibitor SQ 14 225 on blood pressure, heart rate and plasma renin concentration (PRC) was investigated in 15 intact conscious ewes as follows: sodium replete during angiotensin I infusion (n = 4); sodium replete (n = 6); sodium deplete (n = 5); chronic water deprivation (n = 5); AcTH treated sodium replete (n = 6). Following SQ 14 225 mean arterial pressure fell 5 +/- 1 mmHg in sodium replete, 20 +/- 4 mmHg in acutely sodium deplete, 7 +/- 2 mmHg in chronic water deprivation and 6 +/- 2 mmHg in ACTH treated sodium replete sheep. This suggests that the renin-angiotensin system plays no significant role in maintaining the elevated blood pressure of sheep with ACTH induced hypertension. Heart rate rose in all groups except the water deprived animals following SQ 14 225. PRC rose from 5.1 +/- 2.1 pmo1AI/ml plasma/h. to 12.4 +/- 2.0 in sodium replete sheep, from 11.9 +/- 1.0 to 68 +/- 13 in acutely sodium deficient animals, and from 13.3 +/- 4.3 to 32.9 +/- 0.6 in chronically water deprived animals, but showed little change in ACTH treated sheep, falling from 2.3 +/- 0.5 to 1.7 +/- 0.2 pmo1AI/ml plasma/h.

Augmented plasma renin levels in dehydrated sheep with periventricular lesions

Ablation of tissue in the midline anterior wall of the third ventricle (AV3V) of sheep did not consistently alter baseline plasma renin concentration (PRC) in water replete animals, but caused a greatly augmented increase in PRC in response to water deprivation. PRC might increase in these sheep in order to maintain blood pressure, however it is possible that a central inhibitory influence on renal renin release, operative during dehydration, is disrupted by AV3V-lesions.

ACTH hypertension modifies the haemodynamic effects of prostacyclin infusions in sheep.

1. The haemodynamic effects of short‐term prostacyclin infusions (0.05‐0 50 /μg/kg per min) were investigated in conscious adult sheep.

Haemodynamic and renin responses to prostacyclin infusion in Na depleted and Na restricted sheep

The haemodynamic and renin responses to prostacyclin (PGI2) infusion were examined in sheep during sodium depletion and dietary sodium restriction. The haemodynamic effects of PGI2 infusion in sodium depleted and sodium restricted sheep were similar to those obtained in the sodium replete animal. The renin proportionate response to PGI2 was not altered by sodium restriction but blunted by sodium depletion, compatible with the hypothesis that endogenous PGI2 is high in Na depletion.

A COMPARISON OF THE HAEMODYNAMIC EFFECTS OF DIETARY SODIUM RESTRICTION AND ACUTE SODIUM DEPLETION IN THE CONSCIOUS SHEEP

1. The use of a low Na, low K sorghum grain diet supplemented with intraruminal electrolyte infusions has enabled dietary manipulation of sodium status to be studied in the sheep.

DIURETIC AND HAEMODYNAMIC EFFECTS OF MK 447 IN NORMOTENSIVE AND HYPERTENSIVE SHEEP

1. The short term effects of the novel diuretic MK 447 were examined in both normotensive and hypertensive (ACTH treated) conscious sheep.

EFFECTS OF β‐ADRENOCEPTOR BLOCKADE ON PROSTACYCLIN MEDIATED RENIN RELEASE IN SHEEP

1. The effect of prostacyclin (PGI2) infusion on plasma renin concentration (PRC) was examined before and after propranolol treatment in sheep.