Converting Enzyme Inhibitor SQ Research Articles

The Effect of Angiotensin I Converting Enzyme Inhibitor (SQ 14225) on Plasma 18-Hydroxycorticosterone and Aldosterone in Sodium Depleted Conscious Rats

Altered sodium intake is known to cause a greater change in plasma 18-hydroxycorticosterone (18-OHB) level than in plasma aldosterone level, resulting in an increase of plasma 18-OHB/aldosterone ratio in sodium-depleted man and rats. To evaluate the role of endogenous angiotensin II in the high plasma 18-OHB/aldosterone ratio in sodium-depleted rats, we examined the effect of the angiotensin I converting enzyme inhibitor SQ 14225 on plasma 18-OHB and aldosterone in sodium-depleted (SD) and sodium-repleted (SR) conscious rats. Plasma renin activity (PRA) and plasma angiotensin II were higher in the SD rats than in the SR rats. The ingestion of SQ 14225 caused an increase in PRA and a decrease in plasma angiotensin II, whereas these changes were more prominent in the SD rats than in the SR rats. Plasma 18-OHB and aldosterone levels were higher in the SD rats than in the SR rats. The plasma 18-OHB/aldosterone ratio was also higher in the SD rats than in the SR rats. The ingestion of SQ 14225 caused decreases in plasma 18-OHB and aldosterone levels in both the SR and SD rats, whereas the SQ 14225-induced decreases in plasma 18-OHB and aldosterone levels were more prominent in the SD rats than in the SR rats. Thus, the ingestion of SQ 14225 induced a decrease in the plasma 18-OHB/aldosterone ratio in both the SR and SD rats. The decrease in plasma 18-OHB/aldosterone ratio was more prominent in the SD rats than in the SR rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II inhibits the release of [ 3H]acetylcholine from rat entorhinal cortex in vitro

The effects of angiotensin I and II on basal potassium-induced release of [ 3H]acetylcholine were investigated in slices of rat entorhinal cortex. Potassium (10–25 mM) produced a concentration-dependent increase in the release of [ 3H]acetylcholine in the presence of extracellular calcium. Angiotensin II (10 −9-10 −5 M) (but not angiotensin I) reduced the potassium-induced release of [ 3H]acetylcholine in a concentration-related manner to 60% of control levels, but did not effect basal tritium release. The effect of angiotensin II was antagonised by [1-sarcosine, 8-threonine] angiotensin II, an angiotensin II receptor antagonist, but not by agents acting on α- and β-adrenoceptors, muscarinic, nicotinic, histamine or 5-hydroxytryptamine receptors nor by the angiotensin converting enzyme (ACE) inhibitor SQ 29852. The results indicate that angiotensin II acting via an angiotensin II receptor can inhibit the release of [ 3H]acetylcholine in slices of the rat entorhinal cortex. It is hypothesised that the ability of ACE inhibitors to facilitate cognitive processes may be related to a reduced availability of angiotensin II.

Dopaminergic modulation of some central actions of angiotensin II in vivo.

Studies were performed in 12 conscious sheep of both sexes to determine if a brain dopaminergic pathway is involved in modulating the central actions of angiotensin II (Ang II) in regulating body temperature and plasma renin activity (PRA). Previous data showed that intracerebroventricular (ICV) infusion of Ang II significantly decreased PRA and body temperature. In contrast, converting enzyme inhibitor SQ 20881 (SQ) or dopamine (DA) significantly increased PRA and body temperature of sheep. In the present study, ICV infusion of the DA antagonist metoclopramide (MCP) (20 micrograms/min) significantly decreased PRA to 68 +/- 5% of the basal level. When sheep were pretreated with ICV MCP (20 micrograms/min) for 2 hr and then infused ICV with MCP (20 micrograms/min) plus DA (20 micrograms/min), Ang II (25 ng/min), or SQ (1 microgram/min), the PRA and temperature responses to DA, Ang II, or SQ were all abolished or attenuated significantly. The converse did not hold. Sheep pretreated with SQ (1 microgram/min) still showed a significant increase in body temperature (0.43 +/- 0.05 degree C) when infused with DA (20 micrograms/min). These results support the hypothesis that a central DA pathway is involved in the modulation of the actions of centrally administered Ang II on temperature and PRA.

Central effects of angiotensin II and dopamine in sodium-depleted sheep.

The effects of intracerebroventricular (IVT) infusion of angiotensin II (ANG II), the converting enzyme inhibitor SQ 20881, and dopamine were studied in 15 conscious Na-depleted sheep. IVT ANG II (25 ng/min) significantly increased plasma aldosterone (163 +/- 24%) and vasopressin (ADH) (533 +/- 100%). Plasma renin activity (PRA) was decreased to 64 +/- 10% of basal. IVT SQ (1 microgram/min) decreased aldosterone to 70 +/- 10% and ADH to 55 +/- 9% of basal. PRA increased to 124 +/- 10%. There were no significant changes in plasma Na, K, or cortisol levels nor in mean arterial or intracranial pressure after either infusion. Increasing the dose of SQ to 10 micrograms/min resulted in an increased magnitude of change in the same variables. IVT SQ (1 microgram/min) significantly decreased aldosterone level in five nephrectomized sheep. The responses to IVT dopamine (20 micrograms/min) were qualitatively similar to those elicited by IVT SQ. These data support the existence of an endogenous brain renin-angiotensin system (RAS) independent of the renal RAS. ANG II acts centrally to regulate plasma ADH, aldosterone, and PRA levels. The similarity of the responses to SQ and dopamine suggests that a dopaminergic pathway may be involved in these responses.

Interactions between adenosine and angiotensin II in controlling glomerular filtration.

This study examined interactions between adenosine (Ado) and angiotensin II (ANG II) in controlling renal blood flow (RBF) and glomerular filtration rate (GFR). In six normal dogs, intrarenal Ado infusion (1.0 mumol/min) transiently decreased RBF, but during sustained Ado infusion RBF increased to 122 +/- 7% of control, although GFR remained at 75 +/- 6% of control. Blockade of ANG II formation with the converting enzyme inhibitor SQ 14225 (n = 6) almost abolished the transient decrease in RBF but did not prevent the sustained fall in GFR caused by Ado. When circulating ANG II was held constant by intravenous infusion of SQ 14225 and 20 ng . kg-1 . min-1 of ANG II (n = 6), Ado transiently decreased RBF but the return of RBF was much slower than in normal dogs and RBF did not increase above control. Maintenance of constant circulating ANG II did not prevent Ado-mediated decreases in GFR. These observations suggest that Ado-mediated reductions in GFR do not depend entirely on ANG II and may be due to dilation of efferent arterioles by Ado. However, the transient renal vasoconstriction caused by Ado depends on ANG II, and data from this study suggest that part of the waning constrictor response to Ado is due to suppression of renin secretion and endogenous ANG II formation. In circumstances where high ANG II levels are maintained (i.e., ischemic renal failure), Ado may be capable of causing sustained renal vasoconstriction.

Thermal responses to central angiotensin II, SQ 20881, and dopamine infusions in sheep

The thermoregulatory role of brain angiotensin II (ANG II) was tested by intracerebroventricular (IVT) infusion of ANG II or the converting enzyme inhibitor SQ 20881 (SQ) in 15 conscious sheep. Deep body temperature decreased 0.30 +/- 0.07 degree C (SE) during the 3-h period of IVT ANG II (25 ng/min) infusion (P less than 0.05) and increased 0.50 +/- 0.13 degree C during IVT SQ (1 microgram/min) infusion (P less than 0.01). To determine whether the rise in body temperature after IVT SQ infusion might be the result of a central renin-angiotensin system (RAS), SQ was infused IVT in five conscious sheep 20 h after bilateral nephrectomy. This resulted in a significant rise in body temperature of 0.28 +/- 0.05 degree C (P less than 0.05). When vasopressin antidiuretic hormone (ADH) was infused intravenously at the same time of IVT SQ infusion, the rise in temperature was depressed, but ADH did not lower the temperature below basal. IVT dopamine (20 micrograms/min) increased body temperature by 0.40 +/- 0.04 degree C (P less than 0.01), which was qualitatively similar to the result with IVT SQ. These data support the hypothesis that endogenous brain ANG II may play a role in thermoregulation. Furthermore, plasma ADH level, regulated in part by brain ANG II, is probably not the mediator of that thermoregulation. The similar effects of IVT dopamine and SQ on body temperature strengthen the hypothesis that dopamine may be involved in the central action of brain ANG II.

Response of plasma renin activity to hypotension and angiotensin converting enzyme inhibitor in the turtle

We examined the physiological role of the renin-angiotensin system in response to hemorrhagic and pharmacologic hypotension in the freshwater turtle,Pseudemys scripta elegans. Blood pressure (BP), heart rate (HR), plasma renin activity (PRA), and plasma electrolytes were determined for 1 h prior to and 5 h after hemorrhage or vasodilator administration. With hemorrhage (23% blood volume) BP significantly decreased from 26.7 mm Hg to 17.4 mm Hg (P<0.01) within the first hour after hemorrhage and remained below control levels (P<0.05) until reinfusion of the shed blood at 5 h. HR increased within one hour (21 to 31 beats/min,P<0.01) and then slowly fell towards control levels. PRA also increased initially (2.5 to 6.5 ng/ml·h at 1 h,P<0.05). Infusion of the converting enzyme inhibitor SQ 20881 (0.5 mg/kg·h) during hemorrhage prolonged the hypotension, further elevated PRA and blunted the HR increase. The vasodilators diazoxide and papaverine produced the same degree of hypotension as hemorrhage. Diazoxide (4.5 mg/kg) decreased BP from 24.9 to 14.5 mm Hg (P<0.01) and increased PRA with no change in HR. Papaverine (10 mg/kg) produced a similar fall in BP (25.4 to 12.3 mm Hg,P<0.01) with no PRA change and a transient fall in HR. The data suggests that the renin angiotensin system plays a role in the maintenance of BP in the turtle in response to acute hypotension, but this role may be considerably less than observed in other animals, including mammals.

Binding of angiotensins to rat brain tissue: Structure activity relationship

The binding of 3H-angiotensin II to a synaptosome-enriched fraction of the subcortical part of rat brain was studied. In this fraction specific high-affinity binding sites for angiotensin II were demonstrated. The binding sites were saturated at a ligand concentration of 2×10 −9 M. Scatchard analysis revealed a single class of binding sites with an apparent maximal binding capacity of 14 fmoles/mg of protein and an equilibrium dissociation constant, K d , of 0.9 × 10 −9 M. The specific binding at the K d concentration amounted to 59% of the total binding and was reversible. The association and dissociation rate constants (k 1 and k −1) were 0.0212 nM −1 min −1 and 0.0196 min −1, respectively. Binding was dependent on both incubation time and tissue concentration in the incubation mixture. Angiotensins with biological activity in the brain, i.e., angiotensins I, II, III, and the fragments (3–8) and (4–8) competed with 3H-angiotensin II for the binding sites with IC 50's of 9×10 −8 M, 2×10 −9 M, 4× 10 −9 M, 4× 10 −7 M and 4×10 −6, respectively. In the presence of 1 mM of the converting enzyme inhibitor SQ 14,225 the IC 50 for angiotensin I was 2 × 10 −7 M. Competition by the biologically active fragment angiotensin (5–8) could not be demonstrated. The latter peptide, however, was highly metabolized during the incubation under the assay conditions used. The binding potency of the various angiotensins paralleled their dipsogenic and presser potency. The present data indicate the possible physiological involvement of these binding sites as specific receptors in the actions of angiotensins in the brain.

Renal hemodynamic responses to increased renal venous pressure: role of angiotensin II.

Studies were performed to quantitate the effects of progressive increases in renal venous pressure (RVP) on renin secretion (RS) and renal hemodynamics. RVP was raised in 10 mmHg increments to 50 mmHg. Renin secretion rate increased modestly as RVP was increased to 30 mmHg and then increased sharply after RVP exceeded 30 mmHg. Glomerular filtration rate (GFR), renal blood flow (RBF), and filtration fraction (FF) did not change significantly when RVP was elevated to 50 mmHg. GFR and RBF were also measured after the renin-angiotension system (RAS) was blocked with the angiotensin converting enzyme inhibitor (CEI) SQ 14225. After a 60-min CEI infusion, RBF was elevated (32%), GFR was unchanged, FF was decreased, and total renal resistance (TRR) was decreased. As RVP was increased to 50 mmHg, GFR and FF decreased to 36.3 and 40.0% of control, respectively, RBF returned to a value not significantly different from control, and TRR decreased to 44.8% of control. The data indicate that the RAS plays an important role in preventing reductions in GFR during increased RVP because blockade of angiotensin II (ANG II) formation by the CEI results in marked decreases in GFR at high RVPs. The decreases in GFR after ANG II blockade and RVP elevation were not due to lack of renal vasodilation, since TRR was maintained below while RBF was maintained either above or at the pre-CEI levels.

Central effects of angiotensins on drinking and blood pressure: Structure-activity relationships

The dipsogenic and the pressor effect following intracerebroventricular injection of angiotensins and several C-terminal fragments were studied. Angiotensin I (ANG I), ANG II, ANG III and C-terminal hexa-, penta-, tetra- and tripeptide stimulated water intake in water-replete rats and induced significant pressor responses. In both paradigms the most active peptides (in the pmol range) were ANG II, ANG I and ANG III, in that order. Shorter C-terminal peptides appeared to be active, but had to be injected in the nmol range. Latencies to the onset of drinking were less than 45 s for all peptides tested. The C-terminal dipeptide and other dipeptide fragments did not possess detectable dipsogenic activity. The dipsogenic effect of ANG I was inhibited by pretreatment of the animals with the converting enzyme inhibitor SQ 14,225. Drinking induced by both ANG I and ANG (4–8) was antagonized by the ANG II-receptor blocking agent Sar1-Ala8-ANG II.It is concluded that conversion of ANG I into ANG II is a prerequisite for the expression of the observed biological activity in the brain. Short C-terminal fragments are capable of stimulating the ANG II receptors, but a peptide chain of 7 amino acids appears necessary for maximal agonistic activity.

Blockade of angiotensin pressor activity in the freshwater turtle

In order to study the pharmacological characteristics of the renin-angiotensin system in the turtle, Pseudemys scripta elegans, angiotensin I (AI) and angiotensin II (AII) were administered intravenously to conscious turtles along with angiotensin antagonists, a converting enzyme inhibitor, and adrenergic blockers. Both AI and AII produced dose-dependent vasopressor responses. Infusion of the AII analogs [Sar 1, Ala 8] AII or [Sar 1, Ile 8] AII at 10 μg/kg/min significantly reduced the pressor responses to both AI and AII while the pressor action of norepinephrine (3 μg/kg) was unaffected. Neither AII analog exhibited a sustained pressor action at this infusion rate. The converting enzyme inhibitor SQ 20881 (1 mg/kg bolus + 0.5 mg/kg/hr) did not reduce the pressor effect of AII but significantly reduced the response to AI. The α-adrenergic antagonists phentolamine (0.5 mg bolus + 1 mg/kg/hr) and phenoxybenzamine (0.25 mg/kg/min) almost abolished the pressor response to norepinephrine and significantly decreased the vasopressor action of AI and AII. The results suggest that an angiotensin-converting enzyme-like mechanism may exist in the turtle and that the pressor response to angiotensin in the turtle may be due largely to catecholamines.

Importance of circulating angiotensin II for elevation of arterial pressure during acute hypercapnia in anaesthetized dogs.

SUMMARY1. In anaesthetized dogs acute hypercapnia produced by ventilation with 10% CO2 in air caused release of vasoactive substances and changes of arterial pressure. Catecholamines, angiotensin II, bradykinin and prostaglandin‐like substances were bioassayed continuously in arterial blood using the blood‐bathed organ technique of Vane.2. Acute hypercapnia in control dogs causes responses of rat stomach strip, chick rectum and rat colon indicating initial release of noradrenaline, followed by angiotensin II, and occasionally release of prostaglandin‐like substances into the circulation.3. The initial transient, pressor response to hypercapnia coincided with the appearance of noradrenaline, and the secondary progressive rise in arterial pressure was accompanied by increased circulating angiotensin II.4. In dogs treated with the angiotensin converting enzyme inhibitor SQ 20881 (1–2 mg/kg, i.v.), hypercapnia did not cause the secondary elevation of arterial pressure despite pronounced elevation of noradrenaline levels in the circulation. Increased arterial concentrations of bradykinin of less than 1 ng/ml, assayed by a strip of cat jejunum, were detected during hypercapnia in four out of six dogs treated with SQ 20881, but not in untreated dogs.5. Intravenous infusion of the angiotensin antagonist [Sar1‐Ile8]‐angiotensin II (0.5–1.0 μg/kg per min) attenuated the secondary pressor response to hypercapnia and abolished the contractions of rat colon produced by hypercapnia and angiotensin II.6. The results indicate that adrenergic stimulation may be responsible for the transient pressor response on induction of hypercapnia, but elevation of angiotensin II activity in the circulation is of major importance for mediating the secondary progressive rise in arterial pressure during the later stage of acute respiratory acidosis.7. After inhibition of angiotensin converting enzyme, hypercapnia reduces arterial pressure, not only because the vasoconstrictor effect of angiotensin has been removed, but also because inhibition of pulmonary kininase may allow vasodilator kinins to reach the arterial circulation.

Effect of the converting-enzyme inhibitor SQ 14 225 (captopril) in early one-kidney, one-clip hypertension in the rat.

1. Arterial plasma renin activity was significantly elevated in rats with one-kidney, one-clip hypertension of less than 3 weeks duration. 2. Intraperitoneal injection of the angiotensin-converting enzyme inhibitor SQ 14 225 (captopril) caused a dose-related decrease in systolic blood pressure in hypertensive rats. The lowest dose of captopril used (3.5 mg/kg) inhibited conversion of exogenous angiotensin I and maximally potentiated the depressor response to bradykinin, but failed to restore blood pressure to that of the normotensive controls. 3. Removal of the solitary clipped kidney also did not restore blood pressure to normal. Injection of captopril (3.5 mg/kg) 24 h after nephrectomy, when no circulating renin activity was detectable, lowered blood pressure further in hypertensive but not in similarly nephrectomized controls. 4. These results indicate that raised blood pressure in early one-kidney, one-clip hypertension in the rat cannot be entirely attributed to the renin-angiotensin system, even when plasma renin activity is significantly increased. 5. This study has also confirmed a hypotensive action of captopril in anephric rats when plasma renin activity is undetectable.

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.

Drinking and changes in blood pressure in response to precursors, fragments and analogues of angiotensin II in the pigeon Columba livia.

1. The pigeon drank as vigorously in response to intracranial injection of synthetic renin substrate and angiotensin I as to angiotensin II. 2. Mammalian renin injected into the brain caused the water-replete pigeon to drink but it was a less effective dipsogen than in the mammal. As in the mammal, renin-induced drinking was slower in onset and continued for longer than angiotensin-induced drinking. 3. The converting enzyme inhibitor SQ 20881 attenuated drinking in response to intracranial renin, synthetic renin substrate and angiotensin I but enhanced intracranial angiotensin II-induced drinking. Therefore drinking induced by the intracranial injection of precursors of angiotensin II is mediated through local generation of angiotensin II. 4. I.V. injection of angiotensin I was as effective as angiotensin II in causing the pigeon to drink, but synthetic renin substrate was less effective. I.V. doses of angiotensin I and II had to be about 100 times greater than the intracranial doses in order to produce similar intakes. 5. Angiotensin I and II were equally effective pressor agents by I.V. injection in the pigeon but synthetic renin substrate was much less effective. I.V. SQ 20881 inhibited the pressor response to I.V. synthetic renin substrate or angiotensin I but enhanced the angiotensin II-induced response. 6. Aliphatic position 8-substituted analogues of angiotensin II which are competitive antagonists of angiotensin II-induced drinking and pressor responses in the mammal in antagonist:agonist mole ratios as low as 10:1, failed to reduce drinking in response to intracranial synthetic renin substrate or angiotensin II, although not themselves agonists, nor did they prevent the pressor to infusion of angiotensin II even with antagonist:agonist mole ratios as high as 10,000:1. 7. Shortening the angiotensin octapeptide from the N-terminus caused a progressive reduction in intracranial dipsogenic activity. Activity was completely abolished by removing the C-terminal phenylalanine. 8. These results demonstrate that in pigeons, as in mammals, it is angiotensin II which is the biologically active peptide in the control of drinking behaviour and blood pressure by the renin-angiotensin system. Precursors of angiotensin II can be converted to the octapeptide in the avian brain as well as in the circulation. The angiotensin receptors for drinking and blood pressure responses are similar to each other in the pigeon and they are very similar but not identical with the angiotensin receptors for the dipsogenic, pressor and myotropic actions of angiotensin II in mammals.

Role of the renin-angiotensin system in the adaptation of aldosterone biosynthesis to sodium restriction in the rat

The purpose of the present study was to evaluate the role of the renin-angiotensin system in the secretion of aldosterone during restriction of dietary sodium intake. Rats were kept on control or low-sodium diet for one week. On the 7th morning of diet osmotic minipumps filled with the angiotensin converting enzyme inhibitor (CEI) SQ 20,881, or empty pumps, were implanted subcutaneously (sc). The rats were sacrificed 23 h later. Peripheral blood was analyzed for hormones and electrolytes. Adrenal capsular tissue (z. glomerulosa) was incubated for the determination of the conversion of [3H]corticosterone to [3H]aldosterone. Sodium depletion had no effect on plasma sodium, but it increased potassium concentration. Infusion of CEI had no significant effect on plasma electrolytes. Plasma renin activity was increased both by sodium depletion and CEI. The mean serum aldosterone level was twelve times higher in sodium depleted animals than in controls. Aldosterone level was reduced by about 60 per cent in CEI-infused animals both on control and low-sodium diet. The conversion of corticosterone to aldosterone was significantly stimulated by sodium deprivation. This effect was also inhibited by the CEI SQ 20,881.

The renin-angiotensin-aldosterone system and catecholamines in chronic congestive heart failure. Effect of angiotensin I converting enzyme inhibitor SQ 14225 (Captopril).

In order to elucidate the role of the renin-angiotensin-aldosterone system and catecholamines in the pathophysiology of chronic congestive heart failure (CHF), a study was made of the relationship between these humoral factors and the hemodynamic parameters. In 36 patients with various degrees of CHF, urinary norepinephrine (U-NE) was significantly increased in Class III-IV (NYHA) patients with a positive correlation to total systemic vascular resistance (SVR) (p < 0.05) as well as to peripheral venous pressure (VP) (p < 0.05). Plasma renin activity (PRA) was increased in Class IV patients and tended to be positively correlated with SVR. Plasma aldosterone levels (PA) correlated well with PRA (p < 0.01). In six Class III-IV patients, the acute effect of oral angiotensin I converting enzyme inhibitor SQ 14225 (captopril) on mean arterial pressure (MAP), VP, PRA, PA and plasma catecholamines was examined. PRA was consistently increased (306%) and PA decreased (37%) following captopril administration, indicating that captopril effectively inhibited angiotensin 11 formation. MAP fell (17%), especially in two patients with mitral stenosis. The heart rate tended to decrease (7%). VP also fell (27%) with symptomatic improvement. The decline in VP correlated with the decrease in plasma norepinephrine concentrations (P-NE) (p < 0.01). In patients with mitral stenosis, urine volume decreased as blood pressure fell. In two patients with CHF refractory to conventional treatment, captopril induced increased urinary sodium excretion and body weight reduction despite only a slight fall in MAP and was useful as chronic unloading therapy. These results suggest that norepinephrine plays a role in elevating SVR as well as VP, and the renin-angiotensin system also appears to contribute to the rise in SVR in CHF when the circulatory impairment is more severe. Captopril seems to dilate arterioles by reducing angiotensin 11 levels and also to reduce VP by decreasing P-NE. It is a useful therapeutic measure in selected patients with severe CHF.

Response of chronic renovascular hypertension to surgical correction or prolonged blockade of the renin-angiotensin system by two inhibitors in the rat.

1. Removal of the renal artery constriction but not of the clipped kidney restored the blood pressure to normal levels in Goldblatt two-kidney rats with hypertension of more than 4 months' duration. 2. Despite the differences in blood pressure response, both surgical procedures lowered plasma renin concentration to normal or below normal values. 3. Administration of the oral converting enzyme inhibitor SQ 14 225 produced a marked fall in blood pressure in Goldblatt kidney rats with chronic hypertension. However, a prolonged infusion of the angiotensin II antagonist saralasin was quite ineffective. The difference in response to the two inhibitors may have been due to bradykinin potentiation by the converting enzyme inhibitor. 4. Although plasma renin is often elevated in Goldblatt two-kidney rats with hypertension of more than 4 months' duration, the renin-angiotensin system plays no role in the maintenance of blood pressure at this stage.

Chronic blockade of angiotensin II formation during sodium deprivation

The present study was designed to investigate the mechanisms by which the renin-angiotensin system (RAS) regulates arterial pressure (AP) and renal function during chronic sodium deprivation. Intravenous infusion of the converting enzyme inhibitor SQ 14225 (14 microgram.kg-1.mm-1) for 8 days in 12 sodium-deficient dogs caused a marked decrease in AP from 90 +/- 1 to 67 +/- 2 mmHg and a reduction in glomerular filtration rate (GFR), filtration fraction (FF), and plasma aldosterone concentration (PAC). Despite the fall in AP and GFR, urinary Na excretion and effective renal plasma flow (ERPF) increased above control levels. In four dogs, infusion of aldosterone (200 micrograms/day) for 8 days during continuous SQ 14225 infusion restored PAC to levels above control, but did not significantly change AP or renal function from the values observed during SQ 14225 infusion alone. However, infusion of angiotensin II (AII) (10 or 20 ng.kg-1.min-1) for 5--8 days during continuous SQ 14225 infusion almost completely restored AP and renal function to control levels. These data indicate that the RAS plays a major role in regulating AP, renal hemodynamics, and Na excretion during Na deprivation, probably through the direct effects of AII rather than through changes in PAC.

Effect of Tetradecapeptide Renin Substrate on Blood Pressure, Plasma Renin Activity, and Vasopressin and Adrenocorticotropin Concentrations*

The effects of third ventricular injection of tetradecapeptide renin substrate (TDP) and natural renin substrate prepared from dog cerebrospinal fluid were compared in anesthetized dogs. Central injection of 350 pmol TDP caused a long lasting increase in arterial blood pressure, a reduction in PRA, and increases in plasma levels of vasopressin, and ACTH. In marked contrast, central administration of equimolar doses of natural renin substrate had no effect on these variables. Intracranial administration of the converting enzyme inhibitor SQ 20881 prevented the effects of central injection of TDP. Thus, TDP exerts its effects via conversion to angiotensin II and does not necessitate the postulation of the action of an enzyme with renin-like activity in the brain.