Infusion Of Converting Enzyme Inhibitor Research Articles

Cardiac renin-angiotensin system.

Based on molecular, biological, biochemical, and pharmacological data, evidence is presented for a cardiac renin-angiotensin system. Using radiolabeled cRNA probes prepared from specific cDNA fragments, we were able to document renin and angiotensinogen gene expression in atria and ventricles of the rat heart by Northern blot and liquid hybridization analysis. Relative signal strength for both mRNAs was highest in the atria and next highest in the right and left ventricle. We also demonstrated the presence of both angiotensin I and angiotensin II in all anatomical regions of the monkey and rat heart using specific, high pressure liquid chromatography (HPLC) controlled radioimmunoassays (RIAs) for angiotensin peptides. The presence of converting-enzyme activity was also ascertained by direct in vitro determinations. Infusion of angiotensin I into the isolated perfused rat heart resulted in the prompt appearance of angiotensin II; the single pass fractional conversion was 6.42 +/- 0.33%. Dose-dependent inhibition of this effect by simultaneous infusion of converting-enzyme inhibitor supports the existence of a specific intracardiac pathway for the activation of angiotensin II. When the isolated, perfused rat hearts were exposed to infusions of purified renin, angiotensin I, undetectable before renin, was dose-dependently released into the coronary circulation at peak rates ranging from 2.4 +/- 0.7 fmol/min to 1.4 +/- 0.2 pmol/min, of which 7.2 +/- 1.1% was intracardially converted to angiotensin II. All renin effects were blocked in the presence of a specific pentapeptide renin inhibitor. Together, the results of these studies add support to the concept of a functionally active cardiac tissue renin-angiotensin system.

Effects of verapamil and converting enzyme inhibition on bilateral renal function of two-kidney, one-clip hypertensive rats.

Experiments were conducted in two-kidney, one-clip renal vascular hypertensive rats (GHR) to assess the responses of each kidney to acute treatment with the antihypertensive calcium channel blocking agent verapamil in the presence and in the absence of converting enzyme inhibitor (CEI). One group of GHR (0.2 mm inner diam. clip 3 weeks before study) were examined during a control period, and during a second period of infusion of verapamil (600 micrograms h-1 kg-1). A second group of GHR were examined during a control period, during CEI (teprotide, 3 mg h-1 kg-1) infusion and during a third period of verapamil (600 micrograms h-1 kg-1) infusion superimposed on CEI infusion. Although systemic blood pressure (BP) decreased from 175 +/- 4 to 149 +/- 5 mmHg (mean +/- SEM) in response to verapamil alone, renal blood flow for non-clipped kidneys increased from 5.9 +/- 0.4 to 6.5 +/- 0.3 ml/min, indicating a 30% reduction of renal vascular resistance (P values less than or equal to 0.01; n = 9). Glomerular filtration rate (GFR) for non-clipped kidneys (n = 24) increased from 0.91 +/- 0.09 to 1.47 +/- 0.14 ml/min and filtration fraction increased from 0.32 +/- 0.04 to 0.47 +/- 0.03 (P values less than or equal to 0.05). Urine flow rate and absolute and fractional sodium excretion for non-clipped kidneys increased. GFR for clipped kidneys decreased during verapamil. Treatment with CEI alone resulted in nearly identical responses of BP and function of the non-clipped kidney, except filtration fraction was unchanged. The addition of verapamil to ongoing converting enzyme blockade tended to augment the increased GFR of the non-clipped kidney. Plasma renin activity (PRA) increased from 30 +/- 3 to 59 +/- 7 ng of angiotensin (ANG) I h-1 ml-1 with verapamil alone, a significantly larger increment than the increase of PRA from 27 +/- 5 to 39 +/- 9 ng of ANG I h-1 ml-1 in GHR subjected to comparable blood pressure reduction by mechanical aortic constriction. Verapamil resulted in many similar effects on renal function to those observed during blockade of converting enzyme. The increased filtration fraction observed in response to verapamil may be the result of vasodilatation of the afferent arteriole or of an increase in the glomerular ultrafiltration coefficient.

Effects of angiotensin inhibition and renal denervation in two-kidney, one clip hypertensive rats.

Neural and angiotensin-mediated influences that alter hemodynamic and excretory behavior of the nonclipped kidney of two-kidney, one clip hypertensive rats were assessed by sequential acute surgical denervation of the nonclipped kidney and intravenous infusion of converting enzyme inhibitor (SQ 20881), 3 mg/kg X hr. Normal and two-kidney, one clip hypertensive rats (0.2-mm silver clip on the right renal artery 3-4 weeks before study) were prepared to allow study of each kidney. Mean arterial blood pressure of two-kidney, one clip hypertensive rats fell significantly from control values of 149 +/- 6 to 135 +/- 6 mm Hg after denervation of the nonclipped kidney. Despite this decrease in arterial pressure, the nonclipped kidney exhibited significant increases in glomerular filtration rate (from 1.00 +/- 0.08 to 1.24 +/- 0.08 ml/min), sodium excretion (from 88 +/- 39 to 777 +/- 207 nEq/min), fractional sodium excretion (from 0.06 +/- 0.02 to 0.54 +/- 0.14%), and urine flow rate (from 3.7 +/- 0.5 to 8.2 +/- 1.1 microliter/min). A significant decrease in glomerular filtration rate (from 1.12 +/- 0.07 to 0.85 +/- 0.08 ml/min) with no change in excretory function was observed for the clipped kidney following denervation of the nonclipped kidney. Intravenous addition of converting enzyme inhibitor significantly increased renal blood flow (from 7.0 +/- 1.3 to 10.6 +/- 1.5 ml/min) and sodium excretion (from 777 +/- 207 to 1384 +/- 425 nEq/min) for the nonclipped kidney; blood pressure decreased from 135 +/- 6 to 123 +/- 4 mm Hg, and renal vascular resistance decreased significantly (from 22 +/- 3 to 13 +/- 2 mm Hg X min/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of a converting enzyme inhibitor on autoregulation and intrarenal distribution of glomerular filtration in the rat.

The role of the renin-angiotensin system in the autoregulation and distribution of the single nephron glomerular filtration rate (SNGFR) in anaesthetized, normotensive rats was investigated. SNGFR in outer cortical (OC) and inner cortical (IC) nephrons of the left kidney were measured with a modified Hanssen technique at three levels of renal arterial pressure (RAP): at a spontaneous arterial pressure; at a value within the autoregulatory limit, 100 mmHg; and at the lower limit of the autoregulatory range, 70 mmHg. This was done in control rats and in rats given a continuous i.v. infusion of the converting enzyme inhibitor (CEI) captopril (3 mg . h-1 X kg-1 BW). In control rats there was complete autoregulation of SNGFR in both OC and IC nephrons when RAP was reduced to 100 mmHg. Further reduction to 70 mmHg elicited different responses among the cortical layers, associated with a decrease in SNGFR. A fractional redistribution of glomerular filtration rate towards IC nephrons was evident. Administration of CEI at spontaneous RAP increased SNGFR in IC nephrons compared with values in control rats, but did not notably alter SNGFR in OC nephrons. Reduction of RAP to 100 mmHg during CEI infusion caused SNGFR to decrease below control values in both OC and IC nephrons, and the autoregulation as found in control rats was impaired. When RAP was lowered to 70 mmHg during CEI administration there was a progressive decrease in SNGFR in all cortical layers, although absolute changes were much greater in IC nephrons than in OC nephrons.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Bilateral renal function responses to converting enzyme inhibitor (SQ 20,881) in two-kidney, one clip Goldblatt hypertensive rats.

SUMMARY The influenc of the renln-angiotensie n system on individual kidney function of two-kidney, oneclip Goldblatt hypertensive (GH wa) rats evaluates bdy determining renal functional responses during intra-venous infusio on f converting enzyme inhibitor (CEI) (SQ 20,881 0J rag/100, g-hr for) 3.5 bourn. Rats weremade hypertensiv be y placing a 0.25 mm silver clip on the right renal arter 3-y4 weeks prior to study. Normalrats and GH rats were prepare tdo allow urine collections from each kidney. Mean arteria of Gl pressurH erats fell significantly from preinfusio of 15n level3 ± 7s to 126 ± 4 mm Hg during CEI infusion. Despite thisdecrease in arterial pressure, the nondipped kidneys with reduced renal renin activit ± 5 vs 29y (13 ±4 40 ngAl/mg-hr in th clippee d kidney) exhibited dramati in gtomerulac increaser filtrations (GFR rat (fro)e m1.45 ± 0.06 to 2.56 ± 0.3 ml/mln)5 , urine (4.8 flow2 ± 0.71 to 9.11 ± 1.1 ^il/mln)9 , sodium excretion(0.10 ± 0.02 to 1.15 0.3 ± 9 MEq/mln), fractional sodium excretion (0.05 ± 0.02% % to 0.43 ±% 0.18%), andpotassium excretion (0.9 ±4 0.08 to 2.50 ± 0.55 /<Eq/mln). Significant arterial-pressure-associated decreasesIn GFR, urin e flow, and salt excretion were observe in th clippee d d kidney In. normal rats CE,I infusionproduced reduction isn arterial pressure and increase in GFRs , urine flow, and sodium excretion that o werf esmaller magnitude than thos ie observen th nondippee d d kidney of GsH rats. Plasma renin wa activits ysignificantly highe inr GH rats than in normal rats (24.0 ± 2.7 vs 12.8 ± 3.4 n AI/mMir)g . The augmentedrenal response tos CE I by the nondipped kidney suggest that elevated circulating angiotensi a n levels exertsubstantial influence on hemodynamic and excretory functio of thesne kidneys even though intrarenal renin ac-tivity is markedly reduced. This influence may lea tod fluid and electrolyte retention and may partially explainthe apparent failur of the nondippee d kidne toy preven tht e development of hypertension.(Hypertension 3: 285-293, 1981)KEY WORDS • renal hypertensio • glomerulan filtration rate •r sodium • excretionrenin-angiotensin • urine flow

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.

Tubuloglomerular Feedback and Single Nephron Function after Converting Enzyme Inhibition in the Rat

Experiments were done in normal rats to assess kidney, single nephron, and tubuloglomerular feedback responses during renin-angiotensin blockade with the converting enzyme inhibitor (CEI) SQ 20881 (E. R. Squibb & Sons, Princeton, N. Y.) (3 mg/kg, per h). Converting enzyme inhibition was documented by complete blockade of vascular responses to infusions of angiotensin I (600 ng/kg). Control plasma renin activity was 12.5+/-2.7 ng angiotensin I/ml per h (mean+/-SEM) and increased sevenfold with CEI (n = 7). There were parallel increases in glomerular filtration rate from 1.08+/-0.05 to 1.26+/-0.05 ml/min and renal blood flow from 6.7+/-0.4 to 7.5+/-0.5 ml/min. During CEI infusion absolute and fractional sodium excretion were increased 10-fold. Proximal tubule and peritubular capillary pressures were unchanged. Single nephron glomerular filtration rate (SNGFR) was measured from both proximal and distal tubule collections; SNGFR based only on distal collections was significantly increased by CEI. A significant difference was observed between SNGFR values measured from proximal and distal tubule sites (6.0+/-1.6 nl/min) and this difference remained unchanged after CEI administration. Slight decreases in fractional absorption were suggested at micropuncture sites beyond the late proximal tubule, whereas early distal tubule flow rate was augmented by CEI. Tubuloglomerular feedback activity was assessed by measuring changes in proximal tubule stop-flow pressure (SFP) or SNGFR in response to alterations in orthograde microperfusion rate from late proximal tubule sites. During control periods, SFP was decreased 11.2+/-0.4 mm Hg when the perfusion rate was increased to 40 nl/min; during infusion of CEI, the same increase in perfusion rate resulted in a SFP decrement of 6.7+/-0.5 mm Hg (P<.001). When late proximal tubule perfusion rate was increased from 0 to 30 nl/min, SNGFR was decreased by 15.0+/-1.2 nl/min during control conditions, and by 11.3+/-1.3 nl/min during CEI infusion. Attenuation of feedback responsiveness during CEI was also observed at lower perfusion rates with both techniques. These results indicate that blockade of the renin-angiotensin system with CEI reduces the activity of the tubuloglomerular feedback mechanism which may mediate the observed renal vasodilation.

Blood pressure response of nephrectomized hypertensive rats to converting enzyme inhibition: evidence for persistent vascular renin activity.

1. Blood pressure and plasma renin activity were studied after bilateral nephrectomy in groups of rats with hypertension caused by unilateral renal ischaemia with the opposite kidney left intact. 2. Although blood pressure showed only a small fall in the first hour after bilateral nephrectomy, plasma renin activity fell rapidly with a half-life of 10 min. 3. Infusion of converting enzyme inhibitor (SQ20881) produced a 26-1% fall in blood pressure 1 h after nephrectomy, 24-% at 2 h and 4-6% at 6 h. 4. An angiotensin antagonist (Sar1-Ala8-angiotensin II) was infused into hypertensive rats 1 h after nephrectomy; this blocked the vasodepressor action of the converting enzyme inhibitor, indicating that the fall in blood pressure produced by the inhibitor was due to its action upon the renin-angiotensin system. 5. The renin-angiotensin system maintains blood pressure in this model even after plasma renin has fallen to insignificant levels. This supports the view that vascular renin activity has a longer half-life than circulating renin and is important in the control of blood pressure.

Contrasting exchangeable sodium in rats with different types of Goldblatt hypertension.

Contrasting exchangeable sodium in rats with different types of Goldblatt hypertension.