Aortic Angiotensin-converting Enzyme Activity Research Articles

The effects of renin-angiotensin system inhibition on aortic cholesterol content in cholesterol-fed rabbits

To investigate how the renin-angiotensin system (RAS) might be involved in cholesterol-induced atherosclerosis, we studied the effects of a nonsulhydryl angiotensin converting enzyme (ACE) inhibitor, enalapril, and an angiotensin II receptor antagonist, E-4177, in cholesterol fed rabbits. Japanese white rabbits were randomly divided into four groups with the following dietary regimens: group A ( n = 8) received a standard diet; group B ( n = 8) had a 0.5% cholesterol diet; group C ( n = 8) had a 0.5% cholesterol diet plus enalapril (10 mg/kg/day, p.o.); group D ( n = 8) received a 0.5% cholesterol diet plus E-4177 (20 mg/kg/day, p.o.) and were fed these diets for 5 weeks. Enalapril or E-4177 had no significant effect on either the total plasma or the high density lipoprotein (HDL) cholesterol concentrations. However, the aortic cholesterol content in groups C and D was equally significantly less than that in group B. The plasma and aortic ACE activities were significantly reduced only in group C compared with those in the other groups. The aortic ACE mRNA and AT1 mRNA levels were assessed by a reverse transcription polymerase chain reaction (RT-PCR). The aortic ACE mRNA level was only significantly less in group C than in any of the other groups. The aortic AT1 mRNA level increased significantly in group B compared with that in group A and was significantly and equally reduced in both groups C and D compared with that in group B. These data indicate that angiotensin II rather than ACE may therefore be related to aortic cholesterol content. It follows therefore that the inhibition of angiotensin II by either ACE inhibitor or angiotensin II (type 1) receptor antagonist may play a role in prevention of atherosclerosis.

Dissociation between the antiatherosclerotic effect of trandolapril and suppression of serum and aortic angiotensin-converting enzyme activity in the Watanabe heritable hyperlipidemic rabbit.

This study was undertaken to determine whether low doses of the angiotensin-converting enzyme (ACE) inhibitor trandolapril affected atherosclerosis in the Watanabe heritable hyperlipidemic (WHHL) rabbit. Trandolapril (10 micrograms/kg body weight per 48 hours) was begun at 3 months of age and continued for 9 months. The selected dose reduced serum ACE activity but did not influence blood pressure. Both serum and aortic ACE activity were reduced by more than 80% in the trandolapril-treated compared with control WHHL rabbits, similar to the suppression achieved with the 25-fold-higher dose that in our previous studies induced marked inhibition of aortic atherosclerotic lesions in the WHHL rabbit. In contrast to these prior findings, low-dose trandolapril had no effect on aortic surface involvement by atherosclerosis, aortic cholesterol content, or aortic morphology. The data suggest that the antiatherosclerotic action of ACE inhibitors in the WHHL rabbit may not be related directly to arterial enzyme inhibition.

Acute and long-term effects of angiotensin converting enzyme inhibition on larger arteries and cardiac hypertrophy

AIM OF STUDIES: The extent of cardiovascular alterations in hypertension is related quantitatively to the degree of hypertension. However, there is increasing evidence that humoral processes, which are not dependent on blood pressure, are of major importance in these alterations. In particular, angiotensin converting enzyme (ACE) activity seems to be involved. We therefore compared the effects of blood pressure reduction and of acute and long-term ACE inhibition on cardiac hypertrophy, arterial function and morphologic alterations in hypertension. To examine the acute effect of ACE inhibition on arterial compliance, we used an experimental model allowing a pressure-volume determination in the carotid artery in situ to assess arterial compliance in normotensive Wistar-Kyoto and spontaneously hypertensive rats. The pressure-volume relationship was determined after an acute, single, oral administration of either placebo or the ACE inhibitor quinapril in doses of 0.3 and 3 mg/kg. Both doses of quinapril produced a similar relaxation of arterial smooth muscle, approximately 80-90% of the maximum relaxation produced by potassium cyanide. LONG-TERM STUDY: We then studied the long-term effects of ACE inhibition compared with those of hydralazine. Four groups of 4-week-old spontaneously hypertensive rats were treated for 4 months with quinapril at 1 or 10 mg/kg per day, hydralazine at 15 mg/kg per day or placebo. Blood pressure, plasma and aortic ACE activity, left ventricular weight and histomorphometric parameters of the thoracic aorta, the renal and the mesenteric arteries were evaluated. We found a marked dissociation between the effects on blood pressure and cardiovascular structural parameters. Whereas both hydralazine and 10 mg/kg quinapril prevented the development of hypertension and aortic hypertrophy in a pressure-dependent manner, only the ACE inhibitor prevented left ventricular hypertrophy and aortic collagen accumulation. These quinapril effects were observed even with a small non-antihypertensive dose (1 mg/kg); the effect on aortic collagen was related to a reduction in aortic but not plasma ACE. These results indicate that the acute and long-term effects of ACE inhibitors on arterial function and structure go well beyond their antihypertensive actions and seem to be related to inhibition of tissue ACE. However, while clear effects were observed in the particular arterial segment explored, it may not be valid to extrapolate these findings to other arterial segments.

Angiotensin converting enzyme inhibition prevents the increase in aortic collagen in rats.

Four groups of 4-week-old spontaneously hypertensive rats were treated during 4 months with the angiotensin converting enzyme inhibitor quinapril at 1 mg/kg per day (Q1) or 10 mg/kg per day (Q10), hydralazine at 15 mg/kg per day (H), or placebo (P). In the first set of experiments, blood pressure was measured in conscious rats, and plasma and aortic angiotensin converting enzyme activities were evaluated. In the second set of experiments, histomorphometric parameters of the thoracic aorta were evaluated. Mean blood pressure was lower in the Q10 and H groups (136 +/- 16 and 149 +/- 11 mm Hg) compared with the P group (190 +/- 23 mm Hg) (P < .01). The Q1 group showed mean blood pressure values (171 +/- 15 mm Hg) lower than the P group (P < .05) but significantly higher than the Q10 and H groups (P < .01 and P < .05, respectively). Aortic medial cross-sectional area was significantly lower in the H and Q10 groups (455 +/- 61 and 487 +/- 57 x 10(3) microns 2) than in the P group (636 +/- 72 x 10(3) microns 2) (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin I converting enzyme activity in adriamycin induced nephrosis in rats

Activity of the dipeptidyl hydrolase angiotensin converting enzyme (ACE) has been observed to be altered by treatment with adriamycin (ADR). We used an animal model of ADR nephrotoxicity to study the effects on ACE in serum, urine and tissues on days 5, 10, 15, 20, 25 and 30 after ADR administration. Both glomerular and tubular injury occurred as evidenced by heavy proteinuria, albuminuria and increased urine N-acetyl glucosaminidase (NAG) excretion. Serum ACE was signifcaantly elevated on days 20, 25 and 30. Of great interest was the excretion of ACE in urine of treated rats which ran parallel with the total protein excretion above the barely detectable levels found in controls. ACE activity increased in kidney, adrenal gland and liver on days 15, 20, 25 and 30. Heart and brain ACE levels increased on days 25 and 30. Increased ACE activity in aorta and lungs occurred on days 20, 25 and 30. ACE activity decreased in kidney, aorta, heart and brain on days 5 and 10. These observations strongly suggest a contribution of various tissues to elevate the serum ACE level. Urinary ACE may be of potential use as an index for renal glomerular and tubular damage.

Long-term low-dose angiotensin converting enzyme inhibitor treatment increases vascular cyclic guanosine 3',5'-monophosphate.

We investigated functional changes in aortic preparations of spontaneously hypertensive rats treated in utero and subsequently up to 20 weeks of age with the angiotensin converting enzyme (ACE) inhibitors ramipril (0.01 and 1 mg/kg per day) and perindopril (0.01 mg/kg per day). Early-onset treatment with the high dose of ramipril inhibited aortic ACE activity, prevented the development of hypertension, increased aortic vasodilator responses to acetylcholine (10(-8) to 10(-6) mol/L), decreased vasoconstrictor responses to norepinephrine (10(-8) mol/L), and increased aortic cyclic GMP content by 160%. Low-dose ramipril inhibited aortic ACE activity and attenuated the aortic vasoconstrictor response to norepinephrine but had no effect on blood pressure. Low-dose treatment with ramipril and perindopril resulted in a significant increase in aortic cyclic GMP content by 98% and 77%, respectively. Long-term coadministration of the bradykinin B2-receptor antagonist Hoe 140 abolished the ACE inhibitor-induced increase in aortic cyclic GMP. Our data demonstrate that long-term treatment with ACE inhibitors can alter vascular function of compliance vessels independently of the antihypertensive action. The increase in aortic cyclic GMP was due to bradykinin potentiating the action of the ACE inhibitors.

Increase of angiotensin converting enzyme gene expression in the hypertensive aorta.

To investigate the possible role of vascular angiotensin converting enzyme (ACE) in the development and maintenance of hypertension, we examined aortic ACE messenger RNA (mRNA) levels in two-kidney, one clip (2K1C) hypertensive rats. The blood pressure was increased remarkably at 4 weeks (early stage) after clipping and remained elevated at 12 weeks (chronic stage). The aorta ACE mRNA levels were significantly elevated in both early and chronic stages concurrently with the increases in aortic ACE activity and blood pressure. The plasma renin activity rose markedly at 4 weeks, but returned to the normal level at 12 weeks. Neither ACE activity in the lung and plasma, nor ACE mRNA level in the lung was altered at either stage. The aorta and liver angiotensinogen mRNA levels and renal renin mRNA level were increased at 4 weeks but decreased at 12 weeks. These results indicate that the acceleration of all components in the renin-angiotensin system may contribute to the development of 2K1C hypertension in the early stage. In the chronic stage, the increased vascular ACE induced by the elevated ACE mRNA levels in the aorta may play the primary role in the acceleration of local angiotensin II formation and thus may sustain the hypertension.

Gonadectomy-induced reduction of antihypertensive action of angiotensin converting enzyme inhibitor and its role of central renin activity in spontaneously hypertensive rats

Gonadectomy induced a significant retardation of systolic blood pressure (BP) in male and female spontaneously hypertensive rats (SHR). Captopril (5 mg/kg, i.p.), an angiotensin converting enzyme (ACE) inhibitor, significantly decreased BP in all groups, except that the antihypertensive action was significantly inhibited by gonadectomy in both sexes. The plasma ACE activity was increased in orchiectomized males, but this effect did not appear in females. Neither plasma renin activity nor its concentration were changed by gonadectomy in either sex. Aorta ACE activity was not changed by gonadectomy in either sex, while the renin activity was increased only in gonadectomized females. Diencephalon ACE activity was not changed by gonadectomy in either sex, but the renin activity was decreased in these groups. These results suggested that the decrease of BP by gonadectomy in both sexes SHR was closely related to the decrease of renin activity in diencephalon by androgen deprivation with gonadectomy.

Vascular angiotensin converting enzyme activity in spontaneously hypertensive rats and its inhibition with cilazapril

Angiotensin converting enzyme (ACE) activity was examined in large arteries and veins of rats and found to be present in most of the arteries and to a lesser extent in the veins, except for the femoral vessels which showed higher ACE activity in the vein than in the artery. For the aorta and all its branches, ACE activity was higher in the aorta and its branches in spontaneously hypertensive rats (SHR) than in age-matched normotensive Wistar-Kyoto rats (WKY), with the exception of the hepatic, pulmonary and basilar arteries where the levels were similar for SHR and WKY. For the vena cava and brachial vein, ACE activity was also higher in SHR than WKY but for most other veins the activity was the same with the exception of the pulmonary vein where ACE activity was higher in WKY. The acute treatment of SHR with cilazapril, an ACE inhibitor (0.3 and 3 mg/kg orally, for 4h) decreased aortic blood pressure and ACE activity in arterial and venous mesenteric and renal vessels in a dose-dependent fashion. Cilazapril, at the threshold hypotensive dose, markedly decreased ACE activity in each pair of aortic segments, carotid, pulmonary, subclavian, brachial and femoral vessels to a degree which was equivalent to that caused by the high dose. The effect outlasted a fall in blood pressure 24 h later. This was associated with a marked decrease in plasma angiotensin II and III and accumulation of angiotensin 1 at 4 h. No increase in plasma bradykinin or kallidin levels was detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of an Angiotensin-Converting Enzyme (ACE) Inhibitor, SA446, on Tissue ACE Activity in Normotensive, Spontaneously Hypertensive, and Renal Hypertensive Rats

Effects of an angiotensin-converting enzyme (ACE) inhibitor, SA446, on the renin-angiotensin system, particularly on tissue ACE activity, were studied in Wistar-Kyoto normotensive rats (WKY), spontaneously hypertensive rats (SHR), and two-kidney, one-clip renal hypertensive rats (RHR) by repeated oral administration for 7 days. SA446 (45 mg/kg/day p.o.) inhibited ACE activity in the lung, brain, kidney, heart, and whole blood throughout the administration period in WKY, but showed a slight hypotensive action and no inhibition of aorta ACE activity. On the other hand, SA446 had an apparent hypotensive action at the same dose in SHR and inhibited ACE activity significantly in the aorta as well as the kidney and whole blood during the administration period. Furthermore, enzyme activity in the aorta, kidney, heart, and whole blood was also inhibited at a hypotensive dose of SA446 (10 mg/kg/day p.o.) in RHR. The inhibition in whole blood and kidney was almost complete, and the inhibition in the aorta was greater on day 7 than on day 1. The maximum decrease of blood pressure was correlated with the maximum inhibition in aorta ACE activity, but not in brain, lung, or heart ACE activity. In addition, a good positive correlation was observed between the basal blood pressure and the basal aorta ACE activity in WKY, SHR, and RHR, although there was no correlation in the brain, lung, kidney, heart, or whole blood. These results suggest that the antihypertensive action of SA446 by repeated administration may be due to inhibition of arterial ACE activity in addition to inhibition of plasma and kidney ACE activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Central and peripheral inhibition of angiotensin converting enzyme (ACE) in the SHR: correlation with the antihypertensive activity of ACE inhibitors.

A series of five structurally distinct ACE inhibitors were evaluated for their ability to inhibit tissue ACE activity in the SHR after oral administration. In the first series of experiments, the ACE inhibitors captopril, enalapril, pentopril, CGS 14824A and CGS 16617 were given to groups of SHR at doses that produced a 15 to 20 mm Hg reduction in blood pressure within 1 hour. Under these conditions of dose and time, only captopril significantly inhibited brain ACE activity (43%), whereas inhibition of serum ACE activity ranged from 72% to 99% with these agents. Inhibition of aortic ACE activity ranged from 54% to 87%, and lung ACE inhibition varied from 50% to 83%. In the second series of experiments, SHR were administered higher doses of each ACE inhibitor such that these compounds produced peak reductions in blood pressure (-25 mm Hg to -33 mm Hg) within a range of 2 to 6 hours. When tissue ACE activity was measured at the time corresponding to peak reduction in blood pressure, all five ACE inhibitors produced a significant inhibition of brain ACE activity ranging from 21% to 76%. Serum ACE activity was almost completely inhibited by these agents, with the exception of captopril (62% inhibition). The inhibition of aortic ACE activity ranged from 79% to 99%, while the inhibition of lung ACE activity did not increase under these conditions. These data suggest that ACE inhibitors may exert their maximal antihypertensive effects by inhibiting ACE in vascular tissues and brain.

Influence of aging on the aortic angiotensin-converting enzyme activity in rats

Influence of aging on the aortic angiotensin-converting enzyme activity in rats

Effect of sodium intake on the brain and the aortic angiotensin-converting enzyme activity in spontaneously hypertensive rat.

Effect of sodium intake on angiotensin-converting enzyme activity was studied in five areas of the brain (cerebral cortex, midbrain, striatum, thalamus and hypothalamus) and in subcellular fractions of the aorta (homogenate, mitochondria, microsomes and supernatant) in normotensive, spontaneously hypertensive, and stroke-prone spontaneously hypertensive rats. Angiotensin-converting enzyme activity was significantly higher in the hypothalamic area than in the other areas of the brain in spontaneously hypertensive rat. The enzyme activity of subcellular fractions of the aorta showed an extremely high value in the supernatant in normotensive, spontaneously hypertensive, and stroke-prone spontaneously hypertensive rats. Sodium intake resulted in a marked decrease in the aortic converting enzyme activity, while it did in a significant rise of the enzyme activity in the midbrain area in spontaneously hypertensive rat, and in the midbrain and striatum areas in stroke-prone spontaneously hypertensive rat. It is likely therefore that sodium intake lowers the converting enzyme activity of the aorta. Increased converting enzyme activity of the brain in spontaneously hypertensive rats may play a possible role in hypertension induced by sodium intake.