Technique for 24 Hour Recording of Continuous High Fidelity Arterial Pressure and Electrocardiogram in Ambulatory Patients

Angiotensin converting enzyme inhibition by MK 421, SA 446 or captopril (6 mg/kg/day ip) for up to 6 days induced significant fall in systolic blood pressure and plasma angiotensin II concentration. The hypotensive effect was greater in sodium depleted rats than in sodium repleted rats. The hypotensive effect was also accompanied by increased excretion of urinary prostaglandin E₂, however the levels of urinary prostaglandin E₂ in sodium repleted rats were not different from those in sodium depleted rats. Urinary kinin excretion was increased during infusion of MK 421, SA 446 or captopril in sodium depleted rats, whereas no significant change was found in sodium repleted rats. Thus the present results suggest that renal prostaglandin E system may not be essential for the hypotensive effect of these inhibitors. In addition, the greater hypotensive effect of these inhibitors in sodium depleted rats may be in part due to stimulated renal kinin system.     

Renal Kallikrein-Kinin System and the Depressor Effect of Angiotensin Converting Enzyme Inhibitors MK 421, SA 446, And Captopril In Rats

Responses in urinary kallikrein and kinin excretion and systolic blood pressure to MK 421, SA 446 or captopril were studied in normotensive rats fed on a regular or a low sodium diet to assess the role of renal kallikrein-kinin system in their hypotensive effect. MK 421, SA 446 or captopril were infused at a rate of 6 mg/kg/day by osmotic minipump implanted intraperito-neally for up to 6 days. The magnitude of fall in systolic blood pressure was greater on a low sodium diet when compared to on a regular diet, whereas the pattern of the fall was similar on both diets. The magnitude of falls in plasma angiotensin II and aldosterone concentration induced by MK 421, SA 446 and captopril was not significantly different between both regular and low sodium diets. Urinary kallikrein and kinin excretion and sodium excretion were increased during infusion of MK 421, SA 446 or captopril on a low sodium diet, however any significant changes were not found in each of them on a regular diet

The present results suggest that on a low sodium diet the augmented hypotensive response to angiotensin converting enzyme inhibitors in the rats might be due to the enhanced renal kallikrein-kinin system in addition to suppressed renin-angiotensin system     

Renal prostaglandin E in the hypotensive mechanism of MK-421 in conscious rats

To assess the role of renal prostaglandin E in the hypotensive mechanism of MK-421, we evaluated the effects of chronic infusion of MK-421 (6 mg/kg/day i.p.) on systolic blood pressure and urinary prostaglandin E excretion in conscious rats in states of sodium repletion or depletion and also during chronic infusion of norepinephrine (1.8 mg/kg/day i.p.) or vasopressin (7.2 U/kg/day i.p.). The hypotensive effect of MK-421 was greater in sodium depleted than in sodium repleted rats. The hypertensive effect of norepinephrine or vasopressin was inhibited by the simultaneous administration of MK-421. MK-421 induced an increase in the excretion of urinary prostaglandin E, in both sodium repleted and depleted rats. However, simultaneous administration of MK-421 had no influence on the increase in urinary prostaglandin E excretion induced by norepinephrine or vasopressin. In addition, the combined administration of MK-421 with indomethacin (10 mg/kg/day s.c.) still abolished the hypertensive effect of norepinephrine or vasopressin. The disparate effect of MK-421 on urinary prostaglandin E excretion suggests that the renal prostaglandin system is not essential for the mechanism of the hypotensive effect of MK-421.     

No Evidence on Significant Roles of the Prostaglandin-Thromboxane and Kallikrein-Kinin System in the Antihypertensive Effect of MK 421 in Rats Made Hypertensive by Norepinephrine or Vasopressin

Inhibition of angiotensin converting enzyme by MK 4–21 (6 mg/kg/day ip) induced a significant increase in urinary kinin excretion in norepinephrine-infused rats (1.8 mg/kg/day ip), whereas it had no effect on urinary prostaglandin E₂ excretion. In contrast, MK 421 did not induce any significant changes in urinary kinin and prostaglandin E₂ excretion in vasopressininfused rats (7.2 U/kg/day ip). The simultaneous administration of indomethacin (10 mg/kg/day sc), OKY 046 (12 mg/kg/day sc) or aprotinin (100, 000 units/kg/day sc) did not affect the antihypertensive effect of MK 4–21 in rats made hypertensive by chronic infusion of norepinephrine or vasopressin. The present results suggest that the hypotensive effect of MK 421 may depend on a reduced sensitivity of the vasculature to vasoconstrictor substances. In addition, it is also suggested that neither the prostaglandin-thromboxane or kallikrein-kinin systems are essential for the antihypertensive effect of MK 421 in these models of hypertension.     

In vivo comparison of three orally active inhibitors of angiotensin-converting enzyme

This study was designed to compare the activity of three structurally different drugs (SQ 14225 [captopril], SA 446 and MK 421) as inhibitors of angiotensin I-converting enzyme in vivo and to compare their effects on blood pressure in spontaneously hypertensive rats and one clip, two kidney renal hypertensive rats. All the three drugs were potent, orally effective converting enzyme inhibitors. The relative durations of their actions as inhibitors of angiotensin-converting enzyme, from longest to shortest, were as follows: MK 421, SQ 14225 and SA 446. MK 421 appears the most potent on a molar basis. In renal hypertensive rats the drugs appeared equipotent, although the duration of action of MK 421 was prolonged and SA 446 shorter than that of SQ 14225. SA 446 was less effective than the other two compounds in spontaneously hypertensive rats.     

Effects of angiotensin I converting enzyme inhibitors on the renal excretory function, hemodynamics and renin release in isolated perfused rat kidney

Direct renal effects of angiotensin I converting enzyme inhibitors (CEIs), captopril, SA446 and MK421, were examined in isolated rat kidneys perfused with a renin-substrate-free medium. Among three CEIs, only captopril induced a significant natriuresis, whereas SA446 and MK421 did not. UKV, renal vascular resistance and creatinine clearance were not affected by any of these CEIs. Renin release from perfused rat kidneys were not influenced by CEIs under the present experimental conditions. These results suggest that among three different types of CEIs, only captopril possesses natriuretic action in the isolated perfused rat kidney and that this action may be independent of its inhibitory action on angiotensin converting enzyme. It is also suggested that these three CEIs themselves do not have a direct effect on the renal vascular bed.     

Role of renal kallikrein in modulating the antihypertensive effect of a single oral dose of captopril in normal- and low-renin essential hypertensives

The antihypertensive efficacy of angiotensin converting enzyme (ACE) inhibitors may result from the blockade of angiotensin II formation but also, theoretically, from the inhibition of kinin breakdown. To test whether a blunted activity of the kallikrein-kinin system might account for the failure of ACE inhibitors in lowering blood pressure (BP) in patients in whom the renin-angiotensin system (RAS) is not enhanced, 31 essential hypertensives with normal or low plasma renin activity (PRA) were evaluated before and after a single oral dose (50 mg) of captopril. A significant fall, in both systolic and diastolic BP, was obtained in the subgroup of patients who were classified as 'normal-kallikrein hypertensives' according to whether their pretreatment urinary kallikrein excretion was within the normal range, while no significant change in BP was observed in 'low-kallikrein hypertensives'. Furthermore, the mean percentage fall in mean BP, throughout the 2 h following captopril administration, was significantly related to the basal value of urinary kallikrein excretion (r = 0.47, P less than 0.05) in all the patients. Our results suggest that blunted activity of the kallikrein system might be responsible for failure of captopril to lower BP in some hypertensive patients.     

Chronic Effects of Norepinephrine and Vasopressin on Urinary Prostaglandin E and Kallikrein Excretions in Conscious Rats

To assess in vivo functional interactions of vasopressor substances, norepinephrine and vasopressin, with renal prostaglandins and kallikrein-kinin system which are responsible for the vasodepressor mechanism in the kidney, we evaluated chronic effects of norepinephrine(1.8 mg/kg/day ip) and vasopressin(7.2 U/kg/day ip) on urinary prostaglandin E excretion and urinary kallikrein excretion in conscious rats. Both norepinephrine and vasopressin induced a sustained increase in systolic blood pressure. Norepinephrine induced slight but significant increases in urinary prostaglandin E excretion and urinary kallikrein excretion which were sustained for up to 6 days. Vasopressin induced a marked increase in urinary prostaglandin E excretion which was sustained for up to 6 days, whereas it induced a sustained decrease in urinary kallikrein excretion. Circulating angiotensin II levels was not changed by norepinephrine, but was decreased by vasopressin. These results indicate that renal prostaglandin E may not correlate with renal kallikrein-kinin and renin-angiotensin system in the responses to norepinephrine and vasopressin, and that vasopressin may be a more potent stimulator of the synthesis or release of renal prostaglandin E     

Role of Endogenous Angiotensin II and Prostaglandins in the Antihypertensive Mechanism of Angiotensin Converting Enzyme Inhibitor in Hypertension

The role of endogenous angiotensin II and prostaglandins (PGs) in the antihypertensive effect of converting enzyme inhibitor, captopril, was studied in essential hypertension by the separate and the combined administration of captopril and indomethacin. Although plasma angiotensin II was similarly suppressed by the separate and the combined administration of captopril and indomethacin, captopril lowered and indomethacin increased the mean blood pressure. There were negative correlations between the changes in mean blood pressure and in urinary sodium excretion as well as in urinary PGE excretion. These results suggest that endogenous PGs may be implicated in the antihypertensive effect of captopril through the alteration of sodium balance.     

The opposing effects of chronic angiotensin-converting enzyme blockade by captopril on the responses to exogenous angiotensin II and vasopressin vs. norepinephrine in rats

To study the influence of acute and chronic angiotensin-converting enzyme blockade on the pressor response to exogenous angiotensin II, vasopressin and norepinephrine, we gave normal female Wistar rats 100 mg of captopril or 1 ml of 5% glucose twice daily by gavage for 2 weeks. On the 15th day, rats were anesthetized with pentobarbital, and dose-response curves to angiotensin II, lysine-vasopressin, and norepinephrine were obtained before and after intraperitoneal injection of 100 mg/kg of captopril or 1 ml of 5% glucose. Acute as well as chronic converting enzyme blockade enhanced the pressor response to exogenous angiotensin II. Similarly, sensitivity to exogenous vasopressin was increased by both acute and chronic converting enzyme inhibition. In contrast, chronic converting enzyme blockade significantly blunted the response to exogenous norepinephrine, whereas acute blockade tended to accentuate its pressor effect. These results suggest that chronic angiotensin-converting enzyme blockade may partly inhibit sympathetic activity which, in turn, might contribute to the antihypertensive efficacy of this therapeutic approach. These results also point to an important physiological interaction between the two pressor hormones, angiotensin II and vasopressin.     

Renal adaptation to a restriction of sodium intake in the rat: effects of inhibition of the renin-angiotensin system

The relationship between sodium homeostasis and the renin-angiotensin system was assessed through the use of two angiotensin-converting enzyme inhibitors (captopril and enalapril) in the rat. Treatment with captopril (group SQ) or enalapril (group MK) before and during a 6-day period of sodium free diet was associated with sodium wasting; on the sixth day of sodium restriction, sodium excretion was 164 +/- 17 and 144 +/- 10 mumol/24 h in SQ and MK group respectively. In addition, the cumulative Na+ excretion during the 6 day period of sodium-free diet was 1.04 +/- 0.07 mmoles in untreated rats and 1.70 +/- 0.13 and 1.86 +/- 0.14 mmoles in MK and SQ group respectively. At the end of the study, mean arterial pressure was lower in treated than in untreated animals. These findings show that in rats both renal and systemic adaptations to reduced sodium intake are markedly impaired by administration of converting enzyme inhibitors.     

Central Effects of Converting Enzyme Inhibitors

Evidence has accumulated that systemic administration of converting enzyme inhibitors (CEI) such as captopril, MK 421 or SA 446 not only produces an inhibition of the plasma renin angiotensin system (RAS), but also of the RAS in various target organs which are relevant for blood pressure (BP) regulation. A potential target organ is the brain, where a local CE inhibition could contribute to the BP lowering action of CEI. CE in the brain can be inhibited by intracerebroventricular (i.c.v.) injection of CEI as evidenced by an inhibition of the pressor and drinking responses to i.c.v. angiotensin I (ANG I) or renin and by potentiation of the pressor responses to i.c.v. bradykinin. Site of the inhibition is not only the cerebrospinal fluid but also periventricular brain tissue such as the hypothalamus. I.c.v. injection of captopril at doses which inhibit brain CE but do not leak into the peripheral blood were shown to lower BP in conscious stroke-prone spontaneously hypertensive rats (SHRSP), but not in normotensive Wistar Kyoto (WKY) controls. Acute peripheral administration of CEI can produce an inhibition of brain CE. This was shown by an attenuation of the drinking responses to i.c.v. ANG I and renin and by direct measurements of CE activity in brain tissue. Chronic oral treatment with CEI produces changes of brain RAS parameters which suggest an inhibition of ANG II formation in the brain.     

Responses of plasma bradykinin and the renin angiotensin axis to angiotensin II in hyperthyroid patients

The present investigation was undertaken to elucidate the possible interplay between the circulating kinin(s) and the renin angiotensin axis in hyperthyroidism. The responsiveness of plasma aldosterone (p-Ald), kinin (p-BK), plasma renin activity (PRA) and serum angiotensin converting enzyme activity (ACEA) to infusion of angiotensin II at a dose of 4, 8 and 16 ng/kg.min. was asessed in 15 hyperthyroid patients and 10 euthyroid controls. There was impaired angiotensin II induced response of blood pressure in hyperthyroid patients, and basal concentrations of p-Ald were 7.7 +/- 3.8 ng/dl in euthyroid controls and 12.6 +/- 3.1 ng/dl in hyperthyroid patients (p less than 0.05). As compared to the euthyroid controls, the hyperthyroid patients showed a reduced response of plasma aldosterone to angiotensin II infusion. Angiotensin II infusion increased p-BK from basal levels of 19.1 +/- 8.2 pg/ml to 31.0 +/- 7.8 pg/ml (p less than 0.05) only in hyperthyroid patients and did not increase ACEA in either group. Next, the effects of a single administration of captopril (50 mg p.o.) on blood pressure and p-BK in hyperthyroid patients and euthyroid controls were studied. In the two groups blood pressure was not changed by captopril, but p-BK increased significantly. The present results do not support the view that there may be a direct linkage between the kallikrein kinin system and the renin angiotensin axis mediated by kininase II or angiotensin converting enzyme in human peripheral blood. Also it is unlikely that kinin may play a role in the mechanism of reduced responsiveness of aldosterone and blood pressure to angiotensin II in hyperthyroidism.     

Depressor effects of captopril in DOCA-salt hypertensive rats: role of vasopressin

Oral administration of the angiotensin I-converting enzyme inhibitor captopril produced a substantial reduction of blood pressure in DOCA-salt hypertensive rats. After oral administration of captopril (30 mg/kg), mean blood pressure decreased from 172 +/- 11 to 148 +/- 9 mmHg (P less than 0.01) in one hour and its antihypertensive effects lasted for the next seven hours. Plasma vasopressin levels showed a marked elevation in DOCA-salt hypertensive rats compared with control values (22 +/- 5 versus 5 +/- 3 pg/ml). This increase in vasopressin was significantly reduced by captopril from 25 +/- 5 to 8 +/- 6 pg/ml. In addition, whole body vascular reactivity to norepinephrine was examined. Responsiveness was at first attenuated but returned to control value in spite of reduction of both plasma vasopressin and blood pressure. Thus, captopril reduces blood pressure in DOCA-salt hypertensive rats and the fall in blood pressure is accompanied by reduction of plasma vasopressin and attenuation of vascular reactivity.     

Comparative effects of captopril and MK 421 on sympathetic function in spontaneously hypertensive rats

The effects of captopril and MK 421, both orally active angiotensin-converting enzyme inhibitors, on sympathetic function in the pithed spontaneously hypertensive rat were examined. Captopril (100 mg/kg orally) signif icantly inhibited pressor responses to sympathetic nerve stimulation and norepinephrine whereas MK 421 (10 and 100 mg/kg orally) was without effect. Both drugs abolished the angiotensin l response without affecting that to angiotensin II. Because these doses of MK 421 are antihypertensive in the Spontaneously hypertensive rat, it is concluded that inhibition of sympathetic function plays no role in its effect. The role of the sympatholytic action of captopril in its antihypertensive action remains unclear.     

The antihypertensive effect of captopril in essential hypertension: relationship to prostaglandins and the kallikrein-kinin system

Two groups, each with nine essential hypertensive patients, were maintained on 10 mmol sodium daily over 14-17 days and treated in this sequence: placebo; captopril (25 or 50 mg given thrice daily) or indomethacin (50 mg given thrice daily) alone; captopril plus indomethacin, and (4) captopril alone. The initial fall in mean blood pressure induced by captopril (118 +/- 1 to 102 +/- 1 mmHg) was unaffected by the addition of indomethacin. However, if indomethacin treatment preceded captopril, the antihypertensive effect was attenuated (116 +/- 4 to 109 +/- 4), and was associated with significant reductions in urinary prostaglandin and kinin excretion. Addition of captopril to indomethacin returned kinin excretion to placebo levels but did not affect indomethacin-induced reduction in prostaglandin excretion. Captopril alone stimulated plasma renin activity (PRA) fivefold; aldosterone excretion was lowered by 25% and further reduced by indomethacin. Thus, when captopril and indomethacin are administered together, the order of administration is critical to the antihypertensive effect of captopril.     

Atrial natriuretic factor inhibits the hypertension induced by chronic infusion of norepinephrine in conscious rats

To assess the physiological role of atrial natriuretic factors in the regulation of blood pressure and sodium-water excretion, we studied the chronic effects of continuous infusion of a synthetic atrial natriuretic factor of 25 amino acids for up to 3 days on systolic blood pressure, urine volume, and urinary excretion of sodium, prostaglandin E2 and kallikrein in conscious rats, and also evaluated the antihypertensive effect of this substance in rats with hypertension caused by chronic infusion of norepinephrine. Continuous infusion of atrial natriuretic factor (150 micrograms/kg per day) into the jugular vein via osmotic minipumps did not induce any changes in systolic blood pressure, urine volume, and urinary excretion of sodium, prostaglandin E2, and kallikrein for up to 3 days, compared with those in vehicle-infused rats. When the same dose of atrial natriuretic factor was administered simultaneously with 1.8 mg/kg per day of norepinephrine infused intraperitoneally by osmotic minipumps, the systolic blood pressure of conscious rats rose on day 1 to only 127.3 +/- 6.3 mm Hg compared with the rise to 146.3 +/- 1.6 mm Hg when norepinephrine alone was infused (P less than 0.05). The antihypertensive effect of atrial natriuretic factor was sustained for 3 days in rats infused with norepinephrine. The administration of atrial natriuretic factor to rats made hypertensive by 3 days of infusion with norepinephrine alone returned the blood pressure to control levels, and the antihypertensive effect was sustained throughout the experimental period lasting for 3 days.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of angiotensin-converting enzyme inhibitors on the vascular response to norepinephrine

The effects of three types of angiotensin-converting enzyme inhibitor, SQ 14225 (captopril), SQ 20881 (teprotide) and SA 446 (Santen, Osaka, Japan), on the vascular contraction induced by norepinephrine were studied in the perfused rat mesenteric vascular bed. (1) SQ 14225 attenuated in the vascular contraction induced by norepinephrine, but SQ 20881 and SA 446 revealed no effect on vascular reactivity. (2) The effect of SQ 14225 was not altered in the presence of bradykinin or angiotensin II in the perfusate. On the basis of these results it is suggested that the attenuating effect on the vascular response to norepinephrine may be limited to SQ 14225 and that its effect is not mediated through the renin-angiotensin or kallikrein-kinin system.     

Chronic MK421 fails to modify evolution of hypertension in neonatally coarcted pups

In inbred dogs with neonatally induced coarctation hypertension, prior serial studies during the first year after aortic banding showed extracellular volume excess with normal plasma renin activity (PRA). The present studies test the hypothesis that slowly evolving aortic constriction in this model will yield intrarenal angiotensin II excess, peripherally undetectable, with continuous slightly positive sodium balance, and thus that chronic blockade of angiotensin II formation will prevent generation of hypertension. Accordingly, we used MK421 (enalapril, 3 mg/kg twice daily), a long-acting angiotensin converting enzyme inhibitor, or placebo, administered orally, from the time of banding through 4 months after banding in sex-matched littermates randomly assigned to one of four groups: coarcted/MK421; control/MK421; coarcted/placebo; control/placebo. Results indicate that MK421 caused identical lowering of absolute forelimb systolic blood pressure in coarcted and control pups but failed to modify evolution of a significant (p less than 0.005) systolic blood pressure difference in coarcted versus control dogs. Thus, neither temporal course nor final magnitude of relative hypertension was altered by MK421. Efficacy of MK421 was documented by 83% inhibition of the pressor response to angiotensin I at nadir of drug effect and by sustained increases in angiotensin I and renin concentration throughout the period of study. Coarcted and control pups responded similarly to MK421 for all measured variables. Glomerular filtration rate and extracellular volume (measured by [14C]inulin disappearance) did not differ among groups. Thus, chronic administration of MK421 failed to prevent hypertension and did not impair maintenance of normal renal function in the evolving phase of neonatally induced coarctation hypertension. We conclude that, although angiotensin II may participate in the untreated model, it does not appear essential to generation of hypertension. We propose that the renal pressure-natriuresis mechanism regulates distal pressure, that stenosis-related resistance independently determines the proximal-distal difference, and that chronic converting enzyme inhibition lowers the set point of the former without influencing stenosis evolution, thus secondarily lowering proximal pressure by an equal degree.     

Role of the Renin-Angiotensin-Aldosterone and Kallikrein-Kinin Systems in the Control of Fluid and Electrolyte Metabolism,Renal Function,and Arterial Blood Pressure

The long-term effects of angiotensin I converting enzyme (kininase II) inhibition with Captopril on fluid and electrolyte metabolism, aldosterone secretion, renal function, and arterial pressure were evaluated in conscious sodium deficient dogs. Plasma aldosterone concentration (PAC), plasma renin activity (PRA), urinary sodium excretion (U_NaV), arterial pressure (AP), renal blood flow (RBF), glomerular filtration rate (GFR), blood kinin concentration (BK), urinary kinin excretion (UK), and urinary kallikrein activity (UKA) were determined during long-term inhibition of angiotensin I converting enzyme (kininase II). In response to Captopril administration (20 mg/kg/day) PAC decreased from 38.9 ± 6.7 to 14.3 ± 2.3 ng/dl, PRA increased from 3.58 ± 0.53 to 13.7 ± 1.6 ng/ml/hr, U_NaV increased from 0.65 ± 0.27 to 6.4 ± 1.2 mEq/day, AP decreased from 102 ± 3 to 65 ± 2mmHg, RBF increased from 136 ± 7 to 156 ± 8 ml/min, GFR decreased from 65 ± 8 to 36 ± 7 ml/min, BK increased from 0.17 ± 0.02 to 0.41 ± 0.04 ng/ml, UK increased from 7.2 ± 1.5 to 31.4 ± 3.2 ug/day, and UKA decreased from 23.6 ± 3.1 to 5.3 ± 1.2 E.U./day. Aldosterone infusion in sodium deficient dogs maintained on Captopril failed to alter urinary sodium excretion, renal function, or arterial blood pressure. However, angiotensin II infusion (3 ng/kg/min) restored aldosterone secretion, renal function, and arterial blood pressure within three days to levels observed in untreated sodium deficient dogs. The marked alterations in renal function and urinary sodium excretion during angiotensin II infusion indicate that angiotensin II is several times more potent than aldosterone in the long-term control of sodium excretion. Also, our studies demonstrated that the long-term hypotensive and natriuretic actions of inhibitors of angiotensin I converting enzyme (kininase II) are mediated by inhibition of angiotensin II formation.