Enalaprilic Acid Research Articles

Effect of Enalapril Treatment on the Heart of Normal Rats

Previous experiments showed that enalapril (EN) treatment as well as enalaprilic acid, when added to the perfusion bath, diminish the inotropic response of the papillary muscles to isoproterenol (ISO). The main objective of this study was to evaluate, in normal rats, the effect of EN on basal contractility and inotropic response to ISO on the whole perfused ventricles (Langendorff preparation). Blood pressure (BP), increase in body weight (IBW), ventricular weight/body weight ratio (R) and concentration of ventricular proteins and DNA were also analyzed. Five groups were studied: EN10: 5 mg/kg/day, 10 days; EN21(L): 5mg/kg/day, 21 days; EN21(H): 15 mg/kg/day, 21 days. C10 and C21 were untreated controls. Cardiac contractility was evaluated by the maximal developed pressure, maximal rate of rise of pressure and maximal velocity of relaxation; no changes were found due to EN treatments either on basal conditions or on ISO stimulation. Significant differences (p<0.05 vs C21) were: lower BP and R in EN21(L) and EN21(H), slower IBW in EN21(H), decreased ventricular DNA in EN21(H). In conclusion, daily treatment for ten or twenty one days with enalapril does not change either basal cardiac contractile performance or inotropic response to ISO in the Langendorff preparation. Longterm treatment with EN seems to modify nuclear processes involved in cardiomyocite DNA content

Differential effects of enalapril and hydralazine on short-term variability of blood pressure and heart rate in rats.

Using a spectral procedure, we studied the acute and chronic effects of enalapril and hydralazine on the variability of blood pressure (BP) and heart rate (HR) in conscious Wistar rats. In the acute protocol, rats received two injections 25 min apart (saline followed by enalaprilic acid or hydralazine hydrochloride). In the chronic protocol, animals received oral enalapril maleate, hydralazine hydrochloride, or distilled water. A 5-min recording session was initiated on day 12. Acute enalapril and hydralazine amplified the low-frequency (LF) component of the systolic BP (SBP) spectrum. Chronic enalapril reduced the variability of BP, as indicated by the lower variance in SBP distribution. Chronic enalapril preferentially reduced the amplitude of the 400-mHz oscillations of SBP. Acute administration of enalapril or hydralazine resulted in BP variability profiles, suggesting a reflexly mediated vascular sympathetic activation. In contrast, chronic angiotensin-converting enzyme (ACE) blockade with enalapril caused a significant decrease in the LF oscillations of BP. This could reflect a reduced sympathetic outflow to vascular smooth muscles.

The Mechanism and Diagnostic Value of Angiotensin I Converting Enzyme Inhibition Renography

The effect of angiotensin converting enzyme (ACE) inhibition on the sensitivity of radionuclide renography in the diagnosis of a unilateral renal artery stenosis was tested both in a conscious dog model and in the human situation. ACE inhibition (10 mg enalaprilic acid, intravenously) markedly improved the sensitivity of [123I]hippuran renography in 10 renovascular hypertensive dogs with a mild to moderate unilateral renal artery stenosis from 50 to 100%. This improved sensitivity was due to an ACE-inhibition-induced delayed tracer handling at the stenotic side without an appreciable change in the renographic curve at the contralateral side. A similar phenomenon was observed in 15 hypertensive patients with an angiographically proved unilateral renal artery stenosis. Both [123I]hippuran and 99mTc-diethylenetriaminepentaacetic acid (DTPA) handling was delayed on the stenotic side after oral enalapril treatment. However, only a moderate increase in sensitivity was observed comparing control renograms to ACE-inhibition renograms: from 87 to 93% for hippuran, and from 60 to 86% for DTPA. Eight of these 15 patients underwent either surgery or angioplasty resulting in a successful correction of the stenosis. Hypertension was more or less cured in five patients. Each of these patients had shown an ACE-inhibition-induced change in the renogram at the stenotic side, suggesting that such a response may predict the curability of the hypertension. However, of the three patients that showed no blood pressure change upon successful revascularization, two showed a positive ACE-inhibition renogram. In conclusion, in an ideal setting as obtained in animal experiments, ACE inhibition improves the sensitivity of renographic studies to 100%. However, its value in the clinical setting needs more standardization.

Different effects of captopril and other angiotensin converting enzyme inhibitors on cardiovascular preparations

The effects of captopril and of other angiotensin-converting enzyme inhibitors (zofenopril, fosenopril and enalaprilic acid) were tested on the isolated rabbit heart and aorta. Captopril elicited an erratic negative inotropic effect and a reduction in basal coronary perfusion pressure (10 −5 −10 −4 M). The increase of coronary perfusion pressure induced by vasopressin, methoxamine, angiotensin II and Bay K 8644 was partially antagonized by captopril (10 −7−I0 −4 M) in a non-specific manner. These actions were not modified by saralasin or indomethacin and by ex vivo pretreatment with captopril itself. On the aortic strips, the contraction plateau induced by KCI and angiotensin II was partially inhibited (10 −6 − 10 −4 M), while no effect was observed on those induced by noradrenaline, serotonin and PGF 2α. The Ca 2+ concentration-response curve appeared shifted to the right in a noncompetitive manner. The other angiotensin-converting enzyme inhibitors showed no effect up to 10 −4 M on isolated heart or aorta. Results obtained with captopril were consistent with vasorelaxant activity independent of the tissue renin-angiotensin system. Modulatory activity on the intracellular calcium movement may be involved.

Pharmacological evidence for the existence of a local renin‐angiotensin system in porcine interlobar renal arteries

1. Changes in tension in response to cumulative additions of angiotensins (i.e., angiotensinogen, angiotensin I and angiotensin II), bradykinin and acetylcholine were monitored isometrically on ring preparations from porcine interlobar renal arteries. 2. Angiotensins consistently elicited contractile responses, whereas both bradykinin and acetylcholine produced relaxation of the arterial rings when active tone was induced by prostaglandin F2 alpha. 3. Contractile responses to angiotensin II could be completely blocked by the combined action of the cyclo-oxygenase inhibitor, indomethacin (1 microM) and the lipoxygenase inhibitor, nordihydroguairetic acid (NDGA, 10 microM). 4. Relaxant responses to bradykinin were unchanged during blockade of thromboxane A2 synthesis by dazoxiben (30 microM) and proved to be largely resistant to blockade by indomethacin (1 microM) and the prostaglandin I2 (prostacyclin) synthesis inhibitor, tranylcypromine (40 microM). 5. The angiotensin receptor blocker, saralasin (10 and 100 nM) antagonized responses to angiotensinogen, angiotensin I and angiotensin II effectively and with similar potency. Enalaprilic acid, the active metabolite of the converting enzyme inhibitor enalapril (300 nM), attenuated responses to angiotensin I but failed to inhibit those to angiotensinogen up to 1 microM. The serine protease kallikrein (0.001 to 1 mu ml-1) produced a dose-dependent shift to the left of the concentration-response curve for angiotensinogen. 6. It is suggested that the porcine interlobar renal artery possesses a local renin-angiotensin system with activatable angiotensin II forming enzyme(s) within the vessel wall.

Bradykinin-Induced Contractions of Canine Prostate and Bladder: Effect of Angiotensin-Converting Enzyme Inhibition

Alpha-adrenergic, cholinergic, and serotonergic receptor-mediated contractile responses have been well characterized in the genitourinary tissues of several mammalian species. The present study characterizes the in vitro contractile responsiveness of canine bladder and prostate to the peptides, bradykinin, angiotensin I, and angiotensin II. All preparations contracted to 0.15M KCl. Bradykinin elicited contractile responses in both prostate (10−10 to 10−7 M) and bladder (10−10 to 10−6 M). In both tissues, angiotensin II produced minimal responses and angiotensin I failed to elicit contractions. The potent angiotensin converting enzyme (ACE) inhibitor, enalaprilic acid [MK-422] (10−6 M) increased the contractile response of the prostate to bradykinin two-fold while having no effect on bradykinin-induced contractions in the bladder. Enalaprilic acid did not affect the contractile responses of the two tissues to angiotensin I or angiotensin II. The canine urogenital tissue contractile responses to bradykinin, angiotensin I, and angiotensin II may have relevance to human physiology. Previous studies have demonstrated that human prostatic tissue, specifically benign prostatic hyperplasia (BPH), has the highest concentration of ACE activity of tissues evaluated. Bradykinin is a potent peptidergic contractile agent in canine bladder and prostate. The activity of enalaprilic acid to amplify the bradykinin-induced contractions in the canine prostate is consistent with high levels of ACE in the tissue. These data confirm the sensitivity of the canine prostate to bradykinin and report for the first time, the ability of bradykinin to induce contractions in the prostate. These studies support the possibility that bradykinin may be involved in mediating micturition under normal and pathological states such as infravesical obstruction secondary to BPH. Furthermore, the results from these investigations in canine urogenital tissues, if applicable to humans, suggest that urinary function be closely monitored in patients receiving ACE inhibitor therapy. (J. Urol, 144: 390-392, 1990)

Angiotensin converting enzyme inhibitors potentiate the bronchoconstriction induced by substance P in the guinea‐pig

1. The effects of intravenous captopril and enalaprilic acid on the increase in pulmonary inflation pressure induced by different bronchoconstrictor agents were evaluated in the anaesthetized guinea-pig. 2. Captopril and enalaprilic acid (1.6-200 micrograms kg-1) enhanced dose-dependently the bronchoconstriction (BC) induced by substance P. The threshold effective dose was 1.6 micrograms kg-1 and maximal potentiation over the control response was more than 400% for both agents. Enalaprilic acid was also assayed for serum and lung angiotensin converting enzyme (ACE) inhibition in anaesthetized guinea-pigs. This drug produced a dose-dependent inhibition of ACE in both tissues, with ED50 s of 7.6 and 9.4 micrograms kg-1, respectively: this inhibitory activity was positively correlated to substance P potentiation. 3. Captopril (8-1000 micrograms kg-1) enhanced dose-dependently the BC induced by capsaicin. The threshold effective dose was 40 micrograms kg-1 and maximal potentiation about 90%. 4. Captopril (200-1000 micrograms kg-1) did not affect BC induced by bradykinin. However, this response was markedly enhanced (about 200%) by captopril 200 micrograms kg-1 in propranolol-pretreated animals. 5. Captopril and enalaprilic acid (200-1000 micrograms kg-1) slightly (20-40%) but significantly enhanced the BC induced by 5-hydroxytryptamine. However, this response was potentiated to the same extent by a dose of prazosin, which produced a degree of hypotension similar to that observed after administration of the ACE inhibitors. 6. In conclusion, ACE inhibitors potentiate the BC induced by substance P and, to a minor extent, that induced by capsaicin in the anaesthetized guinea-pig. Potentiation of substance P is well correlated with ACE inhibition in guinea-pig serum and lungs. These experimental results may offer a mechanistic interpretation of cough and bronchial hyperreactivity observed in patients receiving treatment with ACE inhibitors.

Effect of enalaprilic acid on cardiac contractile response to beta-adrenergic stimulation.

Studies in two-kidney--one clip hypertensive rats have demonstrated that long-term treatment with enalapril induced regression of cardiac hypertrophy, but the cardiac contractile response to beta-adrenergic stimulation remained depressed. In the present study, we evaluate the contractile response to beta-adrenergic stimulation of isolated papillary muscle in normal rats with isoproterenol (10(-11) M to 10(-4) M) in the presence of enalaprilic acid (10(-6) M or 10(-4) M) or enalaprilic acid (10(-4) M) and angiotensin II (10(-6) M). Myocardial contractility was characterized by maximal developed tension and maximal rate of rise of tension (+T), and the relaxant effect of isoproterenol by the ratio of (+T), and the maximal velocity of relaxation (-T)(+T/-T ratio). The rest tension (g/mm2) and the cross-sectional area (mm2) were similar in all the muscles studied. Enalaprilic acid (either 10(-6) M or 10(-4) M) in the bath did not induce any change in contractile and relaxation parameters. The increment in +T and -T (expressed as percentage) in response to cumulative doses of isoproterenol (10(-11) M to 10(-4) M) was significantly depressed in the presence of enalaprilic acid (10(-4) M) when compared with control hearts in which only vehicle was added before isoproterenol (p less than 0.05). The addition of angiotensin II after enalaprilic acid (10(-4) M) did not normalize the response in +T and -T. Enalaprilic acid diminishes the contractile response of the papillary muscle to beta-adrenergic stimulation. The inhibition of the local angiotensin II does not seem to be involved in this result.

Changes in the venous compliance by bradykinin and angiotensin II and its significance for the vascular effects of cyclosporine-A.

Local infusion of both bradykinin and enalaprilic acid, the active metabolite of the converting enzyme inhibitor enalapril, elicited dose-dependent reduction of the compliance of the saphenous vein in conscious dogs. The competitive bradykinin B1-receptor antagonist, des-Arg9-Leu8-bradykinin antagonized venous responses to both bradykinin and enalaprilic acid effectively and with similar potency whereas the bradykinin B2-receptor antagonist Thi5,8,D-Phe7-bradykinin was about 100 times less potent when tested against bradykinin. Under control conditions local infusion of angiotensin II had no contractile activity but it elicited considerable venodilation after blockade of endogenous thromboxane A2 synthesis by dazoxiben. Blockade of the converting enzyme by enalapril (3 mg/kg i.v.) enhanced the maximal responses to bradykinin. Under these conditions concomitant local infusion of angiotensin II attenuated the venoconstrictor effects of bradykinin. Venous responses to bradykinin were inhibited after oral treatment of the dogs with the thromboxane A2 receptor antagonist BM 13,177 and nearly completely abolished after i.v. administration of the thromboxane synthesis inhibitor dazoxiben. In contrast, venous responses to enalaprilic acid were unchanged by thromboxane A2 receptor blockade and enhanced after dazoxiben. Following oral administration of cyclosporine-A (10 and 30 mg/kg), venous responses to bradykinin were attenuated while those to enalaprilic acid remained unchanged. Concomitant local infusion of the angiotensin II receptor antagonist saralasin (1 microgram/min) reversed completely the cyclosporine-A-induced reduction of the venoconstrictor effects of bradykinin.(ABSTRACT TRUNCATED AT 250 WORDS)

Enalapril Therapy in Patients With Renal Function Impairment

The angiotensin-converting enzyme inhibitor (ACEI), enalapril maleate, is a nonsulfydryl group—containing compound. Accordingly, it is said to be less associated with side effects such as taste disturbance, rashes, proteinuria, and interstitial nephritis; these side effects having been observed with captopril, and attributed to its sulfydryl group. Enalapril is a pro-drug. Because the active compound, enalaprilic acid, is poorly absorbed, the drug is given as an absorbable ester, which is then hydrolyzed to the active compound. This results in a more gradual onset of antihypertensive effect than may be seen with captopril. However, enalapril is a more potent ACEI than captopril, and its pharmacologic half-life is prolonged, permitting once daily dosage. See also p 2358. The consequences of ACEI therapy are complex, multidimensional, and imperfectly understood. 1 The inhibition of the enzyme that converts the inactive decapeptide angiotensin-I into the potent pressor agent angiotensin-II has systemic and intrarenal consequences. Systemically, decreased

The effect of captopril or enalaprilic acid on the Na appetite of Na-deplete rats.

1. The converting enzyme inhibitors, captopril (SQ14 225, Squibb) or enalaprilic acid (MK 422, Merck Sharp and Dohme), were used to evaluate the role of angiotensin II in sodium (Na) appetite of Na-deplete rats given a choice of water and 0.5 mol/l NaCl to drink. Also, the effect of these drugs on taste was evaluated in water-deprived Na-replete rats and in Na-deplete rats given a choice of NaCl, sucrose and water. 2. Intraperitoneal (i.p.) injection of furosemide (20 mg/kg) increased urinary Na loss by 1.3-1.4 mmol and subsequent Na intake by 1.5-1.8 mmol. This increase in Na intake was abolished by a high dose of captopril (50 mg/kg, i.p.) or enalaprilic acid (80 mg/kg, i.p.), but was enhanced by a low dose of captopril (50 micrograms/kg, i.p.). 3. There was no clear evidence that either captopril or enalapril affected taste for NaCl, sucrose or water in water-deprived Na-replete rats. However, the high dose of captopril or enalapril decreased the intake of NaCl and sucrose in Na-deplete rats. 4. Thus, while the results are consistent with the possibility that angiotensin II is involved in Na appetite induced by Na depletion and that the difference between the high and low doses of converting enzyme inhibitors on Na appetite may be related to their relative effectiveness in blocking angiotensin I conversion at central sites, the observation that sucrose intake is decreased by high dose converting enzyme inhibitor in Na-deplete rats suggests that other actions of the converting enzyme inhibitors may be involved.

Angiotensin-Converting Enzyme Inhibitors

Radioinhibitor binding displacement, a new method for the measurement of angiotensin-converting enzyme (ACE) competitive inhibitors, has been used to assess the relative potency of nine synthetic ACE inhibitors. MK351A, tyrosyl derivative of enalaprilic acid was iodinated with 125I and used as the radioligand. [125I]MK351A bound to human serum ACE in a concentration-dependent manner. It was displaced in a concentration-dependent manner by all ACE inhibitors tested. Fifty percent displacement of bound [125I]MK351A (DD50) for each ACE inhibitor correlated well with inhibitor potency ID50, estimated using an ACE enzymatic activity assay using Hip-His-Leu as substrate (r = 0.96, p less than 0.001; n = 9). The radioinhibitor binding displacement assay was used to measure serum concentration of enalaprilic acid (MK422) in human serum samples. Drug concentration estimated by radioinhibitor binding displacement assay correlated closely (r = 0.96, p less than 0.001; n = 22) with the drug concentration measured by a specific radioimmunoassay. The radioinhibitor binding displacement technique using [125I]MK351A as the ligand for human serum ACE has general application to all competitive ACE inhibitors, allowing comparison of in vitro ACE inhibitor potencies and estimation of serum ACE inhibitor concentrations.

Measurement of angiotensin converting enzyme inhibitors in serum by radioinhibitor binding displacement assay

The principle of enzyme radioinhibitor binding displacement was developed to measure the concentration of angiotensin converting enzyme (ACE) inhibitors in rat serum. 125I MK351A, a tyrosyl derivative of enalaprilic acid, and a potent ACE inhibitor, bound in a concentration and time dependent manner to ACE. Binding of 125I MK351A to rat serum ACE was reduced in a concentration dependent manner in vitro by the ACE inhibitors MK521 (lisinopril), S9780, and Ro 31-3113-000 (Cilazapril diacid). This relationship was used to measure MK521 and S9780 in rat serum four hours after oral gavage with MK521, S9490-3 the prodrug ester of S9780, at 1, 2 and 4 mg/kg, or 1 2 hour after intraperitoneal injection of Ro 31-3113-000 (0.0125-0.7 mg kg ). Serum MK521 concentrations, estimated by radio inhibitor binding displacement, and radioimmunoassay, correlated well ( r = 0.94, N = 9, P < 0.001). Serum MK521, S9780 and Ro 31-3113-000 concentrations measured by radioinhibitor binding displacement assay were dose related, and inversely related to serum ACE enzymatic activity. The radioinhibitor binding displacement assay method using 125I MK351A as a ligand for ACE has application to the measurement of any competitive inhibitor of ACE.

Topical ocular hypotensive effects of the novel angiotensin converting enzyme inhibitor SCH 33861 in conscious rabbits.

SCH 33861 is a novel, non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor. Topical administration of the compound to the eye of conscious rabbits was employed to examine actions on intraocular pressure (IOP). Falls in IOP resulted from SCH 33861 (0.001-0.01%) administration. Ocular hypotensive responses were sustained for as long as 24 hrs following a single application of 0.001% SCH 33861. The RSS isomer of SCH 33861, which is 200-fold weaker an ACE inhibitor than SCH 33861, caused only transient falls in IOP at 0.1% concentration. The magnitude of the fall in IOP induced by 0.001% SCH 33861 (4.8 +/- 0.5 mmHg) was comparable to that produced by 0.5% timolol (4.5 +/- 0.3 mmHg). Other ACE inhibitors such as captopril (0.1%) and enalaprilic acid (0.01%) also reduced IOP by 4.0 +/- 0.4 and 4.7 +/- 0.4 mmHg, respectively. These findings indicate that SCH 33861 is 500-fold more potent on a weight basis than is timolol in lowering IOP. No loss of ocular hypotensive activity was observed when SCH 33861 was administered twice daily for 5 days suggesting little, if any, potential for tolerance development. SCH 33861, as well as the other ACE inhibitors, caused neither ocular irritation nor alteration of pupil diameter. These findings suggest that inhibition of ocular ACE may represent an effective means of reducing IOP.

Renal Blood Flow in Essential Hypertension

Renal blood flow is reduced in most patients with essential hypertension. Even in prehypertensive subjects, who may exhibit elevated flow rates through the kidney, renal vascular resistance is already enhanced. Although part of this abnormality is due to structural narrowing of the blood vessels, there is a considerable demonstrable functional component. In a series of investigations, we have studied the renal vascular response to dilatory stimuli. Intravenous saline loading increased renal perfusion but since this maneuver may have increased cardiac output, it is not certain that this reflects a local response only. In subsequent studies, we infused minute amounts of either a converting enzyme inhibitor (enalaprilic acid) or an α1-adrenoceptor antagonist (doxazosin) or an α2-adrenoceptor antagonist (yohimbine) into the renal artery of hypertensive subjects. All types of drugs increased renal blood flow, the effect of doxazosin being the smallest. The results suggest that both endogenous angiotensin II and the adrenergic system (mainly through activation of vascular α2-adrenoceptors) regulate renal vascular tone in essential hypertension.

Lisinopril in hypertensive patients with and without renal failure.

Lisinopril (MK521), a lysine analogue of enalaprilic acid, the bioactive metabolite of enalapril, has a longer half-life than enalaprilic acid, and is excreted unchanged in the urine. Its kinetic profile and antihypertensive and hormonal effects have been investigated in an open study in 3 groups each of 6 hypertensive patients, with normal, moderate and severe impairment of renal function. Serum drug level, blood pressure, converting enzyme activity (CEA), plasma renin activity (PRA), aldosterone concentration (PAC), and serum potassium and creatinine were measured during 1 week following a single oral dose and subsequently following 8 daily doses of 5 mg lisinopril. Accumulation of lisinopril was found in the severe renal failure group. CEA was suppressed to less than 10% of its initial value from 4 to 24 h after the initial dose in all three groups, and the suppression was more marked and lasted longer in patients with severe renal failure. An inverse correlation was found in all patients between log serum lisinopril concentration and log CEA. Lisinopril lowered blood pressure in all three groups over 24 h. PRA rose and PAC fell similarly in the groups. Serum potassium increased in the renal failure groups and creatinine remained unchanged in all groups. Thus, when lisinopril 5 mg is given daily to patients with severe renal failure it may accumulate. The high serum lisinopril concentration does not cause an excessive antihypertensive effect. In patients with severe renal failure, adjustment of the dose or the dosing frequency to the degree of renal failure is recommended to avoid administration of doses in excess of those required to achieve adequate inhibition of converting enzyme.

Onset of action of captopril, enalapril, enalaprilic acid and lisinopril in normal man.

The effects of orally administered captopril, enalapril and lisinopril on plasma concentrations of angiotensin converting enzyme (ACE), angiotensin II (ANGII) and renin (PRC) were studied over a period of 6 hours in 6 normal subjects. A further 4 subjects received intravenous enalapril and enalaprilic acid (enalaprilat). Captopril (25 mg) by mouth caused a fall in pANGII that reached a nadir 30 to 40 minutes after administration but an effect was hardly apparent after 6 hours. Enalapril (10 mg) by mouth had less marked effects on pACE and pANGII with a decline in levels first apparent 1 hour after administration and the lowest levels reached between 3 and 6 hours. Lisinopril (10 mg) produced a progressive fall in pACE and pANGII from 1 hour to reach the lowest values 6 hours after treatment. Intravenous enalaprilat (5 mg) produced an immediate sustained fall in both pACE and pANGII but intravenous enalapril (7 mg) had a biphasic inhibitory effect.

The acute haemodynamic effects of intravenous enalaprilic acid (MK422) in patients with left ventricular dysfunction.

Intravenous enalaprilic acid (2.5 mg) was given to 11 patients with stable cardiac failure (NYHA functional class II-IV). Reductions in mean right atrial, pulmonary artery and pulmonary capillary wedge pressure of 25%, 18% and 30% respectively (P less than 0.01), were observed. Cardiac output rose by 13% (NS) and mean blood pressure fell by 20% (P less than 0.01) with a decrease in systemic vascular resistance of 24% (P less than 0.01). Heart rate was unaltered. The haemodynamic effects correlated with control plasma renin activity (r = 0.78, P less than 0.01). Marked hypotension occurred in several subjects but no other side-effects were noted. The rapid onset of action and mixed venous and arteriolar dilating activity of intravenous enalaprilic acid may be an advantage in some clinical situations where parenteral vasodilating therapy is required.

The effect of converting enzyme inhibition on the enhanced proximal sodium reabsorption induced by chronic diuretic treatment in patients with essential hypertension.

During chronic chlorthalidone treatment of patients with essential hypertension, distal tubular sodium reabsorption is continuously inhibited. At the same time, sodium balance is maintained by an increase of the proximal tubular sodium reabsorption. In the present study, we investigated whether this increase is caused by a stimulated renin-angiotensin system (RAS). For this purpose, the renal effects of converting enzyme inhibition (CEI) were evaluated in 12 patients with essential hypertension who remained hypertensive despite chronic chlorthalidone treatment. After 6 weeks of chlorthalidone, an intravenous injection of 10 mg enalaprilic acid decreased the mean arterial pressure (MAP) from 110 to 102 mm Hg. The effective renal plasma flow (ERPF) increased. However, glomerular filtration rate (GFR) and the fractional excretions of sodium, lithium and free water did not change significantly. After 2 additional weeks of chlorthalidone combined with enalapril 20 mg b.i.d., MAP fell to 90 mm Hg, ERPF remained elevated and plasma aldosterone concentration decreased. As in the acute study, no significant changes were detected in the GFR and the fractional excretions of sodium, lithium or free water. Extracellular fluid volume was not diminished during these 2 weeks. Fractional proximal sodium reabsorption during chronic chlorthalidone therapy was higher when calculated from free water clearance (91%) than from the lithium clearance (71%), but neither of the two were affected by acute or chronic CEI. The results of this study suggest that during chronic diuretic treatment, maintenance of sodium balance by increased proximal reabsorption is not dependent on the stimulated RAS, or alternatively, that this function of the RAS is exactly counterbalanced by another effect of CEI, possibly by the fall in blood pressure.

Angiotensin converting enzyme (ACE), characterization by 125I-MK351A binding studies of plasma and tissue ACE during variation of salt status in the rat.

Angiotensin converting enzyme (ACE) was measured in rat plasma and tissues by analysis of the binding of the radio-inhibitor 125I-MK351A, a tyrosyl derivative of enalaprilic acid. Labelled 125I-MK351A bound to plasma and tissue ACE preparations and was displaced in a concentration-related manner by MK351A. Scatchard analysis yielded a single line from which MK351A binding sites/mg protein and MK351A dissociation constant were calculated. Tissue and plasma ACE from Sprague Dawley rats was studied over a wide range of sodium intakes (low salt, 0.026 +/- 0.012 mmol/24 h; normal salt, 0.58 +/- 0.09 mmol/24 h; and high salt, 10.4 +/- 1.3 mmol/24 h) and during high salt and DOCA treatment. Across the range of sodium states studied there were no consistent changes in plasma, lung, aorta, brain, epididymis or kidney MK351A binding sites/mg protein, or equilibrium dissociation constant. Calculated MK351A binding sites (nmol/mg protein) were 1.64 +/- 0.14 in lung, 0.47 +/- 0.04 in aorta, 0.44 +/- 0.05 in epididymis, 0.18 +/- 0.01 in brain and 0.053 +/- 0.004 in kidney preparations (n = 24 in each group) reflecting reported ACE enzymatic activity in these tissues. Equilibrium dissociation constant KD was uniform within each tissue, but varied between organs. The KD (mol/l X 10(-12)) was 50 +/- 2 in aorta, 57 +/- 2 in lung, 58 +/- 2 in epididymis, 61 +/- 3 in brain, 62 +/- 2 in plasma and 84 +/- 3 in kidney (n = 24 in each group).(ABSTRACT TRUNCATED AT 250 WORDS)