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Biomedical subjects

C S Sweet

Publications and source records attributed to C S Sweet.

At least 37 records · Page 2Linked to original sources
PubMed1992

Etiologic factors of recurrent abortion and subsequent reproductive performance of couples: have we made any progress in the past 10 years?

OBJECTIVES: We hypothesize that the diagnostic yield and pregnancy outcomes of patients with recurrent abortion have improved over the past 10 years. STUDY DESIGN: The study was performed in an academic medical center. Diagnoses and outcomes for group A, a published series of 100 patients investigated for recurrent abortion in the section between 1968 and 1977, was compared with those for group B, the 131 patients seen between 1987 and 1991. A standardized protocol was followed, enhanced by new techniques and autoimmune investigations in the latter group. Results were compiled retrospectively. Descriptive statistics and chi 2 analysis were used. RESULTS: No cause could be found in 37% of patients in group A compared with 24% of couples in group B (p less than 0.05). No clear difference could be shown in the subsequent outcomes of pregnancies. CONCLUSIONS: Our ability to establish a cause of recurrent abortion has improved slightly over the past 15 years. The gain is not yet reflected in successful pregnancy rates. Multicenter trials are indicated.

Abortion, Habitual↗
PubMed1992

In vivo pharmacology of L-158,809, a new highly potent and selective nonpeptide angiotensin II receptor antagonist.

L-158,809 (5,7-dimethyl-2-ethyl-3-[[2'-(1H-tetrazol-5yl)[1,1']-bi- phenyl-4-yl]-methyl]-3H-imidazo[4,5-b]pyridine) is a potent, competitive and specific antagonist of AT1 subtype of angiotensin II (AII) receptors in in vitro radioligand binding and functional isolated tissue assays. The present study was carried out to characterize the in vivo pharmacology of this potent AII receptor antagonist. In conscious, normotensive and anesthetized pithed rats, L-158,809 inhibits AII (0.1 microgram/kg i.v.) elevations in blood pressure without altering pressor responses to methoxamine or arginine vasopressin. In conscious rats, the relative potencies (ED50) were 29 micrograms/kg i.v. and 23 micrograms/kg p.o. Duration of action with single i.v. or p.o. doses exceeded 6 hr in rats. In similar experiments using rhesus monkeys, the potencies of L-158,809 were 10 micrograms/kg i.v. and approximately 100 micrograms/kg p.o. In these rats and monkeys, L-158,809 was 10 to 100 times more potent than DuP-753 (losartan) and approximately 3 times more potent than the metabolite, EXP3174. AII-induced elevation of plasma aldosterone in rats was also inhibited by L-158,809. Unlike angiotensin converting enzyme inhibitors, L-158,809 did not potentiate the hypotensive responses to i.v. bradykinin. L-158,809 was antihypertensive in high renin hypertensive rats (aortic coarction) and volume-depleted rhesus monkeys. The maximum hypotensive responses with acute doses of L-158,809 were equal to those with an angiotensin converting enzyme inhibitor in these renin-dependent animal models. From these in vivo data, L-158,809 is a selective AII receptor antagonist with high potency, good p.o. absorption, long duration and antihypertensive efficacy equal to angiotensin converting enzyme inhibition after single doses.

Administration, Oral↗
PubMed1990

Issues surrounding a local cardiac renin system and the beneficial actions of angiotensin-converting enzyme inhibitors in ischemic myocardium.

Several experimental in vitro and in vivo studies have shown that structurally diverse converting enzyme inhibitors improve contractile dysfunction, as well as reduce arrhythmia production and acute mortality after occlusion of the coronary artery. Biochemical data have demonstrated that some inhibitors of converting enzyme bind better to cardiac angiotensin-converting enzyme (ACE) than others; however, there has not been any demonstrated correlation between inhibition of the enzyme and improvement in cardiac physiology in the acutely dysfunctioning stunned myocardium. It is assumed that ACE inhibitors reduce tissue generation of angiotensin II; however, this relationship as well as peptide levels in coronary venous effluent need to be specifically measured. The multiple substrates of ACE necessitate further work to explore the role of bradykinin and prostacyclin, which have been implicated by some workers as contributing to the beneficial action of ACE inhibitors. A new question is whether sulfhydryl-containing ACE inhibitors are scavengers of toxic free radicals. Captopril, e.g., has been shown to be a free radical scavenger in superoxide-generating systems. Further work is required; however, as one report has recently shown, captopril does not directly scavenge superoxide but acts indirectly as an antioxidant or by altering the concentration of cytochrome c.

Angiotensin II↗
PubMed1989

Cardiac and noncardiac atrial natriuretic factor (ANF) biosynthesis and storage and plasma ANF in the rat model of chronic ventricular dysfunction.

To evaluate the role of atrial natriuretic factor (ANF) in chronic heart failure (HF), the biosynthesis and storage of ANF in cardiac and noncardiac tissues and the level of plasma ANF were measured in rats exhibiting minimal [2-fold rise in left ventricular end diastolic pressure; myocardial infarct (MI) scar length, 25% left ventricle (LV)] and moderate-severe (3-fold rise in left ventricular end diastolic pressure; decreased contractility (dp/dtmax); MI scar length, 47% LV) chronic HF 30 and 60 days after coronary arterial ligation. In rats with moderate-severe HF (30 days post-MI), the cardiac ANF mRNA concentration (determined by dot blot analysis) increased in three heart chambers [LV, 6-fold; left atria (LA), 3-fold; right ventricle (RV), 2-fold], cardiac immunoreactive ANF (IRANF; determined by RIA) concentration increased on the left side (LV, 7-fold; LA, 33%), but was unchanged (RV) or reduced on the right side (right atria, 33%), and plasma IRANF increased 3-fold above sham control values. Excluding the LV (used for MI scar length), the pattern and magnitude of change in ANF mRNA concentration in moderate-severe HF at 60 days were similar to those at 30 days; the cardiac IRANF concentration at this time was the same (LA) or less than (RV, 66%) sham values, and plasma IRANF increased 6-fold above respective sham values. Generally, the changes in the concentrations of cardiac ANF message and peptide and levels of circulating ANF peptide were smaller in rats with minimal HF. The minute quantities of ANF mRNA and IRANF detected in noncardiac tissues (lung, liver, pituitary, aortic arch, brain, kidney, and salivary gland) were unaltered by HF. These findings show that chronic HF, as defined by hemodynamic and histological measurements, specifically and continuously stimulates atrial as well as ventricular ANF biosynthesis; levels of plasma and cardiac ANF are increased early in HF, but with time are subject to modulation. The cardiac ANF system is the prime locus for the effects of HF, as noncardiac ANF biosynthesis and storage are undisturbed by chronic HF.

Animals↗
PubMed1988

Beneficial effects of milrinone and enalapril on long-term survival of rats with healed myocardial infarction.

The long-term survival of rats with healed myocardial infarction and congestive heart failure treated with milrinone, enalapril and the combination of milrinone plus enalapril, was documented. Seven days after sham or coronary ligation, 200 rats (99 sham and 101 myocardial infarcted) were randomized based on electrocardiographic criteria to receive tap water, milrinone (20-40 mg/l drinking water), enalapril (17-25 mg/l) or the combination of milrinone plus enalapril (20-40 mg/17-25 mg per l). The date of spontaneous death was recorded and heart weights and myocardial infarct size (by planimetry) were determined. Long-term enalapril therapy prolonged survival with a median 50% survival (MS50) of 233 days compared to 203 days in the tap water group. Milrinone therapy also prolonged survival with a MS50 of 297 days. The combination therapy prolonged survival with a MS50 of 277 days. In general, there were three times as many rats alive in the treatment groups at the end of one year compared to untreated control groups. Cardiac hypertrophy was evident in all myocardial infarcted groups and heart weights were significantly reduced by all treatments. The average myocardial infarct sizes and the distribution of infarct sizes were not different between groups (36.8-43% of left ventricle). This study demonstrates that long-term therapy with enalapril and milrinone prolongs survival in rats with healed myocardial infarctions. The prolongation of survival was comparable in the milrinone plus enalapril groups, indicating that there was no synergy with these two agents with survival as the end point.

Animals↗
PubMed1987

Cardiac and hemodynamic responses to synthetic atrial natriuretic factor in rats.

To determine the hemodynamic effects of a hypotensive dose of atrial natriuretic factor (ANF), a synthetic peptide containing 26 amino acids of endogenous rat ANF (Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly -Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr-COOH) was studied in two groups of barbiturate anesthetized rats. In the first experiment, a 20-minute infusion of a hypotensive dose, 95 pmole/min i.v., of the synthetic ANF decreased mean arterial pressure (MAP) by 40 +/- 3 mm Hg from a baseline of 128 +/- 5 mm Hg, and cardiac output (CO) (microsphere method) by 7.8 +/- 1.8 ml/min/100 gm from a baseline of 23.5 +/- 1.3 ml/min/100 gm. Synthetic ANF did not significantly affect the total peripheral resistance (TPR) measured at the end of the 20-minute infusion. Sodium nitroprusside (SNP), infused at an equihypotensive dose of 20 micrograms/kg/min i.v., produced the same hemodynamic profile in seven other animals; in contrast, 0.3 mg/kg i.v. of hydralazine (n = 7) lowered MAP by 56 +/- 6 mm Hg and reduced TPR index by 3.0 +/- 0.6 mm Hg/ml/min/100 gm, but did not change CO. Other than an increase in coronary blood during SNF infusion, there were no significant changes in the distribution of cardiac output. Infusion of the saline vehicle had no significant effects on any of these parameters. The results of the second experiment in anesthetized rats confirmed that hypotensive doses of 40 and 100 pmole/kg/min i.v. lowered CO (dye dilution method) from a baseline of 33 +/- 6 to a minimum of 24 +/- 2 ml/min/100 gm (p less than 0.05) without affecting TPR. In addition, synthetic ANF did not significantly affect heart rate (HR) but it slightly reduced cardiac contractility (dp/dt50). These results suggest that the hypotensive dose of synthetic ANF reduced cardiac output, partially by diminishing stroke volume, and perhaps contractility.

Animals↗
PubMed1987

Measurement of cardiac output in anesthetized rats by dye dilution using a fiberoptic catheter.

A method is described for the measurement of cardiac output and oxygen saturation in closed-chest rats using a small (2.4 F) commercially available fiberoptic catheter and a reflection-spectral-photometer. Positioned in the aortic arch, the catheter functions as an oxymeter for oxygen saturation and as a densitometer for measurement of indocyanine green, obviating the need for blood removal and passage through a densitometer. The sensitivity and reproducibility of this method were characterized in 90 rats by thermodilution, radiolabeled microspheres, and electromagnetic flow methods as standard references. Basal cardiac output as well as changes in cardiac output during isoproterenol infusion and blood removal and replacement were measured. In addition, multiple measurements of cardiac output over 1 min were used to document the method's suitability in constructing a ventricular function curve. With the fiberoptic catheter, cardiac output varied predictably with anesthesia, with rats on dial-urethane (n = 23) having values of 150 +/- 39 (SD) ml/min/kg and 2 and 1% enflurane (18-35 rats per group) yielding cardiac outputs of 190 +/- 60 and 236 +/- 77 ml/min/kg, respectively. Pentobarbital produced the least cardiovascular depression (n = 15) with an average cardiac output of 322 +/- 22 ml/min/kg. The average cardiac output with this method in 90 rats (regardless of anesthesia) was 214 +/- 91 (SD). This value was comparable to cardiac output values determined in paired experiments from radiolabeled microspheres (9 rats) 220 +/- 43, electromagnetic flow (11 rats) 177 +/- 33, and a subset of rats with thermodilution (231 +/- 45 ml/min/kg). The within measurement (repeat measurements) variability with the fiberoptic method was consistently less than the rat-to-rat variability when compared to the thermal and radiolabeled microsphere methods, but it was comparable to electromagnetic flow. The method can be used when rapid measurements (4 measurements within 60 s) of cardiac output are required, as in constructing a ventricular function curve, and can readily detect small changes in cardiac output during controlled hemorrhage and isoproterenol infusion. In summary, this method gives measurement of oxygen saturation and cardiac output by dye dilution without blood removal. There is less surgical preparation than required for electromagnetic cardiac output, and it is an alternative to the thermodilution method.

Animals↗
PubMed1987

Increased survival in rats with congestive heart failure treated with enalapril.

Vasodilating drugs such as angiotensin converting enzyme (ACE) inhibitors may extend life expectancy in patients with congestive heart failure (CHF). The purpose of this study was to evaluate whether long-term therapy (365 days) with enalapril (ENAL, an ACE inhibitor), would prolong life in rats with a healed myocardial infarction (MI), an experimental model with hemodynamic characteristics of CHF. Seven days after sham or coronary ligation, when the healing phase of MI was well underway, 132 rats (75 sham, 57 MI) were randomized to receive either enalapril in the drinking water (17-25 mg/L, approximately 1.0 mg/kg/day) or tap water. The date of spontaneous death was recorded, and heart weight and MI size (by planimetry) were determined. Serum ENAL, total ACE concentration, and angiotensin and methoxamine pressor responses were quantified in 12 survivors. Long-term enalapril prolonged survival (p = 0.014) with a median 50% survival of 164 (164-165) days, compared to 84 (64-104) days in rats receiving tap water. There were twice as many MI rats alive at the end of one year on angiotensin converting enzyme inhibition (ACEI) therapy as compared to the untreated group. The average MI size (39-40%) was not different between groups, and there was a significant inverse correlation between date of death and MI size (r = 0.7-0.8) in both treatment groups. Cardiac hypertrophy was evident in all MI rats. Serum ENAL levels, after one year, were at the clinically relevant concentration (2.3 ng/ml) and total serum ACE (inhibitor removed) doubled to 4,300 nmol/h/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Acute and subacute hemodynamic effects of enalaprilat, milrinone and combination therapy in rats with chronic left ventricular dysfunction.

A model of congestive heart failure (CHF) was produced in rats approximately 76 days following surgical occlusion of the left coronary artery. In rats with healed myocardial infarction (MI size = 45% LV), hemodynamic variables were predictably elevated (LVEDP greater than 20 mm Hg) or depressed LV dP/dtmax (5200 mm Hg/sec). The hemodynamic response (MAP, HR, LVEDP, and dP/dtmax) to intravenous infusion of Mil (54 to 347 micrograms/kg) was measured on two occasions, separated by a 7-12 day period of oral treatment (2 mg/kg/day). Enalaprilat was tested in a similar design with the infusion phase (70 micrograms/kg, total dose) separated by oral enalapril (Enal), 1 mg/kg/day. The hemodynamic response to Mil was also examined in rats treated with the ACE inhibitor. At low doses, Mil modestly elevated HR (+17 beats/min) and dose-dependently increased (P less than 0.05) LV contractility by approximately 25%. Higher doses of Mil reduced preload (LVEDP) and afterload (MAP). Oral Mil produced little hemodynamic improvement except modest elevation (+9%) in LV contractility. There was no evidence of tachyphylaxis to i.v. Mil. In contrast, enalaprilat reduced MAP and preload without altering HR or contractility, effects observed after oral treatment. In the presence of the ACE inhibitor, Mil's hemodynamic actions were not enhanced. These experiments demonstrate that ACE inhibition improves ventricular performance by reducing preload and afterload. In this model, Mil improves performance by a direct inotropic mechanism as well as a reduction in afterload.

Animals↗
PubMed1986

Beta 1-selective adrenoceptor antagonists: examples of the 2-[4-[3-(substituted amino)-2-hydroxypropoxy]phenyl]imidazole class. 2.

An attempt to develop a highly cardioselective beta-adrenoceptor antagonist devoid of intrinsic sympathomimetic activity (ISA) focused on exploring structure-activity relationships around (S)-[p-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy] phenyl]-4-(2-thienyl)imidazole. Strategies to reduce or eliminate ISA centered on structural changes that could influence activation of the receptor by the drug itself or by a metabolite. The approaches involved (a) eliminating the acidic imidazole N-H proton, (b) incorporating substituents ortho to the beta-adrenergic blocking side chain, (c) increasing steric bulk around the N-H moiety, (d) decreasing lipophilicity, (e) introducing intramolecular hydrogen bonding involving the imidazole N-H, and (f) displacing the imidazole ring from an activating position by the incorporation of a spacer element. The compounds were investigated in vitro for beta-adrenoceptor antagonism and in vivo for ISA. From these studies, the most successful variation involved the insertion of a spacer between the imidazole and aryl rings. (S)-4-Acetyl-2-[[4-[3-[[2-(3, 4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]phenyl]methyl] imidazole (S-51) was demonstrated to be highly cardioselective (dose ratio beta 2/beta 1 greater than 9333) and devoid of ISA.

Adrenergic beta-Antagonists↗
PubMed1986

Enalapril in experimental hypertension and acute heart failure: comparison with calcium channel blockers.

The hemodynamic effects of enalaprilat (MK-422) and lisinopril (MK-521) were compared with the calcium channel blocker felodipine in dogs with ischemic left ventricular (LV) failure. The combination of nitrendipine plus enalapril was also examined in ischemic failure and in rats with spontaneous hypertension. In anesthetized dogs coronary embolization with 50 micron plastic microspheres reduced cardiac output and LV dP/dt max by approximately 40%, and LV end-diastolic pressure increased to greater than 13 mm Hg. Enalaprilat and lisinopril reduced mean arterial pressure by a maximum of 20 mm Hg and total peripheral resistance by approximately 30%. Left ventricular dP/dt:LVP, which was substantially decreased by embolization, was slightly increased by both angiotensin converting enzyme (ACE) inhibitors. The calcium entry blockers felodipine and nitrendipine qualitatively produced many of the same hemodynamic effects as the ACE inhibitors, but, in addition, they markedly reduced coronary resistance, increased myocardial blood flow, and did not alter cardiac contractility (LV dP/dt max). In spontaneously hypertensive rats single doses of nitrendipine (1.25 to 5.0 mg/kg per os) and enalapril (0.3 and 3.0 mg/kg per os) reduced mean arterial pressure, but differences were observed in the onset (enalapril 2 h versus nitrendipine 0.5 h), the duration of action, and magnitude of effect. In terms of blood pressure lowering, nitrendipine, 5.0 mg/kg per os, was clearly additive to 3.0 mg/kg per os of enalapril, but other combinations (enalapril, 3 mg/kg per os plus 0.625 mg/kg of nitrendipine or enalapril, 0.3 mg/kg per os plus 0.625 mg/kg nitrendipine) were not.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1985

A structurally novel stimulator of guanylate cyclase with long-lasting hypotensive activity in the dog.

Studies were undertaken to characterize the activity of diphenyliodonium hexafluorophosphate (DIFP) as a structurally novel stimulator of soluble guanylate cyclase from rat lung and make comparisons to the activity of sodium nitroprusside (SNP). In addition, the effects of these two compounds on several cardiovascular parameters in anesthetized dogs were determined. DIFP stimulated guanylate cyclase activity within the same concentration range (10-300 microM) as SNP, causing a maximal 2-3-fold activation. The activities of both SNP and DIFP were dependent on the presence of dithiothreitol and inhibited by methylene blue. In anesthetized dogs, DIFP (i.v.) elicited a dose-related, long-lasting fall (greater than 3 h) in mean arterial pressure (MAP) which was accompanied by a reduction in total peripheral resistance and a transient rise in cardiac output. These effects on MAP were similar to those of SNP except they were of a much longer duration. In addition, both SNP and DIFP produced slight bradycardia and reduced negative dP/dt. These results suggest that DIFP and SNP, while structurally dissimilar, activate guanylate cyclase by a related mechanism which may be involved in vascular relaxation leading to reduced blood pressure.

Animals↗
PubMed1985

Hemodynamic effects of synthetic atrial natriuretic factor (ANF) in dogs with acute left ventricular failure.

The hemodynamic and renal electrolyte/function effects of a synthetic peptide (ANF) corresponding to the sequence of the 26 amino acids contained in atrial natriuretic factor (ANF) were assessed in closed-chest dogs in which acute left ventricular failure was produced by coronary artery embolization with 50 micron plastic microspheres. Coronary embolization produced a sustained reduction in cardiac contractility (LV dP/dtmax) and cardiac output which averaged 42 and 44%, respectively. Following a 45 min equilibration period after heart failure induction, most of the hemodynamic functions stabilized. At this time, ANF infused intravenously at 100 pmol/kg per min X 30 min (n = 9) did not lower mean arterial pressure although it increased cardiac output (P less than 0.05) by 17% at only one time period. With the exception of a fall in coronary resistance and an increase in myocardial blood flow, a higher dose of ANF (200 pmol/kg per min) did not consistently alter hemodynamic function. Fractional excretion of sodium (FE Na%) increased 3.4-fold with ANF at 100 pmol/kg per min and 1.8-fold with the 200 pmol/kg per min dose. Neither dose of ANF produced significant effects on renal blood flow (RBF) or glomerular filtration rate (GFR). Plasma angiotensin II which was 91 +/- 20 fmol/ml at baseline increased to 175 +/- 25 fmol/ml (P less than 0.05) 45 min after heart failure induction. However, neither dose of ANF significantly reduced these high circulating angiotensin II levels. These results demonstrate that an infusion of a synthetic ANF stimulated saluresis without altering RBF or GFR, and improved cardiac output in dogs with acute left ventricular failure.

Angiotensin II↗
PubMed1984

Hemodynamic effects of angiotensin and renin inhibition in dogs with acute left ventricular failure.

The effects of enalaprilat (MK-422), an angiotensin converting enzyme inhibitor, were compared to those of SCRIP, a renin inhibitor, in experimentally induced left ventricular failure. In anesthetized dogs, acute left ventricular failure was induced by repeated embolization, via the left main coronary artery, with 50 microns plastic microspheres. Embolization significantly increased left ventricular enddiastolic pressure from 6 +/- 1 to 14 +/- 1 (p less than 0.05) mm Hg and decreased both left ventricular maximal dP/dt (3,135 +/- 338 to 1,636 +/- 126 mm Hg/second, p less than 0.05) and cardiac output (3.0 +/- 0.3 to 1.6 +/- 0.1 liters per minute, p less than 0.05). Embolization also significantly reduced heart rate and mean arterial pressure. These parameters remained stable after induction of heart failure. Forty-five minutes after embolization, 16 dogs received enalaprilat (100 microns/kg intravenously) and six dogs received SCRIP (100 microns/kg intravenously followed by 10 microns/kg per minute). Both agents caused similar reductions in left ventricular end-diastolic pressure (21 percent versus 26 percent) and total peripheral resistance (25 percent versus 32 percent) and rise in peak positive cardiac contractility, as measured by (dP/dt)/P, (12 percent versus 11 percent). The data suggest that inhibition of angiotensin II formation by two agents, each or which acts at a different point in the cascade, results in similar beneficial hemodynamic effects in dogs with acute left ventricular failure. In addition, angiotensin converting enzyme inhibition failed to further increase sodium excretion and glomerular filtration rate caused by embolization. In summary, inhibition of angiotensin II production by two different inhibitors of the renin system causes an improvement in left ventricular performance in a model of acute experimental left ventricular failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

3-Hydroxy-alpha-methyltyrosine progenitors: synthesis and evaluation of some (2-oxo-1,3-dioxol-4-yl)methyl esters.

The (5-methyl-2-oxo-1,3- dioxol -4-yl)methyl and (5-tert-butyl-2-oxo-1, 3- dioxol -4-yl)methyl esters of 3-hydroxy-alpha-methyltyrosine (methyldopa) were prepared and evaluated as progenitors of the amino acid. 1H NMR experiments reveal that the esters are converted cleanly to methyldopa and the corresponding alpha-diketone at pH 7.4, with the 5-methyl derivative undergoing hydrolysis faster than the 5-tert-butyl analogue. Bioavailability studies in dogs show that the esters, particularly the 5-methyl derivative, yield significant plasma levels of methyldopa. Both esters are orally effective antihypertensive agents in spontaneously hypertensive (SH) rats. These studies indicate that (2-oxo-1,3- dioxol -4-yl)methyl esters are viable prodrugs for the latentiation of methyldopa.

Animals↗
PubMed1984

Comparative effects of enalapril, enalaprilic acid and captopril in blocking angiotensin I-induced pressor and dipsogenic responses in spontaneously hypertensive rats.

The role of central angiotensin converting enzyme (ACE), in the maintenance of high blood pressure, was examined in unanesthetized spontaneously hypertensive rats (SHR). Pressor and dipsogenic responses induced by intracerebroventricular (ICV) injections of angiotensin I (AI) were elicited before and 30 min after either captopril (120-800 nanomoles ICV), enalapril (66-460 nanomoles ICV) and enalaprilic acid (70-280 nanomoles ICV). Enalapril was 1.6 (0.7-3.9) and 1.7 (0.9-2.9) times more potent than captopril in inhibiting AI-induced pressor and dipsogenic responses, respectively. Enalaprilic acid was 2.7 (1.1-7.1) and 2.9 (1.9-4.8) times more potent than captopril in inhibiting AI- (ICV administration) induced pressor and dipsogenic responses, respectively. None of the ACE inhibitors, in contrast, reduced the central actions of AII. Basal mean arterial pressure was not reduced by these ACE inhibitors after ICV administration. Administered orally at doses which produced similar hypotensive responses, neither captopril (30 mg/kg) nor enalapril (3 mg/kg) blocked the responses induced by AI given ICV (10 ng). These findings indicate that ACE inhibitors given acutely do not penetrate into the central nervous system sufficiently to block the dipsogenic and pressor responses induced by AI given ICV, and suggest that inhibition of central ACE may not be important to the acute antihypertensive activity of the ACE inhibitors tested.

Angiotensin I↗