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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alacepril (1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine, DU-1219) showed a dose related and long lasting antihypertensive effect in renal hypertensive rats (two-kidney, one-clip), a typical renin dependent hypertensive model. The maximum hypotensive potency of alacepril (1-30 mg/kg) after single oral administration was slightly weaker than that of captopril (1-30 mg/kg). Judging from the AOC (area over the antihypertensive curve) value, the overall antihypertensive activity of alacepril was 3 times more potent than that of captopril on a weight basis. The long lasting antihypertensive effect of alacepril in renal hypertensive rats was also confirmed by once daily successive oral administration (1-2 mg/kg/d). In renal hypertensive dogs, alacepril (3 mg/kg) showed a stable and sustained hypotensive effect, and its duration of action was longer than that of captopril. Although alacepril did not possess a significant in vitro angiotensin converting enzyme (ACE) inhibitory activity, orally given alacepril (5.6-56.1 mg/kg) produced a potent and prolonged in vivo ACE inhibition which was estimated by suppression on angiotensin-I (310 ng/kg i.v.) induced pressor response in conscious normotensive rats. The prolonged in vivo ACE inhibitory activity of alacepril (5.6 mg/kg) was also observed in conscious normotensive dogs. These results suggest that the disposition and metabolism of orally given alacepril are responsible for the prolonged ACE inhibition and, concomitantly, for exerting the long lasting antihypertensive effect. Consequently, alacepril is a novel orally active ACE inhibitor having a potent and prolonged antihypertensive activity, and these properties suggest that alacepril is favorable for the treatment of hypertension.
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PMID:Antihypertensive activity of alacepril, an orally active angiotensin converting enzyme inhibitor, in renal hypertensive rats and dogs. 300 Mar 89

Extracts of mammalian atria, but not ventricles, induce marked diuresis, natriuresis, and reduction in blood pressure when infused systemically in rats and dogs. These extracts also inhibit aldosterone biosynthesis and renal renin release. Natriuretic peptides, 21 amino acids and longer, have been isolated from atria of rodents and man, and share a nearly homologous amino acid sequence at the carboxyterminus. Natriuretic activity resides in a 17-amino acid ring formed by a disulfide bridge, and the C-terminal Phe-Arg appears necessary for full biological potency. The deoxyribonucleic acid-encoding atrial natriuretic peptides have been cloned and the gene structure elucidated. Reduction of the diuretic and natriuretic responses to an acute volume load by right atrial appendectomy first suggested a role for atrial peptides in the physiological response to plasma volume expansion. Subsequently, release of peptides with natriuretic and spasmolytic properties from isolated heart preparations in response to right atrial distension was demonstrated by bioassay and radioimmunoassay. The presence of these peptides in normal rat and human plasma in concentrations of 20-100 pM, and the findings of increased levels in response to acute and chronic plasma volume expansion, rapid atrial tachyarrhythmias, systemic hypertension, congestive heart failure, and renal insufficiency imply that they play an important role in body fluid homeostasis. The mechanisms by which atrial peptides increase renal salt and water excretion are as yet unclear. Renal vascular effects have been consistently demonstrated, and limited evidence for direct actions on tubule ion transport has also been reported recently. In vitro, these peptides cause precontracted vascular and nonvascular smooth muscle to relax, mediated by a direct action on smooth muscle cells. Specific receptors for these peptides have been characterized in crude membranes prepared from whole kidney homogenates and adrenal glomerulosa cells, in intact glomeruli and cultured glomerular mesangial cells, and in intact bovine aortic smooth muscle and endothelial cells. Natriuretic peptides stimulate cyclic guanosine monophosphate accumulation in target tissues, and augment particulate guanylate cyclase activity in membrane fractions, suggesting that cyclic guanosine monophosphate is the second messenger mediating their cellular action.
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PMID:George E. Brown memorial lecture. Role of atrial peptides in body fluid homeostasis. 301 7

The binding of tritiated ligands for various opiate receptor subtypes to brain membranes prepared from spontaneously hypertensive rats and normotensive Wistar-Kyoto rats was determined. The density (Bmax) or the apparent dissociation constant (Kd) for the binding of the mu-ligand (naltrexone) and delta-ligand (Tyr-D-Ser-Gly-Phe-Leu-Thr) to brain membranes of hypertensive and normotensive rats did not differ. However, the Bmax for the binding of kappa-ligand (ethylketocyclazocine, EKC) to brain membranes after the suppression of mu and delta-sites by 100 nM each of unlabeled D-Ala2-MePhe4-Gly-ol5-enkephalin and D-Ala2-D-Leu5-enkephalin, respectively, was significantly greater in hypertensive rats compared to normotensive rats. The Kd values for the binding of 3H-EKC in the two groups did not differ. The binding of 3H-EKC in brain regions was in the order: hypothalamus greater than midbrain greater than striatum greater than cortex greater than pons + medulla. The increase in the binding of 3H-EKC in the brain of hypertensive rats compared to normotensive rats was due to increased binding in the hypothalamus and cortex. These results provide for the first time evidence of selective proliferation of kappa-opiate receptors in the brain of hypertensive rats, and suggest that brain kappa-opiate receptors may play an important role in the pathophysiology of hypertension.
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PMID:Selective proliferation of brain kappa opiate receptors in spontaneously hypertensive rats. 302 39

Because several well-studied strains of rats manifest spontaneous hypertension, we set out to design a renin inhibitor suitable for use in this species. On the basis of the sequence of the renin substrate, a series of substrate analogue inhibitory peptides were synthesized by systematically modifying the P5, P3, P2, P1P1', P2', P3', and P4' positions. In assays against rat plasma renin, we found that modifications at the C-terminal segment have a marked influence on potency, and that a secondary butyl side chain at the P2' position is important for obtaining optimal activity. The structure at the P3' position, however, could vary considerably without significant effect. The steric effect of the P2 position was important; there an isopropyl side chain provided optimal binding between the inhibitor and the enzyme. At the P3 and P5 positions, potency appeared to depend on aromatic side chains. The effects at the P1P1' position of the transition-state residue (3S,4S)-4-amino-3-hydroxy -6-methylheptanoic acid (statine) and its congeners (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA) and (3S,4S)-4-amino-3-hydroxy-5-cyclohexylpentanoic acid (ACHPA) were found to depend on the sequence of the C-terminal segment. For peptides with an unfavorable C-terminal segment (-Ile-Phe-NH2), AHPPA and ACHPA resulted in a surprising retention of potency. For peptides with a favorable C-terminal segment (-Leu-Phe-NH2), the effect of AHPPA was mild, even though ACHPA still significantly enhanced potency. The hypotensive and plasma renin inhibitory effects of three of the analogues were then studied in anesthetized sodium-depleted rats. One of the compounds, acetyl-His-Pro-Phe-Val-Statine-Leu-Phe-NH2 (IC50 against rat plasma renin of 30 nM at pH 7.4), proved to be a potent hypotensive agent and a potentially useful probe for the study of the renin-angiotensin system in rats.
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PMID:Design of rat renin inhibitory peptides. 304 20

To determine precisely the influence of high blood pressure and age on the baroreflex sensitivity (BRS), we measured it in conscious genetically hypertensive (LH), normotensive (LN) and low-blood pressure (LL) rats of the Lyon strains. Groups of male rats were studied at the age of 5, 9, 13, 21 and 40 weeks. Using our previously described technique, their blood pressure (BP) and heart period (HP) were recorded beat by beat, in the conscious unrestrained state. Each animal received 2 or 3 i.v. injections of phenylephrine (PHE, 5 micrograms/kg) and nitroglycerin (NG, 100 micrograms/kg). The BRS (msec/mmHg) was computed as the slope of the closest relationship found between systolic BP (SBP) and HP changes. Otherwise, in the 13-week-old rats, BRS had been measured in basal conditions, after vagal blockade (atropine: 2 mg/kg i.v.) and after beta-adrenergic blockade (propranolol: 2 mg/kg) so as to determine the relative importance of vagal and sympathetic components of the baroreflex. In LN and LL rats, the BRS measured with PHE and NG increased markedly between 5 and 9 weeks of age and then remained stable in LN rats or decreased between 21 and 40 weeks of age in LL rats. In LH rats, BRS remained stable between 5 and 9 weeks of age and increased slightly up to 21 weeks of age. Significant differences between LH and LN rats were observed starting from 9 weeks of age when BRS was measured with PHE and only at 9 weeks of age when it was measured with NG injections. In 13-week-old rats, the cardiac baroreflex response was estimated to depend for 82 p. 100 and 18 p. 100 upon vagal and sympathetic components respectively when BRS was measured with PHE injections and of 68 p. 100 and 32 p. 100 when it was measured with NG injections.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Sensitivity of the cardiac baroreflex in genetically hypertensive rats of a Lyons strain]. 311 93

Mammalian atria have previously been shown to produce a variety of peptides with natriuretic and vasorelaxant activities. Certain of these atrial natriuretic factors (ANF) have been localized immunocytochemically in secretory granules of atrial myocytes. However, the precise sites of action and extra-atrial synthesis or accumulation of ANF have not been identified immunocytochemically. In the present study, immunoreactive ANF was detected in rat atrial myocytes, intercalated cells of the renal collecting ducts, adrenal medullary chromaffin cells, and gonadotrophs of the anterior pituitary using an antibody against synthetic rat ANF-IV (H2N-Arg-Ser-Ser-Cys-Phe-Gly- Gly-Arg-Ile-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly-Leu-Gly-Cys-Asn-Ser-Phe- Arg-Try-COOH). The localization of ANF in specialized cells of the renal collecting tubules and ducts supports suggestions that these structures may be a site of natriuretic action of ANF. In addition, immunocytochemical localization of ANF in the rat adrenal medulla and anterior pituitary suggests the existence of alternate sites of action and/or synthesis. We believe these findings are important for a more complete understanding of the role of ANF in fluid and sodium regulation and of the participation of ANF in the development of sodium-dependent hypertension.
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PMID:Immunocytochemical localization of atrial natriuretic factor in the kidney, adrenal medulla, pituitary, and atrium of rat. 316 Jul 63

A potent renin inhibitor, U-71038 (Boc-Pro-Phe-N-MeHis-Leu psi[CHOHCH2]Val-Ile-Amp), was tested for oral effectiveness. Enzyme kinetic studies indicated that U-71038 was a competitive inhibitor of hog renin with an inhibitor constant (Ki) value of 12 nM. Intravenous as well as oral administration of U-71038 to anesthetized, ganglion-blocked rats infused with hog renin elicited dose-related hypotensive responses. Intravenous administration of U-71038 to conscious, sodium-depleted monkeys caused dose-related decreases of blood pressure and plasma renin activity without affecting heart rate. Similarly, the oral administration of U-71038 at 50 mg/kg to conscious, sodium-depleted monkeys elicited a pronounced hypotension and decrease in plasma renin activity that persisted for 5 hours. The hypotensive responses elicited by intravenous and oral administration of U-71038 to hog renin-infused rats and sodium-depleted monkeys were shown to be due entirely to inhibition of the renin-angiotensin system. A comparison of the results obtained after the intravenous administration of U-71038 with the results obtained after the oral administration of U-71038 implied that at least 10% of the orally administered U-71038 must have been absorbed to cause the observed effects in hog renin-infused rats and sodium-depleted monkeys. The studies demonstrated that an inhibitor of renin with a long duration of action and with oral effectiveness is a feasible entity.
Hypertension 1986 Dec
PMID:An orally active inhibitor of renin. 353 93

The purpose of these experiments was to investigate whether the vasodilator tissue hormone bradykinin contributes to the maintenance of normal blood pressure. A newly synthesized peptide competitive antagonist of bradykinin, the compound Arg-Pro-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg-trifluoracetic acid (B3852), capable of inhibiting the depressor effect of exogenous bradykinin by over 50%, was infused into 10 normotensive rats at a rate of 500 micrograms/0.1 ml/min. Blood pressure rose immediately, from a baseline of 104 +/- 5 to 131 +/- 7 mm Hg at the end of a 5-minute infusion, and returned to baseline within 2 to 3 minutes after discontinuation of the infusion. When similar doses were administered by continuous infusion to previously nephrectomized rats (n = 5) or as an acute bolus to adrenalectomized rats (n = 5), blood pressure rose from 111 +/- 3 to 125 +/- 5 mm Hg and from 112 +/- 4 to 128 +/- 5 mm Hg, respectively. The data suggest that a vasodepressor action of endogenous bradykinin contributes to maintenance of normal peripheral vascular tone, and that this action is not mediated through adrenal catecholamines or renomedullary prostaglandins.
Hypertension 1987 Jun
PMID:Contribution of bradykinin to maintenance of normal blood pressure. 359 81

Inhibition of renin was induced in conscious marmosets with CGP 29 287, Z-Arg-Arg-Pro-Phe-His-Sta-Ile-His-Lys (Boc)-OMe, a renin inhibitor with a prolonged duration of action. In vitro, CGP 29 287 is a potent inhibitor of primate plasma renin (inhibitory concentration, 50%: human = 1 X 10(-9) M; marmoset = 5 X 10(-9) M) and less potent against dog (2 X 10(-7) M) or rat (3 X 10(-5) M) plasma renin. CGP 29 287 is a weak inhibitor of other aspartic proteases such as porcine pepsin or bovine cathepsin D (inhibitory concentration, 50% = 4 X 10(-5) M). In furosemide-treated marmosets, CGP 29 287 lowered blood pressure and inhibited plasma renin activity during intravenous infusion and after intravenous bolus injection. The duration of action after intravenous injection was dose dependent and ranged from 1 hour after 0.1 mg/kg to more than 3 hours after 10 mg/kg. High doses of CGP 29 287 (100 mg/kg) were active after oral administration. In all experiments a close relation between inhibition of plasma renin activity and reduction of blood pressure was found. A maximum hypotensive response to CGP 29 287 was associated with complete inhibition of plasma renin activity, and the recovery of blood pressure was accompanied by recovery of plasma renin activity. The hypotensive effects of CGP 29 287 were smaller in untreated than in furosemide-treated marmosets. CGP 29 287 had no influence on blood pressure in marmosets after bilateral nephrectomy or after pretreatment with a converting enzyme inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension
PMID:Effects of a specific and long-acting renin inhibitor in the marmoset. 392 88

The levels of free and sulfoconjugated catecholamines were measured in the plasma of fasting, recumbent normal subjects before and after an oral load of the catecholamine precursors tyrosine or L-dopa. Basal values of sulfoconjugated catecholamines, measured in plasma samples diluted 1:100 were 7998 +/- 540 pg/ml for dopamine sulfate, 2938 +/- 281 pg/ml for norepinephrine sulfate, and 2958 +/- 288 pg/ml for epinephrine sulfate (n = 37 tests in 15 men); these basal values are higher than those reported previously. Neither free nor sulfoconjugated catecholamine concentrations were changed by a tyrosine load (100 mg/kg) that induced a doubling of the plasma tyrosine level or by a meal low in phenylalanine and tyrosine (but otherwise supplying constituents of normal nourishment) that induced a greater than 50% reduction in the plasma tyrosine concentration. After an oral load of L-dopa (125 mg) the following were observed. (1) An extremely large increase (greater than 100-fold) in dopamine sulfate levels was noted, an increase that was less marked in the same subjects given L-dopa (125 mg) plus the peripheral dopa-decarboxylase inhibitor carbidopa (12.5 mg); as expected, free dopamine concentration also was increased. (2) Neither free nor sulfoconjugated norepinephrine concentrations were altered. (3) Epinephrine sulfate but not free epinephrine concentration was increased (more than ten-fold) after L-dopa ingestion alone; this result was unexpected and has to be confirmed before considering its physiological meaning, if any.
Hypertension
PMID:Oral load of tyrosine or L-dopa and plasma levels of free and sulfoconjugated catecholamines in healthy men. 398 61


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