Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The receptor autoradiographic distribution of opioid peptide receptors in spontaneously hypertensive rats (SHR) was compared to that of Sprague-Dawley (SD) rats, using the highly selective mu and delta opioid receptor ligands, [3H]DAGO (Tyr-D-Ala-Gly-NMe-Phe-Gly-ol) and [3H]DPDPE ([D-Pen2,D-Pen5]enkephalin), respectively. Although the distribution of these binding sites was similar in both strains, SHR showed significantly higher binding densities of mu receptors in 16 of 27 areas examined. These included the patch and matrix components of the caudate-putamen (CPu), olfactory tubercle, endopiriform nucleus, anterior cingulate cortex, ventral tegmental area lateroposteral thalamic nucleus and the ventral part of the dentate gyrus. In contrast, SHR had lower [3H]DAGO binding sites in the CA1 of the hippocampus. Conversely, SHR showed higher binding densities of delta receptors in 7 of 20 areas examined, including the CPu, CA2 and CA3 areas of the hippocampus and the central grey. High-to-low lateromedial gradients of striatal delta receptors were observed in both strains. Because opioid peptides are known to participate in locomotive behavior in rodents and in the control of blood pressure, the present results support a role of opioid peptidergic systems in the manifestation of hyperactivity and hypertension observed in SHR.
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PMID:Receptor autoradiography of mu and delta opioid peptide receptors in spontaneously hypertensive rats. 166 45

We assessed the vasodilator effect of endothelium-derived nitric oxide by inhibiting its formation with NG-monomethyl L-arginine (LNMMA) on systemic and regional hemodynamics in conscious, normotensive rats, using the radioactive microsphere technique. In rats injected with 10 mg/kg LNMMA (n = 8), mean blood pressure increased by 16.2 +/- 2.6 mm Hg, and heart rate decreased by 54.3 +/- 16.7 beats per minute. In comparison with rats injected with 5% dextrose (n = 14), cardiac index was lower by 35.6% (p less than 0.01), and total peripheral vascular resistance was higher by 51.6% (p less than 0.01); regional blood flows were lower and vascular resistance higher in most organs. Changes were significant in the heart, kidney, stomach, large intestine, skin, and adrenals (p less than 0.05). Preinjection of 100 mg/kg L-arginine prevented the pressor response but only partially attenuated the other hemodynamic effects of LNMMA. Combination of LNMMA with the bradykinin antagonist (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg)trifluoroacetic acid (50 micrograms/min for 5 minutes) did not produce systemic or regional effects different from those obtained with LNMMA alone. Combination of LNMMA with indomethacin (10 mg/kg) resulted in additional changes in the cerebral circulation, blood flow decreasing by an additional 44.2% (p less than 0.01) and vascular resistance increasing by 75.3% (p less than 0.01) compared with changes produced by LNMMA alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1992 Feb
PMID:Inhibition of nitric oxide, bradykinin, and prostaglandins in normal rats. 173 88

We investigated the role of kinins in the acute depressor effect of captopril and ramiprilat in spontaneously hypertensive rats. Since the vasodepressor action of kinins may be linked to the generation of prostaglandins and endothelium-derived relaxing factors, we also investigated the role of prostaglandins and nitric oxide in the blood pressure reduction caused by angiotensin converting enzyme inhibitors. To this end, we contrasted the hypotensive effects of captopril (10 mg/kg i.v.), ramiprilat (2 mg/kg i.v.), and the angiotensin II antagonist DuP 753 (30 mg/kg i.v.) in spontaneously hypertensive rats with and without pretreatment with a kinin antagonist (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg-trifluoroacetic acid) (200 micrograms/kg/min i.v.), an inhibitor of nitric oxide synthesis (NG-monomethyl-L-arginine) (15 mg/kg + 10 mg/kg/hr i.v.), or an inhibitor of prostaglandin synthesis (indomethacin) (10 mg/kg i.v.). The kinin antagonist did not affect blood pressure in spontaneously hypertensive rats but did attenuate the hypotensive effect of captopril and ramiprilat; the kinin antagonist did not minimize the depressor action of DuP 753. The nitric oxide synthesis inhibitor increased blood pressure in spontaneously hypertensive rats and attenuated the hypotensive effect of captopril, ramiprilat, and DuP 753, but it did not impede the hypotensive effect of sodium nitroprusside. Pretreatment of hypertensive rats with indomethacin did not modify the acute hypotensive effect of ramiprilat or captopril. These data suggest a contribution of endogenous kinins and nitric oxide to the acute antihypertensive effect of captopril and ramiprilat in spontaneously hypertensive rats and of nitric oxide to the hypotensive effect of DuP 753.
Hypertension 1992 Feb
PMID:Kinins, nitric oxide, and the hypotensive effect of captopril and ramiprilat in hypertension. 173 47

The standard angiotensin I (Ang I) radioimmunoassay for renin activity determination is a useful clinical tool for the diagnosis of high renin levels in certain cases of hypertension. It depends upon the liberation of Ang I from human plasma angiotensinogen. We considered whether a commercially available synthetic tetradecapeptide (TDP), Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser, would produce authentic Ang I upon incubation with protease from human immunodeficiency virus type 1 (HIV-1). This peptide is also known to be cleaved by renin at the Leu-Leu bond to yield the decapeptide Ang I. When the TDP is incubated with the HIV-1 protease, the peptide is readily hydrolyzed. Product formation is linear with respect to time and enzyme concentration. HPLC analysis of reaction products showed two new peaks, as one would expect from the cleavage of a TDP into a decapeptide and a tetrapeptide. Amino acid analysis of HPLC-purified peaks confirmed that the HIV-1 protease cleaves TDP at the Leu10-Leu11 site to produce the desired decapeptide, Ang I. Production of Ang I by the HIV-1 protease, like human renin, is inhibited in the presence of a protease inhibitor. Implications of the discovery of an HIV-1 protease substrate that produces authentic Ang I are discussed in light of a screening assay for soluble HIV-1 protease inhibitors.
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PMID:Could angiotensin I be produced from a renin substrate by the HIV-1 protease? 179 23

Thirty-seven compounds were tested as antagonists of kinin B2- and B1-receptors to identify the chemical changes required to obtain antagonism, improve antagonist affinity, and eliminate residual agonistic activities. Apparent affinity of antagonists was evaluated in terms of pA2 on the rabbit jugular vein, the dog carotid and renal arteries, the hamster urinary bladder, the guinea pig ileum, the rat vas deferens, the guinea pig trachea, and the rabbit aorta, using bradykinin and desArg9-bradykinin as B2- and B1-receptor activators. Replacement of Pro7 of bradykinin with D-Phe leads to antagonism; substitution of Pro3 by Hyp and extension of the peptide chain at the N-terminal with a D-Arg residue improves the affinity of antagonists; acetylation of N-terminal amine function reduces residual agonistic activity; these changes, combined with the replacement of Phe8 by Leu as in Ac-D-Arg[Hyp3,D-Phe7,Leu8]-bradykinin, led to potent full B2-receptor antagonists. Affinity of antagonists differs markedly between highly sensitive (rabbit jugular vein, dog carotid and renal artery), moderately sensitive (hamster urinary bladder, guinea pig ileum, and rat vas deferens), and insensitive preparations (the guinea pig trachea) in which antagonists act as potent stimulants. High concentrations of antagonists block bradykinin completely in the rabbit jugular vein but not in the guinea pig ileum, suggesting that kinins stimulate the moderately sensitive tissues by two mechanisms, of which only one is blocked by antagonists. It thus appears that kinins act on various B2-receptor subtypes or by different action mechanisms.
Hypertension 1991 Jan
PMID:Structure-activity studies of bradykinin and related peptides. B2-receptor antagonists. 184 19

The potent vasodilatory peptide bradykinin is cleaved at the Phe5-Ser6 bond in vitro by the metalloenzyme endopeptidase-24.15 (E.C.3.4.24.15). We now report that intravenous infusion of N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate, a specific active site-directed inhibitor of endopeptidase-24.15, produces an immediate drop in mean arterial pressure of as much as 50 mm Hg in pentobarbital-anesthetized, normotensive rats. Arterial pressure recovers within 5 minutes. The B2 bradykinin antagonist [Arg0,Hyp3,Thi5,8,D-Phe7]-bradykinin attenuates the decrease in mean arterial pressure resulting from treatment with the inhibitor. The endopeptidase-24.15 inhibitor potentiates the hypotensive effect of intravenous bradykinin infusion, increasing the maximal effect of the peptide by 47% and increasing the potency by almost 10-fold, while the response to intra-arterial bradykinin is less affected by the inhibitor. These results support a role for endopeptidase-24.15 in the inactivation of endogenous and exogenous bradykinin and suggest a direct involvement of the enzyme in the control of blood pressure.
Hypertension 1991 Sep
PMID:Inhibition of endopeptidase-24.15 decreases blood pressure in normotensive rats. 165 69

We detected a novel vasoconstrictor in an arginine esterase fraction separated from fractions containing tonin and other esterases that were obtained from a rat submandibular gland extract. When tested on isolated rabbit aorta rings, the substance caused dose-related contractions that were slow in onset, long-lasting, and difficult to reverse by rinsing. The substance acts directly on vascular smooth muscle, since preincubation with plasma or intact endothelium is not required. The fact that the constrictor was destroyed by heat and incubation with pronase suggests that it is a protein. Molecular sieving indicates an estimated molecular weight of 24,000 Da. It has a neutral isoelectric point that is higher than the pI of tonin, from which it can be separated by anion exchange chromatography. A small amount of the vasoconstrictor was obtained by gel filtration and eluted from isoelectric focusing polyacrylamide gels. The purified substance showed a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. It was a potent vasoconstrictor; an estimated concentration of 2.5 nM induced contraction of isolated rabbit aorta rings ranging from 15% to 40% of the maximum contraction obtained by 60 mM KCl. Contraction was completely blocked by 1 mM (p-amidinophenyl)methanesulfonyl fluoride, a serine protease inhibitor. Contractile activity was not affected by hirudin, a thrombin inhibitor, but was completely inhibited by soybean trypsin inhibitor and blunted by aprotinin; thus it may be a trypsin-like serine protease. Purified vasoconstrictor preparation showed hydrolyzing activity on Pro-Phe-Arg-methyl-coumarin amide, a kallikrein substrate. We conclude that a novel vasoconstrictor serine protease is present in the rat submandibular gland.
Hypertension 1991 Jan
PMID:A potent vasoconstrictor in the rat submandibular gland. 198 78

To assess the potential role of the lipoxygenase (LO) pathway in the vasculature in an angiotensin II (ANG II)-dependent model of hypertension, we investigated the effect of LO pathway inhibition on blood pressure in the two-kidney, one-clip (2K,1C) Goldblatt hypertensive rat. The development of renovascular hypertension in 2K,1C rats was attenuated by oral administration of phenidone (Phe, 60 mg.kg-1.day-1), a nonselective LO inhibitor, throughout the 3 wk of observation after renal artery constriction. In contrast, the same treatment protocol had no effect on the evolution of hypertension in the deoxycorticosterone acetate-salt rat, which is considered to be an ANG II-independent form of hypertension. The hypotensive effect of Phe was not associated with changes in plasma renin or aldosterone concentration (PRC and PAC, respectively). In vitro synthesis of 12-hydroxyeicosatetraenoic acid (12-HETE) by aortic segments was increased in 2K,1C hypertensive rats compared with sham-operated rats. In addition, the synthesis of 12-HETE was suppressed by the in vitro addition of Phe (10(-4) M) to aortic-segment incubates obtained from 2K,1C rats and sham-operated rats. Acute administration of Phe (30 or 60 mg/kg) in 2K,1C hypertensive rats produced a rapid and sustained decrease in mean blood pressure (MBP). This decrease in MBP was accompanied by a brisk rise in PRC and PAC. In contrast, bolus administration of indomethacin, a selective cyclooxygenase inhibitor, did not affect MBP, PRC, or PAC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of lipoxygenase pathway reduces blood pressure in renovascular hypertensive rats. 212 26

An increased urinary excretion of thromboxane (Tx)B2 (Geoffroy & al., Hypertension 1986, 4 suppl 3: S37) and an elevated renal sympathetic activity (Sautel & al., Am J Physiol 1988, 255: H736) were simultaneously observed in the developing genetically hypertensive rat of the Lyon strain (LH). In the present work, the relationship between the adrenergic stimulation and prostaglandins (PGs) release was studied using isolated perfused kidney of 8 week-old LH rats and their normotensive controls (LN). Phenylephrine (PHE, 5 - 190 x 10(-8) M) and norepinephrine (NE, 1.2 - 96 x 10(-8) M) were administered in a single pass kidney perfused with a cell free solution and their effects were studied on the renal vascular resistances (RVR) and urinary excretion of TxB2 and 6-keto-PGF1 alpha (6KPGF) measured by specific radioimmunoassays after separation by HPLC. The results (mean +/- SE) obtained before (C) and after PHE and NE perfusions at concentrations: D1 = 31 and 10.5; D2 = 190 and 96 10(-8) M for PHE and NE respectively (* p less than 0.05 ** p less than 0.01 *** p less than 0.001 LH vs LN) were as follows: [table: see text] During the control period, kidneys of LH rats exhibited increased RVR when compared to LN controls but a similar PG excretion. The 2 concentrations of PHE and NE used which produced a similar increase in RVR strikingly stimulated the PG excretion. This effect which was more marked for NE than for PHE did not differ between the 2 strains for 6KPGF but was enhanced for TxB2 in kidney of LH rat.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Adrenergic stimulation and renal synthesis of prostaglandins in genetically hypertensive rats of the Lyons strain]. 212 61

The reaction of the renin-angiotensin system to acute angiotensin converting enzyme inhibition was investigated in a single-blind, crossover study in nine normal volunteers receiving two out of three regimens in random order: the new converting enzyme inhibitor benazepril (20 mg once or 5 mg four times at 6-hour intervals) or enalapril (20 mg). Plasma converting enzyme activity, drug levels, angiotensin I and angiotensin II, active renin, and aldosterone were measured before and 1-4 hours and 14-30 hours after drug intake. Baseline in vitro plasma converting enzyme activity was 97 +/- 15 nmol/ml/min (mean +/- SD) when Hip-Gly-Gly was used as substrate, but with carbobenzoxy-Phe-His-Leu (Z-Phe-His-Leu) or angiotensin I as substrate it was only 20 +/- 4 and 1.7 +/- 0.3 nmol/ml/min, respectively. Discriminating power at peak converting enzyme inhibition was enhanced with the two latter substrates. In vivo converting enzyme activity was estimated by the plasma angiotensin II/angiotensin I ratio, which correlated well with in vitro converting enzyme activity using Z-Phe-His-Leu as substrate (r = 0.76, n = 252). Angiotensin II levels returned to baseline less than 24 hours after drug administration, whereas in vitro and in vivo converting enzyme activity remained considerably inhibited and active renin together with angiotensin I levels were still elevated. A close linear relation was found between plasma angiotensin II and the angiotensin I/drug level ratio (r = 0.91 for benazeprilat and r = 0.88 for enalaprilat, p less than 0.001). Thus, plasma angiotensin II truly reflects the resetting of the renin-angiotensin system at any degree of converting enzyme inhibition. The ratio of plasma angiotensin II to angiotensin I represents converting enzyme inhibition more accurately than in vitro assays, which vary considerably depending on substrates and assay conditions used.
Hypertension 1990 Nov
PMID:Determinants of angiotensin II generation during converting enzyme inhibition. 217 61


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