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)

Felodipine is completely absorbed from the gastrointestinal tract. However, the amount reaching the systemic circulation is reduced to about 15% because of first-pass degradation. The bioavailability is constant within the dose interval of 5 to 40mg orally. The frequency histogram of the area under the plasma concentration-time curve (AUC) seems to be normally distributed. The disposition of felodipine is independent of the administered dose over the intravenous dose interval (1-3 mg). The plasma concentration-time curve declines in 3 distinct phases. The mean elimination half-life of felodipine is approximately 25h. Felodipine is extensively distributed to extravascular tissues. The volume of distribution of felodipine is about 10 L/kg, implying that less than 1% of the amount of drug in the body is localised in the blood. Felodipine is more than 99% bound to plasma proteins. Mean total clearance from the blood is 1 to 1.5 L/min and, therefore, felodipine is considered a high clearance drug. Felodipine is metabolised completely and no unchanged drug is eliminated in the urine. The first step in the metabolism involves oxidation to the corresponding pyridine derivative by the cytochrome P-450 system. Identified metabolites in plasma and urine are devoid of vasodilating activity. Long term treatment, and the presence of hypertension and impaired renal function do not affect the disposition of felodipine. Elderly people may have higher plasma levels than the young and middle-aged. Impaired liver function significantly decreases systemic clearance. Cimetidine and food affect felodipine kinetics, but with negligible clinical implications. Therapeutic concentrations of felodipine do not interact with highly protein-bound drugs and these drugs have no effect on the binding of felodipine to human plasma proteins in vitro. Plasma levels of digoxin and metoprolol tended to increase during felodipine treatment. There is a significant correlation between plasma concentrations of felodipine and haemodynamic effects in both healthy subjects and hypertensive patients during short term as well as during long term treatment.
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PMID:Clinical pharmacokinetics of felodipine. A summary. 332 76

Rats were selectively bred for susceptibility (S) and resistance (R) to the hypertensinogenic effects of excess salt intake by Dahl and further inbred to virtual homozygosity by Rapp (S/JR and R/JR). The S strain has been shown to have a mutation of the cytochrome P-450-dependent 11 beta,18-hydroxylase resulting in the enhanced production of 18-hydroxydeoxycorticosterone (18-OH-DOC) compared to that of the R strain. It is known that this enzyme is also responsible for the hydroxylation of deoxycorticosterone at the 19 position to produce 19-hydroxydeoxycorticosterone. Recently, the excretion of 19-nordeoxycorticosterone (19-nor-DOC), a potent mineralocorticoid, has been shown to be markedly increased in S/JR females compared to that in R/JR females consuming a high sodium diet. While the S/JR rat is spontaneously hypertensive, the course of the disease is greatly accelerated and exacerbated by a high sodium diet. If, indeed, 19-nor-DOC is responsible for the spontaneous hypertension in the S/JR rat, then its production should also be higher in the S/JR rat consuming a normal salt diet. Furthermore, since its production is suppressed by NaCl intake, the excretion should be even higher when not suppressed by a high sodium diet. We measured the urinary excretion of 19-nor-DOC, 18-OH-DOC, and corticosterone in male and female S/JR and R/JR rats consuming a normal sodium diet. The excretions of corticosterone and 18-OH-DOC were significantly higher by S/JR of both sexes than by R/JR, with the excretion by female rats being higher than that by male rats within the same strain. The hierarchy of excretion rates of 19-nor-DOC was: S/JR females greater than R/JR females greater than S/JR males greater than R/JR male rats. These studies indicate that while S/JR rats of both sexes develop higher blood pressures than the R/JR even on a standard salt intake, the excretion of 19-nor-DOC does not correlate well with their blood pressure elevation, since the normotensive female R/JR rat excretes significantly higher quantities of 19-nor-DOC than the hypertensive male S/JR rat. Thus, it is unclear whether 19-nor-DOC is playing a significant role in the pathogenesis of the hypertension in the S/JR rat. It also remains unknown whether the renal site of formation of 19-nor-DOC allows access to the mineralocorticoid target sites in the kidney.
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PMID:19-Nordeoxycorticosterone excretion in male and female inbred salt-sensitive (S/JR) and salt-resistant (R/JR) Dahl rats. 334 46

Cytochrome P-450-dependent mixed function oxidase activity is present in vascular tissue; however, as far as we could determine, the distribution of monooxygenase activity across the blood vessel wall has not previously been assessed. The aryl-hydrocarbon hydroxylase activity was examined by metabolism of benzo[a]pyrene in microsomes prepared from intimal and smooth muscle cell scrapings of the hog thoracic aorta. Microsomes of intimal cells comprising 95% endothelial cells showed an approximately 2.5-fold increase in aryl-hydrocarbon hydroxylase activity compared with that in microsomes prepared from medial smooth muscle cells. Michaelis-Mentin kinetics for the intimal enzyme yielded an apparent Km value of 11.11 microM and an apparent Vmax of 3-OH benzo[a]pyrene of 40 pmol/mg protein/10 min. Aryl-hydrocarbon hydroxylase activity was dependent on nicotinamide adenine dinucleotide phosphate and was inhibited by 7,8 benzoflavone, SKF 525A, and carbon monoxide. The localization of cytochrome P-450-dependent mixed function oxidase primarily to the intimal surface of the aorta may indicate a role for this enzyme system in vasoregulation and the pathogenesis of atherosclerosis.
Hypertension
PMID:Presence of cytochrome P-450-dependent monooxygenase in intimal cells of the hog aorta. 407 22

Aminoglutethimide blocks several cytochrome P-450 mediated steroid hydroxylation steps, including those required for conversion of cholesterol to pregnenolone and for the aromatization of androgens to estrogens. Through these actions it blocks adrenal steroidogenesis and the production of estrogens in extraglandular tissues. Aminoglutethimide is indicated for treatment of certain patients with Cushing's syndrome and breast cancer. Other potential uses (prostate carcinoma, low renin hypertension, etc.) remain investigational. For treatment of Cushing's syndrome, aminoglutethimide is usually given alone or in combination with metyrapone. In women with breast carcinoma, replacement hydrocortisone must be administered with aminoglutethimide to prevent reflex ACTH hypersecretion from overcoming adrenal inhibition. Administration of aminoglutethimide to patients with Cushing's syndrome results in improvement in clinical status in 56% of cases. Results are most favorable in patients with adrenal tumors and patients with ectopic ACTH production. Aminoglutethimide and replacement glucocorticoid produce objective disease regression in 32% of unselected postmenopausal patients with metastatic breast carcinoma and in 52% of women whose tumors are estrogen receptor positive. Responses are similar in duration and frequency to those produced by surgical adrenalectomy and hypophysectomy and the antiestrogen, tamoxifen.
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PMID:Aminoglutethimide: review of pharmacology and clinical use. 676 87

2 aspects of oral contraception (OC) were considered--the risk of arteriosclerotic cardiopathy and the interaction with other drugs. Opinions still diverge on the role of contraceptives in the etiology of myocardial infarction. In contrast to the British studies, the World Health Organization's (WHO) data and US statistics on death from cardiovascular diseases fail to show higher prevalence for OC users. Most likely the data of different countries cannot be compared due to the differing incidence of other cardiovascular morbidity and mortality risk factors such as hypertension, obesity, smoking, physical activity, and genetic predisposition. A recent study examined the prevalence of myocardial infarction in relation to the use of estroprogestinic contraceptives. Rosenberg et al. found that 156 out of 121,944 women (1.2%) had been hospitalized following myocardial infarction, and 23 of them used OCs. The authors concluded that OCs increased the risk of infarction by 1.8. Shapiro et al. studied 369 patients who suffered myocardial infarction and an adequate control group. The overall relative frequency was 4 times in OC users but it was 4.5 times in smokers and 3.9 times in nonsmokers. The smokers who did not use OCs showed a relative frequency of 7.8 times. The risk of arteriosclerotic cardiopathy depends upon the dose of both the estrogenic and progestinic components. When prescribing drugs, physicians should know whether their patients use OCs, since these hormonal steroids may interfere with the expected therapeutic effect. A phenomenon of enzymatic competition may occur which slows down the elimination of the drug, thus exposing the patient to a "relative overdose" despite the assumption of therapeutic doses. It has always been reported that the simultaneous administration of triacetiloleandomycin and OCs causes jaundice. Thus far 15 cases have been reported. OCs tend to enhance the effect of corticosteroids. Vitamin K antagonists, oral anticoagulants, are less effective in OC users. A research study conducted by Patwardhan et al. showed that caffeine is eliminated more slowly in OC users because of a mechanism of enzymatic competition with contraceptive steroids at the level of the hepatic oxygenase system linked to cytochrome P-450. ready been reported that the simultaneous administration of triacetiloleandomycin and OCs causes jaundice. Thus far 15 cases have been reported. OCs tend to enhance the effect of corticosteroids. Vitamin K antagonists, oral anticoagulants, are less effective in OC users. A research study conducted by Patwardhan et al. showed that caffeine is eliminated more slowly in OC users because of a mechanism of enzymatic competition with contraceptive steroids at the level of the hepatic oxygenase system linked to cytochrome P-450.
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PMID:Two problems in oral contraception: arteriosclerotic cardiopathy and drug interactions. 716 61

The vascular wall itself, through a complex interplay of endocrine, neurocrine and autoparacrine mechanisms, plays an active role in vascular homeostasis. The endothelial cell senses humoral and hemodynamic changes and responds by secreting a variety of metabolically active substances that act locally causing either vasodilatation or vasoconstriction. Kallikrein (KK) and the mRNA for KK are present in arteries and veins. Vascular KK releases kinins from kininogen which circulate in plasma and is also present in vascular tissue. Vascular-derived kinins induce vasodilatation through the release of endothelial compounds (prostacyclin, EDRFs and cytochrome P-450). Disturbance in the delicate balance between vasodilators and vasoconstrictors may play a role in the development of hypertension. Vascular kallikrein (VKK) was significantly (P < 0.05) elevated after 2 weeks of development of renovascular and mineralocorticoid hypertension, and blood pressure was only slightly elevated. However, VKK decreased in both experimental models when blood pressure was increased. It is possible that the increase in VKK in the early stages resulted in increased local vasodilatory activity, thus counteracting the rise in blood pressure. As hypertension developed, KK was significantly decreased in arteries. The decrease in arterial KK during established hypertension is most likely secondary to high blood pressure. When the endothelium is damaged by high blood pressure, diabetes, excessive LDL cholesterol or cigarette smoking, a net imbalance favoring vasoconstriction, proliferation and migration of cells and increased lipid deposition predisposes to specific vascular diseases. Converting enzyme inhibitors (CEI) blunt the proliferative response of vascular smooth muscle cells after endothelial injury. The cardiovascular protective effects of CEI are mediated in part by the antihypertrophic, antihyperplastic and antithrombotic effects of kinins. The vascular kallikrein-kinin system has a promising role in the regulation of vascular homeostasis and some of the CEI effects may be explained by potentiation of the vascular-derived kinins.
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PMID:Vascular-derived kinins and local control of vascular tone. 774 91

A case of adrenocorticotropic hormone independent bilateral adrenocortical macronodular hyperplasia (AIMAH) is reported. A 59 year old male was admitted to hospital because of hypertension. Subsequently, hypercortisolism, low plasma adrenocorticotropic hormone (ACTH), loss of diurnal rhythm of ACTH, lack of suppression with high dose dexamethasone were found and bilateral adrenal enlargement was detected by abdominal computerized tomography and adrenal scintigraphy. Bilateral total adrenalectomy was performed under a diagnosis of bilateral adrenal hyperplasia associated with Cushing's syndrome. Both adrenal glands were enlarged in size and weight. Bulging nodules were found at the cut section. Microscopically, a variegated histologic pattern including trabecular, adenoid and zona glomerulosa-like (ZG-like) structures was revealed in the nodules. Immunohistochemical examination disclosed positive staining of cytochrome P-450 17 alpha, negative of 3 beta-HSD in the ZG-like structure. Ultrastructurally, the cells composing the ZG-like structure were similar to those of the ZG in normal adrenal cortex. The authors agree that AIMAH is one of the entities causing Cushing's syndrome, and advise pathologists to keep this disorder in mind when they examine the adrenals in Cushing's syndrome.
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PMID:Adrenocorticotropic hormone-independent bilateral macronodular adrenocortical hyperplasia associated with Cushing's syndrome. 778 95

Spironolactone (SL) is a renal aldosterone antagonist that is used clinically in the treatment of hypertension and congestive heart failure. Among the side effects of the drug are degradation of cytochrome P-450 and inhibition of steroidogenesis in the testes. It has long been recognized that the effects of SL are mediated by metabolites of the drug, but questions remain about the identities of the active metabolites. Because tissue metabolites of SL had not previously been investigated, experiments were done to determine the identities of metabolites in target organs after SL administration to guinea pigs. Metabolites were identified by HPLC and MS. The major plasma metabolite was 7 alpha-thiomethyl-SL (TM) with smaller amounts of canrenone (CAN) and 7 alpha-thio-SL (TH) also present. In kidneys, TM also was the principal metabolite, but CAN was the only other compound consistently found. By contrast, in testes, substantial amounts of SL and TH were present in addition to TM and CAN. It is possible that local metabolism of SL contributes to the differences in metabolite profiles between plasma and target organs. Data also suggest that TM is principally responsible for the renal antimineralocorticoid effects of SL and support the purported role of TH in the degradation of testicular cytochrome P-450.
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PMID:Identification of spironolactone metabolites in plasma and target organs of guinea pigs. 790 88

The catabolism of various calcium channel blockers through cytochrome P-450 is heterogeneous and may be modified by concomitant use of cyclosporin A. In an open study we investigated the antihypertensive effect and clinical tolerance of the dihydropyridine amlodipine and its effects on cyclosporine kinetics in stable hypertensive renal transplant recipients not taking corticosteroids. Ten adult hypertensive patients grafted for 21.4 +/- 8.9 months and well stabilized with normal renal function were included in the study. Renal artery stenosis was ruled out by normal Doppler echography. After 2 weeks of placebo, amlodipine was started at a daily dose of 5 mg. The dose was then adjusted to 10 mg if necessary. Blood and urine chemistries and whole-blood cyclosporine trough levels were measured weekly. Cyclosporine kinetics were determined on a hourly basis before amlodipine administration and after 4 weeks of treatment. Normal blood pressure was obtained with the use of 5 mg/d amlodipine in 7 patients and 10 mg/d in 3, diastolic blood pressure decreasing from 98.7 +/- 3.8 to 81.3 +/- 9.1 mm Hg (P = .0007). Heart rate slightly increased by 10% (P < .02). The drug was well tolerated, and only minor ankle edema was found in 3 patients. Cyclosporine doses were not modified and cyclosporine levels remained unchanged throughout the study. Cyclosporine kinetic parameters were not significantly different at the beginning and end of the study. Bioequivalence was demonstrated indicating that cyclosporine biotransformation was not altered by the concomitant administration of amlodipine.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1994 Sep
PMID:Antihypertensive effect of amlodipine and lack of interference with cyclosporine metabolism in renal transplant recipients. 808 35

Evidence to support a hypertensinogenic role of family 3A cytochrome P-450 (CYP3A) activity is that troleandomycin, a selective inhibitor of CYP3A, decreases both blood pressure and in vivo corticosterone 6 beta-hydroxylation in spontaneously hypertensive rats (SHR). Renal CYP3A activity is markedly increased in SHR compared with Wistar-Kyoto (WKY) rats. Cyclosporine acutely increases both systolic blood pressure and renal total cytochrome P-450 in SHR. We tested the hypothesis that the augmentation of blood pressure by cyclosporine is mediated by a further increase in renal CYP3A activity. Accordingly, we assessed the effect of troleandomycin administration on cyclosporine-induced systolic blood pressure increase and renal and hepatic microsomal CYP3A activity in SHR. Cyclosporine (5 mg/kg SC) given daily in 11-week-old SHR resulted in substantial augmentation of blood pressure after 6 days. This blood pressure increase was attenuated by troleandomycin (40 mg/kg) given either during or after development of hypertension. Cyclosporine increased renal (60%) but decreased hepatic (25%) microsomal CYP3A activity in SHR. In contrast, cyclosporine failed to produce any detectable increase in either blood pressure or renal CYP3A activity in WKY rats. Troleandomycin completely inhibited renal CYP3A activity measured after cyclosporine treatment of SHR, which correlated with its attenuation of the cyclosporine-induced blood pressure increase. These findings suggest that renal CYP3A could play an important role in acute cyclosporine-induced hypertension.
Hypertension 1994 Oct
PMID:Augmented arterial pressure responses to cyclosporine in spontaneously hypertensive rats. Role of cytochrome P-450 3A. 808 15


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