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)

Renal vasodepressor hormone: Medullipin I is the renomedullary vasodepressor hormone secreted by the renomedullary interstitial cells of the renal papilla. It is conveyed to the liver where it is converted to its active form, medullipin II. Medullipin II is a vasodilator that suppresses sympathetic tone and causes diuresis and natriuresis. Its actions are opposite to those of angiotensin II. These are feedback control systems. The secretion and conversion of medullipin is related to the cytochrome P-450 dependent enzyme system of kidney and liver. Deficiency of medullipin: A deficiency of medullipin is considered to contribute to the pathogenesis of various hypertensive states. There are three known causes for such a deficiency, (1) removal of renomedullary interstitial cells by bilateral nephrectomy, renal surgical papillectomy, chemical papillectomy, papillary atrophy or necrosis; (2) decrease in number and damage to renomedullary interstitial cells in accelerated experimental hypertension and malignant hypertension of humans; and (3) dysfunction of renomedullary interstitial cells as mediated by angiotensin II, by resetting of the effect of increased renal artery perfusion pressure, by stimulation of the renal sympathetic nerve, by inhibition of nitric oxide synthesis and possibly by inhibition of cyclo-oxygenase. Secretion of Medullipin I: The main factor influencing secretion of medullipin I by the kidney appears to be the renal artery perfusion pressure. Elevation of this pressure is attenuated by the presence of medullipin I in the renal venous effluent. Lowering the pressure below normal shuts off this secretion. This is opposite to the effects of perfusion pressure on renin secretion, as elevation shuts off renin secretion while depression turns it on.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renal vasodepressor mechanisms: the medullipin system. 815 34

Bradykinin-induced relaxation of precontracted, porcine coronary artery (PCA) rings is mediated by distinctly different endothelium-derived relaxing factors depending on the contractile agent used. Thus when contracted with KCl, bradykinin-induced relaxation of PCA rings is mediated solely by nitric oxide (NO), whereas when contracted with the thromboxane mimetic U46619, a small component of the relaxation is attributable to NO and a large component is attributable to a non-NO mechanism that is independent of cyclooxygenase activity. We hypothesized that the non-NO component was mediated by arachidonic acid (AA) or by a non-cyclooxygenase product of AA metabolism. Bradykinin-induced relaxations of PCA rings precontracted with U46619 in the presence of indomethacin (10 mumol/L) were moderately attenuated by the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 100 mumol/L), whereas when precontracted with KCl, L-NAME abolished the relaxations. AA produced endothelium-dependent relaxations of rings precontracted with U46619 that were unaffected by L-NAME, whereas AA did not relax rings precontracted with KCl. In rings precontracted with U46619, in the presence of L-NAME and indomethacin the phospholipase inhibitors quinacrine (50 mumol/L) and 4-bromophenacyl bromide (10 mumol/L) attenuated bradykinin- but not AA-induced relaxations. Inhibitors of both lipoxygenase (BW 755c [100 mumol/L] and nafazatrom [20 mumol/L]) and cytochrome P-450 (proadifen [10 mumol/L] and clotrimazole [10 mumol/L]) pathways did not eliminate bradykinin- or AA-induced relaxations, although clotrimazole partially attenuated AA-induced relaxations. These findings suggest that bradykinin-induced relaxation of PCA rings is mediated by AA through a mechanism that is not dependent on cyclooxygenase, lipoxygenase, or cytochrome P-450 pathways.
Hypertension 1994 Jun
PMID:Relaxation of porcine coronary artery to bradykinin. Role of arachidonic acid. 820 38

The present study examined the role of cytochrome P-450 metabolites of arachidonic acid in elevating renal vascular resistance in young spontaneously hypertensive rats (SHR). Differences in vascular tone were assessed in the preglomerular vasculature of 3- to 4-week-old prehypertensive SHR (n = 11) and normotensive Wistar-Kyoto (WKY, n = 10) and Wistar-Lewis (n = 10) rats. Pressure-diameter relations to changes in renal perfusion pressure were compared using the juxtamedullary nephron microvascular preparation perfused in vitro with a physiological salt solution. At a pressure of 60 mm Hg, the basal diameters of the interlobular arteries and proximal and distal afferent arterioles of the SHR averaged 43 +/- 2, 17 +/- 0.3, and 11 +/- 0.4 microns, respectively. The diameters of the interlobular arteries and afferent arterioles were 9% to 14% smaller than those of corresponding vessels in WKY and Wistar-Lewis rats. Addition of P-450 inhibitors, ketoconazole (100 mumol/L) or 7-ethoxyresorufin (1 mumol/L), to the perfusate dilated the afferent arteriole of SHR by 7% to 12%, whereas it increased the diameter by only 0% to 6% in control rats and significantly reduced the differences in the pressure-diameter relation in the preglomerular vasculature of SHR and control rats. Inhibitors of P-450 eliminated the contractile response of afferent arterioles to increases in renal perfusion pressure in all three groups. Removal of calcium from the perfusate eliminated differences in the diameters of the preglomerular vasculature in SHR and normotensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1993 Sep
PMID:Elevated renovascular tone in young spontaneously hypertensive rats. Role of cytochrome P-450. 834 28

A high affinity binding site for 14(R),15(S)-EET, one of the major cytochrome P-450 metabolites of arachidonic acid (AA) in blood vessels, liver, kidney and urine of patients with pregnancy-induced hypertension, has been identified in a membrane preparation from guinea pig mononuclear (GPM) cells. Using a radioligand assay, binding of 14(R),15(S)-[3H]EET to its receptor site was saturable, specific and reversible. Scatchard analysis of saturation binding studies yielded a dissociation constant (Kd) of 5.7 x 10(-9) M, and maximum number of binding sites (Bmax) of 2.4 pmol/mg membrane protein. The specificity of the binding site was determined by competition studies. 14(S),15(R)-EET and 8,9-EET had a Ki of 6.3 and 8.8 nM, respectively, followed by 12(R)-HETE and LTD4. 12(S)-HETE and 5,6-EET were even less effective as a competitive inhibitor of radioligand and binding with Ki values from 2 to 20 microM. Receptor antagonists for TxA2, LTB4, LTD4 and PAF failed to displace 14(R),15(S)-[3H]EET from its binding site on GPM cell membranes. The results correlate well with the reported biological functions of 14,15-EET. In view of its potent biological activities, 14,15-EET may exert its cellular function through the binding and activation of its stereo-specific cell surface binding sites or receptor.
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PMID:14(R),15(S)-epoxyeicosatrienoic acid (14(R),15(S)-EET) receptor in guinea pig mononuclear cell membranes. 839 43

Steroid 11 beta-hydroxylase is encoded by two homologous genes, CYP11B1 and CYP11B2, located on chromosome 8q21-22. CYP11B1 encodes a specific cytochrome P-450 (P-450c11) necessary for cortisol biosynthesis, with predominantly 11 beta-hydroxylase and moderate 18-hydroxylase activity, whereas CYP11B2 encodes another isozyme (P-450cmo) necessary for aldosterone biosynthesis, with 11 beta-hydroxylase, 18-hydroxylase and 18-oxidase activities (the latter two termed corticosterone methyl-oxidase I and II; CMO-I and II, respectively). Two steroid biosynthetic defects, both relatively frequent in Israel, are caused by specific mutations in each of these genes. 11 beta-Hydroxylase deficiency is frequent among Jews from Morocco (1 in 5000 to 7000 births), and is characterized by virilization, hypertension, impaired cortisol biosynthesis, and increased deoxycorticosterone and androgens. Affected individuals have a single base substitution in exon 8 of CYP11B1, codon 448, from CGC (arginine) to CAC (histidine). This sequence, normally absent in CYP11B2, constitutes a true point mutation within the heme binding domain of CYP11B1 that results in marked impairment of enzymatic activity. The clinical expression is characterized by a wide range of variability in the signs of both androgen and mineralocorticoid excess, even though an identical mutation was found in all but one of the affected alleles examined. CMO-II deficiency is frequent among Jews from Iran (1 in 4000 births), and is characterized by a typical salt-wasting syndrome, increased 18-hydroxycorticosterone, impaired aldosterone biosynthesis, and a high ratio of these steroids. No mutation was found in CYP11B1, but all individuals affected were homozygous for two missense mutations in CYP11B2. The first, in exon 3, codon 181, from CGG (arginine) to TGG (tryptophane) is a mutation that completely abolishes both CMO-I and II activities, whereas the second, in exon 7, codon 386, from GTG (valine) to GCG (alanine) is a more conservative substitution that produces only a minimal reduction in CMO-I activity. Individuals homozygous for either one of these mutations are asymptomatic.
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PMID:Mutations in human 11 beta-hydroxylase genes: 11 beta-hydroxylase deficiency in Jews of Morocco and corticosterone methyl-oxidase II deficiency in Jews of Iran. 848 57

We have reported that cytochrome P-450-dependent omega-hydroxylation of arachidonic acid is reduced in microsomes prepared from the renal outer medulla of Dahl salt-sensitive (SS/Jr) rats, but the functional significance of this observation is unknown. The present study examined whether long-term induction of renal fatty acid omega-hydroxylase with clofibrate would alter the development of hypertension in Dahl SS/Jr rats. Dahl SS/Jr rats were placed on a high salt diet (8.0% NaCl) and given either vehicle or clofibrate (80 mg/day) in their drinking water. After 4 weeks of a high salt diet, mean arterial pressure averaged 170 +/- 3 mm Hg in vehicle-treated (n = 17) and 127 +/- 2 mm Hg in clofibrate-treated (n = 19) SS/Jr rats. Clofibrate had no effect on arterial pressure in Dahl salt-resistant rats. The antihypertensive effect of clofibrate was reversible. Mean arterial pressure rose from 131 +/- 4 to 182 +/- 8 mm Hg in the first week after clofibrate treatment (n = 6) was discontinued. Clofibrate had no effect on arterial pressure in SS/Jr rats (n = 9) in which hypertension was already established by feeding the rats a high salt diet for 4 weeks before the study. In clofibrate-treated SS/Jr rats (n = 12), the omega-hydroxylation of arachidonic and lauric acids by renal cortical and outer medullary microsomes was greater than that seen in vehicle-treated rats (n = 9).(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1993 Jun
PMID:Clofibrate prevents the development of hypertension in Dahl salt-sensitive rats. 850 11

The macrolide class of antibiotics, including erythromycin and troleandomycin, is associated with clinically significant adverse drug interactions. This results from macrolide inhibition of cytochrome P-450 metabolism of numerous xenobiotics, resulting in elevated serum drug levels and clinical intoxication. Animal studies, however, suggest that clarithromycin, the newest approved macrolide antibiotic, has has less potential for adverse drug reactions. We describe a patient who, on her fifth day of clarithromycin therapy, developed clinical ergotism (i.e., hypertension, lingual ischemia, and peripheral cyanosis) several hours after administration of her usual 2-mg dose of ergotamine tartrate. To our knowledge, this is the first report of clinical ergotism precipitated by clarithromycin-ergotamine interaction and suggests that, like other macrolide antibiotics, ergot preparations should be avoided in patients who are taking clarithromycin.
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PMID:Clinical ergotism with lingual ischemia induced by clarithromycin-ergotamine interaction. 860 32

Renal production of 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P-450-dependent arachidonate metabolite, increases during development of hypertension in spontaneously hypertensive rats, and inhibition of its production prevents hypertension. Since 20-HETE is a potent vasoconstrictor, these findings suggest that 20-HETE may contribute to the development of hypertension by elevating renal vascular resistance. In this study we examined the direct action of 20-HETE on the afferent arteriole, a vascular segment crucial to the control of renal vascular resistance. Rabbit afferent arterioles were microperfused at 60 mm Hg in vitro, and 20-HETE was added to the lumen. Although 20-HETE (10(-10) to 10(-6) mol/L) had no effect on the diameter of non-treated afferent arterioles (n=6), it caused dose-dependent constriction when vascular tone was increased with norepinephrine (0.3 micromol/L); 20-HETE at 10(-6) mol/L decreased diameter by 43 +/- 4% (n=6, P < .001). This constriction was abolished by disrupting the endothelium (n=5). Moreover, pretreatment with the cyclooxygenase inhibitor indomethacin (50 micromol/L) or the thromboxane/endoperoxide receptor antagonist SQ29548 (1 micromol/L) significantly (P < .03) attenuated 20-HETE-induced constriction: 20-HETE at 10(-6) mol/L constricted norepinephrine-treated afferent arterioles by 28 +/- 3% (n=6) and 25 +/- 4% (n=5), respectively. These results demonstrate that an increase in afferent arteriolar tone is required for the vasoconstrictor action of 20-HETE, which is partly mediated by the endothelial cyclooxygenase pathway. THus, increased production of 20-HETE in the kidney and increase in afferent arteriolar tone, both of which often precede the development of hypertension, may synergistically contribute to the development of hypertension by elevating renal vascular resistance.
Hypertension 1996 Mar
PMID:20-HETE requires increased vascular tone to constrict rabbit afferent arterioles. 861 40

Besipirdine displays potent adrenergic activity in a variety of pharmacological and behavioral tests. Based on this property, we evaluated the effects of besipirdine and its N-despropyl metabolite N-despropyl-besipirdine (P7480) on cardiovascular function in rats and dogs. Besipirdine and P7480 bind alpha-2 adrenoceptors (K(I): 380 and 10 nM, respectively) and facilitate the stimulated release of [3H]norepinephrine from rat cortical slices due to presynaptic autoreceptor blockade. In rat aorta rings and the pithed rat, P7480, but not besipirdine, also behaved as a postsynaptic alpha-1 adrenoceptor agonist. In conscious rats, besipirdine (2-10 mg/kg, p.o.) and P7480 (3-10 mg/kg, p.o.) produced dose-related increases in mean arterial pressure. Inhibition of hepatic cytochrome P-450 enzyme activity blocked the pressor effect of besipirdine, but not of P7480; therefore, P7480 mediated besipirdine's pressor effect. The bradycardia after either agent was unaffected. In conscious dogs, besipirdine (0.1-2 mg/kg, p.o.) also produced dose-related hypertension and bradycardia. The hypertension, but not the bradycardia, were sensitive to prazosin (3 mg/kg, p.o.), but not hexamethonium (10 mg/kg, p.o.). Muscarinic and beta-adrenergic receptor blockade studies in anesthetized dogs demonstrated the bradycardia to be due to withdrawal of cardiac sympathetic tone. These findings suggest that besipirdine's peripheral hypertensive effect is primarily mediated by the pressor metabolite P7480, although facilitated norepinephrine release may contribute. Besipirdine's bradycardic action appears to be centrally mediated, because both compounds lacked direct negative chronotropic activity on spontaneously beating guinea pig atria in vitro.
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PMID:alpha-Adrenergic activity and cardiovascular effects of besipirdine HCl (HP 749) and metabolite P7480 in vitro and in the conscious rat and dog. 910 15

Venlafaxine, a phenylethylamine, and nefazodone, a phenylpiperazine compound, are the newest antidepressants to receive approval of the Food and Drug Administration and to be marketed in the United States. Both strongly inhibit serotonin (5-HT) reuptake; venlafaxine also inhibits norepinephrine reuptake, and nefazodone also exhibits 5-HT2-receptor antagonism. Venlafaxine inhibits the cytochrome P-450 2D6 isozyme to a lesser extent than the selective serotonin reuptake inhibitors (SSRIs) and is 27% protein bound. Structurally, the drugs are unrelated to SSRIs and have some clinically important differences in side effect profiles. Nausea, headache, somnolence, and dry mouth are the most frequently reported side effects with both. Sustained hypertension was reported by a limited number of venlafaxine-treated patients.
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PMID:Venlafaxine and nefazodone, two pharmacologically distinct antidepressants. 916 54


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