19-nor-corticosteroids in genetic hypertension. Effects of inhibitors of 11β,18,19-hydroxylase activity
The long-term objective is to understand the role of the adrenal in altering systemic arterial blood pressure. This paper summarizes research on genetic hypertension in the rat and bears a relationship to several forms of human hypertension in which defects of steroid hydroxylases lead to increased...
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| Veröffentlicht in: | Journal of steroid biochemistry and molecular biology 1993-04, Vol.45 (1-3), p.13-18 |
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| container_title | Journal of steroid biochemistry and molecular biology |
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| creator | MELBY, J. C AZAR, S. T DELANEY, M HOLBROOK, M GRIFFING, G. T JOHNSTON, J. O'N |
| description | The long-term objective is to understand the role of the adrenal in altering systemic arterial blood pressure. This paper summarizes research on genetic hypertension in the rat and bears a relationship to several forms of human hypertension in which defects of steroid hydroxylases lead to increased secretion of mineralocorticoids other than aldosterone in genetic and experimental hypertension in rats. We demonstrated that 19-nor-corticosteroids are produced in excess in genetic and experimental hypertension in rats and man. We studied the enzymatic alteration responsible for excessive production of 19-nor-deoxycorticosterone (19-nor-DOC) in the salt-sensitive hypertensive rat S/JR. Biosynthesis of 19-nor-steroids involves hydroxylation of the C-19 methyl group. We characterized the adrenal 11 beta, 18,19-hydroxylase enzyme system in inbred salt-sensitive and resistant rats (R/JR). This system is capable of all three hydroxylations. The Km for 19-hydroxylation was different from S/JR and R/JR but was much greater for 11 beta- and 18-hydroxylation in both. This suggested that the catalytic site for 19-hydroxylation is different from that for 11 beta and 18. The S/JR adrenal enzyme binds the substrate with higher affinity than does the R/JR adrenal enzyme. We were unable to distinguish the cDNAs of the S/JR from the R/JR adrenal enzyme from bovine 11 beta-hydroxylase cDNA by restriction mapping. We were unable to demonstrate restriction length polymorphism. 19-Acetylenic DOC is an inhibitor which preferentially inhibits the 19-hydroxylation of DOC, and does not interfere with the 18- and 11 beta-hydroxylation. This inhibition leads to a reduction in blood pressure in the S/JR Dahl rat. We suggest that an S/JR 19-nor-DOC is involved in the development of salt-sensitivity and hypertension and that inhibition of its formation by acetylenic DOC and other aromatase and non-aromatase inhibitors is associated with reversal of these phenomena. |
| doi_str_mv | 10.1016/0960-0760(93)90116-E |
| format | Article |
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Effects of inhibitors of 11β,18,19-hydroxylase activity</title><source>MEDLINE</source><source>Access via ScienceDirect (Elsevier)</source><creator>MELBY, J. C ; AZAR, S. T ; DELANEY, M ; HOLBROOK, M ; GRIFFING, G. T ; JOHNSTON, J. O'N</creator><creatorcontrib>MELBY, J. C ; AZAR, S. T ; DELANEY, M ; HOLBROOK, M ; GRIFFING, G. T ; JOHNSTON, J. O'N</creatorcontrib><description>The long-term objective is to understand the role of the adrenal in altering systemic arterial blood pressure. This paper summarizes research on genetic hypertension in the rat and bears a relationship to several forms of human hypertension in which defects of steroid hydroxylases lead to increased secretion of mineralocorticoids other than aldosterone in genetic and experimental hypertension in rats. We demonstrated that 19-nor-corticosteroids are produced in excess in genetic and experimental hypertension in rats and man. We studied the enzymatic alteration responsible for excessive production of 19-nor-deoxycorticosterone (19-nor-DOC) in the salt-sensitive hypertensive rat S/JR. Biosynthesis of 19-nor-steroids involves hydroxylation of the C-19 methyl group. We characterized the adrenal 11 beta, 18,19-hydroxylase enzyme system in inbred salt-sensitive and resistant rats (R/JR). This system is capable of all three hydroxylations. The Km for 19-hydroxylation was different from S/JR and R/JR but was much greater for 11 beta- and 18-hydroxylation in both. This suggested that the catalytic site for 19-hydroxylation is different from that for 11 beta and 18. The S/JR adrenal enzyme binds the substrate with higher affinity than does the R/JR adrenal enzyme. We were unable to distinguish the cDNAs of the S/JR from the R/JR adrenal enzyme from bovine 11 beta-hydroxylase cDNA by restriction mapping. We were unable to demonstrate restriction length polymorphism. 19-Acetylenic DOC is an inhibitor which preferentially inhibits the 19-hydroxylation of DOC, and does not interfere with the 18- and 11 beta-hydroxylation. This inhibition leads to a reduction in blood pressure in the S/JR Dahl rat. We suggest that an S/JR 19-nor-DOC is involved in the development of salt-sensitivity and hypertension and that inhibition of its formation by acetylenic DOC and other aromatase and non-aromatase inhibitors is associated with reversal of these phenomena.</description><identifier>ISSN: 0960-0760</identifier><identifier>EISSN: 1879-1220</identifier><identifier>DOI: 10.1016/0960-0760(93)90116-E</identifier><identifier>PMID: 8481338</identifier><language>eng</language><publisher>Oxford: Elsevier Science</publisher><subject>Animals ; Aromatase Inhibitors ; Arterial hypertension. Arterial hypotension ; Biological and medical sciences ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Corticosterone - analogs & derivatives ; Corticosterone - metabolism ; Experimental diseases ; Humans ; Hypertension - genetics ; Hypertension - metabolism ; Medical sciences ; Rats ; Steroid 11-beta-Hydroxylase - antagonists & inhibitors</subject><ispartof>Journal of steroid biochemistry and molecular biology, 1993-04, Vol.45 (1-3), p.13-18</ispartof><rights>1993 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>309,310,314,780,784,789,790,23930,23931,25140,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4728543$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8481338$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MELBY, J. C</creatorcontrib><creatorcontrib>AZAR, S. T</creatorcontrib><creatorcontrib>DELANEY, M</creatorcontrib><creatorcontrib>HOLBROOK, M</creatorcontrib><creatorcontrib>GRIFFING, G. T</creatorcontrib><creatorcontrib>JOHNSTON, J. O'N</creatorcontrib><title>19-nor-corticosteroids in genetic hypertension. Effects of inhibitors of 11β,18,19-hydroxylase activity</title><title>Journal of steroid biochemistry and molecular biology</title><addtitle>J Steroid Biochem Mol Biol</addtitle><description>The long-term objective is to understand the role of the adrenal in altering systemic arterial blood pressure. This paper summarizes research on genetic hypertension in the rat and bears a relationship to several forms of human hypertension in which defects of steroid hydroxylases lead to increased secretion of mineralocorticoids other than aldosterone in genetic and experimental hypertension in rats. We demonstrated that 19-nor-corticosteroids are produced in excess in genetic and experimental hypertension in rats and man. We studied the enzymatic alteration responsible for excessive production of 19-nor-deoxycorticosterone (19-nor-DOC) in the salt-sensitive hypertensive rat S/JR. Biosynthesis of 19-nor-steroids involves hydroxylation of the C-19 methyl group. We characterized the adrenal 11 beta, 18,19-hydroxylase enzyme system in inbred salt-sensitive and resistant rats (R/JR). This system is capable of all three hydroxylations. The Km for 19-hydroxylation was different from S/JR and R/JR but was much greater for 11 beta- and 18-hydroxylation in both. This suggested that the catalytic site for 19-hydroxylation is different from that for 11 beta and 18. The S/JR adrenal enzyme binds the substrate with higher affinity than does the R/JR adrenal enzyme. We were unable to distinguish the cDNAs of the S/JR from the R/JR adrenal enzyme from bovine 11 beta-hydroxylase cDNA by restriction mapping. We were unable to demonstrate restriction length polymorphism. 19-Acetylenic DOC is an inhibitor which preferentially inhibits the 19-hydroxylation of DOC, and does not interfere with the 18- and 11 beta-hydroxylation. This inhibition leads to a reduction in blood pressure in the S/JR Dahl rat. We suggest that an S/JR 19-nor-DOC is involved in the development of salt-sensitivity and hypertension and that inhibition of its formation by acetylenic DOC and other aromatase and non-aromatase inhibitors is associated with reversal of these phenomena.</description><subject>Animals</subject><subject>Aromatase Inhibitors</subject><subject>Arterial hypertension. Arterial hypotension</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Cardiology. Vascular system</subject><subject>Corticosterone - analogs & derivatives</subject><subject>Corticosterone - metabolism</subject><subject>Experimental diseases</subject><subject>Humans</subject><subject>Hypertension - genetics</subject><subject>Hypertension - metabolism</subject><subject>Medical sciences</subject><subject>Rats</subject><subject>Steroid 11-beta-Hydroxylase - antagonists & inhibitors</subject><issn>0960-0760</issn><issn>1879-1220</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM1KxDAUhYMoOv68gUIXIgpTvTdpm2QpMv7AgBtdlzRJnUinGZOM2NfyQXwmiw5uXV3OPR_f4hByjHCJgNUVyApy4BWcS3YhAbHKZ1tkgoLLHCmFbTL5Q_bIfoyvAMAY8l2yKwqBjIkJWaDMex9y7UNy2sdkg3cmZq7PXmxvx1-2GFY2JNtH5_vLbNa2VqeY-XZkFq5xyYefhPj1OUUxHYWLwQT_MXQq2kzp5N5dGg7JTqu6aI8294A8386ebu7z-ePdw831PF-hFCnHRplGYqOLwrSWU27aCrRBC9o21AhlgDdUlUxKsIy2WnEjSoCiKUpgnLIDcvbrXQX_trYx1UsXte061Vu_jjUvRykdh_gPxKrkQAUfwZMNuG6W1tSr4JYqDPVmw7E_3fQqatW1QfXaxT-s4FSUBWPfIvqB0g</recordid><startdate>19930401</startdate><enddate>19930401</enddate><creator>MELBY, J. C</creator><creator>AZAR, S. T</creator><creator>DELANEY, M</creator><creator>HOLBROOK, M</creator><creator>GRIFFING, G. T</creator><creator>JOHNSTON, J. O'N</creator><general>Elsevier Science</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>19930401</creationdate><title>19-nor-corticosteroids in genetic hypertension. Effects of inhibitors of 11β,18,19-hydroxylase activity</title><author>MELBY, J. C ; AZAR, S. T ; DELANEY, M ; HOLBROOK, M ; GRIFFING, G. T ; JOHNSTON, J. 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C</creatorcontrib><creatorcontrib>AZAR, S. T</creatorcontrib><creatorcontrib>DELANEY, M</creatorcontrib><creatorcontrib>HOLBROOK, M</creatorcontrib><creatorcontrib>GRIFFING, G. T</creatorcontrib><creatorcontrib>JOHNSTON, J. O'N</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of steroid biochemistry and molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MELBY, J. C</au><au>AZAR, S. 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We demonstrated that 19-nor-corticosteroids are produced in excess in genetic and experimental hypertension in rats and man. We studied the enzymatic alteration responsible for excessive production of 19-nor-deoxycorticosterone (19-nor-DOC) in the salt-sensitive hypertensive rat S/JR. Biosynthesis of 19-nor-steroids involves hydroxylation of the C-19 methyl group. We characterized the adrenal 11 beta, 18,19-hydroxylase enzyme system in inbred salt-sensitive and resistant rats (R/JR). This system is capable of all three hydroxylations. The Km for 19-hydroxylation was different from S/JR and R/JR but was much greater for 11 beta- and 18-hydroxylation in both. This suggested that the catalytic site for 19-hydroxylation is different from that for 11 beta and 18. The S/JR adrenal enzyme binds the substrate with higher affinity than does the R/JR adrenal enzyme. We were unable to distinguish the cDNAs of the S/JR from the R/JR adrenal enzyme from bovine 11 beta-hydroxylase cDNA by restriction mapping. We were unable to demonstrate restriction length polymorphism. 19-Acetylenic DOC is an inhibitor which preferentially inhibits the 19-hydroxylation of DOC, and does not interfere with the 18- and 11 beta-hydroxylation. This inhibition leads to a reduction in blood pressure in the S/JR Dahl rat. We suggest that an S/JR 19-nor-DOC is involved in the development of salt-sensitivity and hypertension and that inhibition of its formation by acetylenic DOC and other aromatase and non-aromatase inhibitors is associated with reversal of these phenomena.</abstract><cop>Oxford</cop><pub>Elsevier Science</pub><pmid>8481338</pmid><doi>10.1016/0960-0760(93)90116-E</doi><tpages>6</tpages></addata></record> |
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| subjects | Animals Aromatase Inhibitors Arterial hypertension. Arterial hypotension Biological and medical sciences Blood and lymphatic vessels Cardiology. Vascular system Corticosterone - analogs & derivatives Corticosterone - metabolism Experimental diseases Humans Hypertension - genetics Hypertension - metabolism Medical sciences Rats Steroid 11-beta-Hydroxylase - antagonists & inhibitors |
| title | 19-nor-corticosteroids in genetic hypertension. Effects of inhibitors of 11β,18,19-hydroxylase activity |
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