Antihypertensive effects of an aromatase inhibitor in inbred salt-sensitive rats.
Rats susceptible to the hypertensive effect of dietary salt (SS/Jr) have excess urinary 19-nordeoxycorticosterone compared with salt-resistant control rats (SR/Jr). 19-Nordeoxycorticosterone is a hypertensinogenic mineralocorticoid, but whether it contributes to the salt sensitivity of SS/Jr is unknown. This study sought to evaluate the contribution of 19-nordeoxycorticosterone to the salt sensitivity of SS/Jr by lowering its production with an aromatase inhibitor, 10-propargyl-androst-4-ene,3,17-dione (19-acetylenic-androstenedione, 19-AA). This aromatase inhibitor also preferentially inhibits nonaromatizing adrenal 19-hydroxylation, an essential step in the formation of 19-nordeoxycorticosterone. To test this hypothesis, inhibitor (120 mg) or vehicle pellets were implanted into male and female weanling SS/Jr at 42 days of age. A high salt diet (8% NaCl) was started and two additional pellets were implanted at 52 and 62 days of age. Systolic blood pressure was measured in all animals and urinary corticosteroids in males. Compared with vehicle, the inhibitor lowered blood pressure at 50 days of age (when it could first be measured) until 64 days of age in females and 71 days of age in males. Corticosterone and aldosterone levels were not different between 19-AA- and vehicle-treated SS/Jr. 19-Nordeoxycorticosterone levels, however, were mildly reduced with the inhibitor (0.05 less than p less than 0.10). After 28 days of high salt diet all 23 of the 19-AA-treated SS/Jr were alive, whereas almost one half of the control animals had died. These data demonstrate that 19-AA attenuates the hypertension in SS/Jr; this effect may be through reduction in 19-nordeoxycorticosterone production.(ABSTRACT TRUNCATED AT 250 WORDS)
Griffing
G T
GT
Evans Memorial Department of Clinical Research, University Hospital, Boston University Medical Center, MA 02118.
Melby
J C
JC
Holbrook
M
M
Johnston
O N
ON
D000450:Aldosterone / Q000652:urine; D000735:Androstenedione / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D047072:Aromatase Inhibitors; D003348:Cortisone / Q000652:urine; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000652:urine; D005260:Female; D006973:Hypertension / Q000517:prevention & control*; D008297:Male; D010293:Pargyline / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012965:Sodium Chloride / Q000494:pharmacology
D000959:Antihypertensive Agents; D047072:Aromatase Inhibitors; D000735:Androstenedione; D003900:Desoxycorticosterone; D012965:Sodium Chloride; C019026:19-nordeoxycorticosterone; D000450:Aldosterone; D010293:Pargyline; C033071:plomestane; D003348:Cortisone