Chronic inhibition of angiotensin converting enzyme decreases Ca2+-dependent tone of aorta in hypertensive rats.
Long-term effects of a novel angiotensin converting enzyme (ACE) inhibitor, CS-622, on Ca2+-dependent tone in aortic smooth muscles of spontaneously hypertensive rats (SHR) were examined. CS-622 (3 or 10 mg/kg/day), when orally administered to SHR for 21 weeks, exhibited a dose-dependent antihypertensive action. In Krebs-Henseleit solution, removal of Ca2+ caused much greater relaxation in aortas excised from control SHR than those from SHR treated with CS-622. Restoration of Ca2+ from zero to 2.5 mM elicited a marked contraction in aortas from control SHR but only a small contraction in aortas from both CS-622-treated SHR and normotensive Wistar-Kyoto rats. These findings suggested that myogenic tone that resulted from increased Ca2+ permeability in aortas of SHR was suppressed by long-term treatment with CS-622. The aortic tone from the individual rats correlated well with systolic blood pressure in both CS-622-treated and control SHR. The exaggerated myogenic tone in aortas of SHR was attenuated in the medium containing nicardipine but was not altered in the presence of CS-622 diacid (active form of CS-622) at a concentration high enough to fully inhibit aortic ACE. The myogenic tone in normal Ca2+ concentration was not decreased in aortas excised from SHR treated with hydralazine (5 mg/kg/day) for 21 weeks. We conclude that after prolonged administration CS-622 reduced the high vascular tension resulting from increased Ca2+ permeability of vascular smooth muscle membrane in SHR and that the restoration of normal Ca2+ permeability of vascular smooth muscles may underlie long-term antihypertensive action of ACE inhibitors.
Sada
T
T
Cardiovascular Division, Sankyo Co., Ltd., Tokyo, Japan.
Koike
H
H
Nishino
H
H
Oizumi
K
K
D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D009529:Nicardipine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013841:Thiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D013841:Thiazepines; C055603:temocapril hydrochloride; D009529:Nicardipine; D002118:Calcium