Long-term low-dose angiotensin converting enzyme inhibitor treatment increases vascular cyclic guanosine 3',5'-monophosphate.
We investigated functional changes in aortic preparations of spontaneously hypertensive rats treated in utero and subsequently up to 20 weeks of age with the angiotensin converting enzyme (ACE) inhibitors ramipril (0.01 and 1 mg/kg per day) and perindopril (0.01 mg/kg per day). Early-onset treatment with the high dose of ramipril inhibited aortic ACE activity, prevented the development of hypertension, increased aortic vasodilator responses to acetylcholine (10(-8) to 10(-6) mol/L), decreased vasoconstrictor responses to norepinephrine (10(-8) mol/L), and increased aortic cyclic GMP content by 160%. Low-dose ramipril inhibited aortic ACE activity and attenuated the aortic vasoconstrictor response to norepinephrine but had no effect on blood pressure. Low-dose treatment with ramipril and perindopril resulted in a significant increase in aortic cyclic GMP content by 98% and 77%, respectively. Long-term coadministration of the bradykinin B2-receptor antagonist Hoe 140 abolished the ACE inhibitor-induced increase in aortic cyclic GMP. Our data demonstrate that long-term treatment with ACE inhibitors can alter vascular function of compliance vessels independently of the antihypertensive action. The increase in aortic cyclic GMP was due to bradykinin potentiating the action of the ACE inhibitors.
Gohlke
P
P
Department of Pharmacology, University of Heidelberg, Frankfurt, Germany.
Lamberty
V
V
Kuwer
I
I
Bartenbach
S
S
Schnell
A
A
Linz
W
W
Schölkens
B A
BA
Wiemer
G
G
Unger
T
T
D000375:Aging / Q000502:physiology; D000704:Analysis of Variance; D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006973:Hypertension / Q000235:genetics / Q000517:prevention & control*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008431:Maternal-Fetal Exchange; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D020913:Perindopril; D011247:Pregnancy; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*; D012016:Reference Values; D013599:Systole / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D000804:Angiotensin II; C065679:icatibant; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D006152:Cyclic GMP; D017257:Ramipril; D001920:Bradykinin; D020913:Perindopril