Drugs online research references
rambam.health.gov.il
We investigated the mechanism of the antiatherosclerotic effect of the angiotensin-converting enzyme (ACE) inhibitor, ramipril, in the apolipoprotein (apo) E-deficient mice. Mice that received a high dose (5 mg/kg/day) of ramipril supplemented in their drinking water for 10 weeks showed reduced aortic lesion size by 75% compared with placebo-treated mice. At this dosage, ramipril significantly reduced blood pressure from 95+/-5 mm Hg before treatment to 68+/-4 mm Hg at the end of the treatment period. Ramipril also increased the resistance of the mouse low-density lipoprotein (LDL) to CuSO4-induced oxidation, as shown by a prolongation of the lag time required for the initiation of LDL oxidation from 90 min in the placebo-treated mice to >180 min in the ramipril-treated mice. Similarly, a reduction in the maximal LDL-associated conjugated dienes after 180 min of oxidation by 250% in comparison with placebo-treated mice was noted. Ramipril (1 mg/kg/day) that was still adequate to reduce their plasma ACE activity and LDL propensity to lipid peroxidation was insufficient to reduce their blood pressure. This dosage also inhibited the progression of atherosclerosis in the apo E-deficient mice by 74%. The contribution of bradykinin potentiation to the ACE-inhibitor action was assessed by cotreatment of ramipril with the bradykinin B2-receptor antagonist, icatibant (HOE-140, 0.5 mg/kg given subcutaneously twice a day) for a period of 10 weeks. HOE-140 had no effects on ACE activity, LDL lipid peroxidation, blood pressure, or atherosclerosis. In combination with ramipril, no additional effect of HOE-140 on LDL oxidation or on atherosclerosis was noted in comparison with ramipril treatment alone. We thus conclude that the antiatherogenic effect of ramipril in E(0) mice is independent of blood pressure reduction and is not mediated by bradykinin. It seems, therefore, that most of its antiatherosclerotic and antioxidative effects are mediated through the inhibition of angiotensin II production.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10630734&dopt=Abstract
Hypertension. 1993 Nov;22(5):682-7.
Long-term low-dose angiotensin converting enzyme inhibitor treatment increases vascular cyclic guanosine 3',5'-monophosphate.
Gohlke P, Lamberty V, Kuwer I, Bartenbach S, Schnell A, Linz W, Scholkens BA, Wiemer G, Unger T.
Department of Pharmacology, University of Heidelberg, Frankfurt, Germany.
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.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8225528&dopt=Abstract
medinf.mu-luebeck.de
Inhibitors of angiotensin I-converting enzyme (ACE) are very efficacious in the potentiation of the actions of bradykinin (BK) and are able to provoke a B(2) receptor-mediated vasodilation even after desensitization of this receptor. Because this activity cannot be easily explained only by an inhibition of kinin degradation, direct interactions of ACE inhibitors with the B(2) receptor or its signal transduction have been hypothesized. To clarify the significance of degradation-independent potentiation, we studied the vasodilatory effects of BK and 2 degradation-resistant B(2) receptor agonists in the isolated rat heart, a model in which ACE and aminopeptidase P (APP) contribute equally to the degradation of BK. Coronary vasodilation to BK and to a peptidic (B6014) and a nonpeptidic (FR190997) degradation-resistant B(2) agonist was assessed in the presence or absence of the ACE inhibitor ramiprilat, the APP inhibitor mercaptoethanol, or both. Ramiprilat or mercaptoethanol induced leftward shifts in the BK dose-response curve (EC(50)=3.4 nmol/L) by a factor of 4.6 or 4.9, respectively. Combined inhibition of ACE and APP reduced the EC(50) of BK to 0.18 nmol/L (ie, by a factor of 19) but potentiated the activity of B6014 (EC(50)=1.9 nmol/L) only weakly without altering that of FR190997 (EC(50)=0.34 nmol/L). Desensitization of B(2) receptors was induced by the administration of BK (0.2 micromol/L) or FR190997 (0.1 micromol/L) for 30 minutes; the vascular reactivity to ramiprilat or increasing doses of BK was tested thereafter. After desensitization with BK, but not FR190997, an additional application of ramiprilat provoked a B(2) receptor-mediated vasodilation. High BK concentrations were still effective at the desensitized receptor. The process of desensitization was not altered by ramiprilat. These results show that in this model, all potentiating actions of ACE inhibitors on kinin-induced vasodilation are exclusively related to the reduction in BK breakdown and are equivalently provoked by APP inhibition. The desensitization of B(2) receptors is overcome by increasing BK concentrations, either directly or through the inhibition of ACE. These observations do not suggest any direct interactions of ACE inhibitors with the B(2) receptor or its signal transduction but point to a very high activity of BK degradation in the vicinity of the B(2) receptor in combination with a stimulation-dependent reduction in receptor affinity.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10642271&dopt=Abstract
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