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From pharmacological investigations and clinical studies, it is known that ACE inhibitors exhibit additional local actions that are not related to hemodynamic changes and that cannot be explained only by interference with the renin-angiotensin system by means of an inhibition of ANG II formation. Because ACE is identical to kininase II, which inactivates the nonapeptide BK and related kinins, potentiation of kinins might be responsible for these additional effects of ACE inhibitors. ACE inhibition, concentration, and time dependently increased the formation of NO and PGI2 in cultured endothelial cells of different origin and from different species, including humans. The specific B2 kinin receptor antagonist, icatibant, suppressed the ACE inhibitor-induced increase in endothelial cyclic GMP accumulation index for NO-formation and, in parallel, attenuated the increase in PGI2 release. In renovascular models of hypertension associated with a stimulated renin-angiotensin system (two-kidney, one-clip), blood pressure reduction by ACE inhibitors was attenuated by icatibant, whereas in rats with genetic hypertension with normal to low plasma renin, blood pressure reduction through ACE inhibitors was not affected. In experimental atherosclerosis in rabbits, ACE inhibitors were able to preserve endothelial function and vascular reactivity and to reduce surface involvement. In the balloon denudation model of carotid arteries in rats, it was found that ACE inhibition markedly reduced neointima formation. However, when the ACE inhibitor was given together with icatibant, its effect was significantly blunted. Perfusion with ACE inhibitors induced a reduction of the incidence, as well as of the duration, of ventricular fibrillation and improved cardiodynamics and myocardial metabolism. BK perfusion induced comparable cardioprotective effects. In addition, perfusion with ACE inhibitors markedly increased the outflow of BK and related kinins from isolated rat hearts. The antiischemic effect of ACE inhibitors and BK were abolished by the addition of L-NNA (1 x 10(-6) mol/l) or icatibant (1 x 10(-9) mol/l). Similar results were found in dogs and rabbits with myocardial infarction. BK and related kinins also seem to be involved in preconditioning and remodeling. The effect of ACE inhibition in LVH was investigated in rats made hypertensive by aortic banding. ACE inhibition with ramipril, in the antihypertensive dose of 1 mg/kg/day for 6 weeks, prevented the increase in blood pressure and the development of LVH. A lower, nonantihypertensive dose of the ACE inhibitor (10 micrograms/kg/day for 6 weeks) had no effect on the increase in blood pressure or on plasma ACE activity, but also prevented LVH after aortic banding.4+ off

Despite a wealth of data, the mechanism of the direct dilator effect of furosemide on the systemic arterial and venous systems is far from being satisfactorily understood. Therefore, we investigated whether furosemide is capable of stimulating the production of the endogenous vasodilators nitric oxide and prostacyclin in primary cultured bovine aortic endothelial cells by an enhanced synthesis and release of endothelium-derived kinins. Nitric oxide production was assessed in terms of intracellular guanosine cyclic-3',5' monophosphate accumulation; kinin and prostacyclin release were determined by specific radioimmunoassays. Furosemide concentration- and time-dependently increased the formation of nitric oxide and prostacyclin. Maximal increases of both autacoids were already obtained after a 5-min incubation with 3 x 10(-7) to 10(-6) mol/l of furosemide. In the same concentration range, furosemide led to an enhanced release of kinins into the supernatant of the cells. This observation was supported by the inhibitory effect of the specific B2 kinin receptor antagonist icatibant (Hoe 140) on the furosemide-induced increase of nitric oxide and prostacyclin. Thus the hemodynamic effects, and in particular the direct early dilator effect, of furosemide may be explained in part by an enhanced endothelial synthesis and release of bradykinin and related kinins, which in turn stimulates endothelial autacoid formation via B2 kinin receptor activation.

Loss of endothelium-dependent relaxation is an early step in atherogenesis. To test the effect of low-dose felodipine on the progression of this dysfunction, male New Zealand white rabbits were rendered hyper-cholesterolemic with a diet containing 0.25 cholesterol and 3 coconut oil. After a 1-month induction period on this diet, during which the rabbits were identified as low or normal responders to cholesterol. 0.46 mg/kg of felodipine (FELO) or placebo (CON) were given by gavage once daily for a further 3 months. This regimen established FELO plasma levels (14.2 ± 1.3 nM. week 9) corresponding to therapeutic concentrations in humans and an average 13-fold increase in plasma cholesterol from below 1 mM. At the end of the treatment period, relaxation of norepinephrine (1 ± 10 8M)-precontracted proximal thoracic aorta strips to acetylcholine (ACh: 1 ± 10 8-1 ± 10 5M) was determined. Cholesterol exposure was calculated as the area under the curve for serum cholesterol x time[AUC(mM± day 1)]. Despite equal cholesterol load [FELO (n-17): 1.856 182 mM± day) and CON (n-22): 1.851 167 mM± day]. Maximal relaxation to 1 ± 10 7MACh was well preserved in strips from FELO-treated rabbits (29.5 ± 5.7) but suppressed in strips from untreated rabbits (11.0 ± 2.9). For comparison, relaxation in strips from standard diet controls was 49.8 ± 2.9 (n= 15). Moreover, there was a significant inverse correlation (r= -0.74) between percentage ACh relaxation and cholesterol exposure in FELO-treated rabbits. Subgrouping into low and normal responders to cholesterol revealed an almost complete relaxation in FELO low responders (n= 5): 35.9 ± 9.9 at 1.538 ± 482 mM± day. Relaxation in matched untreated CON low responders (n= 5) of 11.5 ± 7. at 1.149 ± 121 mM± day. in contrast, were equally impaired as in normal responding controls. In conclusion, exposure to cholesterol impairs endothelium-dependent relaxation in rabbits. This suppression is significantly reduced by once-daily low-dose felodipine treatment pointing to antiarter-iosclerotic activities at an early stage of atherogenesis.

The purpose of this study was to define the type of kinin receptors in bovine aortic endothelial cells. As a biochemical response we used the cyclic GMP production which can be attributed to the activation of the soluble guanylyl cyclase of the endothelial cells via endothelium-derived relaxing factor. For the first time we demonstrated that in addition to bradykinin (BK) the B1 kinin receptor agonist desArg9BK increased markedly the content of cyclic GMP. Similar to BK the desArg9BK-stimulated cyclic GMP production was transient and concentration dependent. The effects of both kinin agonists were inhibited by NG-nitro-L-arginine. The known B1 kinin receptor antagonist desArg9[Leu8] BK and the newly discovered antagonist desArg9D-Arg[Hyp3,Thi5,D-Tic7,Oic8]BK only inhibited the desArg9BK-stimulated cyclic GMP production. The B2 kinin receptor antagonists D-Arg[Hyp3,Thi5,D-Tic7,Oic8]BK and D-Arg[Hyp2,Thi5,8,D-Phe7]BK inhibited the production of cyclic GMP upon stimulation with BK and surprisingly also with desArg9BK. These findings indicate that bovine aortic endothelial cells possess B1 and B2 type kinin receptors which are associated with the production and/or release of endothelium-derived relaxing factor. Furthermore, it was shown for the first time that the B1 kinin receptor in bovine aortic endothelial cells seems to be quite different from that which exists in isolated tissue preparations. The functional importance of these B1 type receptors with regard to regulation of blood pressure and blood flow remains to be determined.