Abstract-The functional inhibitory characteristics of the angiotensin II type 1 receptor blockers (ARB) candesartan; irbesartan; and losartan and its active metabolite EXP 3174 (EXP) were studied in rabbit aortic strips and rat portal vein preparations in vitro. Moreover, plasma-protein binding was determined, and the binding was high (Ͼ98.5%) for all ARBs. These values were needed to relate the concentrations of the ARBs used in vitro to the nonprotein bound concentrations in clinical use. In both vascular preparations, candesartan caused a marked decrease in the maximal contractile response of the angiotensin II (Ang II) concentration-response curve. Losartan, EXP, and irbesartan caused a rightward parallel shift without any major effects on the maximal response to Ang II. The inhibitory effect of candesartan developed slowly (maximal effect after Ͼ30 minutes) and lasted Ͼ2 hours despite repeated washing of the vessels. The effect of losartan, irbesartan, and EXP had a faster onset, and most of the inhibitory effect disappeared after washing. The duration of the inhibitory effects of the ARBs were not related to lipophilicity of the compounds. Cooling of the rat portal vein preparations to 4°C before administration of candesartan prevented the persistent inhibition of Ang II response seen at 37°C. For the other ARBs studied, the magnitude of inhibition and the speed of recovery of the Ang II response were independent of the incubation temperature before washing. In addition, when candesartan was given to conscious rats, the inhibitory effect on Ang II-induced blood pressure responses persisted during the 24-hour period despite nondetectable plasma concentrations of candesartan at 24 hours. [1][2][3] The tolerability of these compounds seems to be better than that of other antihypertensives, whereas the blood pressure-lowering effect is about the same as for angiotensin-converting enzyme inhibitors and calcium antagonists. 1-3 Regarding efficacy of different ARBs, candesartan and irbesartan were shown to be more effective than losartan in lowering 24-hour blood pressure (BP) in mildly to moderately hypertensive patients. 4,5 Candesartan was described to dissociate slowly from AT 1 -receptors in cell membrane preparations and to cause a more persistent inhibition of the angiotensin II (Ang II)-mediated vascular contractile response when compared with losartan. 6 In isolated vascular preparations from the rabbit, losartan caused a parallel rightward shift in the concentration-effect curves for Ang II, 7 whereas candesartan caused a marked suppression of the maximum contractile response to Ang II. 1,6 Thus ARBs may differ in their antagonism of the Ang II-mediated response, causing surmountable or insurmountable antagonism. 8 The mechanism of the insurmountable antagonism of candesartan and the long-lasting duration of effect is not clear, although it may be related to its slow dissociation from the receptor. 1,6 The aim of our study was to investigate the functional inhibitory characteristics of different ARBs. ...

Grönros J, Wikström J, Brandt-Eliasson U, Forsberg GB, Behrendt M, Hansson GI, Gan LM. Effects of rosuvastatin on cardiovascular morphology and function in an ApoE-knockout mouse model of atherosclerosis. Am J Physiol Heart Circ Physiol 295: H2046-H2053, 2008. First published September 12, 2008 doi:10.1152/ajpheart.00133.2008.-This study investigated the effects of rosuvastatin on plaque progression and in vivo coronary artery function in apolipoprotein E-knockout (ApoE-KO) mice, using noninvasive high-resolution ultrasound techniques. Eightweek-old male ApoE-KO mice (n ϭ 20) were fed a high-fat diet with or without rosuvastatin (10 mol ⅐ kg Ϫ1 ⅐ day Ϫ1 ) for 16 wk. When compared with control, rosuvastatin reduced total cholesterol levels (P Ͻ 0.05) and caused significant retardation of lesion progression in the brachiocephalic artery, as visualized in vivo using an ultrasound biomicroscope (P Ͻ 0.05). Histological analysis confirmed the reduction of brachiocephalic atherosclerosis and also revealed an increase in collagen content in the statin-treated group (P Ͻ 0.05). Coronary volumetric flow was measured by simultaneous recording of Doppler velocity signals and left coronary artery morphology before and during adenosine infusion. The hyperemic flow in response to adenosine was significantly greater in left coronary artery following 16 wk of rosuvastatin treatment (P Ͻ 0.001), whereas the baseline flow was similar in both groups. In conclusion, rosuvastatin reduced brachiocephalic artery atherosclerotic plaques in ApoE-KO mice. Coronary artery function assessed using recently developed in vivo ultrasoundbased protocols, also improved. apolipoprotein E-knockout mouse; ultrasound imaging; atherosclerosis; rosuvastatin THE INHIBITION OF 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase using statins has become a standard treatment regimen in patients with atherosclerosis. In addition to their cholesterol-lowering effects (11,20), statins have been shown to retard the progression of atherosclerosis (36), improve endothelial function (37, 45), reduce systemic inflammatory markers (32, 41), and reduce cardiovascular mortality and morbidity (1). Recently, the clinical regression of coronary artery atherosclerosis was reported with the use of a thirdgeneration statin (35).Despite the success of statins, cardiovascular mortality and morbidity still remain high in developed countries. When one explores new therapeutic strategies to treat atherosclerotic cardiovascular disease, it is increasingly important to demonstrate the beneficial antiatherosclerotic effects on top of the cholesterol-lowering effect of statin as well as potential pleiotrophic effects. In line with this approach, atherosclerotic animal models that can respond to currently available statin treatments are key for translational research.The effects of various statins in atherosclerotic mice are inconclusive. Differences in genetic modifications, sex, diet, as well as differences in the statins themselves, have produced different results (55). ...

The amplitude and velocities of MAM are easily recorded in rabbits with excellent reproducibility and the changes with age seem to be very similar to those in humans. These noninvasive M-mode and tissue Doppler methods are therefore suitable for the investigation of left ventricular function in experimental studies in rabbits.

Myeloperoxidase (MPO) activity is suggested to reduce the function of vascular nitric oxide, thereby contributing to endothelial dysfunction, although data in rodents are inconclusive. We examined vascular contractile and relaxant responses in MPO-deficient (MPO−/−) and wild-type mice to investigate the role for myeloperoxidase in the development of endothelial dysfunction. Carotid and saphenous arteries were taken from 8-month-old mice and studied in a myograph. Responses of carotid arteries to phenylephrine, high potassium, or acetylcholine (Ach) were statistically not different from controls. Treatment with lipopolysaccharide (LPS; to enhance endothelial dysfunction) reduced responses to Ach in MPO−/− but did not affect responses in wild-type. In response to high concentrations of Ach, carotid arteries responded with transient contractions, which were not different between the groups and not affected by LPS treatment. Saphenous arteries from MPO−/− had smaller normalized diameters and developed less contractile force. Vessels from MPO−/− were less sensitive to Ach than controls. These data suggest that mature MPO-deficient mice do not show enhanced endothelial function compared to wild-type mice, even when provoked with LPS treatment. The EDHF response appears to be reduced in MPO deficiency.

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