1 When administered to young spontaneously hypertensive rats (SHRs), dihydralazine (25 mg kg-', daily) and captopril (100mg kg-, daily) prevent with the same efficacy genetic hypertension development (GHD). 2 Dihydralazine treatment increased vascular mesenteric compliance, as shown by a significant decrease in the stiffness of the vessels (-27%), and induced slight reductions in contractility (-12%) and in wall to lumen (W/L) ratio (-15%). After treatment withdrawal, all these parameters returned to control values within 7 weeks, as did blood pressure. 3 Captopril treatment also strongly increased the mesenteric vessels compliance, vessel stiffness being decreased by 16%, and reduced their contractility (-15%) and their W/L ratio (-30%). These effects as well as those exerted on blood pressure persisted up to 7 weeks after treatment ceased although there was a slight trend to a progressive reduction in the intensity of both phenomena. 4 These experiments show that captopril but not dihydralazine has a long-lasting effect in opposing the functional and morphological vascular alterations occurring during GHD in SHRs and this phenomenon probably contributes to a large extent to the sustained preventive effects of the drug against GHD.

Captopril (100mg/kg) administered daily by gavage to young spontaneously hypertensive rats (SHRs) from their 6th to 20th weeks of age almost completely inhibited genetic hypertension development (GHD). This effect was correlated with an early and long-lasting limitation of the progressive increase in peripheral resistance which normally develops in SHRs during their growth. Heart rate, cardiac and systolic indexes remained unchanged, plasma renin concentration was significantly increased and heart weight/body weight ratio was significantly decreased. At last, captopril's GHD preventive effect persisted up to 12 weeks after treatment discontinuation.

As an independent risk factor, UCMS reproduced the endothelial alterations observed in depression but was not sufficient to provoke morphological alterations.

Background and purpose: Atrial fibrillation (AF) is the most common electrical cardiac disorder in clinical practice. The major trigger for AF is focal ectopic activity of unknown origin in sleeves of cardiac muscle that extend into the pulmonary veins. We examined the role of noradrenaline in the genesis of ectopic activity in the pulmonary vein. Experimental approach: Mechanical activity of strips of pulmonary vein isolated from male Wistar rats was recorded via an isometric tension meter. Twitch contractions of cardiac myocytes were evoked by electrical field stimulation in a tissue bath through which flowed Krebs-Heinseleit solution warmed to 36-371C and gassed with 95% O 2 5% CO 2 . Key results: The superfusion of noradrenaline induced ectopic contractions in 71 of 76 different isolated pulmonary veins. Ectopic contractions in the pulmonary vein were not associated with electrically evoked twitch contractions. The effect of noradrenaline on the pulmonary vein could be replicated by the simultaneous, but not separate, application of the a adrenoceptor agonist phenylephrine and the b adrenoceptor agonist isoprenaline. The use of selective agonists and antagonists for adrenoceptor subtypes showed that ectopic activity in the pulmonary vein arose from the simultaneous stimulation of a 1 and b 1 adrenoceptors. The application of noradrenaline to isolated strips of left atrium did not induce ectopic contractions (n ¼ 10). Conclusions: These findings suggest an origin for ectopic activity in the pulmonary vein that requires activation of both a and b adrenoceptors. They also open new perspectives towards our understanding of the triggering of AF.

No abstract

Phosphodiesterase (PDE) 4 inhibitors are a class of drugs that can provide novel therapies for asthma and chronic obstructive pulmonary disease. Their development is frequently hampered by the induction of vascular toxicity in rat mesenteric tissue during preclinical studies. Whereas these vascular lesions in rats have been well characterized histologically, little is known about their pathogenesis and in turn, sensitive and specific biomarkers for preclinical and clinical monitoring do not exist. In order to investigate the early molecular mechanisms underlying vascular injury, time-course studies were performed by treating rats for 2-24 h with high doses of the PDE4 inhibitor CI-1044. Transcriptomics analyses in mesenteric tissue were performed using oligonucleotide microarray and real-time RT-PCR technologies and compared to histopathological observations. In addition, protein measurements were performed in serum samples to identify soluble biomarkers of vascular injury. Our results indicate that molecular alterations preceded the histological observations of inflammatory and necrotic lesions in mesenteric arteries. Some gene expression changes suggest that the development of the lesions could follow a primary modulation of the vascular tone in response to the pharmacological effect of the compound. Activation of genes coding for pro- and antioxidant enzymes, cytokines, adhesion molecules, and tissue inhibitor of metalloproteinase 1 (TIMP-1) indicates that biomechanical stimuli may contribute to vascular oxidant stress, inflammation, and tissue remodeling. TIMP-1 appeared to be an early and sensitive predictive biomarker of the inflammatory and the tissue remodeling components of PDE4 inhibitor-induced vascular injury.

The study was designed to compare the effects of agonists and flow on endothelial reactivity in perfused coronary arteries of spontanously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. To this end, coronary arteries were cannulated at both ends using an arterio-graph system. In the absence of flow and under an intraluminal pressure of 30 mm Hg, SHR arteries had larger internal diameters compared to those of WKY rats (275 ± 10 vs. 239 ± 7 µm, p < 0.01). In preparations preconstricted with serotonin HT, concentration-effect curves were constructed by adding acetylcholine or bradykinin in the bath. On the other hand, the effect of a stepwise increase in intraluminal flow (50–450 µl/min) of physiological salt solution was observed. Agonist-induced dilations were significantly smaller in arteries of SHRs compared to those of WKY rats. Starting flow at the plateau of constriction led to dilations that were also weaker in SHR compared to WKY vessels: 27 ± 6 vs. 61 ± 3, p < 0.001, when expressed as percentage of maximal initial constrictions. The maximal dilation induced by flow in SHR arteries was obtained for a greater value of shear stress compared to that determined in WKY preparations: 81 ± 6 vs. 60 ± 4 dyn/cm², p < 0.01. After endothelium destruction, flow-induced dilation was totally abolished in SHR arteries but only reduced in those of WKY rats. Subsequent additions of sodium nitroprusside induced complete dilations in vessels from both strains. The same protocol was performed in arteries submitted to a perfusion pressure of 90 mm Hg. In these conditions, impairments of agonist-and flow-induced dilations were also evidenced in SHR arteries. These results show that both the endothelium-dependent dilation induced by acetylcholine or bradykinin and the flow-induced dilation are impaired in coronary arteries of SHRs compared to WKY rats. These alterations appear to be due to a deterioration of endothelial cell function in the presence of a normal reactivity of the smooth muscle cells.

The purpose of this study was to investigate the mechanism of the vascular relaxation produced by polyphenolic substances from red wine, with a particular focus on the possible involvement of purinoceptors. With this aim, relaxing responses induced by procyanidin from grape seeds (GSP), anthocyanins, catechin and epicatechin were assessed in rat isolated aortic rings left intact (+E) or endothelium-denuded (-E). In preparations precontracted with noradrenaline, incubation with NG-nitro-L-arginine methyl ester (100 microM, 30 min) fully inhibited the GSP-induced relaxations. Concentration-effect curves to these substances (from 10(-7) to 10(-1) g/L) were determined in depolarized (60 mM KCl) preparations in control condition, after incubation with reactive blue 2 (an antagonist of P2Y purinoceptors, 30 microM), with apyrase (an enzyme which hydrolyses ATP and ADP, 0.8 U/mL) or with alpha,beta-methylene ATP (an inhibitor of ecto ATPases, 10 microM). In (+E) rings, relaxations (expressed as percentage of initial contraction) were 41 +/- 2 and 37 +/- 3 for GSP and anthocyanins, respectively. Only modest relaxations (ca. 10%) were observed in (-E) rings, as it was the case for catechin and epicatechin in (+/- E) rings. Reactive blue 2 or apyrase inhibited the GSP- and anthocyanin-induced relaxations in (+E) rings, while alpha,beta-methylene ATP shifted to the left the relaxation curves obtained with GSP. These data confirm that modest relaxations observed with catechin and epicatechin are not endothelium-dependent but that GSP and anthocyanins induce a relaxing effect, which is related to the integrity of the endothelium and the synthesis and release of nitric oxide (NO). Furthermore, the inhibition by apyrase and the increase by ecto-ATPase inhibition of the GSP- and anthocyanin-induced relaxation suggest that these substances could act via an initial release of nucleotides, which in turn could activate P2Y1 and/or P2Y2 purinoceptors of endothelial cells, trigger the synthesis and release of NO and then lead to relaxation.