To clarify the mechanisms involved in relaxations mediated by endothelium-derived hyperpolarizing factor (EDHF), acetylcholine (ACh)-induced endothelium-dependent relaxations and hyperpolarizations were examined in the rat aorta, the main branch of the mesenteric artery (MBMA) and the first branch of the mesenteric aftery (FBMA). In the presence of 100 microM N(G)-nitro-L-arginine (L-NNA) and 10 microM indomethacin, ACh (1 nM to 100 microM) produced no relaxation in the phenylephrine-precontracted aorta. The L-NNA-resistant relaxations by ACh in MBMA precontracted with phenylephrine were eliminated in the presence of 1 microM nifedipine where contractions were independent of L-type Ca(2+) channel activation. In FBMA precontracted with phenylephrine, the L-NNA-resistant relaxations were only partially inhibited by nifedipine. When vessels had been contracted with 300 nM phorbol-12,13-dibutyrate in the presence of nifedipine, ACh-induced L-NNA-resistant relaxations were observed in FBMA only. Pinacidil produced relaxations in all different-sized blood vessels, although sensitivity was inversely related to vessel size. The extent of the ACh hyperpolarizing responses was much smaller than that by pinacidil in the aorta. The membrane potential changes by ACh and pinacidil were almost the same in FBMA. These results indicate that the contribution of EDHF to endothelium-dependent relaxations increases as the vessel size decreases. This may be partly explained by precontractile processes dependent on Ca(2+) entry through L-type Ca(2+) channels, because Ca(2+) channel deactivation seems to be involved as a major mechanism of EDHF-mediated vasorelaxations. However, EDHF may also generate vasorelaxations by an additional mechanism, probably a reduced Ca(2+) sensitivity of contractile elements, as proposed for ATP-sensitive K(+) channel openers.

Analysis of Variance↗

PubMedDate not supplied

Reduction of endothelial microfilament bundles in the low-shear region of the canine aorta. Association with intimal plaque formation in hypercholesterolemia.

To interrelate in vivo wall shear stress, endothelial microfilament bundle formation, and atherosclerosis localization, we used a mild abdominal aortic stenosis in 11 beagles to produce a range of wall shear stresses above and below the constriction. Six of the beagles were fed standard animal chow supplemented with 5% cholesterol and 10% coconut oil. Wall shear stresses, endothelial microfilament bundles, and intimal plaque localization were assessed along the stenosed aorta. Shear stress was determined in vivo from the near-wall velocity profiles with a 20-MHz, 80-channel, multigate Doppler velocimeter. Content of the microfilament bundles was quantified by planimetry of transmission electron photomicrographs. After 6 weeks, mean shear stress was higher immediately upstream from the throat of the stenosis than at the proximal site (46.1 +/- 7.3 dynes/cm2 versus 24.0 +/- 6.2 dynes/mc2, p less than 0.001) and was significantly lower immediately distal to the stenosis than at the proximal site (9.4 +/- 0.3 dynes/cm2, p less than 0.01). The microfilament bundle content increased immediately upstream from the throat of the stenosis and decreased immediately distal to the stenosis compared with the proximal site in both normocholesterolemic and hypercholesterolemic fat-fed beagles. Intimal plaques formed exclusively immediately distal to the stenosis in the hypercholesterolemic beagles. These findings suggest that a low shear-stress environment attenuates endothelial microfilament bundle formation, thus leading to a predilection for the initiation of atherosclerosis in atherogenic conditions such as hypercholesterolemia.

Actin Cytoskeleton↗

PubMedDate not supplied

Cardiac Na(+) channel dysfunction in Brugada syndrome is aggravated by beta(1)-subunit.

BACKGROUND: Mutations in the gene encoding the human cardiac Na(+) channel alpha-subunit (hH1) are responsible for chromosome 3-linked congenital long-QT syndrome (LQT3) and idiopathic ventricular fibrillation (IVF). An auxiliary beta(1)-subunit, widely expressed in excitable tissues, shifts the voltage dependence of steady-state inactivation toward more negative potentials and restores normal gating kinetics of brain and skeletal muscle Na(+) channels expressed in Xenopus oocytes but has little if any functional effect on the cardiac isoform. Here, we characterize the altered effects of a human beta(1)-subunit (hbeta(1)) on the heterologously expressed hH1 mutation (T1620M) previously associated with IVF. METHODS AND RESULTS: When expressed alone in Xenopus oocytes, T1620M exhibited no persistent currents, in contrast to the LQT3 mutant channels, but the midpoint of steady-state inactivation (V(1/2)) was significantly shifted toward more positive potentials than for wild-type hH1. Coexpression of hbeta(1) did not significantly alter current decay or recovery from inactivation of wild-type hH1; however, it further shifted the V(1/2) and accelerated the recovery from inactivation of T1620M. Oocyte macropatch analysis revealed that the activation kinetics of T1620M were normal. CONCLUSIONS: It is suggested that coexpression of hbeta(1) exposes a more severe functional defect that results in a greater overlap in the relationship between channel inactivation and activation (window current) in T1620M, which is proposed to be a potential pathophysiological mechanism of IVF in vivo. One possible explanation for our finding is an altered alpha-/beta(1)-subunit association in the mutant.

Amino Acid Substitution↗

PubMedDate not supplied

[Real time spectral ultrasonic flowmeter].

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Adult↗

PubMedDate not supplied

Coronary atherosclerosis reduced in patients with familial hypercholesterolemia after intensive cholesterol lowering with low-density lipoprotein-apheresis: 1-year follow-up study. The Osaka LDL-Apheresis Multicenter Trial Group.

To test the hypothesis that aggressive cholesterol lowering results in a rapid regression of coronary atherosclerosis, the effect of low-density lipoprotein (LDL)-apheresis for 1 year on coronary artery diameters was studied in patients with heterozygous familial hypercholesterolemia. LDL-apheresis was performed every 2 weeks in 13 patients with LDL-cholesterol levels > or = 200 mg/dL despite treatment with conventional dietary and drug therapies. Coronary arteriography was performed before and 1 year after the initiation of treatment. The LDL-cholesterol level was decreased by an average of 71% immediately after the initial LDL-apheresis and by 30% before the second apheresis. Such phasic changes were observed throughout the trial. Computer-assisted automated quantitative arteriograms analyzed 101 proximal coronary segments. The mean lumen diameter of angiographically normal sections of each segment was slightly but significantly increased from 2.93 +/- 0.89 mm at baseline to 3.05 +/- 0.93 mm at the follow-up arteriogram (P < 0.05); 54 of the 101 segments showed a lesion stenosed by 20% or more in diameter. The minimal diameter of individual lesions was also significantly increased from 2.17 +/- 0.67 mm to 2.36 +/- 0.76 mm (P < 0.05), and thus the diameter stenosis was significantly reduced from 32.3 +/- 10.5% to 28.2 +/- 12.1% (P < 0.05). It is concluded that 1 year of aggressive cholesterol lowering, using LDL-apheresis, can significantly reduce coronary atherosclerosis in patients with familial hypercholesterolemia.

Adult↗