Blood vessels最新文献

SKF-525A (proadifen) inhibits endothelium-dependent relaxations induced by acetylcholine, arachidonic acid and the calcium ionophore A23187. This suggests that SKF-525A is an inhibitor of endothelium-derived relaxing factor (EDRF) and that EDRF may be a product of arachidonic acid metabolism formed via a cytochrome P-450-dependent pathway or that EDRF release is dependent on cytochrome P-450. We tested this postulate using both isolated rings of rat thoracic aorta and dog mesenteric and femoral artery and the perfusion-superfusion bioassay. Rings of rat thoracic aorta and dog mesenteric and femoral artery with intact endothelium were precontracted with an EC50 concentration of norepinephrine (0.1 nmol/l) or U46619 (0.05 mumol/l) and the relaxation to acetylcholine (ACh), bradykinin, adenosine triphosphate (ATP) or nitroglycerin (GTN) were obtained before, 30 min after addition of, and 30 min after washout of SKF-525A (50 mumol/l). SKF-525A inhibited ACh-induced endothelium-dependent relaxation of rat aortic rings and endothelium-dependent relaxation of the dog mesenteric and femoral artery produced by ACh and ATP, but did not affect relaxation to bradykinin or GTN. The inhibitory effect on SKF-525A on ACh and ATP-induced relaxation was partially reversed upon its washout from the muscle chamber. Pretreatment of the blood vessels with ibuprofen (1 mumol/l) did not attenuate SKF-525A-mediated inhibition of the relaxations to any agonist. Selective exposure of dog femoral artery (donor) to SKF-525A (50 mumol/l) for 60 min did not affect the relaxation responses of endothelium-rubbed coronary artery (bioassay tissue) to basal EDRF nor to the effluent from donor tissues stimulated with ACh (10-1,000 pmol), ATP (1-100 nmol) or bradykinin (3-100 pmol). The results show that SKF-525A exhibited a reversible inhibition of endothelium-dependent relaxation by a smooth muscle mechanism unrelated to the generation of EDRF from endothelium.

Rabbit abdominal aortas and human umbilical arteries are currently used as substrata for the study of platelet adhesion and aggregate formation under flow conditions. Using immunohistochemical and ultrastructural methods, we have analyzed both vessel surfaces. The reactivity towards platelets of the subendothelium (SE) exposed on these vessels after mechanical or enzymatic digestion (alpha-chymotrypsin) was morphometrically quantified and the nature of the interaction studied in the electron microscope. After mechanical damage, the ultrastructural study of rabbit aortas showed a clearly defined internal elastic lamina (IEL). In contrast, umbilical vessels lacked a consistent IEL and masses of amorphous material often located deeper in the media were the main constitutents of the SE. Immunohistochemical labeling of the von Willebrand factor bound to both types of vessel differed considerably. Quantification of platelet interactions after perfusion of citrated blood showed qualitative differences between mechanically damaged rabbit or human vessels. Enzymatic digestion produced a more thrombogenic surface on rabbit aortas (p less than 0.01 vs. nondigested), but decreased their reactivity towards platelets on umbilical arteries (p less than 0.01 vs. nondigested). The ultrastructural study of the interacting platelets revealed that aggregates, when present, were found on the extracellular matrix underlying endothelial cells of rabbit aortas, but interacting with fibrillar structures probably derived from cell elements of the media in the case of umbilical arteries. These findings indicate that rabbit aortas and umbilical arteries possess structural characteristics that result in different thrombogenic properties with respect to circulating platelets.

The characteristics of carbon monoxide (CO)-induced, endothelium-independent relaxation of rabbit aorta were compared with those of nitric oxide (NO)-induced and light-induced relaxation and endothelium-dependent relaxation mediated by endothelium-dependent relaxing factor (EDRF). CO was less than one thousandth as potent as NO as a relaxant. Various findings, including an increase in cyclic GMP associated with CO-induced relaxation, led to the conclusion that CO - like NO, EDRF and light - produces relaxation as a result of its stimulation of guanylate cyclase. LY 83583, which generates superoxide, was a potent, fast-acting inhibitor of acetylcholine-induced endothelium-dependent relaxation and NO-induced relaxation, and a fairly potent, moderately fast-acting inhibitor of photorelaxation, but only a very weak inhibitor of CO-induced relaxation. The ability of LY 83583 as well as hemoglobin to inhibit photorelaxation is consistent with the hypothesis that on radiation a photo-induced relaxing factor is formed which can stimulate guanylate cyclase and which can be inactivated by superoxide and by hemoglobin.

Studies of binding interactions and contractile responses of vascular muscles at alpha 1- and alpha 2-adrenoceptors revealed the following. (1) Agonists at alpha 1- and alpha 2-adrenoceptors may achieve selectivity by virtue of different efficacies despite similar affinities at the two receptors as well as by differing affinities. This implies that their potencies in binding studies may not correlate with potencies in response and that an agonist may produce positive or negative interactions by occupying both alpha 1- and alpha 2-receptors. (2) Agonists at alpha 2-adrenoceptors have the ability in some vascular muscles to release internal Ca2+ (implying an inositol triphosphate mechanism) as well as open Ca2+ channels. However, their contractile abilities are not closely related to function of Na+/H+ or Na+/Ca2+ exchange sites. Amiloride derivatives probably inhibit contractile effects of alpha-agonists and K+ elevation by an action at sites distal to the receptor or Ca channels. (3) The failure of alpha 2-agonists to contract arteries in vitro is not related to the absence of these receptors but most likely to their uncoupling from contractile responses, possibly owing to changes related to the in vitro condition (loss of modulating endogenous substances present in vivo such as angiotensin II or endothelins or to changed physical conditions such as may alter function of stretch-activated channels).

Vasomotion, the rhythmical contraction and relaxation of the arterioles, is a natural property of the arteriolar microcirculation. It is observed clinically through related flow variations (flux motion) which are detected by laser Doppler flowmetry. It presents two distinct regimens: slow and fast waves, with frequencies of 1-2 and 10-20 cpm, respectively. Both activities are found in normal tissues, and their rate of incidence as well as their magnitude become significantly enhanced during abnormal conditions associated with low blood pressure and hypoperfusion. The institution of this activity by abnormal tissue conditions suggests that vasomotion is a reaction of the microcirculation aimed at improving microvascular function.

To test the hypothesis that angiotensin (Ang) I and II are produced by blood vessels, we investigated the formation of both Ang I and Ang II in isolated, perfused rat hindquarters. To characterize the nature of this production further, we modulated plasma renin by total or subtotal nephrectomy and tested the effects of exogenous renin and renin substrate on vascular Ang formation. Assays of the perfusate by high-performance liquid chromatography and radioimmunoassay demonstrated the spontaneous release of Ang I and Ang II from the hindlimb vasculature. Conversion of Ang I to Ang II in hindquarter vasculature was approximately 75% and was totally suppressed by captopril. The spontaneous formation of Ang peptides was abolished by bilateral nephrectomy but was not affected by subtotal 5/6 nephrectomy. The addition of purified rat angiotensinogen to the preparation increased Ang II levels. The infusion of renin into the hindlimb vasculature led to substantial increases in local Ang formation and also raised the perfusion pressure. Both effects were sensitive to captopril and to the renin inhibitor H-142. The data indicate that Ang I and Ang II are produced locally within blood vessels. However, the origin of vascular renin remains controversial. Our results suggest that part of the enzyme is taken up from plasma.

The hormonal regulation of L-type calcium current was investigated in freshly isolated tracheal smooth muscle cells using the whole-cell configuration of the patch-clamp technique. Isoproterenol stimulated the L-type calcium current 2.6-fold through beta-adrenoceptors. Dialysis of these cells with cyclic AMP, cyclic AMP analogues or the catalytic subunit of cyclic AMP kinase had no effect on basal or isoproterenol-stimulated calcium current. The calcium current was stimulated and inhibited by dialysis of the cells with GTP gamma S and GDP beta S, respectively. Evidently, in some smooth muscle cells the beta-adrenoceptor couples directly to L-type calcium channels via a G protein.

The effects of various neurotransmitters on phosphoinositide hydrolysis, mobilization of Ca2+ and release of [3H]-norepinephrine ([3H]-NE) were studied in cultures of sympathetic neurons of chick embryos. [3H]-inositol-1,4,5-triphosphate ([3H]-IP3) was increased in sympathetic neurons by acetylcholine (ACh), muscarine and serotonin (5-HT). Dopamine and norepinephrine did not stimulate phosphoinositide hydrolysis. Intracellular concentration of free Ca2+ ([Ca2+]i) was measured in Indo-1-loaded sympathetic neurons at rest and after addition of test agents. Measurements were made in the cell body and growth cone regions since Ca2+ mobilization is known to be different in different regions of the sympathetic neurons. ACh (nicotinic component was blocked by hexamethonium) and 5-HT failed to increase the [Ca2+]i, in the cell body as well as in the growth cone. The spontaneous release of [3H]-NE was not affected by ACh and 5-HT. Caffeine increased the [Ca2+]i only in the cell body but not in the growth cone and had no effect on the release of [3H]-NE. These results suggest that an IP3-insensitive but caffeine-sensitive pool of Ca2+ is present only in the somatic region of sympathetic neurons and is not coupled to the transmitter release.

Vascular smooth muscle sensitivity to norepinephrine (NE), measured by contractile responses in vitro, varied in different arteries of the rabbit and also in the same vessels in other species. There was a good correlation between variation in the affinity of NE for the alpha 1-adrenoceptor and tissue sensitivity. The variation was continuous and probably not indicative of different receptor subtypes. Solubilization of alpha 1-adrenoceptors from the membrane changed the affinity for specific ligands while reconstitution restored it. Taken together, these results suggest the presence of a factor(s) within the receptor microenvironment capable of modulating affinity and hence tissue sensitivity to NE. In some blood vessels, receptor number was correlated significantly with affinity of the alpha 1-adrenoceptor for NE also. In general, the contribution of receptor number was considerably less than the affinity for NE.