Blood vessels最新文献

The mechanism of the vasodilator action of pinacidil has been studied in rat mesenteric small arteries. The results show, first, that the use of flux studies to make measurements of ion permeability requires knowledge of the membrane potential, especially as regards K+ permeability. Second, the results confirm that the vasodilator effect of pinacidil is due to an increase in K+ permeability. Lastly, the results suggest that the K+ channels involved are sensitive to glibenclamide.

At low concentrations and in physiologic states vasopressin is a potent antidiuretic hormone. Its cardiovascular effects have been more complex and their role in circulatory adjustments to hypovolemia and hypotension difficult to define with precision. Although recognized as a powerful vasoconstrictor, its pressor effect in intact animals, even at high concentrations, is minimal. The reasons for this blunted pressor response have been explored. This report is a review of previously published work from our laboratories which highlights the direct and indirect vasodilator actions of this hormone in animals and humans. The indirect vasodilator effect is caused by inhibition of sympathetic efferents, and facilitation of the baroreflex through a central action of the hormone and its sensitization of arterial baroreceptors as well as cardiac afferents.

The responses of rabbit resistance arteries to pressure and flow have been examined using two in vitro techniques--when mounted isometrically in a myograph and when perfused using a video system that automatically registers diameter. The latter approach allows pressure and flow to be independently controlled. Under such circumstances three responses were studied; myogenic contraction and flow-dependent constriction and dilation. All responses occurred after endothelium removal and were unaffected by indomethacin (10(-60 M). The pressure and flow effects can be elicited separately and have different ionic bases. The effective stimulus for the myogenic response is stretch and that for flow is presumably shear stress. The mechano-transducers for these effects are different and are located either in the vascular smooth muscle cells or their surrounding extracellular matrix.

Cromakalim, pinacidil, nicorandil, diazoxide and RP-49356 belong to the class of drugs termed potassium channel openers. In rat portal vein diazoxide, like cromakalim, abolished spontaneous mechanical and electrical activity and in rat aorta caused an increase in 86Rb efflux and inhibited KCl(20 mM)-induced contractions. However, in contrast to cromakalim, diazoxide (greater than 100 microM) also inhibited mechanical responses evoked by 80 mM KCl in rat aorta suggesting that it possesses pharmacological properties in addition to K channel opening. Since glibenclamide can attenuate the effects of cromakalim and diazoxide in vascular tissues, it is possible that a channel resembling the ATP-sensitive K channel found in pancreatic beta-cells may be involved in the vasorelaxant effects of these agents. However, differences exist in the order of potency of cromakalim and diazoxide for producing smooth muscle relaxation and for decreasing insulin secretion in pancreatic beta-cells. Furthermore galanin (which opens ATP-sensitive K channels in beta-cells) increases mechanical activity in rat portal vein. It is anticipated that new chemical developments will produce K channel opening molecules with greater potency and tissue selectivity.

This study characterizes the contribution of prostanoids to endothelium-dependent responses in two vascular regions of the guinea pig. We compared the mechanisms of relaxation responses to acetylcholine and adenosine triphosphate (ATP) in the coronary vasculature and in the abdominal aorta of the guinea pig. Endothelium-dependent responses were examined in an isolated, potassium-arrested guinea pig heart utilizing a modified Langendorff preparation. Coronary vessels were constricted with prostaglandin F2 alpha and dilated with acetylcholine (10(-9)-10(-6) mol) or ATP (10(-10)-10(-7) mol) before and after exposure to indomethacin (14 microM, n = 6) or ibuprofen (150 microM, n = 5). Helically cut strips of abdominal aorta (n = 6) were suspended in isolated tissue baths for measurement of isometric force. Relaxation to acetylcholine (5.5 x 10(-7) M) and ATP (10(-5) M) was quantified in strips contracted with norepinephrine before and after exposure to indomethacin (14 microM). In addition, the endothelium was damaged by exposing vessels to free radicals generated by electrolysis of the buffer (4 Hz, 9 V, 1 ms, 5 min). Following electrolysis of the buffer, relaxation responses to acetylcholine and ATP were significantly attenuated in both preparations. In the perfused heart, endothelium-dependent dilatation to acetylcholine, but not ATP were significantly inhibited in the presence of indomethacin or ibuprofen. In contrast, acetylcholine- and ATP-induced relaxation responses in the aorta were not altered by indomethacin. We conclude that prostaglandins contribute to acetylcholine-induced dilatation in the coronary bed but not in the abdominal aorta of the guinea pig. Furthermore, in the coronary bed, different endothelial factors mediate relaxation to acetylcholine and ATP.

In vitro experiments on vascular smooth muscle often fail to reveal phenomena clearly demonstrable in vivo. Several recent observations in our laboratory have revealed the facility to uncover responses mediated by receptors whose functional expression had remained hidden with the standard experimental conditions first employed: conversely manipulation of conditions can selectively hide a particular receptor's response. Examples include the uncovering of responses to: 5HT1 receptors by raised O2 tension (via cyclooxygenase products) in human umbilical vessels; alpha 2-adrenoceptors in rabbit saphenous artery by angiotensin II and alpha 2-adrenoceptors in perfused rat tail by elevating tone with vasopressin. The powerful synergism of agonists which cannot on their own cause contraction, can lead to inaccurate interpretations of agonist-antagonist interactions. Finally, the influence of tissue metabolism on receptor expression clearly illustrates the complex processes which must be involved in vivo.

Specific Ca antagonists of the verapamil, nifedipine, and diltiazem type have become the drugs of choice in the therapy of cardiac hyperkinetic disorders and of vascular hypertonicity (spasms). The specific mechanism of vasodilatation by Ca antagonists was substantiated by electrophysiological, radionuclear and mechanical measurements on rather different types of arterial vasculature, including the systemic resistance vessels, as well as on portal veins. The results indicate that the vasodilator efficacy of these Ca antagonists is mainly based on at least three components: (1) Suppression of the generation of Ca-carried membrane spike potentials; (2) decrease of direct transmembrane supply of activator Ca through potential- or receptor-operated membrane channels, and (3) interference with Ca-triggered intracellular Ca release in an indirect way, in that Ca antagonists block the influx of small amounts of trigger Ca or produce depletion of intracellular Ca stores. In any case, contractile activation practically ceases if transmembrane Ca supply is totally cut off upon addition of Ca antagonists to a Ca-deficient medium.

In vitro investigations have identified three major mechanisms which could contribute to the vasodilator action of serotonin (5-hydroxytryptamine, 5-HT): direct vascular smooth muscle relaxation; prejunctional inhibition of noradrenaline release from vascular sympathetic nerve terminals; and release of endothelium-derived relaxing factor (EDRF). In vivo studies have shown that in pig and cat common carotid circulations, rabbit hindquarter and mesenteric circulations, and rat systemic vasculature, direct vascular smooth muscle relaxation may be the predominant mechanism involved, but the contribution of EDRF release remains to be established. In other circulations in vivo (dog femoral and common carotid), prejunctional inhibition of vascular sympathetic tone is the predominant mechanism responsible for serotonin-induced vasodilatation. All of these actions are mediated by 5-HT1-like receptors, but different subtypes seem to be involved in each of these mechanisms. The prejunctional inhibitory receptor has been the most studied; depending on the tissue, these subtypes may resemble 5-HT1A, 5-HT1B, 5-HT1C or 5-HT1D binding sites, or the contractile receptor in dog saphenous vein.

Bovine mesenteric lymphatic vessels have nerves in their walls which in response to field stimulation cause an increase in frequency of spontaneous lymphatic contractions and this could be blocked by alpha-antagonists. When vessels were loaded with [3H]-noradrenaline, 3H-efflux was increased in response to field stimulation and this was potentiated by alpha 2-antagonists and depressed by alpha 2-agonists. Electrical activity in these vessels consisted of a single action potential which preceded each contraction. Mean resting potential was -61 mV +/- 5.7 (SD). Stimulation of postsynaptic alpha-receptors caused a depolarization accompanied by a decrease in membrane conductance while beta-receptor stimulation had the opposite effect. Lymphatic noradrenergic nerves appear to have a role in the living animal since stimulation of the sympathetic chain in anaesthetized sheep increased popliteal efferent lymph flow and this could be blocked by alpha-adrenergic blockers.