摘要:

Mechanoreception, a widely distributed sensory modality, has been shown to be present in certain blood vessels. Changes in physical forces, like sudden increase of transmural pressure or flow velocity (shear stress), trigger changes in blood vessel diameter; the former reduces it while the latter increases vessel caliber. These changes in diameter, which are the result of contraction and relaxation of vascular smooth muscle in the blood vessel media, can serve the purpose of physiological regulation of blood flow (autoregulation) and protection of the intima against damages from high shear forces. The precise location of mechanosensor(s) and the mechanism of mechanoreception and signal transduction are poorly understood. Accumulating evidence suggests that the endothelium may be a site of mechanoreception and that changes in the synthesis/release of endothelium-derived relaxing (EDRF, EDHF, PGI2) and contracting factors (EDCF) result in altered vascular smooth muscle tone and vessel caliber. Increased shear stress stimulates the release of EDRF and PGI2 probably via activation of a K+ channel (inward rectifier) in endothelial cell membrane. Endothelium-dependent vascular contraction evoked by increased transmural pressure may be the result of (1) reduced release of EDRF (canine carotid artery) and (2) stimulation of the release of a still unidentified EDCF(s) (feline cerebral artery). Thus the endothelium can serve as pressure and flow sensor and is capable of transducing changes in mechanical forces into changes of vascular smooth muscle tone by modulating the release of endothelium-derived vasoactive factors. The physiological importance of the mechanoreception by endothelial cells in the intact circulation remains to be determined.

ISSN:1018-1172    

DOI:10.1159/000158816

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

Several mechanisms impair cerebral vasodilatation during chronic hypertension. First, the external diameter of cerebral arterioles is reduced during chronic hypertension by structural ‘remodeling’. Thus, both vascular hypertrophy and remodeling result in encroachment on the lumen. Second, endothelium-dependent dilatation of cerebral vessels is impaired during chronic hypertension. Third, blood flow through cerebral collaterals is impaired by chronic hypertension, so that an important compensatory mechanism is compromised. Impaired vasodilator responses, together with limitation of increases in collateral blood flow, may predispose to cerebral ischemia and stroke during chronic hypertens

ISSN:1018-1172    

DOI:10.1159/000158817

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

Endothelium-dependent relaxations are abolished in the canine basilar artery after subarachnoid hemorrhage. However, the release of endothelium-derived relaxing factor (EDRF) toward the lumen is not reduced. These findings suggest that the responsiveness of the smooth muscle to EDRF is impaired during chronic vasospasm after subarachnoid hemorrhage.

ISSN:1018-1172    

DOI:10.1159/000158818

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

The endothelins (ETs) are a family of newly discovered peptides with potent vasoconstrictor properties. They were first discovered in cultured endothelial cells but ET expression has since been found in many other tissues such as brain and kidney. They are peptides with 21 amino acids formed by hydrolytic cleavage of a larger peptide, big ET. Release of ETs from cultured endothelial cells is modulated by a variety of chemical and physical stimuli and as no storage sites have been identified it is suggested that endothelin release is regulated at the level of transcription or translation. Both big ET and ET-1 are found circulating in the blood. The levels are elevated in shock, myocardial infarction and kidney failure indicative of enhanced formation in these diseases. The literature now abounds with reports on actions of the ETs in vitro and in vivo. The vasoconstrictor properties are powerful and long-lasting. Several studies also show a mitogenic effect, indicating a possible trophic role. It is likely that in the next few years the development of inhibitors of endothelin synthesis and/or action will be of importance in unravelling the role of the ETs.

ISSN:1018-1172    

DOI:10.1159/000158819

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

Molsidomine is an established drug for the treatment of coronary heart disease. It acts via the metabolite SIN-1 through liberation of NO. Experiments have proven the identity of NO and EDRF. Investigation of the molecular mechanism of action of molsidosmine/SIN-1 indicate that molecular oxygen initiates NO formation through a one-electron abstraction from the intermediate. Ex vivo experiments in rats and in vitro studies in human coronary arteries showed that marked tolerance is induced with glyceryl trinitrate, whereas prolonged exposure to SIN-1 does not cause tolerance. Responsiveness to SIN-1 is not modified in nitrate-tolerant human arteries. Stimulation of soluble guanylate cyclase underlies the antiaggregatory actions of EDRF. Likewise SIN-1 inhibits platelet aggregation in various models. In dogs and pigs with critical stenosis molsidomine reduced significantly the frequency and the severity of cyclical reductions of coronary blood flow.

ISSN:1018-1172    

DOI:10.1159/000158820

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

The most direct approach to block the function of the renin-angiotensin system would be to antagonize angiotensin II (All) at the level of its receptor. However, the All receptor antagonists currently available, such as saralasin, are peptides which still retain agonistic activity and lack oral bioavailability. We have identified the N-benzylimidazoles, S-8307 and S-8308, as weak, but selective nonpeptide All receptor antagonists. These initial leads were subsequently converted into more potent compounds, such as EXP6155, EXP6803 and EXP7711, while maintaining the selectivity. The compounds displace 3H-AII from its specific binding sites in adrenal cortical membranes and smooth muscle cells. They competitively inhibit the vasoconstrictor response to All in various in vivo and in vitro preparations, but do not influence those to KC1, norepinephrine, and vasopressin. Converting enzyme and renin are not affected by these agents. In renal hypertensive rats and sodium-depleted dogs our compounds cause a sustained decrease in arterial pressure following intravenous and oral (EXP7711) administration, and are devoid of agonistic properties. Taken together, these nonpeptide structures are true competitive All receptor antagonists and represent a new class of effective antihypertensive agents.

ISSN:1018-1172    

DOI:10.1159/000158821

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

Nonselective β-adrenergic blockers have been reported to affect endothelium-dependent responses in isolated blood vessels in the following ways: (a) cause endothelium-augmented direct relaxations; (b) facilitate the endothelium-dependent relaxations evoked by α2-adrenergic activation, or by acetylcholine; (c) augment the intraluminal release of vasodilator prostanoids, and (d) inhibit endothelium-dependent contractions to anoxia. Important species differences exist in terms of the endothelium-dependent effects of the compounds. If they were to occur in the intact organism, the endothelium-dependent effects of the β-adrenergic blockers could help to explain their vasodilator properti

ISSN:1018-1172    

DOI:10.1159/000158822

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

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 mM100 µM) 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 β-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 β-cells. Furthermore galanin (which opens ATP-sensitive K channels in β-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 selectiv

ISSN:1018-1172    

DOI:10.1159/000158823

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

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.

ISSN:1018-1172    

DOI:10.1159/000158824

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

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.

ISSN:1018-1172    

DOI:10.1159/000158825

出版商:S. Karger AG    

年代:1990

数据来源: Karger