By Prof. Dr. H. Just (auth.), Dr. H. Drexler, Dr. A. M. Zeiher, Prof. Dr. E. Bassenge, Prof. Dr. H. Just (eds.)
In fresh years, we've witnessed a swift enlargement of our wisdom concerning the function of the endothelium within the regulate of vascular tone (and organ perfusion) in wellbeing and fitness and ailment. body structure, pharmacology, and molecular biology have exposed a wealth of knowledge on constitution and serve as of this heretofore principally overlooked "organ". scientific medication is now referred to as upon to outline the scientific importance of those observa tions that indicate the mechanisms of blood coagulation, e.g., the interplay of throm bocytes with the endothelium, vasomotor keep watch over, and in particular, the legislation of delicate muscle tone with effects for vascular resistance and conductance and organ blood move. ultimately, metabolism of lipids with the eternal challenge of athero sclerosis is a vital point. In a moment step, implications concerning the development of present healing con cepts, in addition to the improvement of latest modalities of pharmacotherapy must be mentioned. the subject addressed by way of the 1990 Gargellen convention: Endothelial Mechanisms of Vasomotor regulate, basically is of curiosity for either uncomplicated scientists and clinicians. it's been the purpose of the organizers, the Society for Cooperation in scientific technology (SCMS) with this and the former symposia to foster and help either simple technological know-how and medical examine. examine in drugs this present day indicates significant instructions of improvement: at the one hand, expanding involvement of the fundamental sciences and their method. nonetheless, statistical validation of innovations and healing ideas in huge scale population-and multicenter-studies.
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In recent times, we have now witnessed a fast growth of our wisdom in regards to the function of the endothelium within the regulate of vascular tone (and organ perfusion) in health and wellbeing and illness. body structure, pharmacology, and molecular biology have exposed a wealth of data on constitution and serve as of this heretofore mostly missed "organ".
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Extra resources for Endothelial Mechanisms of Vasomotor Control: With special Reference to the Coronary Circulation
On a molecular basis the sydnonimine derivatives and especially SIN-1 proved to be substantially more active than the organic nitrates such as GTN or ISDN (see Table 3). In contrast to the latter, guanylate cyclase activation was independent from the presence of special thiol-containing compounds such as cysteine (9). The addition of 5 mM L-cysteine even slightly shifted the dosereponse curve of SIN-1 to the right, as shown in Fig. 8. Measuring the initial rate of NO formation, we also observed that the stimulatory potency of the sydnonimines at the guanylate cyclase is very well correlated with the kinetics of NO generation, but not with the formation of the ring-open A-forms, which 45 Bioactivation pathways of nitrovasodilators Table 3.
Obviously, already minute amounts of oxygen molecules in the incubation medium are sufficient to start the reaction sequence of bioactivation, in which an electron is transferred from the nitrogen atom of the sydnonimine to molecular oxygen. It is assumed that an oxidative activation of the morpholino nitrogen of SIN-1A results in the formation of a cation radical, which then facilitates the release of NO. S-nitrosothiols are not direct activators ofguanylate cyclase Finally, we have studied whether S-nitrosothiols are direct activators of the guanylate cyclase, or whether they activate the target enzyme indirectly by the release of NO, as all other known nitrovasodilators do.
Meth and Find Exptl Clin PharmacoI6:583-586 20. Noack E (1990) Mechanisms of nitrate tolerance - influence of the metabolic activation pathways. Z Kardiol 79:Supp12 21. Noack E, Feelisch M (1989) Molecular aspects underlying the vasodilator action of molsidomine. J Cardiovasc Pharmacol14 (Supplll ):S I-S5 22. Noack E, SchrOder H, Feelisch M (1986) Continuous determination of nitric oxide formation during non-enzymatic degradation of organic nitrates and its correlation to guanylate cyclase activation.