ISSN:0272-4391    

DOI:10.1002/ddr.430120202

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractCyclic nucleotide phosphodiesterases catalyze the hydrolysis of 3′,5′ cyclic nucleotides to the corresponding nucleoside 5′ monophosphates. Multiple forms of cyclic nucleotide phosphodiesterase have been identified in both the cardiac muscle and vascular smooth muscle from various species. These isozymes differ in apparent molecular mass, chromatographic properties, substrate specificity, immunologic reactivity, sensitivity to inhibitors, and mode of regulation. The phosphodiesterases play important roles in the regulation of cyclic nucleotide concentrations, which in turn mediate cellular responses to a variety of biological stimuli. The development of phosphodiesterase inhibitors to increase intracellular cyclic nucleotide levels represents an important pharmacological approach to the treatment of various cardiovascular dis

ISSN:0272-4391    

DOI:10.1002/ddr.430120203

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractChanges in the extent of phosphorylation of key regulatory proteins/enzymes that are intimately involved in either intermediary metabolism or contraction/relaxation in both cardiac and vascular smooth muscle (VSM) are regulated by cyclic nucleotides (cAMP/cGMP) or Ca2+. Ca2+regulates phosphorylation by stimulation of kinase activity through two regulatory cofactors: the calcium‐binding protein calmodulin (which activates myosin light chain kinase—MLCK) or phosphatidylserine plus diacylglycerol (which activates protein kinase C—PKC). MLCK is different in VSM vs. cardiac muscle; it is larger and present in higher concentrations in VSM. Myosin light chain phosphorylation is requisite for rapid force generation in VSM and may also be related to stress maintenance. The primary regulatory mechanism in cardiac muscle is thin‐filament linked; myosin light chain phosphorylation is relatively slow and is not related to rapid changes in inotropy. PKC activation in VSM may be related to non‐rapid stress development via phosphorylation of a unique 25‐kDa substrate. Two isozymic forms of cAMP‐dependent protein kinase exist in both cardiac and VSM. Activation of cAMP protein kinase in response to cAMP‐related cardiotonic or vasodilator agents has been reported. However, differences in subsequent phosphorylation of selected substrates exists in cardiac muscle for agents such as PGE and isoproterenol. Activation of cGMP protein kinase has also been demonstrated in cardiac and vascular smooth muscle. A positive relationship appears to exist between kinase activation and relaxation of the latter tissue by ANF. Several substrates for cAMP protein kinase that may be linked to positive inotropy have been identified in cardiac muscle. Phosphorylation of phospholamban increases Ca2+uptake by the sarcoplasmic reticulum. Phosphorylation of a 15‐kDa protein in the sarcolemma may be related to an increase in opening of voltage‐dependent Ca2+channels. On the contractile proteins, phosphorylation of the troponin I subunit as well as phosphorylation of C‐protein may contribute to the increased rate of relaxation observed with β‐agonists. In VSM, phosphorylation of MLCK by cAMP protein kinase decreases affinity of MLCK for Ca2+‐calmodulin and inhibits light chain phosphorylation and subsequent actin‐myosin interactions. However, while MLCK phosphorylation has been demonstrated in intact smooth muscle, functional loss of Ca2+‐calmodulin binding and the relationship to relaxation by β‐agonists have not been apparent. Other substrates for cAMP and cGMP protein kinase have been identified in intact VSM and membranous preparations. Recently, naphthalene and isoquinoline sulfonamide protein kinase inhibitors have been disclosed, which demonstrate different relative potencies for these protein kinases. Moreover, some of these agents are vascular relaxants or platelet aggregation inhibitors. These agents may aid in the search for specific modulators of protein phosphorylation systems and also delineate the role of these s

ISSN:0272-4391    

DOI:10.1002/ddr.430120204

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractThe atrial natriuretic factor (ANF) family of peptides possesses diverse functional properties including smooth‐muscle relaxation, inhibition of aldosterone biosynthesis, and hypotensive activities. These separate activities are most likely mediated by the binding of the peptide to specific receptors located in the target organs. The present study was initiated to more closely examine the relationship between biological activity and the requirements of the various receptors for interaction with ANF and with ANF analogs. Binding affinities (Ki) were measured in plasma membranes isolated from rabbit kidney cortex, aorta, and adrenal, and in cultured rabbit aortic vascular smooth muscle cells (VSMC) using125I‐Tyr‐28‐ANF (1–28) as the ligand. The VSMC were also utilized to quantitate stimulation of cGMP synthesis. Vasorelaxation (pD2) was measured in histamine‐contracted rabbit aortic rings. The activities of 19 ANF (5–28) analogs were compared, and a significant correlation between pD2and Ki (r = −.83;p<0.01) was obtained. The (D)Phe‐8 and Asn‐13 analogs were exceptions to this correlation; pD2= 7.1 and 7.2, and pKi = 6.0 and 8.1, respectively. All analogs examined possessed comparable affinities in the four receptor assays. Conversely, comparison of vasorelaxant and cGMP stimulatory activities resulted in a much larger separation of activities. Tyr‐8 ANF (5–27) did not stimulate cGMP synthesis but relaxed smooth muscle (pD2= 7.9), while ANF (7–23) was 500‐fold less active than ANF (5–28) in the vasorelaxant assay (pD2= 6.1 and 8.9, respectively) but equipotent in the cGMP system. These and other experiments suggest the presence of ANF receptor subtypes and question the causative role of cGMP for inducing vasorelaxation of hista

ISSN:0272-4391    

DOI:10.1002/ddr.430120205

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractThe role of cyclic AMP in modulating the contractile function of cardiac muscle has been the subject of intensive investigation for more than two decades. These studies have shown that the positive inotropic response to cyclic AMP involves multiple components, including adenylate cyclase, the enzyme that catalyzes the conversion of ATP to cyclic AMP, activation of cyclic AMP‐dependent protein kinases, which are responsible for phosphorylating key intracellular proteins, and phosphodiesterase, the enzyme that hydrolyzes cyclic AMP, thereby terminating the response. Several reports have shown, however, that increases in intracellular cyclic AMP are not always accompanied by increases in myocardial contractility, suggesting that cyclic AMP may be compartmentalized within cardiac cells and that only certain compartments are involved in modulating contractility. In addition, although cardiac muscle contains only one form of adenylate cyclase, multiple forms of phosphodiesterase have been identified in ventricular muscle, which vary in their substrate specificity and their response to allosteric effectors such as calmodulin. Recent studies have also shown that these various forms of phosphodiesterase can be located in different regions within the cardiac cell and that only certain forms of the enzyme are involved in modulating the inotropic response to cyclic AMP. This review summarizes the current state of knowledge regarding the involvement of cyclic AMP with cardiac contractile function and also explores several controversial aspects of this involvemen

ISSN:0272-4391    

DOI:10.1002/ddr.430120206

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractThe vascular endothelium is a source of both relaxing and contracting factors. These yet to be identified substances have been termed endothelium‐derived relaxing factor(s) (EDRF) and endothelium‐derived contracting factor(s) (EDCF). The family of EDRF(s) appear to be important mediators of vascular relaxation and platelet disaggregation. Destruction of the endothelium or modulation of its structure, as occurs with coronary artery disease and atherosclerosis, results in impaired coronary and systemic arterial relaxation, vasospasm, and enhanced platelet aggregability. Acute and chronic hypertension blunts EDRF‐induced vascular relaxation. Thus, EDRF appears to represent an endogenous modulator system of vascular smooth muscle‐endothelium‐platelet interaction in humans. Recent evidence supports the possibility that one EDRF may be nitric oxide, whereas a second EDRF may stimulate sodium‐potassium ATP'ase. EDCF may be a family of at least three substances. One substance appears to be a low molecular weight polypeptide, is produced by hypoxia, and promotes a long‐acting vasoconstriction associated with increased calcium influx into vascular smooth muscle. The second EDRF is of unknown origin, is diffusable, released by anoxia and hypoxia, and may facilitate the action of the leukotrienes and lipoxygenase products on vascular smooth muscle. The remaining EDCF may be derived from the actions of lipoxygenases on arachidonic acid and appears to be released by vasoconstrictor agonists, stretch and potassium ion. Further research is required to elucidate the functional role and nature of EDCF(s) on vascular

ISSN:0272-4391    

DOI:10.1002/ddr.430120207

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractRecent findings in several laboratories have demonstrated the important interactions of platelet‐activating factor (PAF) with vascular endothelial cells, and thus the potential role of this lipid mediator in the pathophysiology of the cardiovascular system. PAF potently and specifically stimulates the in situ and in vivo release of tissue‐type plasminogen activator from the vascular endothelium [Emeis and Kluft, 1985]. Several lines of evidence indicate that PAF may play a critical role in the neutrophil adhesion to endothelial cells stimulated with thrombin or leukotrienes [Zimmerman et al., 1985]. PAF is a potent stimulator of Ca+2efflux from endothelial cells, which thus might be an early step in the suspected involvement of the endothelium in in vivo responses to PAF, such as hypotension and increased vascular permeability [Brock and Gimbrone, 1986]. In our own laboratory, we have developed a specific and potent PAF receptor antagonist, L‐652,731, in order to determine the role of PAF in different animal models of disease. Utilizing this receptor antagonist as well as other criteria, PAF is indicated to be a major mediator of the endotoxin‐induced hypotension in rats and soluble immune complex‐induced hypotension and extravasation, also in rats. The immune complex‐induced increased plasma glucosaminidase is partially mediated by PAF, whereas the immediate and complete neutropenia is not indicated to

ISSN:0272-4391    

DOI:10.1002/ddr.430120208

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430120201

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY