摘要:

AbstractThe general challenge of new drug discovery is to translate a new idea in science or medicine into a useful therapeutic agent. The specific challenge of cardiovascular new drug discovery (CVNDD) is to translate a new idea in science or medicine into an agent for the treatment of cardiovascular disease such as hypertension, congestive heart failure, or ischemic heart disease. CVNDD has a fundamental and increasingly important role in providing a maturing world population with medicaments designed to assist the human organism adjust to aging and to changes in its environment. The economic impact of CVNDD is critical to the world pharmaceutical industry. The economic impact of CVNDD is insignificant, however, compared to the potential world health impact of successful CVNDD that generates effective new cardiovascular drugs.There can be no doubt that present cardiovascular drugs have enhanced the quality of life of millions of people worldwide and have contributed to a reduction in the morbidity and mortality of cardiovascular disease. Although the gains have been modest in some areas such as sudden cardiac death, they have been dramatic in other areas, such as stroke. The length and quality of life have been enhanced by the rational discovery, development, and therapeutic use of cardiovascular drugs. The future holds the promise of even more impressive gains through new generations of drugs—more efficacious, safer drugs [Fisher, 1980; Pletscher, 1980; Kaplan and Smith, 1981; Smith, 1983

ISSN:0272-4391    

DOI:10.1002/ddr.430040302

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

年代:1984

数据来源: WILEY

摘要:

AbstractThe importance of calcium in excitation‐contraction coupling in both cardiac and vascular smooth muscle has resulted in an intense research interest into the intracellular regulation of this ion. Selective foci for the modulation of intracellular calcium include the interaction of calcium with the contractile protein apparatus, sites of calcium release and sequestration, and pathways for the extrusion of calcium into the extracellular space. Research efforts directed towards elucidating these phenomena have met with varied degrees of success. The presence of different calcium regulatory systems for contractile protein function, i.e., troponin in cardiac and calmodulin‐myosin light chain kinase in vascular, provides an attractive rationale for the design of selective compounds. The inherent difficulty in studying intracellular release and sequestration presently presently precludes examining the physiological implications of specific inhibition of these phenomena. However, the apparent absence of a sodium‐dependent calcium extrusion pathway in vascular tissue may lead to the design of novel cardiotonics. It is anticipated that further clarification of the similarities and differences in the calcium cycle between these tissues will result in the development of tissue‐selective therapeutic

ISSN:0272-4391    

DOI:10.1002/ddr.430040303

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

年代:1984

数据来源: WILEY

摘要:

AbstractThis comparison of the binding characteristics and pharmacology of 1,4‐dihydropyridines indicates that the high‐affinity binding sites studied in cardiac and smooth muscle cells represent a major site of action of these drugs, and that this site is the Ca2+channel or a closely related protein. Electrophysiological studies suggest that the effects of both Ca2+channel inhibitors and activators are voltage dependent. The apparent lack of agreement between the equilibrium dissociation constants for [3H]1,4‐dihydropyridines and their potency in cardiac muscle may be due to conformational modifications that occur in the 1,4‐dihydropyridine binding site as a result of voltage or other changes during membrane isolation. The selective effect of 1,4‐dihydropyridines for vascular smooth muscle relative to cardiac muscle may be explained, in part, by differences in membrane potentials and Ca2+channel regulatory mechanisms and, in part, by differences in receptor structure. 1,4‐Dihydropyridine antagonists and activators appear to bind to a common site that is not the same as the binding site for nondihydropyridine Ca2+channel

ISSN:0272-4391    

DOI:10.1002/ddr.430040304

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

年代:1984

数据来源: WILEY

摘要:

AbstractThe (Na+‐K+)‐ATPase is a ubiquitous membrane‐bound enzyme that actively transports Na+out of the cell in exchange for a smaller ratio of extracellular K+. The current report focuses on the role of modifiers of (Na+‐K+)‐ATPase activity in the development of new pharmacological agents. More versatile biological test systems are proposed. Possible use of Na+‐K+‐ATPase activity modulators in treatment of hypertension and other diseases are discussed. It is concluded that the ubiquitous distribution and crucial role of the enzyme in normal and diseased cell function merits a critical biological and chemical reappraisal of the enzyme beyond the current narrow viewpoint dealing with the application of glycosides in the treatment of congestive

ISSN:0272-4391    

DOI:10.1002/ddr.430040305

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

年代:1984

数据来源: WILEY

摘要:

AbstractBenzazepine and ergoline derivatives represent two chemical classes from which orally effective dopamine receptor agonists have been developed. The benzazepines SK&F 38393 and SK&F 82526 increase renal and mesenteric blood flow as a consequence of regional vasodilation mediated by vascular (DA1) dopamine receptor stimulation. Renal vasodilation produced by acute administration of SK&F 38393 and SK&F 82526 is associated with variable diuresis and natriuresis, and minimal change in arterial blood pressure and cardiac rate. Pergolide and LY141865 are chemically related to ergoline and inhibit neurogenic release of norepinephrine by stimulating neuronal (DA2) dopamine receptors. As a result of this action, pergolide and LY141865 produce generalized cardiovascular alterations that are characterized by reduced systemic vascular resistance, arterial blood pressure, and cardic rate. SK&F 38393 and pergolide lack beta receptor agonist activity, although each produces alpha receptor mediated vasoconstriction at or slightly above doses activating dopamine receptors. SK&F 82526, LY141865, and LY171555 (the levo enantiomer of LY141865) are more selective DA1and DA2dopamine receptor agonists, respectively, since each is devoid of adrenergic effects over an extended dose range. Potential clinical utilities of DA1dopamine receptor agonists include the treatment of renal insufficiency and arterial hypertension. DA2dopamine receptor agonists may also be useful in treating arterial hypertension, as well as cardiac conditions where facilitation of stroke volume and reduction of myocardial work would be desirable.

ISSN:0272-4391    

DOI:10.1002/ddr.430040306

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

年代:1984

数据来源: WILEY

摘要:

AbstractIn most vascular beds, receptors mediating contraction to serotonin are of the 5HT2type (defined by [3H]‐spiperone binding in brain tissue). Research on vascular serotonin receptors has been prompted by the development of ketanserin, a potent 5HT2‐receptor antagonist. Recent data suggest that ketanserin also possesses α‐receptor antagonist activity and that this property accounts for its antihypertensive activity in spontaneously hypertensive rats (SHR). The multiple blocking activities of ketanserin have prompted a search for more selective 5HT2‐receptor antagonists to elucidate the role of vascular serotonin receptors in blood pressure regulation. Consequently, 1‐(1‐naphthyl)piperazine (1‐NP) and LY53857, an ergoline derivative, have been identified as potent and highly selective 5HT2‐receptor antagonists in vascular tissue. 1‐(1‐napthyl)piperazine and LY53857 show approximately 2,000‐ and 300,000‐fold greater affinity, respectively, for 5HT2‐receptors than for α‐receptors compared to a 60‐fold selectivity of ketanserin. However, neither 1‐NP nor LY53857 lowered blood pressure in the SHR in doses that markedly shifted the pressor response to serotonin but did not antagonize α‐adrenergic receptors. Furthermore, blood pressure reduction in the SHR correlated poorly with the ability of several “5HT2‐receptor antagonists” to bind to 5HT2‐receptors and correlated extremely well with the binding of these agents to α‐receptors. Thus, in SHR, 1) antihypertensive activity of ketanserin occurred in doses that block α‐receptors and not at lower doses that block serotonin receptors, 2) more specific serotonin antagonists that did not block α‐receptors in vivo did not lower blood pressure, and 3) the reduction in blood pressure produced by a series of serotonin receptor antagonists correlated with thei

ISSN:0272-4391    

DOI:10.1002/ddr.430040307

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

年代:1984

数据来源: WILEY

摘要:

Abstractγ‐Aminobutyric acid (GABA) undoubtedly plays an important role as an inhibitory transmitter in the central nervous system. In recent years, evidence has accumulated which strongly suggests that GABA may specifically play a role in the central regulation of cardiovascular homeostasis. GABA apparently mediates a tonic hindbrain inhibition of vagal bradycardia, probably at nucleus ambiguus. In addition, evidence also suggests an additional GABA inhibitory input in the forebrain to sympathetic structures, possibly in the area of the periventricular hypothalamus. Thus, there appear to be at least two anatomically distinct and physiologically opposed GABAergic inhibitory mechanisms which function to control resting heart rate and reflex vagal activity. GABA also seems to be involved to some degree in the control of vasopressin release and respiratory function.Because of the physiological and pharmacological effects of centrally administered GABA or GABA mimetics, it is suggested that such agents might provide the basis for a new class of antihypertensive agents. Activation of central GABA receptors consistently reduces blood pressure and heart rate by a reduction in centrally mediated sympathetic nervous activity and, perhaps, a reduction in vasopressin release. Thus far, the GABA mimetics, THIP, imidazole‐4‐actic acid, muscimol, isoguvacine, isoarecaidine, kojic amine, as well as GABA itself, have all been shown to reduce blood pressure when centrally administered. Conversely, GABA antagonists, such as bicuculline and picrotoxin, raise blood pressure. Prodrugs of GABA or of other GABA mimetics can be used to allow for systemic administration of these agents with subsequent central penetration to provide an antihypertensive effect.Finally, it is suggested that the interaction of GABA with benzodiazepine receptors may allow for the development of new agents which, in addition to reducing stress‐induced cardiovascular responses, may prevent the development of hype

ISSN:0272-4391    

DOI:10.1002/ddr.430040308

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

年代:1984

数据来源: WILEY

摘要:

AbstractSaralasin is the only marketed member of a class of compounds described as angiotensin II receptor antagonists. Its pharmacology is characterized by three general properties: (1) no actions unrelated to the renin‐angiotensin system; (2) a small partial agonist effect in some tissues in vitro and in some animal models in vivo, and (3) a blood‐pressure lowering response to saralasin evidentonlyin animals with an activated endogenous renin angiotensin system. It is suggested that the natriuretic effect of angiotensin II mediated via central nervous system (CNS) mechanisms may be future productive area of research in which to study the actions of angiotensin II antagoni

ISSN:0272-4391    

DOI:10.1002/ddr.430040309

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

年代:1984

数据来源: WILEY

摘要:

AbstractBoth useful and undesirable cardiovascular properties have been associated with naturally occurring and synthetically derived phospholipids. Certain phospholipids may function physiologically (or pathophysiologically) in such processes as blood pressure regulation, cardiac rhythm, and platelet aggregation. Drugs that can modify the synthesis or degradation of endogenous phospholipid mediators or selectively mimic or block their effects may be of interest as potentially useful cardiovascular agents. This article reviews the current literature in this area and defines in chemical, biochemical, and biological terms the potential of the phospholipid‐type compounds in the development of useful cardiovascular drug

ISSN:0272-4391    

DOI:10.1002/ddr.430040310

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

年代:1984

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430040301

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

年代:1984

数据来源: WILEY