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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The past 15 years have been witness to a remarkable growth in knowledge regarding the modulation of "sympathetic traffic" to neuroeffector organs, including vascular tissue. The release of norepinephrine from peripheral sympathetic neurons is now known to be under both negative and positive feedback control. Norepinephrine, when released from peripheral neurons, acts on presynaptic alpha 2-receptors to inhibit further neurotransmission. Vascular postsynaptic alpha 2-receptors, sensitive to circulating catecholamines, subserve vasoconstriction. The antihypertensive agents clonidine, guanabenz and guanfacin likely reduce blood pressure by acting centrally on alpha 2 postsynaptic neurons to limit sympathetic transmission to blood vessels. Clonidine can produce venoconstriction and thereby improve orthostatic hypotension by activating venous alpha 2-receptors. Additional presynaptic dopaminergic receptors (DA2), muscarinic receptors (acetylcholine), opioid receptors, prostaglandin receptors, adenosine receptors (A1) and histamine (H2) receptors are present on sympathetic nerve membranes and, when engaged with the appropriate ligand, can limit the exocytotic process. Gamma-aminobutyric acid and serotonin demonstrate similar roles in reducing sympathetic nerve activity. In contrast to these inhibitory presynaptic mechanisms, facilitation of norepinephrine release appears to occur by way of neuronal angiotensin II receptor activation and perhaps through stimulation of sympathetic nerve membrane beta 2-receptors. An appreciation of these inhibitory and facilitator mechanisms is useful in the treatment of a variety of clinical conditions, including hypertension, heart failure, orthostatic hypotension, septic shock and a number of common withdrawal syndromes.
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PMID:Modulation of peripheral sympathetic nerve transmission. 283 2

The renin-angiotensin system has been shown to participate in the pathophysiology of chronic heart failure in many patients. However, the immediate assessment of this contribution in individual patients may sometimes be difficult. As a pharmacologic estimate of angiotensin II receptor activity, we infused the angiotensin II analogue, saralasin, in 20 patients with severe chronic congestive heart failure (CHF). The infusion resulted in blood pressure responses ranging from an agonist pressor response (increased systemic resistance) in patients with low intrinsic renin-angiotensin system activity, to an antagonist depressor response (decreased systemic resistance) in patients with marked activation of the renin-angiotensin system. The ability of the saralasin response to pharmacologically estimate angiotensin II receptor activity in CHF was further revealed by two physiologic maneuvers that decrease endogenous circulating angiotensin II and angiotensin II receptor occupancy. Both converting enzyme inhibition with captopril and sodium repletion, factors known to decrease endogenous angiotensin II activity, provoked agonist responses to saralasin infusion. Furthermore, saralasin was able to reverse the orthostatic hypotension precipitated by converting enzyme inhibition of angiotensin-dependent vascular tone. In summary, saralasin provided a means to estimate angiotensin receptor activity and may therefore serve as a probe of angiotensin-mediated vasoconstriction in the pathophysiology of chronic CHF.
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PMID:Estimation of angiotensin II receptor activity in chronic congestive heart failure. 632 65

In recent years, endothelial dysfunction and arterial remodelling in various cardiovascular diseases have emerged as two key concepts, with numerous interrelationships. Both endothelial dysfunction and arterial remodelling occur in various pathologies including heart failure, atherosclerosis, restenosis after angioplasty, and pulmonary hypertension, and have modified the therapeutic approach by offering new pharmacological targets: specific receptors not only at the site of the vascular smooth muscle cells but also on the endothelial cells, growth factors that stimulate proliferation of smooth muscle, and receptors and enzymes of the extracellular matrix. Among the various substances under research, the present review will discuss angiotensin II receptor antagonists, endothelin receptor antagonists, nitrates-NO donors, potassium channel activators, and substances interfering with proteoglycans and other components of the extracellular matrix.
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PMID:[Arterial wall: a new pharmacological and therapeutic target?]. 748 94

The renin-angiotensin system (RAS) participates in both cardiovascular homeostasis and diseases. Angiotensin converting enzyme (ACE) inhibitors have been used very successfully in the treatment of hypertension and heart failure. The therapeutic effectiveness of these drugs has been ascribed to their action in limiting the activity of the RAS and suggests that other pharmacological mechanisms that block this system, such as angiotensin II receptor inhibitors, could also be of benefit. Some properties of angiotensin II receptor inhibitors offer potential advantages over ACE-inhibitors. ACE acts on other substrates in addition to angiotensin I (i.e. bradykinin) so that more specific inhibition of the RAS can be achieved with selective angiotensin II antagonists. Data on the existence of both circulating and tissue RAS have been reported, and non-ACE pathways for angiotensin II production have also been described. So, by inhibiting the interaction of the biological active peptide at its receptor level, an angiotensin II receptor antagonist will inhibit the RAS independently of the source or route of angiotensin II synthesis. Peptide angiotensin II antagonists were first reported 20 years ago and the best studied was saralasine; they are potent and selective blockers of angiotensin II responses, but their lack of oral activity, short duration of action and the concomitant partial agonistic activity limited their clinical use. Now are available nonpeptide angiotensin II antagonists with attributes appropriate for clinical development. The preliminary evaluation of these new selective nonpeptide angiotensin II antagonists show their potential therapeutic role in many cardiovascular diseases in which the RAS is involved.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Clinical pharmacology of angiotensin II antagonists]. 763 4

Angiotensin converting enzyme (ACE) inhibitors have been shown to improve morbidity and mortality in patients with heart failure. However, despite the demonstrated clinical benefits many physicians are reluctant to prescribe ACE-inhibitors to the mostly elderly heart failure patients due to concern for side effects which may be related to ACE-inhibitor-induced bradykinin accumulation. Angiotensin II receptor antagonists may provide more effective blockade of the renin-angiotensin-aldosterone system without causing bradykinin accumulation and thus associated side effects. The potential benefits of treating heart failure patients with an angiotensin II receptor antagonist instead of or in addition to an ACE-inhibitor are discussed.
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PMID:Theoretical basis for the use of angiotensin II antagonists in the treatment of heart failure. 763 6

Losartan potassium (Cozaar) is an angiotensin II receptor antagonist (AT1 selective) which has undergone extensive clinical trials for the treatment of hypertension. This literature survey will review some of the pre-clinical findings with losartan in models of heart failure, and where appropriate, we will compare the haemodynamic findings in animals with similar studies completed in patients. The major conclusion from these trials is that losartan has clear haemodynamic benefits in patients in heart failure and that the drug appears to be well tolerated, with a low incidence of adverse experiences related to impaired renal function.
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PMID:Losartan in heart failure: preclinical experiences and initial clinical outcomes. 771 3

Angiotensin converting enzyme inhibitors (ACEIs) are a cornerstone of treatment of hypertension and heart failure yet their mechanism of action is still debated. This study was designed to test whether the ACEI captopril increases skin microvascular blood flow by a bradykinin-dependent mechanism. Local changes in microvascular blood flow were measured in the skin of rabbits and of human volunteers using a laser Doppler flow probe. Captopril injected intradermally increased skin blood flow over the dose range of 10(-12)-10(-8) mol site in rabbits and humans. In both species the response was abolished by coinjecting either a nitric oxide synthase (NOS) inhibitor or a cyclooxygenase inhibitor. Intradermal bradykinin also increased rabbit skin microvascular blood flow; at 10(-11) mol site it increased mean +/- SE basal blood flow by 88 +/- 12%. The responses to bradykinin or captopril were abolished by coinjecting a bradykinin antagonist, a specific bradykinin B2 receptor antagonist, or inhibitors of NOS or cyclooxygenase. Injecting a specific angiotensin II receptor antagonist at a dose that antagonized the constrictor effects of exogenous angiotensin II did not cause a significant increase in rabbit skin blood flow. This suggests that endogenous angiotensin II does not influence microvascular blood flow in this model. The results indicate that captopril increases skin microvascular blood flow in rabbits and humans secondary to an increase in endogenous tissue bradykinin; this stimulates B2 receptors with subsequent release of prostaglandins and nitric oxide. ACEIs may increase microvascular perfusion by a bradykinin-dependent mechanism.
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PMID:Captopril increases skin microvascular blood flow secondary to bradykinin, nitric oxide, and prostaglandins. 789 12

Although prevention of heart failure recently has become a realistic issue, management of heart failure once the syndrome has developed, is mainly supportive, based on the various cardiac and peripheral changes which occur in the course of heart failure. Of these, abnormal neurohormonal activation is of major pathophysiologic and prognostic significance. Consequently, modulation of neuroendocrine activation is now recognized a prime target in the treatment of heart failure, besides diuretic therapy. In this respect, the value of converting enzyme inhibition is well established. Future developments in this area include dopaminergic agents, vasopressin antagonists, angiotensin II receptor antagonists, renin inhibitors, spironolactone and, possibly, ANF peptidase inhibitors. Besides diuretics, necessary when signs of fluid retention are present, the approach to heart failure management involves other pharmacologic issues. In view of abnormal vascular control with vasoconstriction prevailing during progressive heart failure, it clearly makes sense to vasodilate. However, of available vasodilators, only the combination of relatively high dose nitrates and hydralazine has proven to be of clinical significance, in terms of hemodynamics, exercise capacity and survival. It is possible, though, that novel generation dihydropyridine derivatives may prove beneficial as well. Thus far, there has been much debate concerning the usefulness and particularly the safety of positive inotrope therapy and inodilator treatment. Taken together, this concern relates to presence and predominance of cAMP-dependent mechanisms to induce these effects. Thus, sympathomimetic agents and phosphodiesterase inhibitors, such as milrinone or enoximone, are without beneficial effects, but instead shorten survival during long-term therapy. This may be different where compounds which act through cAMP-independent mechanisms, i.e., calcium sensitization or sodium channel stimulation, are concerned, but needs to be confirmed yet.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Congestive heart failure. Drug therapy: central or peripheral approach? 791 52

The 'angiotensin system' is expressed at the whole body, organ/tissue and cellular levels through the action of angiotensin II at specific receptors. An appreciation of the full scope of the actions of angiotensin II (endocrine, paracrine and autocrine) has been made possible by the discovery of the non-peptide angiotensin II receptor antagonists, losartan (DuP 753/MK954)(AT1-selective) and PD123177 (AT2-selective). Virtually all of the known effects of angiotensin II are blocked by losartan and designated AT1. Selective AT1 receptor blockade with losartan lowers BP in angiotensin II-dependent models of hypertension, reduces cardiac hypertrophy, improves haemodynamics in models of cardiac failure and reduces the intimal response to vascular injury. AT2 sites have been localised in distinct parts of the brain and in foetal tissue. The functional role of the AT2 sites remains controversial, but possible roles in neuronal ion channel function and collagen metabolism in fibroblasts have been reported. AT1 (losartan-sensitive) receptor subtypes have now been cloned from several rat tissues, suggesting that selective agents of the future may be even more specifically targeted. New perspectives in the control of the angiotensin system continue to evolve rapidly as the new receptor antagonists and molecular biology techniques expand our understanding of angiotensin II.
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PMID:New perspectives in angiotensin system control. 823 85

Drug induced modification of the renin-angiotensin system is of established benefit in the treatment of hypertension and heart failure. The responses to the angiotensin converting enzyme (ACE) inhibitor enalapril (CAS 75847-73-3) have been studied in essential hypertension and normotensive controls. The kinetics and dynamics of enalapril have been characterised in an integrated concentration-effect model to identify factors underlying responsiveness to the ACE inhibitor. In addition models to predict the response to long-term treatment from changes after the first dose have been developed. Enalapril response could be described by a non linear (Emax) model defined by two parameters - the maximum response (Emax) and the drug concentration required to cause 50% of the maximum response (C50). Acute dosing accurately predicted the Emax after 6 weeks treatment. In addition to individual pharmacokinetics, pretreatment blood pressure was the most important determinant of response to enalapril. In caucasian salt-replete essential hypertension neither age nor plasma renin activity were major factors. However, in states of sodium restriction and/or diuretic treatment, the response to enalapril was greatly increased. The angiotensin II receptor antagonist, losartan has been reported to be without effect on blood pressure in salt-replete normals. Salt restriction together with furosemide for 3 days led to dose-related falls in blood pressure in normal subjects after losartan 25-100 mg. Concentration-effect analysis can be used to describe blood pressure responses, to predict the responses to long-term treatment and also to identify quantitatively important factors determining the response in individual patients.
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PMID:Inhibitors of the renin-angiotensin system. Clinical pharmacology studies on kinetics, dynamics and concentration-effect relationships. 849 75


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