Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuroendocrine activation in acute myocardial infarction (AMI) may have important physiological consequences for myocardial perfusion and function. We measured plasma angiotensin II in 60 patients with AMI within 6 hours of pain and on days 1-3 and day 10. On admission, AII was normal at 9.9 + 1.3 pmol/l (normal range 2-12 pmol/l). At day 3, AII rose markedly to 77.5 + 25.0 in those with heart failure (group 1, n = 13); but AII also rose in uncomplicated patients (group 2, n = 47) to 27.8 + 4.0 (p less than 0.001). At day 10, levels of AII remained high, especially in group 1 (50.5 + 22.2 vs 6.1 + 1.5, p less than 0.005). Thus neuroendocrine activation, present early in AMI, is seen in both uncomplicated infarcts and in those developing heart failure. Angiotensin II mediated vasoconstriction perhaps enhanced by catecholamines could have deleterious effects on myocardial function and perfusion, and indicates the potential for angiotensin-converting enzyme inhibitors in early AMI.
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PMID:Neuroendocrine activation in acute myocardial infarction. 244 Nov 95

Activation of the renin-angiotensin system in acute myocardial infarction may have important haemodynamic consequences. The effects of captopril were assessed in nine patients with acute left ventricular failure complicating myocardial infarction. Plasma angiotensin II was elevated at 16.8 (3.6) pmol/l (mean [SE]) including high levels in three of four patients in the absence of any previous therapy, including diuretics. Repeated low doses of captopril were administered to reduce pulmonary capillary wedge pressure less than 14 mm Hg or to a maximum total dose of 25 mg. Right atrial pressure fell from 12.4 (0.9) to 9.4 (0.7) mm Hg p less than 0.001, pulmonary arterial pressure from 32.7 (3) to 26.4 (2.2) p = 0.01, and pulmonary capillary wedge pressure from 25.7 (2.9) to 19.9 (2.2) p = 0.01. Despite a fall in systemic vascular resistance from 1,540 (110) to 1,330 (76) dyn/s/cm5, and mean arterial pressure from 84.8 (3.9) to 76.7 (2.7) p = 0.001, changes in cardiac output were small: 3.8 (0.3) to 4.2 (0.3) NS. Angiotensin II fell in all patients even after only 3.125 mg to a mean of 3.6 (1.0). These improvements occurred whether basal angiotensin II was elevated or normal, and in the presence or absence of diuretic therapy. At 24 hours, seven patients received captopril in the maximum titrated dose of the previous day. Haemodynamic changes at one hour were of similar magnitude to those during incremental dosing. These results suggest that reduction of angiotensin II exerts beneficial haemodynamic effects in heart failure complicating acute myocardial infarction.
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PMID:Haemodynamic effects of captopril in acute left ventricular failure complicating myocardial infarction. 244 Nov 96

Nitrendipine and cilazapril are two new antihypertensive drugs with different mechanisms of action. Nitrendipine is a calcium antagonist of the dihydropyridine class which decreases directly the smooth muscle tone. Cilazapril is a new long-lasting inhibitor of angiotensin-converting enzyme which suppresses the peripheral vasoconstrictor effect of angiotensin I by inhibiting its transformation in angiotensin II. The goal of the present study was to assess the effects on hemodynamics and regional blood flows (measured with radioactive microspheres) of cilazapril and nitrendipine given alone or in combination. Cilazapril (3 mg/kg) and nitrendipine (0.3 mg/kg) were given intravenously to conscious spontaneously hypertensive rats first alone, then in combination. Both cilazapril and nitrendipine decreased mean arterial pressure to the same extent. Cilazapril increased regional blood flow only in the kidney without changing total cardiac output. In contrast, nitrendipine increased regional blood flow in nearly every organ and markedly enhanced total cardiac output. Cilazapril redistributed the cardiac output distribution toward the kidney, and nitrendipine did not change the cardiac output distribution. The combination of both nitrendipine and cilazapril produced a stronger antihypertensive effect than each drug alone. The peripheral vasodilatation with the combination was not as marked as with nitrendipine alone but was associated with the same redistribution of the cardiac output toward the kidney as with cilazapril. We conclude that after acute intravenous administration the combination of cilazapril and nitrendipine produced hemodynamic effects which cannot be induced by each drug used alone. Such a therapeutic profile may be useful in patients with high blood pressure or heart failure.
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PMID:Effects of nitrendipine and cilazapril alone or in combination on hemodynamics and regional blood flows in conscious spontaneously hypertensive rats. 246 61

Angiotensin II appears to have important actions in modulating sympathetic nerve activity; conversely, sympathetic stimulation alters renin release. Drugs that inhibit angiotensin II formation would be expected then not only to offset the direct vasoconstricting and aldosterone releasing actions of this peptide but also to reduce sympathetic nerve activity. Hypertension and cardiac failure are two major conditions in which converting enzyme inhibitors have found important therapeutic roles; both are considered to be associated with increased activity of the renin-angiotensin-aldosterone and sympathetic nervous systems. However, in spite of considerable experimental evidence for a sympatholytic action of converting enzyme inhibitors, direct proof has been difficult to obtain in humans. In part, this results from the lack of any satisfactory way of assessing sympathetic activity in the clinical situation. Nevertheless, our failure to understand the pathophysiology of disease and the precise mechanism of action of drugs has not precluded exploiting the salutatory effects of inhibition of converting enzyme.
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PMID:The sympathetic nervous system and converting enzyme inhibition. 247 95

1. The effects of heart failure due to chronic myocardial infarction on the responsiveness to injected angiotensin I and ACE inhibition by intravenous cilazapril (1 mg kg-1) were evaluated. 2. For this purpose one group of 17 rats with a 4-week old myocardial infarction was compared with a group of 10 sham operated rats. 3. Heart failure increased markedly the responsiveness of the renal and mesenteric vascular beds to ACE inhibition which produced a vasodilation in these two vascular beds. 4. This increased responsiveness was most likely due to a stimulation of the renin-angiotensin system without any change of sensitivity to angiotensin I of the renal and mesenteric vascular beds. 5. Cilazapril produced the same level of ACE inhibition in both groups of rats.
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PMID:Effects of chronic heart failure on the responsiveness to angiotensin I and to angiotensin converting enzyme inhibition with cilazapril in rats. 252 30

Relaxation delay is an important feature of hypertensive heart disease which impairs diastolic coronary flow and ventricular filling and therefore contributes to heart failure. We investigated the hypothesis that impaired relaxation is a property of the myocardium, rather than the consequence of ischaemia or interstitial fibrosis. A new videomicroscope system was used to define the contraction-relaxation cycle of isolated cardiac myocytes from spontaneously hypertensive rats (SHR) and normotensive control (Wistar-Kyoto, WKY) rats. The SHR cells showed a marked relaxation delay. Angiotensin II (Ang II) increased the contraction maximum by about 35% in WKY rats and induced a relaxation delay. In SHR Ang II greatly potentiated this relaxation delay. Our results demonstrate that impairment of relaxation is a property of the single cardiomyocyte. Angiotensin II induces a relaxation delay that is independent of blood pressure. The combination of hypertrophy and high levels of Ang II potentiates relaxation impairment and may therefore contribute to hypertensive left ventricular failure.
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PMID:Impaired relaxation of the hypertrophied myocardium is potentiated by angiotensin II. 253

Isolated calcium-tolerant rat ventricular cardiomyocytes were used to characterize the effects of atrial natriuretic peptide (ANP), Angiotensin II (AII) and their interaction on the myocardial contraction-/relaxation pattern free of interference from other types of cardiac cells. Binding of 125I-ANP showed a KD of 12 pM and approximately 600 binding sites per cell. At 37 degrees C (rate 140 bpm) ANP decreased the contraction maximum with an EC50 of about 70 pM, maximal decrease was 35%. ANP (10(-7) M) raised cellular cyclic-GMP from 0.76+/-0.12 to 1.32+/-0.13 pmole/10(6) cells (73%, p less than 0.05). Angiotensin II increased contractility by a maximum of 32% at 10(-7) M; the EC50 was 8 x 10(-10) M. AII markedly delayed relaxation (reduction of maximum relaxation velocity from 0.092 to 0.063 mm/s; p less than 0.05). ANP (10(-7) M) increased the effect of AII (10(-8) M) on contractility by 66% without changing relaxation parameters significantly. This unexpected interaction may be relevant in pathological conditions where both AII and ANP are stimulated, such as heart failure or secondary hypertension.
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PMID:Action of atrial natriuretic peptide and angiotensin II on the myocardium: studies in isolated rat ventricular cardiomyocytes. 255 Dec 88

Angiotensin II can stimulate the sympathetic system and inhibit vagal (parasympathetic) outflow under experimental circumstances in animals. Blockade of angiotensin II formation by angiotensin-converting enzyme (ACE) inhibitors might therefore be expected to result in a reduction of sympathetic activity and enhanced parasympathetic activity. Whether this is so in normotensive or hypertensive humans and in human cardiac failure is unclear, since available techniques for recording activity of the sympathetic and parasympathetic systems are imperfect. Nevertheless, most evidence that comes from measurements of venous norepinephrine suggests that the ACE inhibitors have little or no effect on sympathetic activity in normotension and hypertension, although the activated sympathetic system in severe cardiac failure is probably suppressed. It appears that the ACE inhibitors have a parasympathomimetic action that may contribute to the hemodynamic effects of these drugs. Additional information using direct recordings of sympathetic traffic or measurements of norepinephrine "spillover" is needed to clarify the effects of ACE inhibitors on the sympathetic system.
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PMID:Sympathetic nervous system during converting enzyme inhibition. 257 49

1. Angiotensin II (AII) acts as a potent pressor agent directly, by virtue of its vasoconstrictor activity and indirectly, by the volume expansion resulting from stimulation of aldosterone release from the adrenal cortex, leading to sodium and water retention. Various approaches of interfering with the enzymatic cascade leading to the production of AII have been made in an attempt to define therapeutic agents for the control of hypertension and heart failure. 2. AII receptor antagonists, to date, lack oral activity and have a relatively short duration of action, limiting their clinical usefulness. Inhibitors of angiotensin converting enzyme block AII production, are orally active and have been used successfully in the control of hypertension and in the treatment of congestive heart failure. 3. An ideal approach to the blockade of the renin-angiotensin system (RAS) is the inhibition of renin, an enzyme with only one known substrate (angiotensinogen) which catalyzes the first and rate-limiting step in the RAS. Early attempts to discover a renin inhibitor focused on immunologic inhibitors of renin, fragments of the prorenin sequence and compounds related to pepstatin, a potent pentapeptide inhibitor of pepsin and less potent inhibitor of renin. None of these approaches proved feasible for a variety of reasons including poor absorption, short duration of action and weak activity. 4. Substrate analogs offer the greatest promise for clinically useful renin inhibitors. Most recently, synthesis of compounds mimicking the enzyme transition state, the condition of greatest binding affinity, has resulted in renin inhibitors with potencies in the nanomolar range, which have shown hypotensive activity. These compounds contain at least one peptide bond and have limited oral activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renin inhibitors: specific modulators of the renin-angiotensin system. 265 8

The inter-relationship between the pharmacokinetic and pharmacodynamic behaviour of ACE inhibitors is reviewed. First, some of the methods which have been used to assess the pharmacodynamics of ACE inhibitors in humans are presented. They include humoral assays (e.g. ACE activity in plasma, renin activity, etc.), haemodynamic changes (blood pressure, total peripheral resistance, etc.) and agonist challenges (angiotensin I infusions). Subsequently a pharmacokinetic-dynamic model is described, based on biochemical processes obtained after ACE inhibition, which seems to be useful for the interpretation of the complex processes. The various correlations between plasma drug concentration on the one hand and plasma ACE activity, angiotensin II concentration in plasma or blood pressure on the other, are discussed on the basis of this model. From the model obtained it becomes obvious that under many circumstances the release of the inhibitor from ACE binding is the step which in fact determines the pharmacodynamically relevant elimination rate of the drug at low concentrations, whereas at high concentrations the elimination of the drug is mainly dependent on kidney (and/or liver) elimination rate. The dynamic-kinetic correlations are then presented for some ACE inhibitors in various disease states: arterial hypertension, heart failure, old age, renal failure, liver disease. In a final section the kinetic and dynamic relevance of interactions of ACE inhibitors with food and other drugs is described (e.g. prostaglandin inhibitors, diuretics, digoxin and cimetidine). Despite the great body of literature which deals with the kinetic and/or dynamic properties of ACE inhibitors, precise knowledge of the relationship between their kinetic and dynamic behaviour is rather limited and there is a clear need for further studies to elucidate this complex topic, thereby improving therapeutic possibilities with these useful new compounds.
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PMID:Angiotensin-converting enzyme inhibitors. Relationship between pharmacodynamics and pharmacokinetics. 284 18


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