Percutaneous aortic valvuloplasty for aortic stenosis in the elderly.
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Aged↗
Biomedical subjects
H Ikram
Publications and source records attributed to H Ikram.
Chronic inhibition of endopeptidase 24.11 in essential hypertension: evidence for enhanced atrial natriuretic peptide and angiotensin II.
AIM: To determine the renal, endocrine and haemodynamic effects of an orally active inhibitor of the neutral endopeptidase EC 3.4.24.11 in essential hypertension. METHODS: Two groups of 12 white male patients with essential hypertension were treated with candoxatril at 25 mg every 12 h (group 1) or at 200 mg every 12 h (group 2) for 5 days in double-blind, placebo-controlled, crossover studies. RESULTS: Candoxatril enhanced natriuresis over the initial 48 h of treatment. Twenty-four-hour diurnal hormone profiles (day 4) showed modest elevations in plasma atrial natriuretic factor (ANF) concentrations and more clear-cut increases in plasma and urinary cyclic GMP. Plasma angiotensin II and aldosterone concentrations were also significantly increased. Plasma catecholamine concentrations were significantly increased by the higher dose of candoxatril. Blood pressure (day 4, 24-h intra-arterial recordings) fell significantly with both doses. The infusions of exogenous ANF and angiotensin II on day 5 showed that candoxatril impaired the metabolic clearance of both ANF and angiotensin II with consequent enhancement of the biological effects of both effector peptides. CONCLUSIONS: Candoxatril augments the effects of ANF and lowers blood pressure in patients with hypertension. However, the antihypertensive effects may be offset by increased angiotensin-aldosterone and sympathetic nervous system activity. The blood pressure response to endopeptidase inhibition in hypertensive patients may depend on the relative effects on humoral vasodilator (including ANF) and vasoconstrictor (including the angiotensin-aldosterone and sympathetic) systems.
Adult↗
Electrophysiological effects of atrial natriuretic peptide on the cardiac conduction system in man.
We assessed the effect of atrial natriuretic peptide (ANP) on electrophysiological parameters in man. Electrophysiological parameters were measured before, at 15, and at 30 minutes after the commencement of ANP or placebo infusions (six patients in each group). ANP levels were normal prior to infusion and rose with ANP to 159 +/- 43 pmol/L, but were stable during placebo infusion. No change in heart rate or blood pressure occurred in either group. ANP infusion resulted in significant falls in intraatrial conduction time (60 +/- 15 to 49 +/- 15 msec), PR interval (170 +/- 21 to 155 +/- 16 msec), right atrial effective refractory period (232 +/- 33 to 218 +/- 33 msec), and ventriculoatrial refractory period (452 +/- 148 to 393 +/- 183 msec) while no change was seen with placebo. We conclude that ANP infusion appears to affect atrial refractoriness and velocity of conduction and atrioventricular nodal refractoriness. However, the mechanism of action and clinical significance of this observation remain to be determined.
Adolescent↗
Brain natriuretic factor: regional plasma concentrations and correlations with haemodynamic state in cardiac disease.
OBJECTIVE: To document regional plasma concentrations of brain natriuretic factor (BNF) and their relations to concurrent concentrations of atrial natriuretic factor, cyclic guanosine monophosphate, and haemodynamic state. DESIGN: Regional blood sampling from a systemic artery and vein, renal vein, and coronary sinus together with concurrent haemodynamic indices in patients coming forward for left and right cardiac catheterisation. SETTING: Tertiary referral centre. PATIENTS: 22 consecutive unselected patients coming forward for left and right cardiac catheterisation or electrophysiological studies in the course of standard diagnosis for a range of cardiac disorders. MAIN OUTCOME MEASURES: Significant arteriovenous gradients for plasma BNF concentration were found across the lower limb, the kidney, and the heart. These were less than concurrent arteriovenous gradients in plasma atrial natriuretic factor (ANF). Arterial concentrations of plasma BNF were positively related to concurrent concentrations of ANF (r = 0.72, p < 0.01) and cyclic guanosine monophosphate (r = 0.52, p < 0.05). Arterial plasma concentrations of BNF showed a significant positive correlation with right atrial pressure and pulmonary artery wedge pressure and an inverse relation to cardiac output. CONCLUSIONS: Regional plasma concentrations of BNF indicate cardiac secretion of this peptide and clearance in a number of tissues. Renal clearance is proportionally greater than that found across the limb. Absolute and proportional arteriovenous gradients of this peptide are considerably less than for concomitant concentrations of ANF suggesting slower metabolic clearance of BNF. Plasma BNF concentrations rise with increasing cardiac impairment and are related to indices of cardiac function. These findings are consistent with a role for BNF in the neurohumoral response to cardiac impairment.
Adult↗
Endopeptidase 24.11 inhibition by SCH 42495 in essential hypertension.
The detailed integrated renal, hormonal, and hemodynamic effects of acute (first dose) and established (4 days) inhibition of endopeptidase 24.11 by SCH 42495 (200 mg, every 12 hours) were documented in eight patients with essential hypertension in a double-blind, balanced random-order, crossover study. SCH 42495 suppressed plasma endopeptidase activity (> 90%, P < .001) for the duration of the dosing period. Initially, plasma atrial natriuretic factor levels increased markedly (+123%, P < .01) and remained elevated, although to a lesser extent (+34%, P < .01), with established enzyme inhibition. Cyclic guanosine monophosphate in both plasma and urine remained elevated throughout the treatment period. Significant augmentation of sodium excretion in excess of placebo values (96 +/- 27 mmol sodium, P < .001) was established in the initial 24 hours of dosing but later became attenuated, with a mild antinatriuresis (P < .01) in the latter 3 days of treatment. Blood pressure, heart rate, the renin-angiotensin-aldosterone system, and plasma norepinephrine levels were all initially (first dose) unchanged. With established enzyme inhibition (day 4), however, blood pressure was significantly lower (mean 24-hour values, 9.3 +/- 3/-3.8 +/- 1 mm Hg, P < .05 for both systolic and diastolic pressures) than matched placebo values, whereas heart rate was higher (2.7 +/- 1 beats per minute, P < .01). Mean 24-hour values of plasma renin activity (+33%, P < .05), aldosterone (+36%, P < .05), and norepinephrine (+40%, P < .001) were all clearly increased above placebo values with established enzyme inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Twenty-four hour profile of the anti-hypertensive action of isradipine in essential hypertension.
Isradipine, 2.5 mg twice daily and placebo were administered for 4 weeks to 11 untreated essential hypertensives in a double-blind, random order, crossover study. At the end of each phase patients were assessed by 36 h of continuous intra-arterial blood pressure monitoring, surface electrocardiography, and measurement of endogenous creatinine clearance, serum biochemistry and plasma renin activity. Arterial pressure was significantly reduced by isradipine, with mean reduction in systolic blood pressure of 11.0 mmHg and diastolic pressure of 13.2 mmHg over 24 h. There was no significant change in heart rate, endogenous creatinine clearance, serum biochemistry or plasma renin activity.
Adult↗
Cardiac natriuretic peptides in heart failure.
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Animals↗
A testing time for heart disease.
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Apolipoproteins A↗
Hemodynamic effects of nitroprusside on valvular aortic stenosis.
The effects of acute reduction of left ventricular (LV) loading in valvular aortic stenosis (AS) were examined. Thirty-five consecutive patients with AS (peak-to-peak aortic valve gradient 66 +/- 26 mm Hg, aortic valve area 0.65 +/- 0.22 cm2) were given intravenous sodium nitroprusside (1 to 3 micrograms/kg/min) to reduce systolic aortic pressures by greater than 10 mm Hg (mean aortic pressure 99 +/- 15 to 80 +/- 15 mm Hg; p less than 0.001). Overall, nitroprusside infusion resulted in little change in cardiac index (2.72 +/- 0.61 to 2.67 +/- 0.58 liters/min/m2; p = not significant). Individual patients had a range of responses. Fourteen patients (group 1) had an increase in cardiac index (2.42 +/- 0.59 to 2.74 +/- 0.67 liters/min/m2; p less than 0.001), whereas 21 (group 2) had a decrease or no change (2.93 +/- 0.56 to 2.61 +/- 0.52 liters/min/m2; p less than 0.001). Comparison of these subgroups showed that a cardiac index increase with nitroprusside was significantly predicted by a higher LV end-diastolic pressure (26 +/- 12 vs 15 +/- 6 mm Hg), lower LV ejection fraction (44 +/- 18 vs 62 +/- 12%). smaller aortic valve area (0.52 +/- 0.12 vs 0.74 +/- 0.22 cm2) and lower cardiac index (2.42 +/- 0.59 vs 2.93 +/- 0.56 liters/min/m2) (all values groups 1 and 2, respectively). It is concluded that there is a disparate response to acute vasodilatation in AS. Potentially beneficial effects are seen in a subgroup of patients, especially those with increased filling pressures and impaired LV function.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Tissue plasminogen activator using a rapid-infusion low-dose regimen for unstable angina.
The clinical effect of a low-dose rapid-infusion intravenous regimen was assessed using human recombinant tissue-type plasminogen activator (rt-PA) in unstable angina. Fifty patients with unstable angina pectoris were randomly assigned to blinded treatment with either placebo (24 patients) or low-dose (20 mg bolus, 30 mg infusion over 1 hour) intravenous rt-PA (26 patients). Before randomization, all patients were treated with aspirin, twice-daily subcutaneous heparin, and maximally tolerated antianginal therapy. Of the 50 patients assigned, 26 received rt-PA and the outcome was successful in 15 (58%) (angina settled, no myocardial infarction or urgent intervention) compared with 9 (38%) successful outcomes in the 24 who received placebo (0.5 greater than p greater than 0.1). Angina remained refractory in 8 (31%) of the rt-PA group and in 13 (54%) of the placebo group (0.1 greater than p greater than 0.05). Urgent interventions were required in 6 patients (23%) who received rt-PA and in 11 patients (46%) who received placebo. Three patients in each group sustained a myocardial infarction within 72 hours of entering the trial and there were 3 deaths (1 in the active treatment group, 2 in placebo group) within 2 weeks of the trial (p = not significant). Administration of intravenous rt-PA was not associated with any complications. Low-dose rt-PA administration in patients with unstable angina was associated with a tendency to stabilization of anginal symptoms and a reduction in the need for urgent intervention. However, these trends did not achieve statistical significance.
Aged↗
Endothelin-induced changes in intracellular calcium concentration in rat vascular smooth muscle cells: effects of extracellular calcium and atrial natriuretic factor.
The purpose of this study was to examine whether different mechanisms might underlie the changes in intracellular calcium concentration ([Ca2+]i) stimulated by high and low concentrations of endothelin, and whether atrial natriuretic factor (ANF) has an inhibitory effect on endothelin-induced [Ca2+]i changes in cultured rat vascular smooth muscle cells (VSMCs). In calcium-replete buffer, cultured monolayers of rat VSMCs superfused with endothelin at a high concentration (10 nM) exhibited a marked transient rise in [Ca2+]i, followed by a sustained elevation, whereas a low concentration of endothelin (0.1 nM) induced a sustained monophasic elevation. When calcium-free buffer was used, 10 nM endothelin induced a transient rise in [Ca2+]i of lesser amplitude, whereas 0.1 nM endothelin did not produce a significant rise. Pretreatment of VSMCs with ANF and cosuperfusion with endothelin failed to inhibit either transient or sustained endothelin-induced changes in [Ca2+]i in calcium-replete buffer.
Animals↗
Comparison of the effect of renin inhibition and angiotensin-converting enzyme inhibition in ovine heart failure.
The acute hemodynamic and hormonal effects of incremental doses of a specific ovine renin inhibitor (RI: EMD 52 297) and captopril were compared in an ovine model of heart failure. Both RI and captopril inhibited the renin-angiotensin II (ANG II) system, although the decrease in plasma aldosterone (ALDO) was significant only during captopril infusion. Both agents exhibited strong vasodilator properties with similar decreases in mean arterial pressure (MAP, maximum decrease: RI = -20.5 +/- 2.2 mm Hg, p less than 0.001; captopril = -19.8 +/- 1.7 mm Hg, p less than 0.001) and left atrial pressure (LAP, maximum, decrease: RI = -6.8 +/- 1.5 mm Hg, p less than 0.01; captopril = -6.9 +/- 0.4 mm Hg, p less than 0.01) along with a slight increase in cardiac output (CO, maximum increase: RI = 0.54 +/- 0.11 L/min; captopril = 0.79 +/- 0.26 L/min). The slope of the response between MAP and LAP was similar in all animals, indicating that the agents have a similar effect on cardiac preload and afterload. The similar hemodynamic actions of RI and captopril in this model of congestive heart failure suggest that beneficial effects are due to inhibition of ANG II. Thus, orally active renin inhibitors may offer a useful therapeutic alternative when side effects preclude use of angiotensin-converting enzyme (ACE) inhibitors.
Aldosterone↗
Acute hemodynamic, hormonal, and renal effects of neutral endopeptidase inhibition in ovine heart failure.
The effects of neutral endopeptidase inhibition (NEP-I) were studied in 6 conscious sheep with heart failure (HF) induced by rapid ventricular pacing for 7 days. Measurements were performed 1 h before and for 6 h after intravenous (i.v.) bolus administration of vehicle and SCH 39370 (1.25 and 5 mg/kg) on separate days. After the higher dose, an index of serum NEP activity decreased from 0.83 +/- 0.05 to 0.13 +/- 0.07 nmol/ml/min (p less than 0.001) at 1 h and then returned to control levels at 6 h. Plasma atrial natriuretic peptide (ANP) and cyclic GMP rose from 328 +/- 28 and 20.2 +/- 4.3 to a peak of 570 +/- 65 pmol/L (p less than 0.001) and 28.7 +/- 6.3 nmol/L (p less than 0.05) respectively. Natriuresis and diuresis were significant and left atrial pressure (LAP) decreased from 21.9 +/- 1.1 to 20.1 +/- 0.8 mm Hg (p less than 0.05). Despite high endogenous ANP levels in HF, NEP-I further increases both ANP and its "second messenger." Its natriuretic and hemodynamic effects are consistent with enhanced ANP activity in renal and vascular tissues, suggesting that NEP-I may be useful for treating HF.
Analysis of Variance↗
Angiotensin II receptor antagonism in ovine heart failure: acute hemodynamic, hormonal, and renal effects.
The hemodynamic, hormonal, and renal effects of angiotensin II-type 1 receptor antagonism (AT1A) have not been documented previously in heart failure (HF) or compared with angiotensin-converting-enzyme inhibition (ACEI). Accordingly, we investigated the acute (2-h) response to losartan (1 and 10 mg/kg iv) or vehicle (N saline) followed by captopril (12.5 mg) on separate days in an ovine model of HF induced by 7 days of rapid ventricular pacing. Losartan induced a significant rise in plasma renin activity (PRA) and plasma angiotensin II levels (P less than 0.01 and P less than 0.001, respectively), in association with a fall in the plasma aldosterone-to-PRA ratio (P less than 0.001) and plasma atrial natriuretic peptide (P less than 0.05). Mean arterial and left atrial pressure both fell significantly after losartan (P less than 0.001), whereas the rise in cardiac output was not sustained. The response to captopril was similar except for plasma angiotensin II, which declined (P less than 0.001). Glomerular filtration and urine sodium excretion were maintained despite a fall in renal perfusion pressure. In conclusion, the vasodilatation and renal effects of AT1A were similar to ACEI. Thus AT1A may be a useful therapeutic alternative to ACEI in HF.
Angiotensin Receptor Antagonists↗
Effect of inhibition of endopeptidase 24.11 on responses to angiotensin II in human volunteers.
The effects of endopeptidase 24.11 inhibition on angiotensin-induced changes in plasma angiotensin II, aldosterone, and atrial natriuretic factor concentrations and blood pressure were assessed in normal volunteers. Two groups, each consisting of eight normal volunteers, received stepwise infusions of angiotensin II (2, 4, and 8 ng/kg per minute) on day 5 of dose administration with 25 mg every 12 hours (group 1) or 100 mg every 12 hours (group 2) of an oral inhibitor of endopeptidase 24.11 (UK 79300, candoxatril) or placebo in balanced randomized, double-blind, placebo-controlled crossover studies. Both doses of candoxatril significantly enhanced achieved plasma angiotensin II concentrations during infusions (group 1, p < 0.001; group 2, p < 0.01; overall treatment effect for combined data, p < 0.001). This effect was most pronounced at the highest dose of angiotensin II (treatment-time interaction, p < 0.0001 for combined data) and tended to be more marked with the higher dose of candoxatril (treatment-group interaction, p = 0.08). The pressor response to angiotensin II was clearly enhanced by the lower dose of candoxatril; peak systolic and diastolic pressures exceeded placebo values by approximately 10 mm Hg (p < 0.001 and p < 0.05 for systolic and diastolic pressures, respectively). This effect of candoxatril was absent in group 2, which (unlike group 1) had exhibited a modest natriuretic response (sustained cumulative negative sodium balance, -70 +/- 21 mmol; p < 0.01) to the higher dose of inhibitor. Baseline plasma aldosterone concentrations and the incremental aldosterone response to angiotensin II infusions were not significantly altered by low-dose (group 1) candoxatril.(ABSTRACT TRUNCATED AT 250 WORDS)
Aldosterone↗
Angiotensin converting enzyme inhibitors versus digoxin for the treatment of congestive heart failure.
Angiotensin converting enzyme (ACE) inhibition and digoxin may be used in the management of heart failure. Digoxin increases myocardial contractility in vitro, and has a modest but durable beneficial effect in congestive heart failure due to impaired left ventricular systolic function. ACE inhibitors have clear beneficial effects in all grades of heart failure and, in addition, modify the natural history and reduce mortality. Comparative studies in mild to moderate heart failure reveal a tendency towards greater benefits and tolerability of ACE inhibitors over digoxin. ACE inhibition is indicated, in conjunction with diuretic therapy, for all grades of heart failure. Digoxin is best reserved for patients with atrial fibrillation and a rapid ventricular response, and for those whose heart failure is not controlled with an ACE inhibitor plus a diuretic. In patients with heart failure following myocardial infarction, digoxin is of modest benefit. Digoxin should be administered slowly and carefully to avoid acute vasoconstriction and toxicity. Provisional data suggest ACE inhibitors are also beneficial in these patients. However, the results of clinical trials presently in progress are required to clarify their role following myocardial infarction.
Angiotensin-Converting Enzyme Inhibitors↗
Acute inhibition of endopeptidase 24.11 in essential hypertension: SCH 34826 enhances atrial natriuretic peptide and natriuresis without lowering blood pressure.
The acute renal, endocrine, and hemodynamic effects of the orally active endopeptidase inhibitor SCH 34826 (400 mg every 6 hours for five doses) were investigated in a group of 6 male patients [with established mild to moderate essential hypertension and left ventricular (LV) hypertrophy] in a balanced random-order double-blind, placebo-controlled cross-over study. Plasma atrial natriuretic factor (ANF) concentrations increased (p < 0.05) to fourfold control values after the first dose of inhibitor, but later postdose increments of ANF were less pronounced. Plasma cyclic GMP also increased significantly (p < 0.05). These effects were associated with a transient modest but significant (p < 0.05) increase in sodium excretion (50 mmol sodium in excess of placebo values) that was complete in 24 h. Mean 24-h urinary excretions of cyclic GMP and immunoreactive ANF were also significantly increased by 55 and 86%, respectively. Other urine indexes (including other electrolytes, volume, creatinine, aldosterone, and cortisol) and renal hemodynamics [including glomerular filtration rate (GFR) and effective renal plasma flow (RPF)] were unchanged. Renin-angiotensin-aldosterone system (RAAS) activity was not significantly altered. Plasma epinephrine increased after the initial three doses of SCH 34826. Systolic blood pressure (SBP) and heart rate (HR) were not altered by SCH 34826. Diastolic BP (DBP) increased slightly (p = 0.044). Acute inhibition of endopeptidase 24.11 by SCH 34826 in essential hypertension caused significant increments in plasma ANF and cyclic GMP together with modest natriuresis. No antihypertensive effect was observed in the first 30 h of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Atrial Natriuretic Factor↗
Acute haemodynamic effects of dopexamine in patients with coronary arterial disease.
We assessed the acute haemodynamic effects of dopexamine 1 microgram/kg/min and 3 micrograms/kg/min in 21 patients with coronary arterial disease following routine catheterisation. Patients were aged 38 to 72 years and left ventricular ejection fraction ranged from 23 to 79%. Dopexamine was well tolerated in all patients except one in whom transient ventricular arrhythmias occurred with 3 micrograms/kg/min. No patient developed angina. Dopexamine increased cardiac index (2.6 +/- 0.4 to 3.2 +/- 0.1 (P less than 0.001) and 4.0 +/- 1.0 1/min/m2 (P less than 0.001), control to 1 microgram/kg/min and 3 micrograms/kg/min, respectively) and decreased systemic vascular resistance index (3356 +/- 1506 to 2318 +/- 809 (P less than 0.001) and 2252 +/- 1973 dyne.sec.cm-5/m2 (P less than 0.001], but did not affect systemic arterial, pulmonary arterial or right atrial pressure. Maximum positive dP/dt was increased (1294 +/- 324 to 1597 +/- 505 (P less than 0.001) and 2199 +/- 819 mmHg/sec (P less than 0.001] as was left ventricular stroke work index (44 +/- 20 to 51 +/- 21 (P less than 0.05) and 56 +/- 27 g.m/m2 (P less than 0.001) control to 1 microgram/kg/min and 3 micrograms/kg/min, respectively). Left ventricular end diastolic pressure fell with 3 micrograms/kg/min from 19.8 +/- 6.9 to 12.4 +/- 4.6 mmHg (P less than 0.05) in patients with preserved left ventricular ejection fraction (greater than 50%, n = 6), but not in those with impaired left ventricular ejection fraction (less than 50%, n = 15), otherwise the effects in these two subgroups were similar. We conclude that dopexamine has both inotropic and vasodilator properties.(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiac Catheterization↗