Biomedical subjects

M de Gasparo

Publications and source records attributed to M de Gasparo.

At least 37 records · Page 2Linked to original sources

PubMed1999

The AT2 receptor: fact, fancy and fantasy.

The angiotensin AT2 receptor subtype was recently cloned and pharmacologically characterized but its function still remains elusive and controversial. It is a member of the G-protein coupled receptor superfamily with a minimal sequence homology with the AT1 receptor, responsible for the known effect of angiotensin II. The AT2 receptor displays a totally different signaling mechanisms from the AT1 receptor and involves various phosphatases. It is expressed at low density in adult tissues but up-regulated in pathological circumstances. Clearly, the AT2 receptor has antiproliferative properties and therefore opposes the growth promoting effect linked to the AT1 receptor stimulation. It is also reported that the AT2 receptor regulates ionic fluxes, affects differentiation and nerve regeneration, has anti-angiogenic and anti-fibrotic properties and stimulates apoptosis. However, the results, although suggestive, are sometimes equivocal. Obviously, the AT2 receptor plays a role in the pathogenesis and remodeling of cardiovascular and renal diseases. A more extensive knowledge of the AT2 receptor could therefore contribute to the understanding of the clincial beneficial effects of the AT1 receptor antagonists.

Animals↗

PubMed1999

Effects of angiotensin type-I receptor blockade on pericardial fibrosis.

BACKGROUND: Reoperative cardiac surgical procedures are associated with a significantly greater complication rate than that of the initial procedure. Enhanced collagen synthesis can occur due to increased production of angiotensin II (Ang-II) and subsequent activation of Ang AT(1) receptor. Accordingly, the goal of the current study is to test the hypothesis that increased Ang AT(1) receptor activity following pericardiotomy contributes to pericardial thickening and fibrosis. MATERIALS AND METHODS: Adult pigs were randomly assigned to three protocols: (1) pericardiotomy with 28-day recovery period (n = 5); (2) pericardiotomy with Ang AT(1) receptor blockade instituted throughout the 28-day recovery period using 60 mg/day valsartan (n = 5); and (3) sham controls (n = 6). Pericardium samples were collected and analyzed by biochemical and histomorphometrical methods. Pericardial fibrosis occurred postpericardiotomy as indicated by increased hydroxyproline content from normal value of 50 +/- 3 microg/mg to 75 +/- 4 microg/mg (P < 0. 05). RESULTS: Pericardial thickness was increased postpericardiotomy to 2.7 +/- 0.4 mm compared to normal values of 0.4 +/- 0.05 mm (P < 0.05). Ang AT(1) receptor blockade reduced pericardial thickness by 50% and the relative degree of fibrosis was comparable to that of the normal group. CONCLUSIONS: The results from this pericardial fibrosis animal model suggest that Ang AT(1) receptor activation contributes to the development of pericardial thickening and collagen accumulation in the postoperative period. Thus, Ang AT(1) receptor inhibition may provide a novel therapeutic strategy to prevent pericardial fibrosis that follows cardiac surgical procedures.

Angiotensin Receptor Antagonists↗

PubMed1998

Sex differences and age-related changes in human serum aminopeptidase A activity.

Given that aminopeptidase A is primarily responsible for cleaving aspartic acid and converting angiotensin II to angiotensin III, the purpose of the present study was to evaluate the activity of aminopeptidase A by determination of glutamate aminopeptidase activity (GluAP) and aspartate aminopeptidase activity (AspAP) (reported respectively as aminopeptidase A and angiotensinase A activities) in human serum during development and ageing, in an apparently healthy population of 139 male and 148 female subjects. To measure GluAP and AspAP we used glutamyl- and aspartyl-2-naphthylamide as substrates. Significant age-related increases were observed in GluAP activity in males and females and in AspAP activity in females. In males, there were no age-related differences in AspAP activity. A significant correlation was observed between age and GluAP activity in the population analysed as a whole or according to sex. No correlation was demonstrated between age and AspAP activity either in the whole population or according to sex. These results may reflect the evolution of the functional status of susceptible circulating substrates during development and ageing.

Adolescent↗

PubMed1998

Angiotensin AT1 receptor inhibition in pacing induced heart failure: effects on left ventricular myocardial collagen content and composition.

The progression of left ventricular (LV) dilation with congestive heart failure (CHF) is associated with an increased incidence of morbidity and mortality. The LV myocardial extracellular matrix has been implicated to play an important role in maintaining chamber shape and myocyte alignment. While angiotensin II AT1 receptor (Ang AT1) receptor activation has been demonstrated to contribute to increased vascular resistance with the CHF, whether activation of the myocardial Ang AT1 receptor system contributes to LV dilation and myocardial collagen remodelling with CHF remains unclear. The goal of this study was to examine the effects of Ang AT1 receptor inhibition on LV geometry and myocardial collagen content and structure with the development of pacing CHF. Pigs (25 kg) were instrumented in order to measure LV function in the conscious state and were assigned to one of three groups: (1) Pacing CHF: rapid atrial pacing (240 bpm) for 3 weeks (n = 7); (2) Pacing CHF and Ang AT1 Block: concomitant Ang AT1 receptor blockade (valsartan, Novartis, Basel 60 mg/day) and rapid pacing (n = 7); (3) sham controls (n = 7). The Ang AT1 receptor antagonist was delivered by osmotic minipump and this dose has been demonstrated previously to significantly blunt the Ang-II pressor response. LV pump function and geometry was assessed by echocardiography and LV myocardial collagen content by computer assisted histomorphometry and biochemistry. In the pacing CHF group, LV fractional shortening was reduced (17 +/- 2 v 45 +/- 1%) and LV end-diastolic dimension increased (5.91 +/- 0.09 v 3.75 +/- 0.07 cm) compared to controls (P<0.05). In the pacing CHF and Ang AT1 blockade group, LV pump function and dimensions were similar to untreated pacing CHF values. The relative content of LV myocardial fibrillar collagen was reduced with pacing CHF (7.6 +/- 0.4 v 11.3 +/- 0.6%) compared to controls (P<0.05), and was similarly reduced in the pacing CHF and Ang AT1 receptor blockade group (8.3 +/- 0.4%, P<0.05). LV myocardial hydroxyproline was reduced with pacing CHF compared to controls (2.35 +/- 0.21 v 2.89 +/- 0.42 mg/gdwt, P<0.05). While reduced with pacing CHF and Ang AT1 receptor blockade (2.54 +/- 0.25 mg/gdwt), this was not significantly different from controls (P=0.23). Ang AT1 receptor inhibition in this model of CHF did not appear to favorably affect the degree of LV dilation and myocardial collagen structure. These results suggest that activation of the myocardial Ang AT1 receptor may not significantly contribute to LV remodelling with pacing CHF.

Animals↗

PubMed1998

Angiotensin converting enzyme inhibition, AT1 receptor inhibition, and combination therapy with pacing induced heart failure: effects on left ventricular performance and regional blood flow patterns.

BACKGROUND: AT1 receptor activation has been demonstrated to cause increased vascular resistance properties which may be of particular importance in the setting of congestive heart failure (CHF). The overall goal of this study was to examine the effects of ACE inhibition (ACEI) alone, AT1 receptor blockade alone and combined ACEI and AT1 receptor blockade on LV pump function, systemic hemodynamics and regional blood flow patterns in the normal state and with the development of pacing induced CHF, both at rest and with treadmill induced exercise. METHODS AND RESULTS: Pigs (25 kg) were instrumented in order to measure cardiac output (CO), systemic (SVR) and pulmonary vascular (PVR) resistance, neurohormonal system activity, and myocardial blood flow distribution in the conscious state and assigned to one of 4 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n = 7); (2) ACEI (benazeprilat, 3.75 mg/day) and pacing (n = 7); (3) AT1 receptor blockade (valsartan, 60 mg/day) and rapid pacing (n = 7); and (4) ACEI and AT1 receptor blockade (benazeprilat/valsartan, 1/60 mg/day, respectively) and pacing (n = 7). Measurements were obtained at rest and with treadmill exercise (15 degrees, 3 miles/h; 10 min) in the normal control state and after the completion of the treatment protocols. With rapid pacing, CO was reduced at rest and with exercise compared to controls. ACEI or AT1 blockade normalized CO at rest, but remained lower than control values with exercise. Combination therapy normalized CO both at rest and with exercise. Resting SVR in the CHF group was higher than controls and SVR fell to a similar degree with exercise; all treatment groups reduced resting SVR. With exercise, SVR was reduced from rapid pacing values in the ACEI and combination therapy groups. PVR increased by over 4-fold in the rapid pacing group both at rest and with exercise, and was reduced in all treatment groups. In the combination therapy group, PVR was similar to control values with exercise. Plasma catecholamines and endothelin levels were increased by over 3-fold with chronic rapid pacing, and were reduced in all treatment groups. In the combination therapy group, the relative increase in catecholamines and endothelin with exercise were significantly blunted when compared to rapid pacing only values. LV myocardial blood flow at rest was reduced in the rapid pacing only and monotherapy groups, but was normalized with combination therapy. CONCLUSION: These findings suggest that with developing CHF, combined ACE inhibition and AT1 receptor blockade improved vascular resistive properties and regional blood flow distribution to a greater degree than that of either treatment alone. Thus, combined ACEI and AT1 receptor blockade may provide unique benefits in the setting of CHF.

Angiotensin I↗

PubMed1998

AT1 angiotensin II receptor inhibition in pacing-induced heart failure: effects on left ventricular performance and regional blood flow patterns.

BACKGROUND: AT1 angiotensin II (AT1 Ang II) receptor activation has been shown to cause increased vascular resistance in the systemic (SVR), pulmonary (PVR), and coronary vasculature which may be of particular importance in the setting of congestive heart failure (CHF). The overall goal of this study was to examine the effects of acute AT1 Ang II receptor inhibition on left ventricular (LV) pump function, systemic hemodynamics, and regional blood flow patterns in the normal state and with CHF, both at rest and with treadmill-induced exercise. METHODS AND RESULTS: Pigs (25 kg) were instrumented to measure cardiac output (CO), SVR, and PVR, and LV myocardial blood flow distribution in the conscious state and were assigned to one of two groups: (1) pacing-induced CHF (240 bpm for 3 weeks, n = 6) or (2) sham controls (n = 5). Measurements were obtained at rest and after treadmill exercise (15 degrees for 10 minutes). Studies were repeated 30 minutes after intravenous infusion of a low (1.1 mg/kg) or high (125 mg/kg) dose of the AT1 Ang II antagonist, valsartan. The low dose of valsartan reduced the Ang II pressor response by approximately 50% but had a minimal effect on arterial pressure, whereas the high dose eliminated the Ang II pressor response and reduced resting blood pressure by approximately 20%. With CHF, CO was reduced at rest (2.5+/-0.2 v 3.9+/-0.1 L/min) and with exercise (6.4+/-0.5 v 7.8+/-0.5 L/min) compared with controls (P < .05). Valsartan at the low and high dose increased resting CO by 28% in the control and CHF groups, but did not affect CO with exercise. Resting SVR in the CHF group was higher than controls (2,479+/-222 v 1,877+/-65 dyne x s x cm(-5), P < .05), but SVR fell to a similar degree with exercise (1,043+/-98 v 1,000+/-77 dyne x s x cm(-5)). The low and high dose of valsartan reduced resting SVR by more than 30% in both the control and CHF groups. PVR was increased by more than twofold in the CHF group at rest. The high dose of valsartan reduced resting PVR with CHF, but had no further effect with exercise. LV myocardial blood flow was reduced with pacing CHF, particularly with exercise. With exercise and CHF, a low or high dose of valsartan reduced coronary vascular resistance, but LV myocardial blood flow remained reduced from normal values. CONCLUSIONS: Heightened AT1 Ang II receptor activity occurred in this model of CHF, which contributed to alterations in systemic hemodynamics and vascular resistive properties. By using a low dose of a selective AT1 Ang II receptor antagonist reduced SVR, PVR, and coronary vascular resistive properties and therefore may provide beneficial effects in a setting of CHF.

Angiotensin II↗

PubMed1998

Angiotensin AT1 receptor inhibition, angiotensin-converting enzyme inhibition, and combination therapy with developing heart failure: cellular mechanisms of action.

BACKGROUND: Past studies have shown that angiotensin-converting enzyme inhibition (ACEI) alone, angiotensin AT1 receptor blockade (AT1 block) alone, and combined treatment have differential effects on left ventricular (LV) function and geometry with developing congestive heart failure (CHF). The purpose of this study was to more carefully examine the cellular basis for these differential effects by using a model of pacing CHF. METHODS AND RESULTS: Pigs were randomly assigned to five groups: (1) rapid pacing (240 bpm) for 3 weeks (n = 9), (2) concomitant ACEI (benazeprilat, 0.187 mg/kg/day) and pacing (n = 9), (3) concomitant AT1 block (valsartan, 3 mg/kg/day) and pacing (n = 9), (4) concomitant ACEI and AT1 receptor blockade (benazeprilat/valsartan, 0.05/3 mg/kg/day, respectively) and pacing (n = 9), and (5) sham controls (n = 10). The dosage protocol was based on obtaining a 50% reduction in angiotensin I and angiotensin II pressor response with no significant effects on mean basal arterial pressure. In the pacing group, LV fractional shortening (LVFS) fell compared with control group (13.4+/-1.4 v 39.1+/-1.0%, P < .05). With AT1 block, LVFS was unchanged from pacing only. ACEI and combined treatment increased LVFS from pacing values (25.2+/-0.9 v 20.9+/-1.9%, respectively, P < .05). LV myocyte shortening velocity was reduced with chronic pacing compared with control group (27.2+/-0.6 v 58.6+/-1.2 microm/s, P < .05) and remained reduced with AT1 block (28.0+/-0.5 microm/s, P < .05). Myocyte shortening velocity increased with ACEI or combination treatment (36.9+/-0.7 v 42.3+/-0.8 microm/s, respectively, P < .05). Concomitant treatment with either ACEI or AT1 blockade normalized myocyte action potential duration. In the combined ACEI and AT1 blockade group, all parameters of the myocyte action potential were unchanged from control values. CONCLUSIONS: This study showed that combined ACEI and AT1 receptor blockade produced beneficial effects on myocyte contractility and electrophysiology when compared with either monotherapy alone and therefore may provide unique benefits with CHF.

Action Potentials↗

PubMed1998

Synergistic effects of combined converting enzyme inhibition and angiotensin II antagonism on blood pressure in conscious telemetered spontaneously hypertensive rats.

OBJECTIVE: To investigate the chronic effects of combined administration of an angiotensin II receptor antagonist (valsartan) and an angiotensin converting enzyme inhibitor (benazeprilat) on blood pressure and heart rate in conscious telemetered spontaneously hypertensive rats. METHODS: Blood pressure and heart rate were monitored (by radiotelemetry) during 2-week infusions of 0.5-10 mg/kg valsartan per day and 0.5-10 mg/kg benazeprilat per day, alone or in combination, into conscious spontaneously hypertensive rats. Also, responses of blood pressure in conscious spontaneously hypertensive rats to exogenous angiotensin I and II were determined. RESULTS: Synergistic antihypertensive effects were observed when valsartan and benazeprilat were coadministered at submaximal monotherapy doses in the range 0.5-1.5 mg/kg per day. For all combination groups, the area over the curve (mmHg x days) for lowering of blood pressure was significantly greater (synergy) than that predicted from the sum of the monotherapy responses. Combination therapy abrogated pressor responses to angiotensin I more effectively than did comparable doses of the monotherapies. CONCLUSIONS: These results demonstrate that combination therapy aimed at interrupting operation of the renin-angiotensin system simultaneously at multiple sites can prevent the partial escape which occurs during chronic angiotensin converting enzyme inhibitor monotherapy. Furthermore, multiple-site intervention results in a more efficacious antihypertensive response than that achieved with high doses of the individual monotherapies.

Angiotensin Receptor Antagonists↗

PubMed1998

Does blockade of angiotensin II receptors offer clinical benefits over inhibition of angiotensin-converting enzyme?

Angiotensin AT1 receptor antagonists represent a new class of drugs for the treatment of hypertension. They are specific for the renin-angiotensin system, selective for the angiotensin AT1 receptor, and act independently of the angiotensin II synthetic pathway. Blockade of the renin-angiotensin system at the receptor level should therefore be more complete. The high circulating levels of angiotensin II following angiotensin AT1 receptor blockade could be beneficial in stimulating other unblocked angiotensin receptors, especially the AT2 receptor. It has been proposed that the angiotensin AT2 receptor, which is re-expressed or up-regulated during pathological circumstances, counterbalances the effect of the stimulation of the angiotensin AT1 receptor. Through this mechanism, angiotensin AT1 antagonists may be superior to ACE inhibitors in cardiac and vascular remodelling as well as in kidney insufficiency. Long-term trials are required to demonstrate the possible clinical superiority of this new class of antihypertensive agents.

Angiotensin Receptor Antagonists↗

PubMed1997

Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing-induced heart failure: I. Effects on left ventricular performance and neurohormonal systems.

BACKGROUND: The goal of this study was to determine the effects of ACE inhibition (ACEI) alone, AT1 angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade on LV function, systemic hemodynamics, and neurohormonal system activity in a model of congestive heart failure (CHF). METHODS AND RESULTS: Pigs were randomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) ACEI (benazeprilat, 0.187 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (3) AT1 Ang II receptor blockade (valsartan, 3 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (4) ACEI and AT1 Ang II receptor blockade (benazeprilat/valsartan, 0.05/3 mg x kg(-1) d(-1)) and rapid pacing (n=9), and (5) sham controls (n=10). In the pacing group, LV fractional shortening (LVFS) fell (13.4+/-1.4% versus 39.1+/-1.0%) and end-diastolic dimension (LVEDD) increased (5.61+/-0.11 versus 3.45+/-0.07 cm) compared with control (P<.05). With AT1 Ang II blockade and rapid pacing, LVEDD and LVFS were unchanged from pacing-only values. ACEI reduced LVEDD (4.95+/-0.11 cm) and increased LVFS (20.9+/-1.9%) from pacing-only values (P<.05). ACEI and AT1 Ang II blockade reduced LVEDD (4.68+/-0.07 cm) and increased LVFS (25.2+/-0.9%) from pacing only (P<.05). Plasma norepinephrine and endothelin increased by more than fivefold with chronic pacing and remained elevated with AT1 Ang II blockade. Plasma norepinephrine was reduced from pacing-only values by more than twofold in the ACEI group and the combination group. ACEI and AT1 Ang II receptor blockade reduced plasma endothelin levels by >50% from rapid-pacing values. CONCLUSIONS: These findings suggest that the effects of ACEI in the setting of CHF are not solely due to modulation of Ang II levels but rather to alternative enzymatic pathways and that combined ACEI and AT1 Ang II receptor blockade may provide unique benefits for LV pump function and neurohormonal systems in the setting of CHF.

Aldosterone↗

PubMed1997

Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing-induced heart failure: II. Effects on myocyte contractile processes.

BACKGROUND: The goal of this study was to determine the effects of ACE inhibition alone, AT1 angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade in a model of congestive heart failure (CHF) on isolated LV myocyte function and fundamental components of the excitation-contraction coupling process. METHODS AND RESULTS: Pigs were randomly assigned to one of five groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant ACEI (benazeprilat, 0.187 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (3) concomitant AT1 Ang II receptor blockade (valsartan, 3 mg/kg/d) and rapid pacing (n=9), (4) concomitant ACEI and AT1 Ang II receptor blockade (benazeprilat/valsartan, 0.05/3 mg x kg(-1) x d(-1)) and rapid pacing (n=9), and (5) sham controls (n=10). LV myocyte shortening velocity was reduced with chronic rapid pacing compared with control (27.2+/-0.6 versus 58.6+/-1.2 microm/s, P<.05) and remained reduced with AT1 Ang II receptor blockade and rapid pacing (28.0+/-0.5 microm/s, P<.05). Myocyte shortening velocity increased with ACEI or combination treatment compared with rapid pacing only (36.9+/-0.7 and 42.3+/-0.8 microm/s, respectively, P<.05). Myocyte beta-adrenergic response was reduced by >50% in both the rapid pacing group and the AT1 Ang II blockade group and improved by 25% with ACEI and increased by 54% with combined treatment. Both L-type Ca2+ channel density and the relative abundance of sarcoplasmic reticulum Ca2+ ATPase density were reduced with rapid pacing and returned to control levels in the combined ACEI and AT1 Ang II blockade group. CONCLUSIONS: The unique findings of this study were twofold. First, basic defects in specific components of the myocyte excitation-contraction coupling process that occur with CHF are reversible. Second, combined ACEI and AT1 Ang II blockade may provide unique benefits on myocyte contractile processes in the setting of CHF.

Analysis of Variance↗

PubMed1997

Myocardial electrophysiological properties in the presence of an AT1 angiotensin II receptor antagonist.

INTRODUCTION: Blockade of the AT1 angiotensin II (Ang II) receptor has been shown to provide anti-hypertensive effects. However, whether AT1 Ang II receptor antagonists influence myocardial electrophysiological properties remains unclear. METHODS AND RESULTS: Accordingly, atrial and ventricular myocardial electrophysiological properties were examined in adult rat (n = 13) and guinea pig (n = 9) myocardial preparations in the presence of the specific AT1 Ang II receptor antagonist, valsartan (CGP 48933; 0.5, 5, or 500 mumol/L). These concentrations reflect up to 100 fold higher drug concentrations than those observed in clinical trials. Transmembrane potential data were recorded using standard microelectrode techniques at baseline and following superfusion with valsartan. The lower concentrations of valsartan (0.5 and 5 mumol/L) had minimal effects on myocardial electrophysiology. In the presence of 500 mumol/L of valsartan, resting membrane potential increased from baseline in both rat (-82.3 +/- 4.1 vs -76.8 +/- 5.8 mV, p < 0.05) and guinea pig (-81.6 +/- 2.9 vs -76.9 +/- 2.0 mV, p < 0.05) atrial myocardium. Action potential duration at 90% repolarization was increased in guinea pig atrial (91.7 +/- 1.4 vs 80.0 +/- 5.6 ms, p < 0.05) and ventricular (131.1 +/- 8.1 vs 118.7 +/- 8.3 ms, p < 0.05) myocardium following exposure to 500 mumol/L of valsartan. In a separate series of experiments, Ang II (1.0 mumol/L) had no effect on atrial or ventricular action potential characteristics in either species. CONCLUSION: Thus, the effects of valsartan, which were observed only at concentrations 100 fold higher than those reported in clinical trials, may be due to non-specific drug interactions with the myocyte sarcolemma.

Angiotensin Receptor Antagonists↗

PubMed1997

Pharmacokinetic and pharmacodynamic interaction of single oral doses of valsartan and furosemide.

OBJECTIVE: Pharmacokinetic and pharmacodynamic interactions between single oral doses of valsartan (160 mg) and furosemide (40 mg) were investigated in an open, randomized, three-period crossover study in twelve healthy male subjects. METHODS: A washout period of one week was observed between treatments. Pharmacokinetic measurements included plasma concentrations of valsartan and furosemide, and urinary excretion of the latter. Plasma renin activity (PRA), plasma angiotensin II, blood pressure, heart rate, as well as urinary water and electrolyte excretion were determined as pharmacodynamic variables. Efficiency of furosemide for sodium and water excretion was calculated as the ratio of the measured pharmacodynamic effect and the urinary excretion of furosemide. RESULTS: Simultaneous administration of valsartan and furosemide did not modify the pharmacokinetics of valsartan. In contrast, Cmax, AUC, and urinary excretion of furosemide were significantly reduced following simultaneous treatment with valsartan. Inter- and intra-individual variability of the pharmacokinetic variables was high for both furosemide and valsartan. PRA and angiotensin II increased, and blood pressure decreased after all treatments. These effects were most pronounced after the combined treatment. The decrease in blood pressure was additive, at most, while the increase in PRA and angiotensin II appeared to exceed simple addition. No relevant effects on heart rate were observed. The diuretic effect of furosemide, as assessed by urinary water and electrolyte excretion, was unchanged after co-administration of valsartan, despite the lower bioavailability of furosemide after the combined treatment.

Administration, Oral↗

PubMed1997

Pharmacokinetics and pharmacodynamic effects of the angiotensin II antagonist valsartan at steady state in healthy, normotensive subjects.

OBJECTIVE: Pharmacokinetics, pharmacodynamic effects and tolerability of 200 mg valsartan, once-daily for 8 days, were investigated in 16 healthy, normotensive volunteers on a normal sodium diet. METHODS: This was a double-blind, placebo-controlled, randomized crossover study. Drug concentrations in plasma and urine, angiotensin II (Ang II) concentrations in plasma, systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR) in the supine position and 3 min after passive head-up tilting, as well as safety parameters (ECG, clinical chemistry and hematology, renal water and electrolyte excretion) were measured over 24 h after the first dose (day 1) and at steady state on day 8. RESULTS: Absorption and distribution of valsartan were rapid (Cmax, 2 h; t1/2 lambda 1 < 1 h), followed by a slower terminal elimination phase (t1/2 lambda 2, 6 h) on days 1 and 8, with little accumulation in plasma (increase of 20% on day 8). Less than 10% of the dose was excreted unchanged in urine. The increase in plasma Ang II (Cmax, 6 h) was significantly enhanced at steady state. Supine SBP and DBP significantly decreased on day 8 only, by an average of -3.6 and -2.4 mmHg, respectively, versus placebo, without a concomitant increase in HR. Upon passive tilting, the increase in DBP, normally reinforced by sympathetic renin release, was slightly but significantly blunted on day 1 (-2.0 mmHg) and day 8 (-4.0 mmHg) of treatment with valsartan versus placebo. The orthostatic reflex increase in HR was slightly enhanced compared with placebo by an average of 2.8 beats min-1 on day 1 and by 2.9 beats.min-1 on day 8. Valsartan was well tolerated and had no influence on ECG, clinical laboratory parameters, and water, electrolyte and uric acid excretion. CONCLUSIONS: Pharmacokinetics of valsartan are unchanged after multiple once-daily dosing, with little (expected) accumulation in plasma. Effects of 200 mg valsartan on blood pressure in healthy subjects on a normal sodium intake are small and become more prominent after repeated dosing. Indirect evidence of AT1 blockade by valsartan is demonstrated by an increase of plasma Ang II and by a blunted DBP response to passive tilting. The decrease in blood pressure at steady state enhances the increase in plasma Ang II. Valsartan is well tolerated and is devoid of effects on water, electrolyte and uric acid excretion at 200 mg per day in healthy normotensive volunteers.

Adult↗

PubMed1997

Dose-dependent inhibitory effects of angiotensin II on visual responses of the rat superior colliculus: AT1 and AT2 receptor contributions.

Angiotensin II (Ang II) has traditionally been regarded as a peripherally circulating and acting hormone involved in fluid homeostasis and blood pressure regulation. With the rather recent localization of Ang II receptors within the mammalian brain, renewed interest has emerged in the hope of elucidating the central impact and function of this hormone. One region that has been clearly demonstrated to express Ang II receptors is the superior colliculus (SC). This mesencephalic structure plays an important role in sensory visuomotor integration. Receptors for Ang II (of both the AT1 and AT2 subtypes) have been localized within the superficial layers of this structure, i.e. the areas that are visually responsive. In the hopes of characterizing the role of Ang II in the SC, we have attempted to physiologically activate these receptors in vivo and observe the effects of Ang II on visually evoked responses. In the attempt to identify the receptor subtype(s) responsible in mediating these effects, Ang II was injected concomitantly with selective receptor ligands. Experiments were performed on adult rats prepared in classical fashion for electrophysiological studies. Through microinjection of Ang II, and the simultaneous recording of visually evoked potentials to flash stimulation, we have observed that this peptide yields a strong suppressive effect on visual neuronal activity. By injecting Ang II at various concentrations (10(-3)-10(-10) M), we have further observed that the effects of this peptide express a dose-related dependency. Injection of Ang II in progressively more ventral layers yielded less pronounced effects, demonstrating physiologically the discrete localization of these receptors in the stratum griseum superficiale. Coinjection of Ang II with Losartan yielded a near complete blockade of Ang II suppressive effects, suggesting that AT1 receptors play a prominent role in mediating these responses. However, coinjection of Ang II with PD 123,319 yielded a slight, yet significant partial blockade. Coinjection of Ang II with both the AT1 and AT2 receptor antagonists yielded a complete blockade of the Ang II effect. Finally, some of the results suggest that the AT2 receptor ligand CGP 42,112 may possess agonist properties. Taken together, these findings suggest that the AT1 receptor is predominantly involved in mediating Ang II responses in the SC and there also appears to be some indication of AT2 receptor involvement. However, the underlying mechanisms (such as receptor interactions), the exact specificity of the ligands used, and the possibility of other receptor subtype implication have yet to be explored fully.

Angiotensin II↗

PubMed1997

Removal of endogenous leptin from the circulation by the kidney.

OBJECTIVE: This study was performed to test the hypothesis that the kidneys play a primary role in the clearance of endogenous leptin from the circulation of obese rats. DESIGN: Zucker (fa/fa) obese rats were anaesthetized and subjected to various surgical manipulations of the kidneys. One hour after surgery arterial blood samples were taken at 1 h intervals for times upto 8 h. Plasma leptin concentrations were determined by radioimmunoassay. RESULTS: Bilateral nephrectomy induced a rapid increase in plasma leptin concentrations above control values. In contrast, continuous intravenous re-injection of voided urine did not increase circulating leptin concentrations, indicating that leptin is not present in the urine in large quantities. This conclusion was confirmed by the very low levels of detectable leptin in urine. Leptin is not metabolized across the renal circulation and is extracted intact by the kidney. Simultaneous measurement of renal plasma flow established renal leptin extraction at approximately 59 ng/ min for both kidneys. Following intravenous infusion of leptin, renal clearance and whole body clearance were equal. This finding indicates that the kidneys alone are responsible for the systemic elimination of leptin in Zucker rats. Seven hours after bilateral ureteral ligation, a procedure which lowers glomerular filtration, plasma leptin concentrations were elevated. The renal extraction of leptin did not change over a wide range of plasma leptin concentrations suggesting that renal leptin extraction is a high capacity, non-saturable process most probably glomerular filtration. CONCLUSION: Endogenous leptin is rapidly cleared from the circulation by the kidney by glomerular filtration followed by metabolic degradation in the renal tubules.

Animals↗

PubMed1997

Interactions between nitric oxide and angiotensin II on renal cortical and papillary blood flow.

This study examined the role of angiotensin II (Ang II) on the effects of nitric oxide (NO) synthesis blockade on renal cortical and papillary blood flow in innervated and denervated kidneys of volume-expanded Munich-Wistar rats with hormonal influences on the kidney that were held constant by intravenous infusion. Cortical (CBF) and papillary (PBF) blood flow were measured by laser-Doppler flowmetry. A low dose of N omega-nitro-L-arginine methyl ester (L-NAME, 3.7 nmol x kg[-1] x min[-1]) reduced CBF only in innervated kidneys, and this effect was abolished by subsequent administration of valsartan (an AT1 antagonist). L-NAME 3.7 nmol x kg(-1) x min(-1) improved PBF autoregulation by lowering PBF to the range of 100 to 140 mm Hg of perfusion pressure, and this effect was attenuated or abolished by valsartan in innervated and denervated kidneys, respectively. These results indicate that the cortical and medullary vasoconstriction induced by a low dose of L-NAME are caused by potentiation of the vasoconstrictor influence of renal sympathetic nerves and Ang II. A higher dose of L-NAME (37 nmol x kg[-1] x min[-1]) lowered CBF and PBF in both innervated and denervated kidneys. This effect of L-NAME on the cortical circulation was abolished by valsartan, but this AT1 antagonist had no effect on the medullary vasoconstriction produced by NO synthesis blockade. Therefore, a higher dose of L-NAME induces a renal cortical vasoconstriction through potentiation of the renin-angiotensin system, whereas the fall of PBF seen after L-NAME 37 nmol x kg(-1) x min(-1) seems to be caused primarily by NO suppression. This Ang II potentiation produced by L-NAME in the renal cortex seems to be mediated by AT1 receptors, because it was unaffected by PD123319 (an AT2 antagonist). The results of the present study indicate that NO is an important modulator of the vasoconstrictor influence of Ang II in the renal cortical circulation of the rat. However, although there are some interactions between NO and renal nerves and Ang II on the medullary circulation, the renal medullary vasoconstriction produced by L-NAME appears to be caused primarily by NO suppression, with little influence of the renal vasoconstrictor systems.

Angiotensin II↗

PubMed1996

Localization of the angiotensin II receptor subtypes in the human atrium.

Angiotensin II has two major receptor subtypes, designated AT1 and AT2. Both have been detected in the heart of several species, but most of the known functions of angiotensin II seem to be mediated through the AT1 receptor. The major objective of this study was to specify the cell type on which the AT2 receptor is located in the atrium of human heart. Right atrial biopsies from patients with coronary artery disease were tested in membrane binding assays and found to contain high levels of angiotensin II receptor (820 +/- 175 fmol/mg), 82 +/- 2% of which was of the AT2 subtype. Cryostat sections of these biopsies were incubated with 125I-[Sar1,Ile8] angiotensin II in the presence of selective concentrations of the cold ligands losartan and CGP 42112A to detect the subtypes using microscopic autoradiography. High local densities of the AT2 receptor were observed. Comparison of the labelling patterns thus obtained with adjacent sections stained for vimentin, collagen, neurofilaments or acetylcholinesterase revealed that the high densities of AT2 receptor were always associated with fibrous tissue. However, the AT1 receptor was in general evenly distributed over the tissue at low concentrations. Higher local concentrations of this receptor subtype were observed on nervous tissue. The present finding of high densities of the AT2 receptor on fibroblasts at sites of fibrosis may have important clinical implications. Further studies to elucidate the function of this receptor subtype in the heart are therefore essential and the clinical consequences of the use of AT1 antagonists on post-infarction remodelling should be investigated.

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