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Biomedical subjects

J F Giudicelli

Publications and source records attributed to J F Giudicelli.

At least 163 records · Page 9Linked to original sources
PubMed1987

Systemic and regional hemodynamic characterization of alpha-1 and alpha-2 adrenoceptor agonists in pithed rats.

In pithed rats, blood pressure dose-response curves to i.v. cirazoline, methoxamine and phenylephrine (full alpha-1 adrenoceptor agonists) exhibited higher maxima than those to B-HT 920, M-7, UK-14,304 (full alpha-2 adrenoceptor agonists) and indanidine (Sgd 101/75: partial alpha-1 adrenoceptor agonist). For an 80 mm Hg increase in blood pressure, full alpha-1 adrenoceptor agonists enhanced total peripheral, renal and mesenteric vascular resistances significantly more than alpha-2 adrenoceptor stimulants or indanidine. In contrast, all compounds produced a similar degree of hindquarter vasoconstriction, suggesting that both types of alpha adrenoceptors have the same functional importance in this skeletal muscle vascular bed. Application of a multivariate discriminant analysis to the drug-induced changes in the total peripheral and mesenteric vascular resistances associated with a pressor effect of 80 mm Hg allowed their assignment to two distinct groups corresponding to the full alpha-1 and the full alpha-2 adrenoceptor agonists plus indanidine. All investigated compounds in low doses increased cardiac output, which returned to base-line values after high doses of alpha-1 but plateaued after high doses of alpha-2 adrenoceptor agonists or indanidine. alpha-1 adrenoceptor agonists decreased whereas alpha-2 stimulants and indanidine successively increased and then decreased renal blood flow. Finally, all investigated compounds increased hindquarter blood flow at low doses but decreased it at high doses. The ratios of the doses of cirazoline required to produce a 100% rise in systemic and local vascular resistances in the presence or in the absence of prazosin were of similar magnitude. This was also true for M-7 when studied in the presence or in the absence of yohimbine. These findings suggest pharmacological identity within alpha-1 as well as within alpha-2 adrenoceptor populations in all investigated vascular beds. Finally, the calcium entry blocker diltiazem did not affect the increases in systemic and regional resistances evoked by cirazoline but depressed profoundly the effects of M-7 and indanidine. In conclusion, full alpha-1 and alpha-2 adrenoceptor agonists can be discriminated easily on the basis of their systemic and regional hemodynamics in the pithed rat. That the hemodynamic effects of the partial alpha-1 adrenoceptor agonist indanidine are similar to those of alpha-2 adrenoceptor agonists and susceptible to calcium channel blockade suggests that the alpha-1 adrenoceptors stimulated by this drug have the same coupling modality as alpha-2 adrenoceptors and share with the latter the same functional expression when stimulated.

Adrenergic alpha-Agonists↗
PubMed1987

[Atrial natriuretic factor. Systemic and regional hemodynamic profile and interaction with the alpha-adrenergic system in pithed SHR rats].

The hemodynamic effects of ANF (1 and 5 micrograms/kg/min) and its potential interactions with the sympathetic system were investigated at the systemic and regional (pulsed Doppler) levels in the pithed SHR. ANF dose-dependently decreased cardiac output CO, renal (RBF), mesenteric (MBF) and hindquarter (HQBF) blood flows and increased the corresponding vascular resistances: total peripheral (TPR), renal (RR), mesenteric (MR) and hindquarter (HQR), all these effects being significant at 5 micrograms/kg/min. Mean blood pressure (MBP) and heart rate were also significantly decreased at 5 micrograms/kg/min. ANF significantly reduced the responses to cirazoline of MBP, TPR and RR (1 microgram/kg/min) and of MR (5 micrograms/kg/min) but did not affect those of HQR ANF also significantly reduced the responses to UK-14,304 of MBP, TPR and MR (5 micrograms/kg/min) but did not affect those of RR and HQR. These data indicate that (a) ANF, in the absence of reflex phenomenons, exerts intrinsic regional vasoconstrictor effects, (b) ANF exhibits a postsynaptic sympatho-inhibitory effect. The latter is more marked vs the alpha 1-(especially renal) than vs the alpha 2-adrenoceptor-mediated responses but does not affect the hindquarter vascular bed, which suggest that its contribution to the overall antihypertensive action of ANF is of limited importance.

Animals↗
PubMed1986

Effects of lidocaine on myocardial contractility and baroreflex control of heart rate in conscious dogs.

The effects of intravenous lidocaine (30 and 60 micrograms X kg-1 X min-1 during 30 min) at steady-state plasma levels (1.9 +/- 0.2 and 3.5 +/- 0.2 micrograms/ml, respectively) were investigated in conscious dogs, previously instrumented for measurements of arterial and left ventricular (LV) pressures, isometric myocardial contractility indexes (LV peak rate of tension development [dP/dt] and LV [dP/dt]/DP40), and heart rate. In addition, before and at the end of lidocaine infusions, arterial baroreflex responses were tested by bolus injections of nitroglycerin and phenylephrine. Whereas LV peak dP/dt and LV (dP/dt)/DP40 were significantly decreased after the low dosage of lidocaine, these indexes returned to control values after the 10th min of infusion of the high dosage. Moreover, eight out of 14 dogs exhibited continuous tremors, tachycardia, hypertension, and increase in contractility after the 10th min of lidocaine infusion (60 micrograms X kg-1 X min-1), although their lidocaine plasma levels (3.7 +/- 0.2 micrograms/ml) did not differ from those of the whole group. When these dogs were pretreated by combined alpha- and beta-adrenoceptor blocking drugs, none of them had tremors, and there was a constant depressant effect on cardiac chronotropism and inotropism. A specific enhancement of baroreflex sensitivity after phenylephrine injection was observed at the high lidocaine dosage. It is concluded that a central stimulation of both components of the autonomic nervous system modulates the direct effects of therapeutic plasma levels of lidocaine on cardiac chronotropism and inotropism in conscious dogs.

Animals↗
PubMed1986

Effect of mechanical ventilation on hepatic drug pharmacokinetics.

Mechanical ventilation was able to induce a decrease in cardiac output and regional blood flow, especially hepatic flow. Thus, hepatic elimination of drugs with a high hepatic-extraction ratio, which was linked to alteration in hepatic blood flow, could be reduced during mechanical ventilation. The aim of this work was to determine the effect of mechanical ventilation on pharmacokinetic parameters of lidocaine, which is a well-known nonrestrictive elimination drug at the hepatic level. Five patients (mean age, 58 years) with normal hepatic function and quite similar gasometric parameters before and after weaning from mechanical ventilation were studied. With a washout period of 48 hours between mechanical ventilation and spontaneous ventilation, each patient was submitted to the following protocol: lidocaine in a bolus (1.5 mg/kg intravenously), followed by infusion (1.0 to 1.7 mg/min for 120 minutes). The results were that the peak plasma concentration after the bolus during mechanical ventilation was 3.22 +/- 0.37 mg/L (mean +/- SE) vs 2.40 +/- 0.35 mg/L during spontaneous ventilation (p less than 0.02). Steady-state plasma concentration during mechanical ventilation was 2.10 +/- 0.20 mg/L vs 1.64 +/- 0.16 mg/L during spontaneous ventilation (p less than 0.01). Total clearance was 604.2 +/- 87.0 ml/min during mechanical ventilation vs 775.0 +/- 112.1 ml/min during spontaneous ventilation (p less than 0.01). Elimination half-life was 245.2 +/- 50.6 minutes during mechanical ventilation vs 160.0 +/- 40.6 minutes during spontaneous ventilation (p less than 0.05). Distribution volume was 188.6 +/- 50.2 L during mechanical ventilation and 183.0 +/- 50.8 L during spontaneous ventilation (not significant). These preliminary data clearly demonstrated a decrease in lidocaine elimination in patients submitted to mechanical ventilation, but the magnitude of dosage adjustment of such a highly hepatic-extracted drug in patients submitted to mechanical ventilation remains to be investigated.

Adult↗
PubMed1986

Systemic and regional pre- and post-junctional sympathoinhibitory effect of perindopril in spontaneously hypertensive rats.

The interaction between converting enzyme inhibition and sympathetic system activity at systemic and regional (renal, mesenteric, hindlimb) levels was investigated in adult pithed spontaneously hypertensive rats (SHR) using perindopril (5 mg/kg orally every day for 8 days) and the pulsed Doppler technique. Perindopril induced a decrease in systolic blood pressure and in regional vascular resistance which was abolished by binephrectomy. In addition, the drug had a sympathoinhibitory effect on the systemic vasopressor and the regional vasoconstrictor responses to cirazoline, especially UK 14304, an effect which was kidney-dependent (abolished by binephrectomy) and postjunctional, and spinal cord stimulation, an effect which was kidney-independent and most likely prejunctional in its mechanism.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1986

[Peripheral hemodynamic and biological effects of perindopril in the healthy subject. Dose-effect relationship].

The effects of three doses of perindopril (4.8 and 16 mg), a new angiotensin I-converting enzyme inhibitor, and of a placebo on systemic blood pressure, heart rate, brachial artery flow and diameter, forearm vascular resistance and the renin angiotensin system biological parameters (plasma converting enzyme activity PCEA, renin activity PRA and aldosterone PA) were compared during a double-blind cross-over study performed in six healthy volunteers. Perindopril dose-dependently inhibited PCEA, increased PRA, augmented brachial artery flow and diameter and decreased forearm vascular resistance, whereas it did not affect systemic blood pressure and heart rate. The perindopril-induced increase in brachial artery flow was related (a) at the low dose to the sole arteriolar and (b) at the two highest doses to both arteriolar and large vessels dilatation. Finally, during the ten first hours following drug intake, there was a significant correlation between perindopril-induced PCEA inhibition and brachial artery flow increase.

Adult↗
PubMed1986

Myocardial and vascular effects of perindopril, a new converting enzyme inhibitor, during hypertension development in spontaneously hypertensive rats.

The effects of a new angiotensin I converting enzyme inhibitor (ACEI), perindopril (P), on genetic hypertension development (GHD), on mesenteric arteriolar compliance and reactivity to noradrenaline and on myocardial and aortic hypertrophy, have been investigated at intervals in SHRs. P (4 mg/kg, q.d.) was administered by gavage from the 4th to the 20th week of age and measurements were performed 20 hr after the preceding drug intake. P completely prevented GHD, maintaining systolic blood pressure (SBP) below 130 mmHg during the whole treatment period. Furthermore, 7 weeks after treatment withdrawal, SBP of previously treated SHRs was still significantly lower than that of controls. Vascular compliance and internal diameter of the mesenteric arteriole were significantly increased in P-treated SHRs as compared to controls at the age of 20 weeks but these effects did not persist 7 weeks after treatment withdrawal. P did not affect mesenteric arteriolar reactivity to noradrenaline. Finally, P significantly reduced myocardial and aortic hypertrophy in SHRs. Thus P strongly opposed the morphological and functional vascular alterations which usually occur in SHRs during GHD. This property, presumably related to converting enzyme inhibition within the vascular wall, probably contributes to a large extent to, but is not exclusively responsible for, the drug-induced prevention of GHD.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1985

[Clinical pharmacology of enalapril].

Enalapril is an inhibitor of the converting enzyme which transforms angiotensin I into angiotensin II, an octapeptide with pharmacological properties uniformly tending to increase blood pressure. The enalapril molecule is not active until it has been hydrolyzed into enalaprilic acid in the liver. This acid induces a very strong (85-95%), very early (maximum at 2 hours) and long lasting (20% at 72 hours) blockade of the angiotensin-converting enzyme, resulting in a paralleled fall in systolic and diastolic blood pressure. The fall begins with a 2.5 mg dose of the drug, is maximum with 10 mg and is not increased by higher doses. No tachyphylaxis has been observed with prolonged administration. The fall in blood pressure is due to reduction of peripheral resistance, without changes in heart rate and cardiac output. There is no sodium retention. The two main pharmacokinetic features of the drug are its very long half-life and the 100% urinary excretion of the active metabolite. The drug can be taken as a single dose at any moment of the day. The only known interaction is with propranolol, which reduces by one-third the bioavailability of enalapril. Side-effects are uncommon and mild.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1985

Vasodilating beta-adrenoceptor blocking drugs do not redistribute myocardial flow during acute coronary ligation in dogs.

The effects of two nonselective beta-adrenoceptor blocking drugs, additionally endowed with vasodilating properties with different mechanisms: labetalol which blocks alpha-adrenoceptors, and bucindolol which nonspecifically relaxes vascular smooth muscle, were investigated on regional myocardial blood flow (RMBF) distribution in ischemic and nonischemic areas and on ST-segment elevation in ischemic areas during intermittent coronary artery occlusion in dogs. Both labetalol and bucindolol reduced heart rate, arterial blood pressure and myocardial oxygen consumption. However, they did not affect coronary vascular resistance and did not induce any favorable coronary blood flow redistribution phenomenon either from the epicardium to the endocardium or from the nonischemic to the ischemic areas. These results indicate that the inability of labetalol and bucindolol to favorably redistribute RMBF was due to the fact that their vasodilating properties counteract one major determinant of RMBF redistribution. i.e. the beta-adrenoceptor blockade-induced increase in regional coronary vascular resistance. Finally, both labetalol and bucindolol dose dependently decreased ST-segment elevation in ischemic myocardial areas.

Adrenergic beta-Antagonists↗
PubMed1985

Vasodilator synchronized retroperfusion: quantitative assessment of flow-function relation in acutely ischemic canine myocardium.

To investigate whether addition of vasodilator drugs can increase the beneficial effects on the ischemic myocardium of diastolic synchronized retroperfusion (DSR), low doses of verapamil (2 micrograms/kg/min) or nitroglycerin (0.7 microgram/kg/min) were infused through DSR in open-chest dogs undergoing 180 minutes of proximal left anterior descending coronary artery occlusion. Verapamil-DSR (n = 6), nitroglycerin-DSR (n = 6) or DSR alone (n = 8, controls) were started 10 minutes after the onset of occlusion and maintained for 170 minutes. Regional myocardial blood flow (MBF) (microspheres) and left ventricular function (endocardial ultrasonic crystals) were simultaneously assessed in nonischemic and ischemic zones in the 3 groups, before and after 10 and 180 minutes of coronary occlusion. DSR alone significantly increased ischemic regional MBF, endocardial/epicardial flow ratio and endocardial segmental length shortening. Verapamil DSR increased both nonischemic and ischemic regional MBF but reduced the endocardial/epicardial flow ratio and worsened ischemic contractile function. Nitroglycerin DSR did not modify ischemic transmural flow compared with DSR alone, but abolished the beneficial endocardial/epicardial blood flow redistribution, resulting in no additional improvement of contractile function. Thus, ischemic MBF and function are not improved by addition of small amounts of verapamil or nitroglycerin to the arterial retroperfusate in this model of acute myocardial ischemia.

Acute Disease↗
PubMed1985

Comparative beta-adrenoceptor blocking effect and pharmacokinetics of bucindolol and propranolol in man.

The beta-adrenoceptor blocking properties and pharmacokinetics of bucindolol 150 mg were compared to those of propranolol 80 mg and a placebo in a double-blind trial in 6 healthy volunteers. Heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressures and peak expiratory flow rate (PEFR) at rest and during vigorous exercise, and plasma renin activity (PRA) at rest, were measured before and at intervals up to 24 h after oral administration of the drugs. Bucindolol reduced exercise tachycardia and decreased exercise PEFR, thus behaving as a non-selective beta-adrenoceptor blocking drug. In contrast to propranolol, bucindolol did not reduce resting HR and PRA, probably because of its intrinsic sympathomimetic activity. It decreased resting DBP in relation to its peripheral vasodilator properties. The effects of bucindolol developed as early as 30 min after administration and lasted up to 24 h, whereas its Tmax and T 1/2 were 1.6 and 3.6 h respectively. Comparison of the time courses of plasma bucindolol and the cardiac beta-adrenoceptor blockade strongly suggests that in man bucindolol undergoes an extensive first-pass effect, leading to the formation of one or more active metabolites.

Adrenergic beta-Antagonists↗
PubMed1985

Prospective study of the potentiation of acenocoumarol by amiodarone.

The influence of oral amiodarone on the anticoagulant effect of the coumarin derivative acenocoumarol has been investigated prospectively in 10 patients with normal renal, hepatic and haematological function and who were not in cardiac failure. The daily dose of acenocoumarol was sufficient to produce a prothrombin activity of 25 to 35%. When the prothrombin time had become stable amiodarone 600 mg/d was administered for 1 week followed by 400 mg/d for the next 3 weeks. A decrease in prothrombin activity from 30.5 to 20.2% was observed, associated with a decrease in vitamin K coagulation factors, after a mean of 4 days following commencement of amiodarone. In 6 patients a prothrombin activity less than 20% required a 60% reduction in the dose of acenocoumarol after 1 week of amiodarone 600 mg, and a 33% reduction after 3 weeks of amiodarone 400 mg. There was no correlation between the plasma amiodarone and the decrease in prothrombin activity. Inhibition of acenocoumarol metabolism by amiodarone is the most likely explanation of these findings.

Acenocoumarol↗
PubMed1985

Beta-adrenoceptor blocking effects and plasma levels of bornaprolol and propranolol in man.

The beta-adrenoceptor blocking effects and pharmacokinetics of bornaprolol (FM 24), a new beta-adrenoceptor blocking agent, have been compared with those of propranolol and a placebo in a double-blind trial in 6 healthy volunteers. Heart rate, systolic and diastolic blood pressures and peak expiratory flow rate were measured at rest and at the end of 3 min vigorous exercise on a bicycle ergometer, before and 2,24 and 48 h after single oral doses of bornaprolol (120, 240 and 480 mg) and propranolol (40, 80 and 160 mg). Plasma renin activity at rest and the plasma concentrations of the two drugs were determined. Bornaprolol significantly reduced resting heart rate, dose-dependently lowered exercise-induced tachycardia and decreased peak expiratory flow rate and plasma renin activity. In addition, exercise-induced tachycardia was significantly reduced by bornaprolol up to 48 hours after drug intake (pharmacodynamic half-life approximately 63-86 h) and there was a correlation between this reduction and the log plasma bornaprolol concentration over the 48-h period. Thus, bornaprolol behaved in man as a non-cardioselective and long-lasting beta-adrenoceptor blocking drug, probably devoid of intrinsic sympathomimetic activity.

Adult↗
PubMed1985

The effect of enalapril on baroreceptor mediated reflex function in normotensive subjects.

The effects of enalapril, 20 mg orally, on the responses to baroreflex activation and deactivation by respectively phenylephrine and nitroglycerin were investigated in normotensive subjects on a normal sodium diet, with simultaneous measurement of plasma renin activity (PRA), converting enzyme activity (PCEA), aldosterone and catecholamines. Enalapril, 4 h after administration, lowered artificial blood pressure without modifying heart rate and plasma catecholamines. PCEA was abolished, PRA increased and plasma aldosterone decreased. Enalapril (a) displaced to the left the baroreflex set-point, (b) did not affect baroreflex sensitivity since the slopes of the RR-interval/systolic blood pressure regression lines remained unchanged during both activation and deactivation and (c) did not modify baroreflex efficacy since the maximal RR-interval responses as well as the overall RR-interval-time products to identical blood pressure variations were not modified. Thus, enalapril induced a resetting of the baroreflex, which probably accounts for the lack of reflex tachycardia observed during the drug-induced fall in blood pressure.

Adult↗
PubMed1984

Attenuation by diltiazem of arterial baroreflex sensitivity in man.

The effect of oral diltiazem 120 mg, on the responses to baroreflex activation and deactivation by phenylephrine and nitroglycerin, respectively, were investigated in normotensive subjects, with simultaneous measurement of plasma catecholamine levels. Diltiazem significantly reduced the tachycardia induced by bolus injections of nitroglycerin and abolished the concomitant increase in plasma noradrenaline. It also significantly decreased the bradycardiac response to phenylephrine infusion. Diltiazem reduced, although not significantly so, the bradycardia induced by boluses of phenylephrine. The overall reduction in baroreflex sensitivity, which might contribute to the limited tachycardiac effect of diltiazem in man, is consistent with the drug-induced attenuation of the sympathetic and also of the parasympathetic components of the baroreceptor reflex.

Adolescent↗