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Biomedical subjects

J F Giudicelli

Publications and source records attributed to J F Giudicelli.

At least 145 records · Page 8Linked to original sources
PubMed1989

[Potassium agonists: regional vasodilator profile in rats].

The systemic and regional (kidney, mesentery, hindlimb) hemodynamic effects of (a) two potassium agonists: cromakalim (1 to 8 micrograms.kg-1.min-1/15 min) and SR 44866 (0.125 to 2 micrograms.kg-1.min-1/15 min) and (b) a calcium antagonist, nicardipine (0.5 to 2 micrograms.kg-1.min-1/15 min) have been investigated by the pulsed doppler technique, and compared in the anesthetized normotensive rat. The two potassium agonists and nicardipine lowered blood pressure (BP) and total peripheral resistance (TPR) dose-dependently and slightly increased heart rate. Cardiac output (QC) remained unchanged. SR 44866 was as potent as nicardipine in reducing BP and about three to four times more potent than cromakalim (the DE20s, doses producing a 20 p. 100 decrease in BP, being: SR 44866: 0.7 micrograms.kg-1.min-1, cromakalim: 2.8 micrograms.kg-1, nicardipine: 0.8 micrograms.kg-1.min-1). At these equihypotensive doses, the three drugs (a) similarly decreased TPR (SR 44866: -16 p. 100, cromakalim: -17 p. 100, nicardipine: -19 p. 100, (b) reduced mesenteric vascular resistance (MVR) (SR 44866: -18 p. 100, cromakalin: -20 p. 100, nicardipine: -21 p. 100) and renal vascular resistance (RVR) (SR 44866: -16 p. 100, cromakalim: -21 p. 100, nicardipine: -13 p. 100 to the same extent as TPR, but (c) SR 44866 and nicardipine reduced hindlimb vascular resistance (HVR) to a larger extent than TPR (SR 44866: -25 p. 100, nicardipine: -25 p. 100.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

[Prodrugs].

Prodrugs are pharmacologically inert and nontoxic chemical compounds which are transformed in vivo into pharmacologically and therapeutically active compounds, i.e. drugs. Prodrugs are used to solve problems which cannot be solved by the drugs themselves. There are three types of problems: problems arising before the drug enters the body (solubilization, stabilization and improved acceptability); problems associated with the penetration and fate of the drug in the body (absorption, barrier crossing, duration of action); problems relating to the therapeutic target (selective local delivery). The principal prodrugs that solve these problems and the mechanisms of the solutions they provide are described and discussed.

Administration, Oral↗
PubMed1988

Comparison of the effects of Bay K 8644 and aortic constriction on regional myocardial blood flow and function in canine nonischemic and ischemic myocardium.

The effects of Bay K 8644, aortic constriction, and a placebo on regional myocardial blood flows (RMBFs) and contractile function (RCF) were compared in three groups of open-chest anesthetized dogs during coronary stenosis. Bay K 8644 was investigated in two doses: 0.1 micrograms/kg, which exhibited no systemic hemodynamic effect, and 1 microgram/kg, which significantly increased arterial pressure. Aortic constriction was performed to raise afterload to the same extent as Bay K 8644 1 microgram/kg. As compared with placebo, Bay K 8644 0.1 microgram/kg, significantly increased coronary resistance, decreased RMBFs without changing RCF in nonischemic myocardial zones, and affected neither RMBFs nor RCF in ischemic zones. In nonischemic myocardium, Bay K 8644 1 microgram/kg increased RMBFs without affecting RCF, whereas aortic constriction did not modify RMBFs but decreased RCF. In ischemic myocardium, both Bay K 8644 1 microgram/kg and aortic constriction increased RMBFs but did not affect RCF. Thus, the low dose of Bay K 8644 exerts a direct and selective coronary vasoconstrictor effect that has no deleterious consequences on nonischemic RCF. Despite this intrinsic coronary vasoconstrictor effect, the high dose of Bay K 8644 increases RMBFs and maintains RCF in both ischemic and nonischemic zones in relation with the drug-induced increases in coronary perfusion pressure (both zones) and in contractility (nonischemic zones).

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1988

Lack of presynaptic effects of ketanserin on cardiac noradrenergic nerve terminals in the SHR.

The potential cardiac presynaptic effects of ketanserin (K) (0.01-3.00 mg/kg IV) were investigated in pithed SHR in 4 experimental conditions: (a) basal heart rate (HR); (b) HR increased by selective cardiac sympathetic stimulation (SS); (c) HR increased by aminophylline infusion; and (d) HR increased by SS and brought back to basal value by clonidine. Control groups were treated with saline. In the 4 types of experiments, K, starting from 0.3 mg/kg, induced almost identical and dose-dependent decreases in HR (maximal reduction: 45 beats/(min at 3 mg/kg). Thus we conclude: (1) that K is devoid of any presynaptic facilitatory effect on norepinephrine release since it was unable to raise HR in experiment D; (2) that K is devoid of any presynaptic inhibitory effect on norepinephrine release since it lowered HR to the same extent in both experiments B (noradrenergic tachycardia) and (non-noradrenergic tachycardia); and C (3) that the bradycardia which was induced by high doses of K (much above those required to block 5-HT2 and alpha 1-adrenergic receptors) and which was of similar magnitude in the 4 experimental conditions is probably due to a direct, nonspecific depressant effect of K on the sinus node.

Animals↗
PubMed1988

Evaluation of the natriuretic and beta-adrenoceptor-blocking effects of tienoxolol in normal volunteers.

The beta-adrenoceptor blocking and diuretic properties of tienoxolol (150 mg and 300 mg) were investigated and compared to those of a placebo in a double-blind, cross-over trial in six healthy volunteers. Heart rate (HR), systolic and diastolic blood pressures, peak expiratory flow rate (PEFR) at rest and during vigorous exercise, plasma renin activity (PRA) and aldosterone levels at rest, and diuresis and urinary electrolyte excretion values were measured before and at intervals up to 24 h after oral administration of the drugs. In addition, the clearances of electrolytes, uric acid, and creatinine were calculated, as well as the fractional sodium excretion (Fe Na%) before and 4 h and 24 h after drug intake. Finally, tienoxolol plasma levels were measured. Tienoxolol significantly and dose-dependently reduced exercise-induced tachycardia. This effect started 1 h after drug administration, peaked between 4 h and 6 h (-12% and -17% from control values at 150 mg and 300 mg, respectively), and lasted at least 12 h. Resting HR was decreased at 300 mg (P less than 0.05), PRA was decreased at both doses (P less than 0.05), but PEFR was not drug-affected. 24-h cumulative sodium excretion was increased (+24% at 150 mg [NS], +38% at 300 mg [P less than 0.01]) as compared to placebo, and Fe Na% did not change, regardless of the dose administered. 24-h cumulative diuresis was moderately increased by tienoxolol (NS), whereas creatinine clearance rose after the 300-mg dose, suggesting that tienoxolol might increase glomerular filtration rate. Plasma aldosterone levels remained unchanged. Finally, the elimination half-life of tienoxolol was 7.5 h. Thus, in healthy volunteers, tienoxolol behaves as an early acting and relatively long-lasting selective beta 1-adrenoceptor blocking drug endowed with significant natriuretic properties.

Adrenergic beta-Antagonists↗
PubMed1988

Peripheral haemodynamic effects of perindopril compared in patients with congestive heart failure and in normal volunteers.

The effects of perindopril, 4 mg orally, on brachial artery blood flow and diameter (pulsed Doppler) and on forearm vascular resistance were investigated and compared in six normal subjects and 10 congestive heart failure patients (New York Heart Association class III or IV). Pre-drug values of brachial artery blood flow and diameter were significantly lower in patients with congestive heart failure than in normal subjects, the reverse being true for forearm vascular resistance. In normal subjects perindopril increased brachial artery blood flow and decreased forearm vascular resistance, while in patients with congestive heart failure the same effects were observed but they were more pronounced and brachial artery diameter was increased. In patients with congestive heart failure, when perindopril effects were maximal, brachial artery blood flow remained below the baseline values of normal subjects but brachial artery diameter was normalized. Finally, there was a correlation between the drug-induced decrease in forearm vascular resistance and basal plasma noradrenaline values in all subjects taken together. These results indicate that: (1) the renin-angiotensin system plays a major role in vasoconstriction in patients with congestive heart failure; (2) this vasoconstriction affects both large arteries and arterioles; (3) perindopril is able to considerably improve peripheral haemodynamics in congestive heart failure; and (4) this improvement is linked to the initial sympathetic tone.

Adult↗
PubMed1987

Ketanserin: systemic and regional hemodynamics in spontaneously hypertensive rats. Role of alpha 1-adrenoceptor blockade.

The systemic and regional hemodynamic effects of ketanserin were investigated in spontaneously hypertensive rats (SHRs) using either the pulsed Doppler or the microsphere technique. In addition, the contribution of ketanserin alpha 1-adrenoceptor blocking properties to these hemodynamic effects was assessed. Ketanserin, directly after infusion or secondarily after bolus injection, induced dose-dependent decreases in blood pressure and regional vascular resistances. Peripheral vasodilatation was not homogeneous, affecting in a decreasing rank order: muscle = spleen greater than brain = kidney = total peripheral resistance = liver greater than mesentery = skin. Cardiac output and hindlimb blood flow increased, renal blood flow was maintained whereas mesenteric blood flow was decreased. Prazosin pretreatment, followed by PGF 2 alpha infusion in order to restore initial vascular tone, reduced the ketanserin-induced decrease in blood pressure (by about 70%) and abolished the drug-induced reductions in regional vascular resistances, indicating that these effects in SHRs were mostly due to the alpha 1-adrenoceptor blocking properties of the drug.

Adrenergic alpha-Antagonists↗
PubMed1987

Systemic and regional hemodynamic profile of five angiotensin I converting enzyme inhibitors in the spontaneously hypertensive rat.

The effects of 5 angiotensin I converting enzyme (ACE) inhibitors--captopril, enalapril, perindopril, trandolapril and ramipril--on general and regional hemodynamics were investigated (using radioactive microspheres) and compared in anesthetized adult spontaneously hypertensive rats. The 5 treatments were administered daily by gavage for 8 days in doses inducing identical decreases in arterial blood pressure. This effect was entirely due to a decrease in total peripheral resistance inasmuch as cardiac index was not affected by the 5 ACE inhibitors. In addition, despite their different chemical structures, all exhibited the same regional vasodilator pattern, which thus appears to be related only to ACE inhibition. The vascular beds resistances were decreased in the following order: renal greater than splenic = liver greater than skin greater than total peripheral greater than muscle = brain. Simultaneously, and despite the decrease in perfusion pressure, most regional blood flows and especially renal blood flow were increased. Finally, renal vasodilator effects of ACE inhibitors were observed even after doses that lacked any effect on total peripheral resistance.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Pharmacokinetics, converting enzyme inhibition and peripheral arterial hemodynamics of ramipril in healthy volunteers.

The effects of a 10 mg dose of ramipril, a new angiotensin I converting enzyme (ACE) inhibitor, on systemic blood pressure, heart rate, brachial artery blood flow, brachial artery diameter, carotid artery blood flow, carotid artery diameter, forearm vascular resistance, plasma ACE and renin activities and plasma aldosterone were investigated. Ramipril's effects in 6 healthy volunteers on a normal sodium diet were compared with those of placebo over a 24-hour period after oral drug intake in an open cross-over trial. Ramipril inhibited plasma ACE activity, an effect that peaked at 3 to 4 hours and persisted up to at least 24 hours. Plasma renin activity increased from 4 to 12 hours after drug intake and plasma aldosterone was slightly decreased. Systemic blood pressure in the supine position was slightly decreased between 6 and 8 hours after drug intake but heart rate remained unaffected. Ramipril significantly increased brachial artery blood flow, brachial artery diameter and carotid artery blood flow and decreased forearm vascular resistance between 3 and 8 hours after drug administration. These peripheral arterial vasodilating effects were more marked in the muscular resistance vessels and affected both large arteries and arterioles in the brachial vascular territory. A correlation was found between the log of plasma concentrations of ramipril diacid metabolite and the drug-induced plasma ACE activity inhibition and increase in brachial artery blood flow. There was also a correlation between these 2 latter effects. A plasma ACE activity inhibition of 80% was required to induce significant increases in brachial artery blood flow and carotid artery blood flow.

Adult↗
PubMed1987

Ketanserin and the arterial baroreceptor reflex in normotensive subjects.

The effects of oral ketanserin 40 and 120 mg on the responses to baroreflex activation and deactivation by phenylephrine and nitroglycerin, respectively, were investigated in normotensive subjects. Plasma catecholamine levels were measured at the same times. Two hours after the administration of ketanserin, and regardless of its effect on arterial pressure (no change after 40 mg, decrease after 120 mg), there was no alteration either in resting heart rate or baroreflex sensitivity during baroreceptor activation or deactivation. The lack of reflex tachycardia in response to the drug-induced hypotension may be related to the alpha 1-adrenoceptor blockade-mediated sympathoinhibitory effect of ketanserin, which leaves unaffected both plasma catecholamines and the normal reactivity of the sympathetic system.

Adult↗
PubMed1987

Pharmacokinetics and biological effects of captopril and hydrochlorothiazide after acute and chronic administration either alone or in combination in hypertensive patients.

The pharmacokinetics of free unchanged captopril, total captopril and hydrochlorothiazide (HCTZ) were investigated in three groups of patients with moderate essential hypertension and normal renal function on the first and on the 45th days of an oral treatment with either captopril (50 mg once daily, n = 7) or HCTZ (25 mg once daily, n = 10) or their combination captopril 50 mg + HCTZ 25 mg once daily, n = 8. Simultaneously, the effects of the three treatments on plasma converting enzyme activity (PCEA) and plasma renin activity (PRA) were measured. Elimination half-lives of total captopril after acute (7.8 +/- 2.3 h) or chronic (7.0 +/- 0.5 h) captopril dosing were similar to those of HCTZ after acute (6.5 +/- 1.0 h) or chronic (8.0 +/- 2.5 h) HCTZ dosing. Elimination half-life of free unchanged captopril was 0.81 +/- 0.09 h after acute and 0.96 +/- 0.03 h after chronic captopril dosing. Addition of HCTZ to captopril induced no major change in free and total captopril pharmacokinetic parameters, in PCEA inhibition and in PRA increase (as they were determined after captopril alone) on acute as well as on chronic treatment. Addition of captopril to HCTZ induced no major change in HCTZ pharmacokinetic parameters and in PRA increase compared with those determined after HCTZ alone. Chronic treatment with captopril + HCTZ resulted, like chronic captopril treatment, in no accumulation of captopril, in no significant modification of free and total captopril pharmacokinetic parameters and of PCEA inhibition (as determined after acute administration) but led to a significant enhancement of the acutely induced increase in PRA. Chronic treatment with captopril + HCTZ resulted, like chronic HCTZ treatment, in no accumulation of HCTZ, in no significant modification of HCTZ pharmacokinetic parameters (as determined after acute administration) but also led to a significant enhancement of the acutely induced increase in PRA. Thus, the longer duration of the antihypertensive action of captopril + HCTZ as compared to that of captopril cannot be ascribed to a pharmacokinetic or biological interaction between captopril and HCTZ.

Adult↗
PubMed1987

Arterial and venous effects of verapamil in normal volunteers.

1. The effects of verapamil (120 mg orally) and a placebo on arterial pressure, heart rate, PR interval, arterial flows and diameters of the brachial and carotid arteries (pulsed Doppler technique), forearm vascular resistance, and venous diameter and compliance (cutaneous microstrain gauge and plethysmography) have been compared over a 10-hr period in six healthy volunteers during a double-blind and cross-over study. 2. Verapamil reduced diastolic blood pressure by approximately 10 mm Hg, did not affect heart rate and increased PR interval by approximately 15%. 3. Verapamil significantly increased brachial and carotid arterial blood flows by 56% (P less than 0.01) and 16% (P less than 0.05), respectively, but the diameters of these vessels were not significantly modified (+7 and +4%, respectively, NS). Forearm vascular resistance decreased by 40% (P less than 0.01), indicating that verapamil preferentially dilates small arteries. All these effects peaked at 2 h after drug intake and lasted for 6 h. 4. Verapamil increased hand dorsal vein diameter and flow by 95% (P less than 0.05) and 80% (P less than 0.05), respectively, from 2 to 4 h after drug intake but venous compliance, assessed by the venous diameter/venous flow ratio, was not significantly modified (from 0.71 to 0.69, NS), thus indicating that veins are not directly affected by this drug.

Adult↗
PubMed1987

Effects of four angiotensin I converting enzyme inhibitors on regional myocardial blood flow and ischemic injury during coronary artery occlusion in dogs.

The effects of 4 angiotensin I converting enzyme inhibitors (ACEI), captopril, enalapril, ramipril, and trandolapril, were investigated on regional myocardial blood flow (RMBF, radioactive microspheres) distribution in ischemic and nonischemic zones and on ST-segment elevation in ischemic zones during intermittent coronary artery occlusion in anesthetized dogs. The 4 ACEI inhibited plasma ACE activity to an almost similar extent. All similarly reduced systemic blood pressure, an effect related to a decrease in systemic vascular resistance. Heart rate and myocardial contractility were not affected, but myocardial oxygen consumption presumably decreased because of the reduction in afterload. RMBF and their distribution (between epicardial and endocardial layers and between nonischemic and ischemic zones) were not modified by ACEI. Coronary vascular resistance was slightly decreased in nonischemic zones. ACEI had no effect on ST-segment elevation in ischemic zones. Thus, in this experimental model, all ACEI exhibited the same profile, including no change in RMBF and affording no protection against ischemic injury.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Antihypertensive drugs and baroreceptor reflex control of heart rate and blood pressure.

The arterial baroreceptor reflex (BR; aortic and carotid sinus BR) and the cardiopulmonary BR are the most important reflexes acting as buffer systems for the maintenance of arterial pressure around a fixed physiologic value. They act as permanent inhibitory systems on the central cardiovascular structures and they can be either activated or deactivated by using selective techniques. During chronic hypertension there are structural alterations of the peripheral and/or central components of the BR that become "reset", with a shift in the function curve relating BR activity to blood pressure (BP) in the direction of higher pressure values. As a consequence of the hypertension-induced resetting phenomenon, both the threshold pressure and sensitivity of BR are disturbed. However, if BR resetting during hypertension clearly decreases the sensitivity of BR control of heart rate (HR), BR control of peripheral resistance and arterial pressure as a whole is preserved and even increased when hypertension develops. Thus, this apparent discrepancy between BR control of HR and BP during hypertension demonstrates that evaluation of an antihypertensive therapy on reflex control of HR alone cannot predict what will happen to BR control of the whole cardiovascular system. Regarding BR control of HR, in contrast to the classical arteriolar vasodilators such as hydralazine and its derivatives, the majority of the modern antihypertensive drugs do not evoke reflex tachycardia in response to lowering of BP in normotensive or hypertensive subjects. Although the intrinsic pharmacologic mechanisms of action of these drugs on BR may be quite different (e.g., alpha 1-or beta-adrenoreceptor blocking agents, converting enzyme inhibitors, certain calcium-channel blockers of the phenyldihydropyridine group, and so on), they all shift in a parallel manner the set-point of the BR response curve towards lower pressures, with no change in HR or R-R interval. Generally, this resetting phenomenon occurs after several weeks or months of antihypertensive therapy, but it can also occur acutely (e.g. after IV injection) after administration of drugs such as prazosin or ketanserin. Finally, antihypertensive agents such as clonidine and methyldopa can simultaneously reset the BR and increase its sensitivity, thus leading to almost complete restoration of control of HR response despite the concomitant decrease in BP. Regarding BR control of blood pressure, only captopril and especially celiprolol (a beta 1-adrenoreceptor blocking drug with vasodilating properties) are able to restore almost normal BR control of arterial pressure.

Antihypertensive Agents↗
PubMed1987

Perindopril, converting enzyme blockade, and peripheral arterial hemodynamics in the healthy volunteer.

The effects of three doses (4, 8, and 16 mg) of perindopril, a new angiotensin I converting enzyme inhibitor, on systemic blood pressure, heart rate, brachial and carotid artery flow and diameter (assessed by the pulsed Doppler technique), forearm vascular resistance, plasma converting enzyme and renin activities, and plasma aldosterone were investigated in the normal volunteer and compared with those of a placebo over a 24-h period following oral drug intake in a double-blind, crossover trial. Perindopril dose-dependently decreased plasma converting enzyme activity, an effect that peaked at 3-4 h and persisted up to at least 48 h. Plasma renin activity increased for 12 h and plasma aldosterone was slightly decreased. Systemic blood pressure and heart rate were not drug-affected but perindopril dose-dependently augmented brachial and carotid artery flow, indicating an increase in peripheral arterial compliance. These vasodilating effects, which lasted up to 10 h after drug intake, affected both large arteries and arterioles, the latter being more sensitive, however, and were more marked in the muscular resistance vessels.

Adult↗