Systemic and regional hemodynamic effects of perindopril in congestive heart failure.

The acute systemic and regional hemodynamic responses to a single oral dose (4 mg) of the angiotensin converting enzyme inhibitor perindopril were investigated in 10 patients with severe congestive heart failure. Perindopril produced significant and long-lasting decreases in systemic vascular resistance (-18%), right atrial pressure (-60%), and mean pulmonary capillary wedge pressure (-28%), whereas it significantly increased cardiac index (+ 12%). Brachial (+ 130%, pulsed Doppler technique) and renal (+ 34%) blood flows were also significantly increased whereas hepatic blood flow remained unchanged. Brachial flow/cardiac output and renal flow/cardiac output ratios increased significantly from 0.8 to 1.6 and from 13.2 to 16.5, respectively. The maximal decreases in forearm and renal (but not in systemic) vascular resistances were correlated with the basal plasma norepinephrine concentrations but not plasma epinephrine concentrations or plasma renin activity. We conclude that in severe heart failure (a) perindopril considerably improves systemic hemodynamics and exerts an inhomogeneous vasodilating effect, resulting in a redistribution of flows toward the forearm and renal territories, (b) norepinephrine is a major determinant of the arteriolar tone in these two vascular beds, and (c) the pulsed Doppler is a particularly suitable method to non-invasively detect and assess hemodynamic improvements in heart failure patients.

[Non-invasive regional and cardiac output determination in healthy volunteers. Predictive value]. / Débits cardiaque et régionaux non invasifs chez le volontaire sain. Intérêt prédictif.

The effects of nifedipine (20 mg), propranolol (80 mg), the nifedipine (20 mg) + propranolol (80 mg) combination and a placebo on cardiac [heart rate (HR), cardiac output (CO, Doppler determination)] and systemic [mean arterial pressure (MAP), systemic vascular resistance (SVR)] and regional hemodynamic [brachial blood flow (BBF) and arterial diameter (BAD) (pulsed Doppler), forearm vascular resistance (FVR)] parameters were investigated during the 3 hours following their random administration in a double blind and cross over study performed in 6 healthy subjects. At their peak effects, (a) nifedipine decreased SVR (-17 p. 100, p less than 0.01), increased HR (+ 12p. 100, p less than 0.001) and CO (+ 18 p. 100, p less than 0.001), did not change MAP and increased BBF (+31 p. 100, p less than 0.001) with a vasodilating effect which affected both large and small arteries; (b) propranolol decreased HR (-14 p. 100, p less than 0.05) and CO (-25 p. 100, p less than 0.01), increased SVR (+25 p. 100, p less than 0.01), did not change MAP and decreased BBF (-28 p. 100, p less than 0.05) with a vasoconstrictor effect which affected both large and small arteries; (c) in the nifedipine-propranolol combination, nifedipine neutralized propranolol-induced systemic and regional vasoconstrictor effects while propranolol antagonized nifedipine-induced increases in HR and CO. Thus, the favorable synergistic effects of the nifedipine-propranolol combination in hypertensive patients could be demonstrated in healthy subjects inasmuch as MAP was decreased and peripheral vascular blood flows were preserved.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional antagonism between PK 11195, a peripheral benzodiazepine receptor antagonist, and nicardipine at the vascular level in healthy subjects: a peripheral hemodynamic study.

The effects of PK 11195, a peripheral benzodiazepine receptor antagonist (200 mg orally), of nicardipine (20 mg orally), of their combination, and of a placebo on brachial and carotid arteries, diameters, and flows were determined and compared over a period of 8 h after drug intake during a double-blind and cross-over study performed on six healthy volunteers. Simultaneously, plasma concentrations of both drugs were measured. PK 11195 significantly increased carotid and more markedly brachial arteries, flows (20 and 39%, respectively), and diameters (4 and 7%, respectively) and decreased forearm vascular resistance. Thus, PK 11195 preferentially affected the resistance vascular beds where it dilated both large arteries and arterioles. The intensity and duration of the peripheral vasodilating effects of PK 11195 were similar to those of nicardipine. Simultaneous administration of PK 11195 and nicardipine abolished almost all the peripheral vasodilating effects of both drugs. This finding, which was not related to a pharmacokinetic interaction between PK 11195 and nicardipine, demonstrates that in humans a functional antagonism develops between these two drugs at the vascular level.

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.