Pharmacokinetics of intravenous cilazaprilat in normal volunteers.

The pharmacokinetics of 1 mg, 2 mg and 4 mg of cilazaprilat administered intravenously were determined in a group of eight volunteers. The fall in plasma concentration was polyphasic. Elimination was predominantly by renal excretion of the unchanged drug. The mean renal clearance values following 1 mg, 2 mg and 4 mg doses were 5.3 +/- 0.5, 8.1 +/- 0.5, and 9.8 +/- 0.5 l h-1 and plasma clearances were 7.8 +/- 0.5, 10.4 +/- 0.5 and 11.8 +/- 0.6 l h-1, respectively. Thus, plasma and renal clearances were dose dependent. ACE inhibition was greater than 82% for the first 4 h and about 55% at 24 h, after all three doses. There were no significant haemodynamic effects at any dose.

The pharmacokinetics and bioavailability of cilazapril in normal man.

1. The pharmacokinetics of cilazapril and its active metabolite, cilazaprilat, were investigated in a three-part crossover study in 12 healthy male volunteers aged 19-38 years, excluding one subject who withdrew from the study. 2. Single 2.5 mg oral doses of cilazapril, and equivalent oral and intravenous doses of cilazaprilat were administered as aqueous solutions to the fasted subjects. There was an interval of 1 week between treatments. Concentrations of cilazapril and cilazaprilat in plasma and urine, and activities of angiotensin converting enzyme (ACE) in plasma were measured by radioenzymatic methods. 3. After 10 min infusion of cilazaprilat, the mean plasma concentration was 194 ng ml-1, and ACE inhibition was almost 100%. The decline in concentrations was polyphasic, with mean half-lives for the periods 1-4 h and 24-168 h of 0.90 and 46 h, respectively. Between 4 and 24 h the decline was non-linear, and ACE inhibition decreased from 91% to 67%. Urinary recovery of cilazaprilat averaged 91% of dose. 4. After oral cilazapril, the parent drug was rapidly absorbed and rapidly eliminated, with a mean maximum plasma concentration of 82 ng ml-1 at 0.83 h and a single elimination half-life of 1.3 h. Cilazaprilat peaked at 36 ng ml-1 about 1.7 h after dosing and the decline in concentrations was biphasic, with half-lives of 1.8 h and 45 h. After oral cilazaprilat, plasma concentrations were considerably lower, and the peak later (2.2 h). 5. Urinary recovery data indicated an absolute bioavailability for cilazaprilat of 57% (range 45-75%) from oral cilazapril, but only 19% (range 8-40%) from oral cilazaprilat.(ABSTRACT TRUNCATED AT 250 WORDS)

A pharmacokinetic study of cilazapril in elderly and young volunteers.

1. Cilazaprilat is an inhibitor of angiotensin converting enzyme (ACE) and is the active metabolite of cilazapril. The pharmacokinetics of cilazaprilat, and the inhibition of plasma ACE were investigated in 12 elderly and 12 young healthy volunteers. 2. Single oral 1 mg doses of cilazapril were given to the elderly (age range 65-83 years) and the young (age range 18-31 years) in an open study. Plasma and urinary cilazaprilat concentrations, and plasma ACE activities were measured up to 72 h after dosing by radioenzymatic methods. 3. Cilazapril was well tolerated in both young and elderly subjects. Small falls in blood pressure were observed up to 8-24 h after dosing. 4. The mean peak plasma cilazaprilat concentration in the elderly (11.5 ng ml-1) was significantly greater (P less than 0.02) than the corresponding value in the young (8.3 ng ml-1). Total and renal clearances were significantly lower (both P less than 0.05) in the elderly (12.8 and 5.11 h-1) than in the young (16.0 and 7.21 h-1). Total urinary recovery of cilazaprilat was similar for the two groups at about 43% of dose. 5. Plasma ACE inhibition was slightly greater in the elderly but the mean inhibition in the two groups did not differ by more than 10% at any time-point from 1-72 h. 6. The plasma concentrations of cilazaprilat required for 90% ACE inhibition were similar at 4.7 and 4.8 ng ml-1 in the elderly and young respectively. 7. It is concluded that the age-related changes in cilazaprilat kinetics and in the degree of ACE inhibition are small.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial receptor discharge in dogs with chronically induced difference in blood volume.

1. Urinary responses to stimulation of atrial receptors have been found to be greater in dogs with a high blood volume than in dogs with a low blood volume. Two groups of dogs with different blood volume were examined by distending a large balloon in the left atrium, to stimulate atrial receptors and find out whether the increase in atrial receptor discharge was different in the two groups of dogs. 2. The relationship between atrial receptor discharge and left atrial pressure was determined in twenty-six fibres studied in four dogs with a high blood volume and sixteen fibres studied in three dogs with a low blood volume. 3. The slope of the relationship representing the increase in atrial receptor activity during increases in left atrial pressure, and the activity at each left atrial pressure, were significantly greater in dogs with a high blood volume than in dogs with a low blood volume. 4. This study has shown that the atrial receptor discharge and their responses to increases in left atrial pressure are greater in dogs with a high blood volume than in those with a low blood volume.

Effect on efferent cardiac vagal nerve fibres of distension of the urinary bladder in the dog.

In dogs anaesthetized with chloralose, the effect of distension of the urinary bladder on the activity in efferent vagal nerves was studied; the urinary bladder was distended with warm saline, and the carotid sinuses were vascularly isolated and perfused with blood at constant flow. In one group of efferent vagal nerve fibres distension of the bladder always caused a decrease in activity. These fibres also responded to stimulation of receptors in the carotid region by an increase in activity and to stimulation of superficial branches of the left radial nerve by a decrease in activity. Another group of vagal nerve fibres which did not respond to stimulation of receptors in the carotid region, also did not respond to distension of the urinary bladder. It is concluded that distension of the urinary bladder results in the response of a decrease in activity in efferent cardiac vagal nerve fibres, onto which converge the effects of stimulating receptors in the carotid region and the somatic nerves.

Involvement of the reflex increase in heart rate in the differences in urinary responses to stimulation of atrial receptors in dogs with different blood volumes.

The effect of increasing heart rate by increasing the rate of atrial pacing in the absence of any reflex effects from atrial receptors, by cooling the vagi to 12 degrees C, was studied in two groups of dogs with different blood volumes. In one group of nine dogs with a high blood volume increasing heart rate, by an amount similar to that reflexly obtained in response to stimulation of atrial receptors, resulted in significant increases in urine flow and sodium excretion; in another group of eight dogs with a low blood volume similar increases in heart rate did not result in a diuresis or natriuresis. The findings suggest that the effects of an increase in heart rate in combination with differences in blood volume could contribute to the previously reported differences in the urinary responses that result from stimulation of atrial receptors in dogs with different blood volumes.

Effect of distension of the urinary bladder on efferent cardiac sympathetic nerve fibres which respond to stimulation of atrial receptors.

The effect of distension of the urinary bladder on the activity in the efferent cardiac sympathetic nerves which responded to stimulation of atrial receptors or those which responded to stimulation of carotid baroreceptors or chemoreceptors, was studied in dogs anaesthetized with chloralose; the urinary bladder was distended with warm saline, small balloons were positioned at the right pulmonary vein-atrial junctions and distended with 1 cm3 saline, and the carotid sinuses were vascularly isolated and perfused with blood at constant flow. The efferent cardiac sympathetic nerve fibres which responded to stimulation of carotid baroreceptors and chemoreceptors by a decrease in activity always responded with an increase in activity in response to distension of the urinary bladder. In contrast, in those efferent cardiac sympathetic nerve fibres which did not respond to an increase in carotid sinus pressure, but responded to stimulation of atrial receptors by an increase in activity, distension of the urinary bladder neither caused a significant change in activity nor produced a reproducible pattern of response. It is concluded that the efferent cardiac sympathetic nerve fibres which respond to stimulation of atrial receptors are separate from those which respond to distension of the urinary bladder.

The effect on the efferent vagal nerves to the heart of stimulating atrial receptors in the dog.

In chloralose-anaesthetized dogs, distension of small balloons at the pulmonary vein-atrial junctions to stimulate atrial receptors with myelinated vagal afferent nerves causes an increase in heart rate but does not influence the activity in efferent vagal cardiac nerves. However, distension of these small balloons also stimulates atrial receptors with non-myelinated vagal and sympathetic afferent nerves, which are thought to affect the heart rate and activity in efferent vagal cardiac nerves. In the present investigation, seven dogs anaesthetized with chloralose were studied by distension of small balloons at the pulmonary vein-atrial junctions and in the left atrial appendage, and by graded cooling of the vagal nerves in the neck; cooling to 9 degrees C was used to prevent the increase in activity in myelinated vagal afferent nerves to distension of the small balloons and cooling to 0 degree C was used to prevent responses to the distension in all vagal afferent nerves. Eleven vagal efferent nerve fibers were studied which responded to stimulation of carotid baroreceptors and chemoreceptors. Distension of the small balloons did not affect the activity in these eleven efferent vagal nerve fibres, with the vagi at 37 degrees C or during vagal cooling to 9 degrees C or to 0 degree C. The results indicate that upon distension of the small balloons, none of the three types of atrial receptor influence the activity in efferent vagal cardiac nerves. The results support the conclusion that stimulation of atrial receptors with myelinated vagal afferent nerves, responsible for the reflex increase in heart rate, does not influence the activity in efferent vagal cardiac nerves.

Does stimulation of the left atrial receptors affect the activity in efferent vagal nerves to the heart in decerebrate dogs?

In anaesthetized dogs with an intact neuraxis, distension of small balloons at the pulmonary vein--atrial junctions to stimulate atrial receptors with myelinated vagal afferent nerves causes an increase in heart rate but does not influence the activity in efferent vagal cardiac nerves. However, it has been suggested from experiments performed in decerebrate dogs that stimulation of atrial receptors causes a tachycardia partly mediated by a decrease in activity in efferent vagal nerves. In the present study in chloralose-anaesthetized dogs, following total decerebration (four dogs) or partial decerebration (four dogs) at the level of the mid-brain, distension of the small balloons caused an increase in heart rate but did not affect the activity in efferent vagal nerve fibres which responded by an increase in activity to stimulation of carotid baroreceptors and chemoreceptors. These results show that stimulation of the left atrial receptors in totally or partially decerebrate dogs causes an increase in heart rate but does not influence the activity in efferent vagal cardiac nerves.

The effects of stimulation of left atrial receptors on efferent vagal nerves to the dog heart.

There is a controversy as to whether the increase in heart rate in response to stimulation of atrial receptors is mediated solely by the sympathetic or by both the sympathetic and vagal nerves to the heart. In dogs anaesthetized with chloralose the activity in vagal efferent nerve fibres from the cardiac branches of the right vagus nerve was recorded. The effects of distension of small balloons at the right pulmonary vein-atrial junctions on this activity was investigated. Distension of the small balloons caused an increase in heart rate in all dogs. Distension of the small balloons had no effect on vagal efferent fibres whether these were affected by carotid occlusion or not (seven dogs), or whether they were affected by changes in the pressure or nature of the blood perfusing the vascularly isolated carotid sinuses or not (nine dogs). It is concluded that the increase in heart rate seen in response to stimulation of left atrial receptors by distension of small balloons at the pulmonary vein-atrial junctions does not involve vagal efferent nerves.