The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension.

Digitalis glycosides exert both excitatory and inhibitory autonomic actions in animals and produce vasoconstriction in normal humans but produce vasodilation in heart failure patients. To determine whether or not these contrasting vascular responses are due to differing autonomic actions of the drug, we compared the responses to intravenous administration of Cedilanid-D (0.02 mg/kg) in eight normal subjects (mean age, 23 +/- 1 years) and eight patients with moderate-to-severe heart failure (mean age, 52 +/- 5 years, NYHA Class III-IV). Hemodynamics and efferent sympathetic nerve activity to muscle (MSNA) were measured during 5-minute periods before (control) and 20 minutes after drug administration. In the heart failure patients, Cedilanid-D significantly increased systolic and pulse pressures, whereas mean arterial pressure was unchanged. There was a decrease in right atrial pressure and a tendency for a decrease in pulmonary artery diastolic pressure with a slowing of heart rate. Cardiac index increased by 24 +/- 7%. Short-term administration of digitalis in these heart failure patients produced a fall in forearm vascular resistance (from 37.6 +/- 8.2 to 31.8 +/- 8.1 units, p less than 0.05) and an early, profound, and sustained decrease in MSNA (from 831.0 +/- 118.4 to 474.4 +/- 103.6 units/100 heart beats, p less than 0.01). Digitalis glycosides produced different vascular and MSNA responses in the normal subjects. In the normal volunteers, the drug significantly increased systolic, mean, and pulse pressures and decreased central venous pressure and heart rate. Despite the significant increase in arterial pressure, there was no change in forearm vascular resistance (from 11.7 +/- 1.0 to 12.7 +/- 1.0 units, p = NS) or MSNA (from 494.8 +/- 88.5 to 369.1 +/- 60.5 units/100 heart beats, p = NS), suggesting a sympathoexcitatory response in normal subjects. To determine whether or not the digitalis-induced sympathoinhibition in the heart failure patients was simply due to an inotropic effect (stimulation of inhibitory cardiac mechanoreceptors), we studied the responses of seven additional patients with heart failure before and during administration of dobutamine (3.4 +/- 0.4 micrograms/kg/min). Dobutamine produced a 34 +/- 3% increase in cardiac index, no significant change in systemic arterial pressures, a decrease in pulmonary artery diastolic and right atrial pressures, and no change in heart rate or forearm vascular resistance (from 30.2 +/- 4.3 to 26.5 +/- 4.7 units, p = NS).(ABSTRACT TRUNCATED AT 400 WORDS)

Sympathoinhibitory responses to digitalis glycosides in heart failure patients. Direct evidence from sympathetic neural recordings.

The sections in this article are:


1
Techniques
1.1
Carotid Sinus Massage

1.2
Electrical Stimulation of Carotid Sinus Nerves

1.3
Section or Anesthesia of Carotid Sinus Nerves and Vagi

1.4
Occlusion of Common Carotid Arteries

1.5
Neck Chamber

1.6
Vasoactive Drugs

1.7
Nonselective Techniques




2
Arterial Baroreceptor Control of Heart Rate
2.1
Autonomic Mediation

2.2
Other Properties

2.3
Relationship to Base-Line R-R Interval

2.4
Relationship to Respiratory Cycle




3
Arterial Baroreceptor Control of Atrioventricular Conduction and Ventricles

4
Carotid Baroreceptor Control of Blood Pressure

5
Carotid Baroreceptor Influence on Cardiac Output and Total Peripheral Resistance

6
Arterial Baroreceptor Control of Regional Circulations

7
Arterial Baroreceptor Control of Veins

8
Set Point of Carotid Baroreflex

9
Aortic Baroreflexes

10
Factors That Modify Arterial Baroreceptor Control of Circulation
10.1
Age

10.2
Exercise

10.3
Mental Stress

10.4
Sleep

10.5
Anesthesia

10.6
Central Blood Volume and Posture




11
Pathological States
11.1
Hypertension

11.2
Heart Disease

11.3
Carotid Sinus Syndrome

11.4
Other Pathological Conditions




12
Modification of Arterial Baroreflexes by Drugs
12.1
β-Adrenergic Antagonists

12.2
Cardiac Glycosides

12.3
Antihypertensive Drugs

Arterial Baroreflexes in Humans

Cardiac dysfunction in animals has been associated with impairment of arterial and cardiopulmonary baroreflex control of the circulation. Chronic heart failure in human beings is associated with neurohumoral excitation, which could result in part from impairment in the inhibitory influence of baroreflexes. We postulated that (1) patients with left ventricular dysfunction (LVD) have impaired baroreflex modulation of vascular resistance and (2) administration of a digitalis glycoside would immediately restore baroreflex sensitivity. Eleven patients with LVD (NYHA class, 2.8 +/- 0.2, mean +/- SEM; baseline left ventricular ejection fraction, 18 +/- 2%; cardiac index, 2.4 +/- 0.21/min/m2; and pulmonary capillary wedge pressure, 26.0 +/- 3.2 mm Hg) were compared with 17 normal control subjects. We measured forearm vasoconstrictor responses to simulated orthostatic stress with use of lower body negative pressure (LBNP) at -10 and -40 mm Hg to unload cardiopulmonary and arterial baroreceptors. Baseline forearm vascular resistance (FVR) was higher in patients with LVD than in normal subjects: FVRLVD, 68.8 +/- 15.3 U; FVRN, 23.2 +/- 2.1 U (p less than .001). During unloading of baroreceptors with LBNP -10 mm Hg, normal subjects developed vasoconstriction (delta VRN at LBNP -10 mm Hg, +5.7 +/- 1.6 U) but patients with LVD failed to have vasoconstriction and tended to develop vasodilation (delta FVRLVD at LBNP -10 mm Hg, -8.6 +/- 8.5 U) (p = .05, normals vs patients with LVD at LBNP -10 mm Hg). A more marked disparity in response was seen during unloading of baroreceptors of LBNP -40 mm Hg: delta FVRN at LBNP -40 mm Hg, +16.6 +/- 1.5 U; delta FVRLVD at LBNP -40 mm Hg, -10.3 +/- 9.6 U (p less than .001, normals vs patients with LVD). Despite high baseline values for FVR, patients with LVD developed vasoconstriction during intra-arterial infusions of norepinephrine, thereby excluding a nonspecific depression of vascular reactivity as the mechanism for abnormal responses to LBNP in patients with LVD. We also studied the short-term effects of administration of a digitalis glycoside, ouabain 0.0075 mg/kg (seven patients) or lanatoside C (Cedilanid-D) 0.02 mg/kg (three patients), on baroreflex-mediated vasoconstrictor responses to LBNP in the patients with LVD. Digitalis glycoside reduced baseline FVR from 71.8 +/- 16.6 to 48.6 +/- 12.0 U (p less than .02). Responses to LBNP tended to be normalized after administration of digitalis glycoside: delta FVR during LBNP -40 mm Hg, -11.1 +/- 10.5 U before and +7.8 +/- 5.6 U after the drug (p less than .05).(ABSTRACT TRUNCATED AT 400 WORDS)

Selective impairment of baroreflex-mediated vasoconstrictor responses in patients with ventricular dysfunction.

A reduction in the correlation dimension of heartbeat intervals precedes imminent ventricular fibrillation in human subjects

Data in animals indicate that large amounts of digitalis potentiate arterial baroreflexes and that this factor may be important for the cardiovascular effects of the drug. To determine if arterial baroreflex potentiation also exists after administration of therapeutic doses of digitalis in man, we studied how stimulation and deactivation of arterial baroreceptors by phenylephrine and nitroglycerin injection affect heart rate and how stimulation and deactivation of carotid baroreceptors by neck suction and pressure affects blood pressure and heart rate. The study was performed in 29 normotensive or hypertensive subjects before and after injection of Lanatoside C (0.8 mg i.v.). Baroreceptor stimulation reduced heart rate and blood pressure, while baroreceptor deactivation increased both of these variables. The bradycardic and hypotensive effect of baroreceptor stimulation increased significantly after digitalis both in normotensive and hypertensive subjects. However, the tachycardic and hypertensive responses to baroreceptor deactivation were not affected by digitalis. Thus, therapeutic doses of digitalis in man enhance baroreceptor reflexes, and both the heart rate and the blood pressure reflex effects are involved. However, the enhancement occurs to a marked degree only with baroreceptor stimulation and is not evident with baroreceptor deactivation.

L. Preti

Papers

Digitalis and baroreceptor reflexes in man.