The Effect of Norepinephrine on Cardiac Output, Arterial Blood Pressure, and Heart Rate in Dogs Treated With Chlorothiazide*†

Abstract

Forearm blood flow in normal human subjects was found to decrease progressively during intravenous infusions of norepinephrine as the rate of infusion increased (2). After 1 week of treatment with chlorothiazide, the same subjects responded to the same doses of norepinephrine with progressive increases in flow. 20, 1961 (1). Supported by Grant H-2644 from the National Heart Institute, Bethesda, Md., and aided by grants from the Iowa and American Heart Associations.t Established Investigator of the American Heart Association.§ Advanced Research Fellow of the American Heart Association.1 1 Postgraduate Trainee under Grant HTS-5367 from the National Heart Institute. that treated and untreated animals were available for study on the morning of the eighth day.The dogs were lightly anesthetized with 10 mg thiopental sodium per kg and treated with 0.3 mg decamethonium bromide per kg. A cuffed endotracheal tube was inserted immediately, and intermittent positive pressure breathing was instituted with a Harvard respiratory pump. Two cardiac catheters were introduced through the external jugular vein so that their tips lay in the main pulmonary artery and right atrium. Needles were inserted into the left carotid and femoral arteries and into a femoral vein. Pressures were recorded from the femoral artery and right atrium with Statham strain gauges. Drugs were given through the needle in the femoral vein. The catheter in the pulmonary artery was filled with indocyanine green dye and connected through a three-way stopcock to a dye reservoir and injection system. The needle in the carotid artery was connected through small-bore, nylon tubing to the cuvet of a Gilford densitometer. Dye curves were obtained by drawing blood through the densitometer with a constant speed pump after injections into the pulmonary artery. Endexpiratory CO2 concentration was monitored with a Spinco CO2 analyzer. Dye curves, CO2 concentration, and blood pressure were recorded with a Sanborn direct-writing oscillograph.Ventilation was adjusted by manipulating the controls on the respiratory pump so that end-expiratory CO2 concentration, after it became stable, was about 4 per cent. The rate and depth of breathing were not changed after this initial adjustment. Repeated doses of 0.075 mg decamethonium per kg were given at 20-minute intervals to maintain skeletal muscle relaxation. After the animal was prepared, 15 to 20 minutes were allowed for blood pressure and heart rate to become stable. Then l-norepinephrine bitartrate was infused intravenously at rates of 0.1, 0.2, and 0.4 Ag of norepinephrine base per kg per minute. Each dose was repeated once in each animal. The doses were given in random order both in the untreated and treated groups, using the same 6 X-6 Latin square (3). Observations on cardiac output, heart rate, and blood pressures were made immediately before and at the end of 2.5 minutes of norepinephrine infusion. Exactly 10 minutes were allowed between infusions. Electrically integrated mean right atrial pressures were recorded thro...

Reduced Vascular Response to Angiotensin Ii in Secondary Hyperaldosteronism*

“…Friedman and Allardyce (25) also showed the importance of ionic distribution, particularly of sodium, in the maintenance of tension in artery segments. Chlorothiazide 4 has been shown to modify the pressor response to infused l-norepinephrine (26)(27)(28), and dogs given prior treatment with 3,4-dihydrochlorothiazide 5 have a diminished pressor response to angiotensin (29). These were all acute experiments.…”

Altered Vascular Responsiveness: Initial Hypotensive Mechanism of Thiazide Diuretics

“…The authors concluded, therefore, that the decreased response to norepinephrine was dependent upon the plasma volume reduction and that the natriuretic effect of the drug was only a permissive factor. Other groups subsequently confirmed the findings that the chlorothiazide congeners alter the vascular responses to a variety of pressor and depressor agents as well as the responses to adrenergic nerve stimulation (17)(18)(19)(20)(21)(22)(23)(24). The results of the present study, therefore, suggest that the attenuated pressor responsiveness does not apparently relate to the same mechanism reducing arterial pressure since the depressed pressor responses occurred without a simultaneous actual reduction in arterial pressure.…”

Comparison of the Effect of Some Diuretics on Blood Pressure and Renal Haemodynamics in Dogs

“…These facts might explain the recorded reduction in systemic arterial blood pressure, renal blood flow and renal vascular resistance caused by Esidrex@ administration. Moreover, the resultant reduction in systemic arterial blood pressure could be explained by the decrease in pressor responsiveness to physiologically active pressor substances, e. g., norepinephrine has been found to be present after oral administration (ALEKSANDROW et al, 1959;FEISAL et al, 1961;FRIES et al, 1960;ECKSTEIN et al, 1962;and PEREDA et al, 1963), intravenous infusion (BEAVERS and BLACKMORE, 1958), and during intra-arterial infusion (GILLENWATER et al, 1962; and JACKSON and DUFF, 1963) of thiazides.…”