Robert W. Wilkins

Peripheral venoconstriction in human congestive heart failure.

A method for measuring venous tone in the limb segment of man in vivo was used to study the problem of cardiac decompensation. Venoconstriction was present in patients with heart failure and it tended to remit as the patients improved.

The Effects of Intravenous Apresoline (Hydralazine) on Cardiovascular and Renal Function in Patients with and without Congestive Heart Failure

Intravenous Apresoline is a powerful renal vasodilator in cardiac as well as in noncardiac patients. In hypertensive patients in congestive heart failure, the drug produces a striking improvement in both cardiovascular and renal function. The increases in renal plasma flow are inconsistently related to changes in arterial pressure and cardiac output Unlike many hypotensive drugs, Apresoline usually causes no decrease in the renal excretion of sodium and water. Circulatory collapse produced by the drug may occur in the presence of an increased cardiac output but is accompanied by a deterioration of the arterial pressure pulse and a reduction in sodium and water excretion.

Blood Pressure Responses to the Valsalva Maneuver in Cardiac Patients with and without Congestive Failure

Compensated cardiac patients, like normal subjects, on performing the Valsalva maneuver show a decrease in systolic, diastolic, and pulse pressures during the blowing effort and a characteristic hypertensive overshoot after the release of the strain. Cardiac patients in congestive failure show the failure response with a maintenance of the systolic, diastolic, and pulse pressures during the expiratory strain and an absence of the overshoot afterwards. Experimental and clinical observations in patients indicate that this failure response is due to elevation of the right ventricular diastolic pressure, which interferes with the normal obstruction of venous return during the blowing effort of the Valsalva maneuver.

Serotonin and Antiserotonins I. Their Circulatory, Respiratory, and Renal Effects in Man

Serotonin, (5 hydroxy-tryptamine), a naturally occurring compound, is pharmacologically active on intravenous injection in man. It consistently increases the pulse rate but has a variable pressor depressor, or biphasic effect on the arterial pressure. The mode of action of serotonin on these functions is not clear. Serotonin consistently and characteristically increases ventilation. However, it does not cause striking circulatory changes in the kidney although it usually produces moderate antidiuresis. The benzyl analog of serotonin (BAS) (1-benzyl-2-methyl-3-methoxy-tryptamine), both intravenously and orally, reduces or prevents the symptoms caused by serotonin. Intravenously, BAS in addition has demonstrable antiserotonin effects on the characteristic blood pressure and respiratory responses to serotonin.

CHLOROTHIAZIDE IN HYPERTENSION: STUDIES ON ITS MODE OF ACTION

Some years ago studies begun in this laboratory implicated the kidney in the homeostasis of arterial pressure.‘, I t was found that when venous cuffs were inflated on the limbs so as to pool a sizable volume of blood out of the active circulation the kidneys promptly reduced their output of water to as little as 10 per cent, and of sodium to as little as 40 per cent, of control levels. These responses occurred in normotensive, hypertensive, and splanchnicectomized subjects. Exactly similar antidiuretic changes were found to occur in response to the administration of hypotensive drugs?, It was postulated that such antidiuretic responses might represent one “protective” mechanism operating to offset the effect of, or to produce resistance to, drugs or other procedures tending to lower arterial pressure. On the basis of this hypothesis and the related observation that strong diuresis of a hypertensive patient with congestive heart failure might be followed by a marked fall in blood pressure, we initiated a long-term study on the value of diuretics in the treatment of hypertension. In recent years an attempt has been made in this laboratory to examine the effects of every available diuretic, including chlorothiazide, in hypertensive patients. The first patients given chlorothiazide were either in congestive heart failure or seriously ill with hypertension that had not responded satisfactorily to medical or surgical treatment. FIGURE 1, which was published recently,b shows one of these early cases in whom previously neither ganglionic blocking agents (because of side effects) nor splanchnicectomy (because of failure to lower blood pressure) had been satifsactory. Relatively small doses of chlorothiazide after splanchnicectomy were effective in restoring blood pressure to normal along with a marked improvement in symptoms. FIGURE 2 shows one of the two other illustrations published a t the same time;6 both of these unfortunately contained an error in the time label where, for clarity of illustration, the scale had been broadened. It now shows the time scale correctly labeled in weeks instead of months at the end and demonstrates the fact that the hypotensive effect of chlorothiazide was potent not only in combination with other drugs, but also alone. This observation has been confirmed by ourselves6 and others7 in a number of patients. The past several months have seen a rapid expansion of interest in and information on chlorothiazide. I t is now possible to draw on observations in more than 100 patients whom we observed and an approximately equal number followed by other physicians in this hospital, particularly on R. H. Smithwick’s service. This expanded experience furnishes a second, and in some ways a sobering, look a t this most interesting antihypertensive drug. Turning from a mere affirmation of the drug’s hypotensive power to an examination of its mode of action, it has been reported6, that chlorothiazide

Relationship between Diuretic and Antihypertensive Effects of Chlorothiazide and Mercurial Diuretics

Both chlorothiazide and parenteral mercurial diuretics have an antihypertensive as well as a natriuretic action. Previous observations have suggested that the antihypertensive effect is not due solely to sodium depletion. This paper expands these observations on a larger group of normotensive and hypertensive subjects and presents new studies on the effects of fluorohydrocortisone and SC-8109 (a steroidal antagonist), upon the sodium excretion and blood pressure of hypertensive patients during treatment with one of the diuretics.

The Mechanism of Limb Segment Reactive Hyperemia in Man

The roles of vasodilator metabolites and/or reduced local intra-arteriolar pressure in producing the reactive hyperemia which follows the sudden release of arterial occlusion were studied. It was found that slight increases of metabolic activity during the period of occlusion increased the reactive hyperemia considerably. Maintenance of intra-arteriolar pressure during arterial occlusion depressed the resultant reactive hyperemia. It was concluded that both factors contribute to the reactive hyperemia. The blood flow “debt” incurred during arterial occlusion was almost invariably “overpaid” during the reactive hyperemia period.

Studies of Circulation Time During the Valsalva Test in Normal Subjects and in Patients with Congestive Heart Failure

Circulation times (P32 from the antecubital and femoral veins to a peripheral artery) and roentgenographic studies of the pattern of venous distribution of a radio-opaque substance (Diodrast introduced through a cardiac catheter into the axillary vein and the inferior vena cava below the diaphragm) have been performed during the expiratory effort of the Valsalva maneuver. In normal subjects the circulation times were increased by the duration of the expiratory effort and the Diodrast injections were stagnated in the veins outside the thoracic cavity. These effects were in striking contrast to those in patients with congestive failure in whom the circulation times were retarded only partially if at all and the Diodrast injections continued to flow freely towards the right atrium during the expiratory effort. Thus, in patients with congestive failure the Valsalva maneuver does not interrupt the venous return to the right atrium as it does in normal subjects.

The effect of local compression upon blood flow in the extremities of man

Abstract The effect of locally applied pressures of 10 to 50 mm. Hg on the extremities was investigated by three methods: (a) thermometric; (b) blood gasometric; and (c) plethysmographic. The results indicated that local pressures of remarkably low amounts may impair the circulation. Skin temperature measurements showed a definite effect with pressures as low as 20 mm. of mercury. At this pressure, the arteriovenous oxygen difference rose about 25 per cent, and plethysmographic tracings showed an equal decline in blood flow. With a local pressure of 30 mm. Hg, the blood flow decreased about 25 per cent as measured both by the blood gasometric and the plethysmographic methods. Even at 10 mm. Hg the plethysmograph revealed a 10 per cent decline in blood flow.

Serotonin and Antiserotonins II. Clinical Studies, Especially in Essential Hypertension with the Benzyl Analog of Serotonin (BAS)

Serotonin, a smooth-muscle constrictor, has been suggested as possibly important in the pathogenesis of arterial hypertension. The benzyl analog of serotonin (BAS) was developed as an antimetabolite of serotonin, and has certain demonstrable antiserotonin effects in man. Orally it has moderate antihypertensive and other clinical effects resembling those of reserpine, which also has a definite antiserotonin action. However, there is question whether the clinical effects of oral BAS or of reserpine in hypertension are due to antiserotonin or other pharmacologic actions. BAS is clinically useful in the therapy of some patients with essential hypertension.