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Evaluation of angiotensin as a therapeutic agent
Appraisal therapy
Evduation
and reappraisal Edited by
Arthur
C. DeGraff
of cw@etmsin
of cardiac
and Alan F. Lyon
as a therapeutic
agent
Mark M. Singer, M.D. Arthur C. DeGra$, M.D.* Alan F. Lyon, M.D. New York, N. Y.
I
t is believed that renin, when secreted by the renal juxtaglomerular cells, activates circulating angiotensin I, an alpha2-globulin decapeptide complex which, through enzymatic degradation, becomes angiotensin I I. Angiotensin 11, henceforth called simply angioknsin, is an octapeptide which derives most of its medical interest from its marked pressor activity. It was purified in 1956, and synthesized a year later. Angiotensin amide is now available for clinical use. It exerts its pressor action primarily by increasing the peripheral resistance through direct stimulation of arteriolar smooth muscle. An indirect effect via arteriolar innervation has also been postulated. Within a few minutes after this agent is administered intravenously, it is broken down in the blood to inactive peptides. In normal individuals who receive single large doses, the pressor response is accompanied by a decrease in cardiac output. A mild reflex elevation of venous pressure caused by venoconstriction occurs; this is abolished by anesthesia and atropine, and is less intense than that seen with l-norepinephrine. Other effects include a gradual rise in pulmonary and right atria1 pressures, inconsequential change in coronary blood From
The Cardiac Therapy Research Unit. Bronx York. N. Y. Received for publication June 11. 1963. *Address: 850 Park Ave.. New York 21. N. Y.
566
flow, and decrease in renal plasma flow, glomerular filtration rate, and excretion of sodium. If factors that control the secretion of aldosterone are held constant, angiotensin can promote a 32 to 250 per cent increase in the secretion of aldosterone by direct stimulation of the zona glomerulosa of the adrenal. This may not be seen in some decompensated cirrhotic patients whose adrenals may be producing aldosterone maximally. Although present in free form, the normal blood content of angiotensin has not been accurately measured. In certain hypertensive patients a slower rate of degradation may explain the reported higher blood levels and the increased total exchangeable pool of angiotensin. The hypertensive patient seems to possess an increased sensitivity to the agent, which has led some to speculate as to the possible existence of a’genetic enzymatic defect in this disease. Utilizing the observation of hypersensitivity to angiotensin, a test for the potential detection of pre-hypertensive subjects has been suggested. Duration of the skin blanching produced by the intradermal injection of 0.1 microgram of angiotensin in saline is said to be more pronounced in the hypertensive than in the normal subVeterans
Administration
Hospital,
West
Kingsbridge
Road,
New
Volume Number
66 4
Evaluation
ject, but because of the overlap in results this test cannot be considered to be reliable at present. Angiotensin has been suggested for use in most forms of shock in which a pressor agent is indicated. It is presently not recommended for the treatment of shock in acute myocardial infarction. The drug is 5 to 10 times more potent than levarterenol, but, unlike the latter, it can be given alone intravenously, intramuscularly, or subcutaneously without producing local tissue damage. However, only the intravenous route has been recommended clinically. In hemorrhagic shock, the response to angiotensin is less likely to produce adverse electrocardiographic changes than is that to I-norepinephrine. As with renin, a linear dose-pressure response curve is observed. When large doses are infused, an initial arterial pressure peak is followed by a partial decline without alteration of the responsiveness to I-norepinephrine. The hypertensive effect is nullified by papaverine, adenosine triphosphate, theophylline ethylenediamine, and chlorothiazide, but not by adrenolytic agents. Interestingly, hexamethonium, pentolinium, and tetraethylammonium enhance the vascular response to angiotensin. Tachyphylaxis has not been a problem. The drug is costlier than levarterenol. The cirrhotic patient with ascites may exhibit a reduced pressor response to angio-
of angiotensin
as therapeutic agent
567
tensin, similar to that seen with norepinephrine. Also, pregnant women are less sensitive to the vasopressor effect of angiotensin; the response returns to normal in the puerperium. In the severe hypertensive or decompensated cirrhotic patient the infusion of pressor doses of angiotensin can produce increased diuresis and natriuresis while depressing the secretion of aldosterone. These varied actions of angiotensin are most interesting. Other than as a valuable research tool, its clinical use should be considered to be premature. A recent clinical report on patients in shock described a reduction in cardiac output and urinary flow rate which was measurably greater than that produced by several other pressor drugs, in dosage that had a comparable effect on the blood pressure. This is presumably due to its lesser venoconstrictive effect. Thus, it should be reserved for trial in shock that does not respond to the well-established pressor agents. It is for these reasons that details on dosage and clinical usage have been omitted deliberately in this discussion. A better understanding of its clinical pharmacology and mechanism of action, and further controlled clinical trials will ultimately establish the true therapeutic worth of this fascinating drug. Nonproprietary Hypertensin.
name:
angiotensin.
Trade
name:
Evduation
and reappraisal Edited by
Arthur
C. DeGraff
of cw@etmsin
of cardiac
and Alan F. Lyon
as a therapeutic
agent
Mark M. Singer, M.D. Arthur C. DeGra$, M.D.* Alan F. Lyon, M.D. New York, N. Y.
I
t is believed that renin, when secreted by the renal juxtaglomerular cells, activates circulating angiotensin I, an alpha2-globulin decapeptide complex which, through enzymatic degradation, becomes angiotensin I I. Angiotensin 11, henceforth called simply angioknsin, is an octapeptide which derives most of its medical interest from its marked pressor activity. It was purified in 1956, and synthesized a year later. Angiotensin amide is now available for clinical use. It exerts its pressor action primarily by increasing the peripheral resistance through direct stimulation of arteriolar smooth muscle. An indirect effect via arteriolar innervation has also been postulated. Within a few minutes after this agent is administered intravenously, it is broken down in the blood to inactive peptides. In normal individuals who receive single large doses, the pressor response is accompanied by a decrease in cardiac output. A mild reflex elevation of venous pressure caused by venoconstriction occurs; this is abolished by anesthesia and atropine, and is less intense than that seen with l-norepinephrine. Other effects include a gradual rise in pulmonary and right atria1 pressures, inconsequential change in coronary blood From
The Cardiac Therapy Research Unit. Bronx York. N. Y. Received for publication June 11. 1963. *Address: 850 Park Ave.. New York 21. N. Y.
566
flow, and decrease in renal plasma flow, glomerular filtration rate, and excretion of sodium. If factors that control the secretion of aldosterone are held constant, angiotensin can promote a 32 to 250 per cent increase in the secretion of aldosterone by direct stimulation of the zona glomerulosa of the adrenal. This may not be seen in some decompensated cirrhotic patients whose adrenals may be producing aldosterone maximally. Although present in free form, the normal blood content of angiotensin has not been accurately measured. In certain hypertensive patients a slower rate of degradation may explain the reported higher blood levels and the increased total exchangeable pool of angiotensin. The hypertensive patient seems to possess an increased sensitivity to the agent, which has led some to speculate as to the possible existence of a’genetic enzymatic defect in this disease. Utilizing the observation of hypersensitivity to angiotensin, a test for the potential detection of pre-hypertensive subjects has been suggested. Duration of the skin blanching produced by the intradermal injection of 0.1 microgram of angiotensin in saline is said to be more pronounced in the hypertensive than in the normal subVeterans
Administration
Hospital,
West
Kingsbridge
Road,
New
Volume Number
66 4
Evaluation
ject, but because of the overlap in results this test cannot be considered to be reliable at present. Angiotensin has been suggested for use in most forms of shock in which a pressor agent is indicated. It is presently not recommended for the treatment of shock in acute myocardial infarction. The drug is 5 to 10 times more potent than levarterenol, but, unlike the latter, it can be given alone intravenously, intramuscularly, or subcutaneously without producing local tissue damage. However, only the intravenous route has been recommended clinically. In hemorrhagic shock, the response to angiotensin is less likely to produce adverse electrocardiographic changes than is that to I-norepinephrine. As with renin, a linear dose-pressure response curve is observed. When large doses are infused, an initial arterial pressure peak is followed by a partial decline without alteration of the responsiveness to I-norepinephrine. The hypertensive effect is nullified by papaverine, adenosine triphosphate, theophylline ethylenediamine, and chlorothiazide, but not by adrenolytic agents. Interestingly, hexamethonium, pentolinium, and tetraethylammonium enhance the vascular response to angiotensin. Tachyphylaxis has not been a problem. The drug is costlier than levarterenol. The cirrhotic patient with ascites may exhibit a reduced pressor response to angio-
of angiotensin
as therapeutic agent
567
tensin, similar to that seen with norepinephrine. Also, pregnant women are less sensitive to the vasopressor effect of angiotensin; the response returns to normal in the puerperium. In the severe hypertensive or decompensated cirrhotic patient the infusion of pressor doses of angiotensin can produce increased diuresis and natriuresis while depressing the secretion of aldosterone. These varied actions of angiotensin are most interesting. Other than as a valuable research tool, its clinical use should be considered to be premature. A recent clinical report on patients in shock described a reduction in cardiac output and urinary flow rate which was measurably greater than that produced by several other pressor drugs, in dosage that had a comparable effect on the blood pressure. This is presumably due to its lesser venoconstrictive effect. Thus, it should be reserved for trial in shock that does not respond to the well-established pressor agents. It is for these reasons that details on dosage and clinical usage have been omitted deliberately in this discussion. A better understanding of its clinical pharmacology and mechanism of action, and further controlled clinical trials will ultimately establish the true therapeutic worth of this fascinating drug. Nonproprietary Hypertensin.
name:
angiotensin.
Trade
name: