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AN EXPLANATION OF HYPERTENSION PRODUCED BY NARROWING THE RENAL ARTERY HERBERTG. LANGFORD, M.D.* In 1934 Goldblatt described a simple method ofproducing hypertension by bilateralnarrowing ofthe renalarteries.Theconditionresembledhuman hypertensive disease in many ways. It seemed likely that understanding the mechanism involved would contribute to an explanation of the human disease. Groups headed by Page, Braun-Menendez, Pickering, and others seized upon a probable culprit, renin. This enzyme is found only in the kidney and acts upon a plasma protein to release a potent hypertensive agent, angiotensin. The results of infusing angiotensin mimic in most respects the hemodynamic changes ofrenal hypertension. Constricting the renal artery is followed by increased renin in the kidney. The work of Skeggs, Peart, Bumpus and Page, and Schweyzer which culminated in isolation, chemical description, and synthesis ofangiotensin intensified study of this mechanism, and for a time it seemed likely that renal hypertension would seen be explained. Only the final step remained —finding increased renin or angiotensin in the blood ofrenal hypertensive animals. I. Evidence against Renin Since then a series of blows have been dealt to the idea that the reninangiotensin system is the important agent maintaining hypertension after renal artery constriction or similar manipulations. Some of these appear to be serious objections while others are less serious but do cast doubts on the primacy ofthese substances in maintaining hypertension. * Associate Professor ofMedicine and Chief, Endocrine and Hypertension Division, Department ofMedicine, University ofMississippi School ofMedicine,Jackson 6, Mississippi. These concepts have beenshaped by conversation with many workers, especially Arthur Guyton, Michael Raddiffe-Lee, William Cook, and Sir George Pickering. Dr. Havilah Babcock kindly criticized the presentation. The work has been supported in part by Cardiovascular Research Grant No. H-5857 Ci from the National Institutes ofHealth. 372 Herbert G. Langford · Hypertension by Narrowing the Renal Artery Perspectives in Biology and Medicine · Spring 1963 One of the more recent studies, and one which strikes directly at the heart of the matter, is the report by Paladini upon angiotensin levels in dogs with chronic renal hypertension produced by partial clamping ofthe renal arteries. He and Scornik [i], using a sensitive method, were able to show that angiotensin blood levels were in all cases within normal limits in chronic hypertension though levels increased in most instances soon after severe clamping of the renal artery. In like manner Peart [2] has stated his inability to find increased concentrations ofrenin in renal venous blood in hypertensive patients, using a very sensitive assay method. Present studies suggest that angiotensin is the prime controller ofaldosterone secretion. Therefore, the aldosterone secretionrate should indirectly approximate angiotensin activity. Carpenter, Davis, and Ayers [3] have shown that the aldosterone secretion rate in chronic renal hypertensive dogs is within normal limits also. Laragh [4] found a normal aldosterone secretory rate, in chronic essential hypertensive patients, as have other workers. However, Genest [5] found moderately fluctuating elevations of urinary aldosterone in similar patients. Skeggs [6] found a significant difference between the mean angiotensin level ofpatients with severe chronic essential hypertension and that oftheir controls. Some patients had normal levels. We have found angiotensin in renal venous blood coming from the offending kidney in surgically correctable disease and have not found it from the opposite kidney [7]; but not enough was present to account for the blood pressure elevation. It seems apparent from the weight of evidence applied to a direct pressor hypothesis that angiotensin is not the sole final common pathway. Also, renin tachyphylaxis has obstructed acceptance of the renin hypothesis . If repeated doses of renin are given at short intervals, or if an amount ofreninwhich will produce pronouncedly elevated blood pressure is infused at a steady rate, responsiveness decreases progressively, until finally blood pressure is not appreciably elevated at all. When renin tachyphylaxis is produced in the renal hypertensive animal, no decreased hypertension is observed. This has been used as an argument against renin participating in such blood pressure elevation. Cross-transfusion studies in general have failed to find significant amounts ofcirculating pressor substances . We have shown that when the total renal venous outflow of the hypertensive dog with one kidney removed and the artery of the other kidney narrowed is directed to a recipient, the donor's...


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