Early Career and Work with Antihypertensive Drugs, 1940-1949
When Freis started medical school, his intent was to enter medical practice. In 1942, after his internship and a year as house physician at Boston City Hospital he joined the U.S. Army Air Forces (now the U.S. Air Force). As a military physician, his main duties were to run the laboratory service, first at Lincoln Air Force Base in Nebraska, then at the Rheumatic Fever Research Program at Gowen Field in Boise, Idaho. By the time he was discharged in 1945, he knew he wanted to make his career in clinical research. He began a cardiology residency with Robert Wilkins at Evans Memorial Hospital in Boston in 1946. Wilkins had been working with Reginald Smithwick, a leading neurosurgeon, in assessing the cardiovascular and circulatory changes associated with a new procedure, sympathectomy. This operation, in which some of the sympathetic nerves in the thoracic and lumbar regions were severed, was the newest treatment for severe hypertension. Freis initially hoped to do same sort of hemodynamic research. However, Wilkins was asked by James Shannon, then director of the Squibb Institute for Medical Research (and later National Institutes of Health director), to work with the Squibb in exploring possible drug treatments for hypertension. Freis was soon assigned to evaluate clinically any drugs that might emerge in this project.
What is hypertension? Blood pressure is the force in the arteries when the heart beats (systolic pressure) and when the heart is at rest (diastolic pressure), as measured in millimeters of mercury (mm Hg) in a manometer or sphygmomanometer. This measurement is expressed as "systolic/diastolic," e.g., 120/80. The definition of "high" blood pressure--hypertension--has varied over time. Currently it is defined in adults as a blood pressure greater than 140 mm Hg systolic pressure or greater than 90 mm Hg diastolic pressure. In most cases of hypertension, the exact cause is still unknown; in some rare cases (perhaps 5 percent), it is caused by a curable condition such as kidney or adrenal gland disorders, or a congenital deformity of the aorta (coarctation). Over time, high blood pressure weakens the heart by forcing it to work harder, weakens the walls of the arteries (increasing the chance of hemorrhagic stroke or aneurism), and exacerbates atherosclerosis (the buildup of plaques in the arteries that narrow or block them). This damage to the arteries also impairs kidney function and can damage the blood vessels in the eyes. Yet for most of its course, hypertension produces no symptoms; patients are often unaware they have it, which is why it was later characterized as "the silent killer."
In the 1940s, when Freis began working with cases of hypertension, most physicians believed that only "malignant" or very high blood pressure was harmful. They reasoned that older people actually needed higher blood pressure, because blood vessels normally become more narrow with age. If a person's blood pressure did not increase with age, the flow of blood through vital body organs would be inadequate, and organ function would be impaired. Besides this, there seemed little reason to treat a condition that was not causing any distressing symptoms for the patients. Early indications that high blood pressure could be dangerous, for example, a 1928 report published by the American Society of Actuaries that linked higher blood pressure to earlier deaths, were largely dismissed by physicians. The patients that Wilkins and Freis were seeing suffered from malignant hypertension, with diastolic pressures over 115 mm Hg. In these cases, severe damage--notably, congestive heart failure, kidney failure, and damage to the eyes--was already apparent, and without treatment the patients were unlikely to live long.
Pentaquine, the first drug Freis tested, was an outgrowth of the World War II anti-malarial program. During the initial evaluation of pentaquine it had been observed that normal volunteers developed orthostatic hypotension (low blood pressure when standing up) after several days of doses higher than those used for the routine treatment of malaria. Pentaquine did reduce blood pressure in hypertensive patients, but had toxic side effects that ruled out its routine use. During the trial, however, a patient with malignant hypertension was referred by Dr. Smithwick. Smithwick was unable to perform a sympathectomy on the man because he was a poor surgical risk. Pentaquine lowered his diastolic blood pressure from 160 to 100, and reversed many of the hypertensive signs such as headache, bloody urine, and congestive heart failure. This dramatic response to the medication convinced Freis and Wilkins of the value of the chemotherapeutic approach. Together with Joseph Stanton, Freis searched the medical literature for other likely drugs to test. An older medicinal herb, veratrum viride, looked promising. Veratrum had been analyzed by pharmacologist Otto Krayer at Harvard, and demonstrated hypotensive properties at doses below toxic levels. Freis and his colleagues were able to confirm these findings, and to generate quantitative evidence that acute reduction of blood pressure resulted in immediate improvement in heart function, and cleared the clinical and hemodynamic signs of congestive heart failure. They also found that kidney function was not impaired by lowering the blood pressure. With subsequent patients, they discovered that sometimes intensive treatment with drugs modified the patients' blood pressure so that even between treatments (which often had to be injected) the pressure didn't return to pre-treatment levels.
Veratrum was far from a perfect treatment, however. Side effects included severe and prolonged nausea and vomiting. Freis and Stanton obtained and tested some of the individual veratrum components in hopes of eliminating side effects, but to no avail. At about the same time, Walter Kempner achieved some success treating hypertensive patients with a diet consisting mainly of fruit and rice. It became clear that the diet worked because it included so little sodium, and that if sodium were limited to 200 mg. per day or less, the effect would be the same. The lower sodium levels meant that patients retained less water, and thus the blood volume decreased, which in turn reduced the blood pressure. Freis and his team found that lower doses of veratrum could be used if a low-sodium diet were followed, thus reducing the incidence of side effects. They also tried diuretics to reduce the blood volume by increasing the production of urine. The only diuretic drugs available at the time were mercury compounds. Though they worked, they were not suitable for routine use, as they had to be given by daily injection, and the mercury compounds carried the risk of toxicity.