Parathyroid Hypertensive Factor

Researcher name: 
R.Z. Lewanczuk, MD, FRCPC

Parathyroid Hypertensive Factor (PHF) was first discovered in 1987 at the University of Alberta in collaboration with Dr. P. Pang. For years, high blood pressure (hypertension) was thought to represent a single disease. In the early 1980s, however, it became apparent that patients with high blood pressure could be grouped according to various metabolic characteristics.

Parathyroid Hypertensive Factor (PHF) was first discovered in 1987 at the University of Alberta in collaboration with Dr. P. Pang. For years, high blood pressure (hypertension) was thought to represent a single disease. In the early 1980s, however, it became apparent that patients with high blood pressure could be grouped according to various metabolic characteristics. One group of patients, in particular, was known to have low blood calcium levels but increased levels of parathyroid hormone – the hormone responsible for maintaining blood calcium. Because increased levels of this hormone always seemed to be associated with high blood pressure in this group of patients, it was suggested Parathyroid Hormone (PTH) might be the cause of the high blood pressure in these people. Previous work done by Dr. Pang, however, had shown that PTH, when injected into animals, actually decreased blood pressure. Thus, we felt that PTH could not be the cause of high blood pressure.

Because blood calcium should be high if the PTH is high, yet it was low in this one group of hypertensive patients, we hypothesize that some "factor" was blocking the action of PTH. Our first experiments involved taking blood plasma from spontaneously hypertensive rats – rats which showed all the characteristics of this type of human hypertension – and injecting it into rats with normal blood pressure, looking to see if the effects of PTH could be blocked by some factor in the hypertensive rats' plasma. Indeed, not only did some factor block the action of PTH, but it also increased blood pressure in rats. Further studies have since shown that this factor will also sensitize humans or animals to other factors known to increase blood pressure. Because it was known that removal of the parathyroid glands in spontaneously hypertensive rats would decrease the blood pressure, we thought that the parathyroid gland might also be the source of this new factor. Again, removal of the parathyroid glands form spontaneously hypertensive rats resulted in a decrease in blood pressure and in the disappearance of the factor from the plasma. When the parathyroid glands from spontaneously hypertensive rats were transplanted into rats with normal blood pressure, blood pressure would increase and the factor would appear in blood. For this reason, we have termed this new factor "Parathyroid Hypertensive Factor " or "PHF".

PHF has since been found in a proportion of human hypertensive patients – namely the ones with lower calcium and higher PTH levels. This group of patients also represents the salt sensitive patients (people in whom blood pressure is effected by salt) and comprises about 40% of people with high blood pressure. As one fifth to one quarter of people in Canada have high blood pressure, this represents a significant number of people with this factor. Because PHF is produced in the parathyroid gland, calcium in the diet prevents its release, just as calcium prevents the release of parathyroid hormone. Thus, calcium is an effective treatment in patients with high blood pressure and PHF. Similarly, as PHF acts by constricting arteries (a calcium dependent) process drugs that block calcium entry into arterial muscle cells are useful in patients with high blood pressure due to PHF.

Why is the discovery of PHF significant? First of all, PHF represents a significant cause of high blood pressure in about 40% of hypertensive patients (i.e.: in one out of ten adults in the population at large) and one cannot cure a disease until one knows the cause. Secondly, measurement of PHF can enable doctors to determine which patients with high blood pressure will benefit by decreasing the salt or increasing the calcium in their diet. Thirdly, it allows a doctor to predict which high blood pressure medications will work in a particular patient. Until now, the effect of salt, calcium or pills in any given patient with high blood pressure could not be predicted except by trial and error. Finally, there is some suggestion that PHF measurement may actually be able to predict which people are at risk of developing high blood pressure, thus enabling screening of the population.

How has the work on PHF impacted on Canada? Canada is now recognized as the leading country in PHF research. We now have 11 international collaborative projects dealing with PHF. This has meant that over three million dollars in research money has been spent in Canada on this project over the last three to four years. More importantly, as a kit is developed to measure PHF, the possibility exists for major commercial development. If every patient with high blood pressure had PHF measurement once, this would represent forty to fifty million tests in North America alone! Similarly, an industry based on the manufacturer of PHF-blocking drugs could also be established in Canada. Such benefits will not come cheaply, however. At present, the cost of purifying one gram of PHF would be about $9 billion! Luckily, we need much less than this amount at present but clearly a more effective way of purifying or synthesizing PHF will have to be developed.

Finally, we are grateful to Zenyaku-Kogyo Company of Japan for funding most of the work on PHF. I personally am grateful to the Alberta Heritage Foundation for medical research and the Medical Research Council of Canada for personal support in this research. We would also like to acknowledge Searle Canada Inc. for supporting one of our Canadian PHF clinical studies.