Jie J. Shan*, Richard Z. Lewanczuk, Christina G. Benishin and Peter K.T. Pang Pages 559 - 570 ( 12 )
<p> One major challenge in the design of therapeutics is our lack of understanding of the causes of diseases. Very often the drugs developed are for symptomatic treatment, but not directed towards counteracting the causative agents. Such drugs will improve the well-being of the patient at the level of the tissue affected by the disease. However, such chemicals often lack specificity and result in substantial side effects. For the development of drugs, it is necessary to understand the cellular mechanisms of the disease so that a pharmacological antagonist to such cellular events can be designed. Unfortunately such cellular mechanisms are often very basic to other healthy cells, which will then be affected by the antagonistic drugs also. Serious side effects may then result. Great effort has been made to design target tissue specific drugs so that untoward pharmacological actions on other tissues can be reduced. Tbe best approach, however, is to have a good understanding of the identity of the causative factor which produces the specific deleterious effects on the diseased tissue. Specific antagonists to the causative factor can produce highly specific beneficial effects with much reduced untoward side effects. Unfortunately, in the case of many diseases, in spite of intense efforts by many investigators, the causes of such diseases are still largely unknown. Furthermore, while the causative agents in many cases can be endogenous factors, they can also be exogenous. In addition, most diseases such as hypertension, cancer etc. are generally recognized as heterogeneous in nature. The possible multiple causes of the same disease symptoms make it more difficult to adopt such an approach for drug design. The present paper is a summary of our recent efforts to understand the cellular mechanisms of certain diseases and the endogenous factors which may influence such mechanisms. Such an approach helps us identify an endogenous factor which may be involved in the cause of certain diseases. </p><p> The following is a brief summary of the paper. One unique feature about all living cells is the low (0.1 µM) intracellular free calcium concentration [Ca2+li, as compared to the high (]- 1.5 mM) extracellular ionic calcium concentration. The maintenance of low [Ca<sup>2+</sup>Ji is an important pre-requisite for the well-being of cells. A known fact is that excessive [Ca<sup>2+</sup>li can cause many diseases such as hypertension, type-II diabetes, some forms of cancer etc. and cell death is associated with elevated [Ca<sup>2+</sup>Ji. How cells regulate calcium can be an important aspect in our understanding of some of these diseases. How factors or hormones influence [Ca<sup>2+</sup>li balance may help us to recognize the causes of diseases. In our studies, we show that calcium regulating hormones such as parathyroid hormone, vitamin D metabolites and female sex hormones (estrogen and progesterone) do play significant roles in [Ca<sup>2+</sup>Ji regulation, especially at the level of calcium channels. Parathyroid hormone (PTH), 24,25- dihydroxyvitamin D3 (24,25D), estrogen and progesterone all tend to inhibit calcium channels in vascular smooth muscle cells (VSMC), and decrease [Ca<sup>2+</sup>li stimulated by other vasoconstrictors. This is followed by vasodilation. On the other hand, 1,25- dihydroxyvitamin D3 (1,25D) tends to increase the calcium channel activity resulting in an increase in [Ca<sup>2+</sup>h in VSMC. These results may help explain the involvement of female sex hormones and vitamin D metabolites in the regulation of blood pressure. </p><p> Furthermore, we have discovered a new hormone, parathyroid hypertensive factor (PHF), which originates from the parathyroid gland under some pathological conditions. The main action of PHF is to raise the basal equilibrium of [Ca<sup>2+</sup>li thus increasing the sensitivity of cells to other stimulatory substances. As a result, the function of cells becomes defective, leading to diseases. It is suggested that PHF may be part of the causative mechanism of the low-renin, salt-sensitive form of hypertension. </p><p> Recent studies suggest that excessive PHF may be the causative factor for other diseases. PHF may be a basal [Ca<sup>2+</sup>li modulator. The presence of excessive PHF in the circulation may result in the expression of diverse disease symptoms. It is anticipated that, when discovered, PHF-specific antagonists or PHF-synthetic pathway inhibitors can become important cause-targeted therapeutic agents with specific desirable effects and minimal side effects. These studies of [Ca<sup>2+</sup>li regulation are therefore important in our understanding of health and diseases. </p>