Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1998-11-13
2001-02-06
Dudash, Diana (Department: 1619)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S673000, C514S674000, C514S920000, C514S930000, C514S290000, C424S009200, C435S003000, C435S007100
Reexamination Certificate
active
06184254
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of endocrinology and neurobiology. More particularly it concerns the mechanisms by which extracellular Ca
2+
and the steroid hormone 1,25 (OH)
2
vitamin D
3
modulate vascular smooth muscle force generation.
2. Description of Related Art
Essential hypertension is a major health problem in the U.S. with an estimated 50 million adults being affected (Gifford, 1993) and is characterized by an increase in peripheral resistance in the face of normal cardiac output (Folkow, 1982). There is a clear pattern of inheritance and influence of the environment (Lifton, 1996) and untreated hypertension is a significant risk factor for stroke, myocardial infarction, coronary artery disease, renal failure, and premature death (Gordon et al., 1977). Standard therapy is directed toward lowering blood volume (diuretics and salt restriction), or reduction of vascular tone (vasodilators, pressor antagonists, and sympatholytics) (The Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, 1993). Although medical management of hypertension has contributed to a large reduction in stroke incidence over the past two decades, reduction in risk of myocardial infarction has not shown a parallel improvement (Anderson et al., 1991). Thus, cardiovascular disease remains the number one cause of death in the U.S.
Available antihypertensive compounds have unwanted side effects or clear contraindications. Diuretics and beta adrenoreceptor antagonists are indicated as first line therapy (The Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, 1993) but are associated with significant untoward effects including erectile dysfunction and fatigue (&bgr;-blockers), and are contraindicated in renal failure (diuretics). These observations underscore the need for novel therapeutic approaches to hypertensive disease. One area of blood pressure research which has potential for the development of novel pharmacological strategies, but has remained untapped, is the study of the relationship between Ca
2+
homeostasis and blood pressure regulation.
Relationship Between Systemic Ca
2+
Homeostasis and Blood Pressure.
Evidence linking blood pressure and systemic Ca
2+
homeostasis includes the clinical observation that primary hyperparathyroidism is associated with hypertension and that parathyroidectomy frequently lowers blood pressure (Mallette et al., 1974; Massry et al., 1986), epidemiologic data associating regional hardness of water with death from cardiovascular disease (Sharrett and Feinleib, 1975), and Ayachi's seminal demonstration that elevated dietary calcium intake lowers blood pressure in the spontaneously hypertensive rat (SHR) (Ayachi, 1979) which has been amply confirmed (Arvola et al., 1993; Bukoski and McCarron, 1986; DiPette et al., 1989; Kageyama and Bravo, 1987; McCarron et al., 1981). Epidemiologic surveys (Ackley et al., 1983; Belizan and Villar, 1980; Fogh-Anderson et al., 1984; Garcia-Palmieri et al., 1984; Harlan et al., 1984; McCarron et al., 1982) and clinical trails (Bucher et al., 1996a; 1996b; Grobbee and Hofman, 1986; McCarron and Morris, 1985; Strazullo et al., 1986) also support a link between Ca
2+
intake and blood pressure in humans. For example, analysis of NHANES data showed a significant inverse correlation between blood pressure and calcium intake (McCarron and Morris, 1982); and surveys of pregnant women showed a correlation between gestational hypertension and calcium intake (Belizan and Villar, 1980; Bucher et al., 1996a). Although clinical trials have shown only a small overall blood pressure lowering effect of Ca
2+
supplementation (McCarron and Morris, 1985), sub-groups have been shown to respond to Ca
2+
supplementation with a significant fall in blood pressure (Resnick et al., 1985a; 1985b).
Mechanisms Linking Ca
2+
Homeostasis with Blood Pressure.
Several hypotheses have been proposed to explain the apparent link between Ca
2+
homeostasis and blood pressure and have been recently reviewed (Bukoski et al., 1995). These include Ca
2+
induced modulation of calciotropic hormone levels, alterations in Na and water balance, or changes in sympathetic nerve activity. In contrast with these ideas, work in two areas has prompted proposal of a novel hypothesis which states that the perivascular CaR, acting as a sensor for extracellular Ca
2+
, responds to changes in interstitial Ca
2+
concentration with the release of a local vasodilator substance. One area was the discovery that extracellular Ca
2+
relaxes isolated arteries at low physiologic concentrations (Bian et al., 1995); the other was the molecular demonstration of the parathyroid CaR (Brown et al., 1993b; Garrett et al., 1995c).
Modulation of Vascular Tone by Extracellular Ca
2+
.
It has long been recognized that extracellular Ca
2+
can suppress arterial force generation (Bohr, 1963; Cow, 1911; Holman, 1958). The physiologic significance of this action of Ca
2+
has been unclear, however, since only very high concentrations of extracellular Ca
2+
have generally been shown to induce relaxation (Bohr, 1963; Hollaway and Bohr, 1973; Webb and Bohr, 1978). Recent work, however, has demonstrated that raising extracellular Ca
2+
from as little as 1.0 mM to 1.5 mM relaxes isolated arteries (Bian et al., 1995) and that cumulatively raising extracellular Ca
2+
above 1.5 mM causes nearly complete relaxation with an ED
50
value of 2.4±0.17 mM, n=12. Relaxation induced by Ca
2+
dependent on the release of an endothelium-derived relaxing factor, or on the production of NO, but is associated with the release of a vasodilator substance from the adventitial surface of the artery. These results, and observations that Ca
2+
induced relaxation is associated with decreased myofilament Ca
2+
sensitivity and can be blocked by K
+
channel antagonists led to the proposal that a Ca
2+
receptor that is similar or identical to that described in parathyroid gland plays a mediating role in contrast to persistent reports that the CaR is not expressed in vascular smooth muscle (Brown et al., 1993a; 1995).
Ca
2+
Homeostasis and Cell Function.
Serum ionized Ca
2+
is normally regulated within tight limits and is a function of the amount of Ca
2+
absorbed by the intestine, reabsorbed from the load filtered by the kidney, and the net sum of Ca
2+
deposition into and resorption from the bone mass. A simplified view of the endocrine mechanisms that regulate Ca
2+
homeostasis can be gained by considering the dynamic systemic responses that occur in response to changes in serum Ca
2+
(Bukoski et al., 1995). An increase in serum ionized Ca
2+
is recognized by the membrane spanning, G protein coupled CaR of the parathyroid cell which in turn elicits a decrease in the release of parathyroid hormone (PTH) (Brown et al., 1993a; 1995). The rise in Ca
2+
also activates a CaR on the thyroid C cell which increases calcitonin release (Garrett et al., 1 995a,b). A fall in serum Ca
2+
has the opposite effect of increasing PTH and decreasing calcitonin. PTH acts at the level of bone to increase release of Ca
2+
into the plasma, and the fall in calcitonin releases its suppressive effect on bone Ca
2+
resorption. PTH also acts as the kidney where it increases reabsorption of Ca
2+
and stimulates the production of 1,25 (OH)
2
vitamin D
3
which in turn acts via genomic and non-genomic mechanisms to increase intestinal absorption and renal reabsorption of Ca
2+
(Nemere et al., 1993). The net result is an increase in serum Ca
2+
at the expense of changes in calciotropic hormone levels.
Two important concepts for the working hypothesis are implicit in this model. One is that interfaces exist in the epithelial linings of the gut and kidne
Bian Ka
Bukoski Richard D.
Board of Regents , The University of Texas System
Dudash Diana
Fulbright & Jaworski L.L.P.
Sharareh Shahnam
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