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R Z Lewanczuk

Publications and source records attributed to R Z Lewanczuk.

18 recordsLinked to original sources
PubMed1992

Combined effect of dietary calcium and calcium antagonists on blood pressure reduction in spontaneously hypertensive rats.

Calcium supplementation and calcium channel blockers are known to have antihypertensive effects in similar subsets of hypertensive patients, as well as in spontaneously hypertensive rats (SHR). To investigate this apparent paradox, we placed 12-week-old SHR on one of three dietary levels of calcium (0.2, 0.4, or 0.8%), as well as on one of four doses of nifedipine (0, 50, 150, or 300 mg/kg food) for 8 weeks. We performed a similar experiment using four verapamil doses (0, 300, 900, or 1,800 mg/kg food). In the nifedipine experiment, two-way analysis of variance showed significant independent antihypertensive effects of both nifedipine (p less than or equal to 0.0001) and calcium (p less than 0.0001) and significant interaction (p = 0.0034), the latter suggesting a synergistic effect. In the verapamil experiment, both calcium and verapamil again had significant independent antihypertensive effects (p = 0.006 and p = 0.004, respectively), but there was no significant interaction. Although the effects of the calcium supplement or calcium antagonist alone were significant, such hypotensive responses were not optimal or predictable or clearly dose-dependent. However, the combination of a calcium supplement and calcium antagonist resulted in predictable or dose-dependent effects, and the optimal effect was reflected in the reduction of the SHR pressure to normal range for Wistar-Kyoto (WKY) rats. These results appear to indicate that supplementary calcium and calcium channel blockers act by different mechanisms in lowering blood pressure (BP), and that the combination of those differing mechanisms of action may have potential therapeutic benefit.

Animals↗
PubMed1992

Parathyroid function in hypertension.

PHF, secreted by the PTG, induces hypertension by increasing vascular smooth muscle calcium uptake and thereby increasing intracellular calcium levels. PHF secretion is inhibited by dietary calcium and the effects of PHF are blocked by calcium channel antagonists. This explains the paradox whereby both calcium and calcium channel blockers may be effective antihypertensive agents. PHF may be secreted by a specific cell type in the parathyroid gland, numbers of which seem to correlate with PHF levels. Thus, the parathyroid gland does seem to play a role in some forms of hypertension, but this role is probably not due to its production of PTH, but may be related to the secretion of the new factor--PHF.

Animals↗
PubMed1992

Pharmacokinetics of sotalol enantiomers in humans.

The chiral beta-blocker, sotalol (STL), is marketed as a racemic mixture. Although both STL enantiomers have equal Class III antiarrhythmic activity, beta-blocking activity has been ascribed mainly to the R-enantiomer. The pharmacokinetics of STL enantiomers were studied in young (mean age 32 +/- 3 years), healthy male volunteers after oral administration of 160 mg. Subsequent plasma and urine samples were collected over 24 hours, and STL enantiomer concentrations were determined using a stereospecific high-performance liquid chromatography assay. There were no significant differences between pharmacokinetic parameters of enantiomers. The area under the time-concentration curves (mean +/- standard deviation [SD]) were 6.95 +/- 0.85 and 6.76 +/- 1.2 (mg/L)hour for S- and R-STL, respectively. Maximal plasma concentrations of S- and R-STL were 615 +/- 167 and 619 +/- 164 ng/mL, respectively, which were obtained on average, 3.13 +/- 0.60 hours after dosing. The mean residence time (mean +/- SD) was 13.2 +/- 1.2 and 12.9 +/- 1.8 hours for S- and R-STL, respectively. Respective renal clearance values for S- and R-STL were 8.98 +/- 1.5 and 9.46 +/- 2.3 L/hour, and were approximately 1.5 times greater than creatinine clearance. Renal clearance constituted approximately 76% of the oral clearance. Although stereoselective disposition of STL was absent after racemate administration, these results should not be extrapolated to patients with significantly altered physiology, or to the pharmacokinetics of S-STL after administration of pure-S-STL.

Adult↗
PubMed1991

Purification of parathyroid hypertensive factor from plasma of spontaneously hypertensive rats.

Parathyroid hypertensive factor (PHF) is a newly described hypertensive factor that may be related to elevation of blood pressure in 30-40% of North American essential hypertensive patients. PHF is also found in several animal models of hypertension, including spontaneously hypertensive rats, and deoxycorticosterone acetate salt hypertensive rats. Plasma collected from spontaneously hypertensive rats (SHR) was used in the present study for purification of PHF. Plasma was dialyzed at a molecular mass cutoff of 1 kDa, and then ultrafiltered at a molecular mass cutoff of 5 kDa. PHF activity, as determined by bioassay (characteristic delayed hypertensive response in normotensive rat) was retained in the fraction that was greater than 1 kDa and less than 5 kDa. Dialyzed and ultrafiltered SHR plasma was fractionated by molecular-exclusion chromatography, either with Bio-Gel P-6 liquid chromatography, or TSK 2000 SW HPLC. The biological activity was detected in a discrete region corresponding to a molecular mass of 2.5-3 kDa. When the molecular-exclusion fraction was subsequently fractionated by reverse-phase HPLC, biological activity was located in a single discrete peak, which did not occur in plasma from normotensive rats prepared in a similar manner. The biologically active fraction of PHF was inactivated by trypsin; this and its UV spectrum indicate the presence of a peptide structure.

Animals↗
PubMed1991

Parathyroid hypertensive factor is present in DOCA-salt but not two-kidney-one-clip hypertensive rats.

In order to determine whether the expression of parathyroid hypertensive factor (PHF) is secondary to hypertension or whether it is specifically related to low-renin hypertension, PHF levels were measured in DOCA-salt and two-kidney-one-clip (2K-1C) hypertensive rats. Despite equivalent elevations of blood pressure, PHF was detected in the DOCA-salt rats, but not in the 2K-1C rats (17.5 +/- 3.1 mm Hg, P less than .0001 v 0.9 +/- 2.8 mm Hg, P = NS, respectively). Moreover, PHF levels correlated with mean arterial pressure in the DOCA-salt group (r = 0.91, P less than .0001). We conclude that PHF expression is not a secondary phenomenon caused by hypertension, but rather may be causally related to the development of low-renin forms of hypertension.

Animals↗
PubMed1991

Parathyroid hypertensive factor, a circulating factor in animal and human hypertension.

A new circulating hypertensive factor (parathyroid hypertensive factor; PHF) was shown to exist in the plasma of spontaneously hypertensive rats (SHR) but not in that of normotensive rats. PHF produced a delayed increase in blood pressure with a peak response at 45 min (bolus injection) or 60 to 90 min (continuous infusion). This increase in blood pressure was coupled with an in vitro increase in calcium uptake in rat tail artery with a similar time course. The involvement of calcium in the mechanism of action was supported by the inhibitory effect of calcium antagonists on the vascular action of PHF. Furthermore, PHF increased the intracellular free calcium concentration in cultured smooth muscle cells from rat tail artery. Parathyroidectomy and parathyroid transplant experiments indicated the parathyroid origin of PHF. A culture of parathyroid glands from SHR, but not from normotensive rats, produced in the medium a factor which has the same biological property and HPLC retention time as plasma PHF. A novel cell type was described in the parathyroid gland of SHR, but not normotensive rats, and the percent of these cells correlated significantly with plasma PHF level and blood pressure. In some hyperparathyroid patients, plasma PHF and hypertension were found, both of which disappeared after surgical removal of the parathyroid gland. In both animal models and human studies, PHF seems to be associated with low or normal plasma renin and salt-sensitive type of hypertension.

Animals↗
PubMed1991

Intracellular ions in salt-sensitive essential hypertension: possible role of calcium-regulating hormones.

To study the blood pressure, ionic, and hormonal responses to chronic dietary salt loading, we measured RBC pHi, Mgi, Nai, and Cai, and compared these with serum levels of Ca-io, 1,25-D, and free levels of PHF in salt-sensitive and salt-insensitive essential hypertension subjects on low and high (200 mEq/day less than UNaV less than 50 mEq/day) dietary salt intakes. As a group, salt loading significantly increased diastolic blood pressure (7.6 +/- /3%), Nai (25.5 +/- /8%) and Cai (27.0 +/- /11%), while Mgi (-14.2 +/- 7%) and pHi (-0.03 +/- /0.01 pH units) fell. Significant changes in pHi, Cai, and Mgi occurred only in SS individuals, who also exhibited elevated levels of 1,25-D and of PHF in association with suppression of Ca-io. Altogether, the pressor response to salt was inversely related to the basal pHi (p less than 0.001), and to the degree of salt-induced suppression of Ca-io (p less than 0.001) and Mgi (p less than 0.001), while being directly related to the basal PHF (p less than 0.001) and to the salt-induced stimulation of 1,25-D (p less than 0.005). We hypothesize that elevated levels of 1,25-D and PHF coordinately shift intracellular cation levels and stimulate cellular calcium uptake from the extracellular space. As such, these calcium-regulating hormones may be responsible, at least in part, for salt-sensitive hypertension.

Biological Factors↗
PubMed1990

Parathyroid origin of a new hypertensive factor.

Many physiological abnormalities have been described in essential hypertension, yet the cause of this condition remains unknown. Included among the reported abnormalities are alterations in serum and tissue calcium levels, abnormalities in calcium regulating hormones, and the involvement of the parathyroid gland in some forms of hypertension. In the current study, the authors review evidence suggesting that a newly described hypertensive factor may explain a number of these abnormalities. This factor was first described in spontaneously hypertensive rat (SHR) plasma and is characterized by its ability to raise blood pressure in a delayed manner in normotensive rats, as well as by its ability to increase calcium uptake in vascular smooth muscle. The factor seems to be produced by the parathyroid gland, yet it is distinct from parathyroid hormone. Histological studies suggest that the factor may be produced by a specific cell type in the parathyroid glands. Given the parathyroid gland dependency of this factor, the authors have tentatively named it "parathyroid hypertensive factor," or "PHF."

Animals↗
PubMed1990

The effects of dietary calcium on blood pressure in spontaneously hypertensive rats may be mediated by parathyroid hypertensive factor.

A high calcium intake has been shown to attenuate the degree of hypertension in spontaneously hypertensive rats (SHR) and some human hypertensives. Conversely, a low calcium intake has been associated with an increase in blood pressure in both groups. In the present study, the effects of a high (2%), medium (0.6%) and low (0.02%) calcium diet on mean arterial pressure (MAP) and on the expression of a novel circulating hypertensive factor--parathyroid hypertensive factor (PHF)--were examined in SHR. In rats on the low calcium diet, MAP and PHF activity were significantly higher at 8 weeks than in the other two groups. In the high calcium group, MAP was significantly lower than in the other two groups, although it was elevated compared to week 0 values. PHF activity was not detected in the plasma of this high calcium group. Overall, MAP was highly correlated with PHF activity (r = 0.78, P = .0001). These results suggest that the effects of dietary calcium on blood pressure in SHR may be mediated by a novel circulating hypertensive factor, PHF, such that a high calcium diet inhibits, and a low calcium diet stimulates, the expression of this factor.

Animals↗
PubMed1990

Vascular and calcemic effects of plasma of spontaneously hypertensive rats.

Circulating substances that increase intracellular calcium, and other circulating substances that increase blood pressure, have been described in hypertensive animals and humans. In this study, we report the existence of a factor of the plasma of spontaneously hypertensive rats that does both. These effects were dose-dependent, and the time course for such effects was correlated with the time course for potentiation of pressor agents by the plasma. In addition, the plasma of spontaneously hypertensive rats was found to inhibit the depressor effects of parathyroid hormone. Our results confirm the presence of a circulating hypertensive factor in the plasma of spontaneously hypertensive rats, which may act by increasing calcium uptake in vascular smooth muscle. These findings may also help explain the secondary increase in parathyroid hormone noted in some forms of human and experimental hypertension.

Animals↗
PubMed1990

A new circulating hypertensive factor in the plasma of essential hypertensive subjects.

The pressor responses to dialyzed plasma extracts from normotensive (n = 15) and essential hypertensive (n = 14) human subjects were evaluated in anesthetized Sprague-Dawley rats. Hypertensive but not normotensive plasma raised mean arterial pressure (23.6 +/- 3.6 versus -0.5 +/- 2.5 mmHg, P less than 0.0001), and this effect was correlated significantly with its ability to stimulate 45Ca uptake in rat tail artery vascular smooth muscle (r = 0.883, P less than 0.002). These data suggest a humoral contribution to the pathophysiology of essential hypertension in at least some individuals. The time-course and molecular weight distribution of the dialyzed plasma suggest that this effect is not due to known vasopressor substances, but to a factor we tentatively term plasma hypertensive factor.

Animals↗
PubMed1990

Parathyroid hypertensive factor.

A new circulating hypertensive factor, parathyroid hypertensive factor (PHF), has been demonstrated in the plasma of spontaneously hypertensive rats (SHR) but not in that of normotensive rats. PHF produced a delayed increase in blood pressure with a peak response after 45 min (bolus injection) or 60-90 min (continuous infusion). This increase in blood pressure was coupled with an in vitro increase in calcium uptake in the rat tail artery which had a similar time-course. The evidence that calcium is involved in the mechanism of action is supported by the inhibitory effect of calcium antagonists on the vascular action of PHF. Furthermore, PHF increased the intracellular free calcium concentration in cultured smooth muscle cells from the rat tail artery. Parathyroidectomy and parathyroid transplant experiments indicated that PHF originated in the parathyroid gland. Cultured parathyroid glands from SHR but not from normotensive rats produced a factor in the medium with the same biological property and retention time on high performance liquid chromatography as plasma PHF. A novel cell type was described in the parathyroid gland of SHR, but not normotensive rats, and the percentage of these cells was correlated significantly with the plasma PHF level and the blood pressure level. In some hyperparathyroid patients, plasma PHF and hypertension were both present, and both disappeared after surgical removal of the parathyroid gland. In both animal models and human studies, PHF seems to be associated with low or normal levels of plasma renin and the salt-sensitive type of hypertension.

Animals↗
PubMed1989

Parathyroid origin of a new circulating hypertensive factor in spontaneously hypertensive rats.

The parathyroid gland has been causally associated with some forms of hypertension, yet parathyroid hormone (PTH) has been shown to possess hypotensive properties. Recently, we described the presence of a circulating hypertensive factor in spontaneously hypertensive rat (SHR) plasma, the expression of which is associated with a novel cell type in the parathyroid gland. In order to determine whether this hypertensive factor might be produced by the parathyroid gland, the effects of parathyroidectomy and parathyroid transplantation on mean arterial pressure (MAP) and hypertensive factor activity were studied. Parathyroidectomy, but not sham operation, decreased MAP in SHR and resulted in the disappearance of the hypertensive factor from the plasma. Transplantation of SHR parathyroid glands into Sprague-Dawley (SD) rats resulted in an increase in MAP and the appearance of the factor in the plasma, whereas transplantation of SD parathyroid glands into SHR had exactly the opposite effect. SD to SD transplantation had no effect on MAP or hypertensive factor activity. Infusions of PTH gave opposite effects to hypertensive factor infusions. These results suggest that the hypertensive factor is parathyroid gland-dependent but is not PTH. On this basis, we have proposed that the factor be referred to as "Parathyroid Hypertensive Factor," or "PHF."

Animals↗
PubMed1989

A novel cell type in the parathyroid glands of spontaneously hypertensive rats.

Recently, we described a circulating hypertensive factor, present in the plasma of spontaneously hypertensive rats (SHR). This factor seems to be produced by the parathyroid gland but is not identical to parathyroid hormone (PTH). In view of these findings, we attempted to search for histological differences in parathyroid glands between SHR and normotensive Wistar-Kyoto (WKY) rats by light and electron microscopy. Novel cells, distinct from normal chief cells, were frequently found in parathyroid glands of SHR rats, whereas they were scarcely observed in WKY rats. Our findings suggest that the novel cells are involved in the development of hypertension in SHR rats.

Animals↗
PubMed1989

In vivo potentiation of vasopressors by spontaneously hypertensive rat plasma: correlation with blood pressure and calcium uptake.

Previous studies have shown that plasma from Spontaneously Hypertensive Rats (SHR) can potentiate the action of various vasopressors. Recently, we described a novel circulating hypertensive factor in the plasma of SHR rats which increases calcium uptake in vascular smooth muscle. In order to determine whether this factor might be responsible for the previously described pressor potentiation, the effect of dialyzed SHR plasma on the in vivo sensitivity of normotensive rats to norepinephrine, angiotensin II and arginine vasopressin was examined. Results of this study showed that SHR plasma potentiated the effects of all three pressor agents with peak potentiation occurring approximately 45-60 min post-plasma injection. The time course of pressor potentiation was similar to those for the hypertensive and cellular calcium effects of the plasma. These results suggest that a single factor may be responsible for the hypertensive, calcemic and pressor-potentiating effects of SHR plasma.

Angiotensin II↗
PubMed1989

Effects of spontaneously hypertensive rat plasma on blood pressure and tail artery calcium uptake in normotensive rats.

Previous studies have described the presence of humoral hypertensive factors in spontaneously hypertensive rats (SHR). Other studies have described factors that increase calcium uptake in vascular tissue. In this study, we attempted to confirm, and thereby correlate, the presence of both types of factors in SHR plasma. Intravenous infusion or bolus administration of dialyzed SHR plasma consistently induced an increase in blood pressure in normotensive rats. This hypertensive response was somewhat delayed, with peak blood pressures occurring 45 minutes after bolus administration and 90 minutes after infusion of SHR plasma. Spontaneously hypertensive rat plasma also increased 45Ca uptake in isolated normotensive rat tail arteries in a dose-dependent manner, with a time course similar to that for the hypertensive response to bolus administration. These findings suggest, therefore, that a substance exists in SHR plasma that can increase intracellular calcium in vascular tissues and thereby increase blood pressure.

Animals↗