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R Z Lewanczuk

Publications and source records attributed to R Z Lewanczuk.

At least 19 recordsLinked to original sources
PubMed1997

Contemporary practice patterns in the management of newly diagnosed hypertension.

OBJECTIVE: To determine what proportion of patients with hypertension are managed in accordance with guidelines established by the Canadian Hypertension Society. DESIGN: Retrospective medical record review. SETTING: Outpatients seen in primary care offices and internal medicine referral clinics in Edmonton. PATIENTS: All 969 adults who presented with a new diagnosis of essential hypertension from Sept. 1, 1993, to Dec. 31, 1995. OUTCOME MEASURES: Initial laboratory tests performed, advice concerning nonpharmacologic treatment given, antihypertensive drugs prescribed and any contraindications to thiazide diuretics or beta-adrenergic blocking agents documented. RESULTS: The mean age of the 969 patients in the sample was 52.5 years; 129 (13%) of the patients were older than 70 years of age; and 500 (52%) were women. Most of the patients (704, 73%) had mild or moderate diastolic hypertension. In the 617 patients who underwent laboratory tests related to hypertension, the creatinine level was determined in 466 (76%), the cholesterol level in 372 (60%), a urinalysis was conducted in 378 (61%), the serum potassium level was checked in 343 (56%), the sodium level in 323 (52%) and an electrocardiogram was performed in 303 (49%). Liver function tests, which are not recommended in the guidelines, were performed in 338 patients (55%). Although there were differences in prescribing among physicians in the 711 patients given first-line therapy, most (238, 34%) were prescribed angiotensin-converting-enzyme (ACE) inhibitors. Lifestyle modification, without drug therapy, was suggested for 180 (25%) of the patients. Although the guidelines recommend their use for first-line drug therapy, only 82 patients (12%) were given beta-adrenergic blocking agents and only 75 (11%) were given thiazide diuretics. Of the patients who were prescribed an antihypertensive other than a thiazide or beta-adrenergic blocking agent as first-line drug therapy, only 161 (43%) had a documented contraindication to thiazides or beta-adrenergic blocking agents. CONCLUSIONS: There is variation in the contemporary care of patients with hypertension. Further studies are required to determine the reasons underlying physicians' noncompliance with the evidence-based guidelines established by the Canadian Hypertension Society.

Adult↗
PubMed1996

Parathyroid hypertensive factor predicts efficacy in the treatment of essential hypertension with verapamil.

Parathyroid hypertensive factor (PHF) is a circulating hypertensive factor, levels of which are inversely related to renin profile. Given this relationship, it was hypothesized that a PHF level might serve as an alternate predictor of antihypertensive efficacy in hypertensive patients, avoiding the difficulties associated with renin profiling. To test this hypothesis, thirty patients with essential hypertension were placed on 240 mg once daily of a slow release verapamil preparation for a period of one month following a one month run-in period. Results showed an average reduction in mean arterial pressure (MAP)of -7 mmHg (range -5 to - 18) and an average reduction in PHF of -4 mmHg (range 7 to -28). Pre-treatment PHF level correlated with the blood pressure response to verapamil (r = -0.61, p = 0.0004). There was no correlation between any index of renin status and blood pressure. The only other correlation of note was between normalized, ionized calcium and change in blood pressure (r = -0.46, p =0.02). In a forward stepwise multivariate model with MAP as the dependent variable, PHF and normalized, ionized calcium levels were the only biochemical or demographic predictors of response to verapamil. These results suggest that PHF level may be useful in determining the initial choice of antihypertensive agent in hypertensive patients.

Adult↗
PubMed1996

Resistant hypertension: an overview.

OBJECTIVE: To review the factors contributing to treatment resistance in hypertensive patients and assess the evidence from therapeutic trials in these patients. DESIGN: A MEDLINE search using the words 'resistant hypertension', 'refractory hypertension' and 'treatment resistance, hypertension' was carried out to identify relevant articles. The bibliographies of articles were used to screen for other relevant articles. All available English-language articles on the epidemiology, prognosis and management of hypertension resistant to standard treatment were reviewed. RESULTS: Resistant hypertension is an important public health problem and a common reason for referral of patients to specialized hypertension clinics. Patients with uncontrolled hypertension are at increased risk of stroke, myocardial infarction, congestive heart failure and renal failure. Many factors may play a role in the development of resistant hypertension, including misdiagnosis (pseudoresistance), noncompliance, occult secondary causes for hypertension, volume overload, obesity, cigarette smoking, excess alcohol intake, sleep apnea, interfering medications and suboptimal combinations of antihypertensives. Only beta-blockers and thiazide diuretics have been demonstrated to reduce cardiovascular morbidity and mortality in hypertension. The trials evaluating third-line agents in patients with resistant hypertension have demonstrated additional blood pressure lowering with all classes of agents, and the randomized controlled trials have not demonstrated any statistically significant differences between the agents in either efficacy or tolerability. CONCLUSIONS: Evaluation of the patient with resistant hypertension should include 24 h ambulatory blood pressure monitoring and an extensive search for hypertensive end organ damage. Contributing factors should be sought and stepped care should still form the basis for treatment decisions. The choice of third-line agent should be dictated by the patient's renin profile, current medication and any concomitant diseases.

Adrenergic beta-Antagonists↗
PubMed1995

Protein binding of sotalol enantiomers in young and elderly human and rat serum using ultrafiltration.

The protein binding of sotalol (STL) enantiomers was evaluated using an ultrafiltration technique with serum from young (32 +/- 2 years, n = 5) and elderly (73 +/- 6 years, n = 5) male and female humans, and young (8 weeks, n = 4) and elderly (60 weeks, n = 3) male Sprague-Dawley rats. Serum samples were collected and immediately frozen at -20 degrees C. Within 1 week, the serum samples were thawed at room temperature, and adjusted to pH 7.4 using 0.05 M phosphate buffer, pH 5.0. Aliquots were spiked with 250 ng mL-1 and 500 ng mL-1 of each STL enantiomer, placed in ultrafiltration sets (Microsep, 30K molecular weight cut-off), capped, equilibrated to 37 degrees C, and centrifuged at 1850g for 1.5 h at 37 degrees C. Aliquots of ultrafiltrate and unspun serum were analysed for STL enantiomer concentration using a stereospecific HPLC assay. In all groups, bound fraction was less than 7% for both STL enantiomers. There were no significant differences in bound fraction between groups, or between enantiomers. Adsorption of STL enantiomers to the ultrafiltration device and membrane, evaporative loss of serum samples during centrifugation, and protein concentration in each ultrafiltrate sample were all negligible. It is concluded that the binding of STL in human and rat serum at therapeutic concentrations and physiological temperature and pH is negligible and non-stereoselective.

Adrenergic beta-Antagonists↗
PubMed1995

Pharmacokinetics of verapamil and norverapamil enantiomers after administration of immediate and controlled-release formulations to humans:evidence suggesting input-rate determined stereoselectivity.

Verapamil is a racemic calcium channel-blocking drug that undergoes extensive hepatic first-pass metabolism to an active metabolite, norverapamil. The enantiomers of verapamil and norverapamil have differing negative inotropic, chronotropic, and dromotropic activities and differing effects on vascular smooth muscles; the S-enantiomers having greater activity. It is hypothesized that the R/S concentration ratio of verapamil enantiomers may be input-rate dependent. The pharmacokinetics of verapamil and norverapamil enantiomers were studied in 11 young, healthy male and female volunteers after oral administration of 80 mg immediate-release (IR) verapamil every 8 hours, and a 240 mg dose once daily of controlled-release (CR) formulation on two separate occasions. Both dosage regimens were continued for 1 week with a minimum 1-week period between the two drug treatments. After the last dose of each regimen, plasma samples were collected over the period corresponding to the dosing interval. Enantiomer concentrations were determined using a microwave-facilitated precolumn derivatization with high performance liquid chromatographic quantification. Stereospecific assay revealed that: (1) stereoselective R- and S-enantiomer disposition occurred regardless of formulation administered; (2) a trend of R:S concentration ratios of verapamil differed between the two formulations; and (3) fluctuations between Cmax and Cmin values of the two formulations were statistically different over respective dosing intervals (greater fluctuation after CR administration). Using nonstereospecific data analyses, however, the pharmacokinetic parameters for verapamil and norverapamil were similar for both formulations over a 24-hour period. We suggest that kinetic differences can be attributed to differences in release rates of drug from the tablet matrices. The relative bioavailabilities of verapamil and norverapamil from the two products may, therefore, be subject to input rate-dependent processes.

Adult↗
PubMed1994

PHF: the new parathyroid hypertensive factor.

Parathyroid Hypertensive Factor (PHF) was discovered in SHR rats as a circulating substance with a unique delayed (60-90 min) hypertensive effect when injected into a normotensive assay rat. Subsequently, this correlation with hypertension was established in humans, especially in low-renin, salt-sensitive patients. Animal model studies also confirmed this correlation. Endocrinectomy and glandular replacement studies suggested that the parathyroid gland was the source of PHF. Subsequently, glands and cells in culture were also shown to secrete the substance. Other studies verified the parathyroid origin of PHF. The mechanism of action of PHF was shown to rely mainly on the opening of L-type calcium channels in vascular smooth muscle cells with an increase in [Ca2++]i. It is known that diseases other than hypertension often show increased [Ca2++]i and clinical features similar to hypertension, among them Type II diabetes. A recent study shows a correlation between circulating PHF level and Type II diabetes irrespective of the blood pressure status of the patient. It is suggested that PHF may be a [Ca++]i modulator, an excessive amount of which in the circulation may act on various target tissues, resulting in various disease symptoms with hypertension as an example. There may be many other such PHF-related diseases yet to be identified.

Animals↗
PubMed1994

Mechanism of the vascular action of parathyroid hypertensive factor.

The present studies investigated the effect of parathyroid hypertensive factor (PHF) on intracellular calcium regulation in VSMC. Nifedipine inhibited the hypertensive effect of PHF in Sprague-Dawley (SD) rats in vivo. PHF amplified the L-type calcium current in vascular smooth-muscle cells (VSMCs) isolated from SD rat tail artery. PHF potentiated the tension induced by norepinephrine (NE) in the presence of normal added CaCl2 and inhibited the tension dependent on Ca2+ release from intracellular calcium store(s) induced by NE in SD rat tail artery helical strips. PHF potentiated the intracellular free calcium concentration ([Ca2+]i) increment induced by KCl in cultured VSMCs from SD rat tail artery. All of the in vitro cellular calcium effects of PHF temporally correlated with its delayed hypertensive effect in vivo. PHF did not affect the accumulation of inositol phosphates in SD rat tail artery. Infusion of theophylline blunted the hypertensive effect of PHF in SD rats, suggesting that PHF may stimulate phosphodiesterase (PDE) activity. We suggest that PHF may potentiate the effects of other vasoconstrictors on calcium channels and increase [Ca2+]i, which would then lead to an increase in the responsiveness of the VSMC to other vasoconstrictors, and therefore an increase in blood pressure. The action of PHF may involve stimulation of PDE activity.

Animals↗
PubMed1994

Serum-mediated intracellular calcium changes in normotensive and hypertensive red blood cells: role of parathyroid hypertensive factor.

To study cellular calcium metabolism in hypertension, we investigated the effects of human serum, and of the circulating pressor substance, parathyroid hypertensive factor (PHF), on the cytosolic free calcium (Cai-f) content of erythrocytes from normotensive and essential hypertensive subjects. In their own serum, basal Cai-f was higher in hypertensive than in normotensive and essential hypertensive subjects. In their own serum, basal Cai-f was higher in hypertensive than in normotensive subjects (mean +/- SEM; 39.4 +/- 4.0 vs. 23.4 +/- 2.7 nM; p < 0.05). Without serum, Cai-f was lower and not significantly different (23.0 +/- 3.1 vs. 18.2 +/- 2.7 nM; p = not significant). Addition of serum to serum-free erythrocytes increased Cai-f, and reestablished the Cai-f gradient in hypertensive cells (31.4 +/- 0.8 vs 23.0 +/- 2.3 nM; p < 0.05). PHF levels were directly related to basal Cai-f (r = -0.648; p < 0.05) and to the serum-induced rise in Cai-f (r = 0.600; p < 0.05). Furthermore, semipurified PHF, but not similarly prepared normotensive serum, increased Cai-f in normal human erythrocytes (PHF: +83.9 +/- 37.3% vs. +14.5 +/- 27.5%; p < 0.05). We conclude that circulating factors in general, and PHF in particular, may account for the increased basal Cai-f of hypertension, and thus at least partially contribute to te pathophysiology of the hypertensive process.

Aged↗
PubMed1994

Clinical aspects of parathyroid hypertensive factor.

To determine the clinical significance of parathyroid hypertensive factor (PHF), physiological studies previously performed in animal models of hypertension were parallelled by human studies. These studies revealed that PHF-like activity is present in human hypertension, where it correlates with the salt-sensitive, low-renin state. As in spontaneously hypertensive rats, both supplemental calcium and calcium-channel blockers appear to be useful in the treatment of PHF-related hypertension. In primary hyperparathyroid patients, PHF presence is linked with the presence of hypertension. Postparathyroidectomy blood pressure falls in parallel with PHF levels. These preliminary human studies suggest that PHF may be a useful marker in the treatment of hypertension.

Animals↗
PubMed1994

Parathyroid hypertensive factor and non-insulin-dependent diabetes mellitus.

The recently discovered parathyroid hypertensive factor (PHF) has been shown to increase intracellular free calcium levels. High intracellular calcium can cause insulin resistance, as seen in non-insulin-dependent diabetes mellitus (NIDDM) patients. We therefore compared plasma PHF activity in NIDDM patients and nondiabetic control subjects using a rat bioassay. More NIDDM patients (65%) than non-diabetic controls (33.3%) had detectable PHF activity. When injected into rats, plasma of 185 NIDDM patients caused an average increase of 4.89 +/- 0.68 mm Hg in rat mean arterial pressure (MAP). This change was significantly greater than a slight drop of 0.42 +/- 0.96 mm Hg (mean +/- SE) for the 127 nondiabetic control subjects (Student's t test, p < 0.001). A higher percentage of the NIDDM patients than of the non-diabetic patients were hypertensive. However, a stratified analysis showed that diabetic patients consistently had significantly higher PHF levels than did nondiabetic patients, regardless of being hypertensive or not. PHF activity did not correlate with age, sex, body mass index, or the type of hypoglycemic agent taken. However, multivariate logistic regression analysis showed a positive correlation between cholesterol and PHF level among the diabetic patients (p = 0.03), but such a correlation did not exist among the non-diabetic controls. Our data indicate that elevated PHF may be responsible for insulin resistance in a fraction of NIDDM patients and suggest that PHF may be related to serum cholesterol levels in NIDDM.

Adult↗
PubMed1994

Effects of weight reduction on circulating parathyroid hypertensive factor levels.

This study evaluated changes in parathyroid hypertensive factor (PHF) in 18 obese individuals. PHF levels were measured prior to the onset of a low calorie diet (800 kcal/day), and at 3-4 weeks, 7-8 weeks, and 11-12 weeks after initiation of the diet. Blood pressure, forearm vascular resistance, and platelet intracellular calcium ([Ca2+]i) levels were also measured at the same time. Although blood pressure, vascular resistance, and platelet [Ca2+]i decreased significantly in association with the low-calorie diet and weight reduction, PHF levels did not change significantly during the 12-week diet period. We conclude that PHF levels do not track with reductions in blood pressure, vascular resistance, and platelet [Ca2+]i levels in obese individuals.

Animals↗
PubMed1994

Purification and structural characterization of parathyroid hypertensive factor.

Parathyroid hypertensive factor (PHF) has been purified from two sources of material: plasma of spontaneously hypertensive rats (SHRs) and culture medium from organ culture of SHR parathyroid glands. Chromatographic characteristics of PHF from these two sources are identical. Biological activity of PHF (assayed as the characteristic delayed hypertensive response in normotensive rats) is sensitive to degradation by treatment in base, and the enzymes trypsin, chymotrypsin, phospholipase C, and phospholipase D. PHF activity may also be extracted from source material with chloroform: methanol (4:1). A hypothetical structure for the active component of PHF is suggested. This is comprised of a peptide liked to a lysophospholipid.

Animals↗
PubMed1994

Clinical aspects of parathyroid hypertensive factor.

Parathyroid hypertensive factor (PHF) in rats: PHF is an endogenous hypertensive substance which was originally associated with hypertension in spontaneously hypertensive rats (SHR). In this model, PHF was shown to act by increasing intracellular calcium levels in vascular smooth muscle and was linked with a characteristic pattern of abnormalities in overall calcium regulation. The action of PHF was blocked by calcium antagonists, suggesting that the effect of PHF was to increase extracellular calcium uptake. In SHR the parathyroid glands were shown to be the site of PHF secretion. This secretion was inhibited by an increase in dietary calcium. PHF was further shown to be unique to low-renin forms of hypertension, that is, those forms of hypertension characterized by abnormalities in calcium metabolism. PHF in humans: PHF was subsequently found in human low-renin salt-sensitive hypertension. As in SHR, calcium supplementation can lower PHF levels in humans. Similarly, there is circumstantial evidence for the parathyroid origin of PHF in humans. In human hypertensive patients, the presence of PHF has been shown to predict a favorable therapeutic response to calcium channel blockade. Recently, many of the abnormalities in calcium metabolism present in low-renin hypertension have also been described in other disease states. Notable among these diseases is non-insulin dependent diabetes mellitus. A survey of human non-insulin dependent diabetes mellitus has revealed that PHF was present in a disproportionate number of these patients independently of the blood pressure level. The significance of this latter finding needs to be explored, but PHF may prove to have relevance in diseases other than hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

1,25-dihydroxyvitamin D as a cardiovascular hormone. Effects on calcium current and cytosolic free calcium in vascular smooth muscle cells.

Clinical and in vitro evidence suggests a role for the calcium regulating hormone, 1,25-dihydroxyvitamin D (1,25D) in human and experimental hypertension. To establish the cellular basis for this association, we utilized the whole-cell version of the patch clamp method and fluorescence spectroscopic techniques to measure voltage-dependent calcium channel activity and cytosolic free calcium concentrations ([Ca2+]i) in rat tail artery-derived smooth muscle cells, before and after the addition of 1,25D. 1,25D significantly increased the calcium channel current over the range of test pulses, from -40 to +60 mV, in a dose- and time-dependent manner, appearing by 5 to 10 min of exposure, with maximum effects by 15 min. At 10 and 30 nmol/L, the current increased to 149 +/- 10% and 221 +/- 13% of basal activity of 37.75 +/- 7.7 pA and 37.7 +/- 4.5 pA, respectively. Similarly, at 10 and 100 nmol/L, 1,25D increased cytosolic free calcium levels 115 +/- 2% and 171 +/- 11%, from basal values of 99 +/- 32 nmol/L and 116 +/- 10 nmol/L, respectively. These effects of [Ca2+]i developed slowly over 3 to 4 min. Peak values were achieved by 30 min of incubation and were reversible with removal of 1,25D from the medium. Altogether, these direct effects of 1,25D on calcium current and [Ca2+]i in vascular smooth muscle cells support a role for 1,25D in vascular physiology, and provide a cellular basis for better understanding the involvement of 1,25D in hypertensive vascular disease.

Animals↗
PubMed1993

Identification and purification of parathyroid hypertensive factor from organ culture of parathyroid glands from spontaneously hypertensive rats.

Parathyroid hypertensive factor (PHF) is a newly described hypertensive factor isolated from the plasma of spontaneously hypertensive rats (SHR). Recent studies have suggested that the primary origin of PHF is the parathyroid gland (PG). In the present investigation, PG from spontaneously hypertensive rats (SHR), as well as from normotensive rats, were isolated and maintained in culture. The PG from SHR, but not normotensive rats, released PHF into the culture medium. Omission of calcium from the culture medium stimulated the release of PHF. For purification of PHF, parathyroid gland culture medium (PGCM) was first dialyzed at 1000 mwco, and then ultrafiltered at 5000 molecular weight cut-off (mwco). PHF activity was retained in the fraction that was greater than 1000 daltons and less than 5000 daltons. Dialyzed and filtered SHR PGCM was fractionated by molecular exclusion HPLC. Biologically active PHF was collected in a discrete region. The biologically active molecular exclusion fraction was subsequently fractionated by reverse-phase HPLC (C-8). PHF was collected in a single discrete peak, which did not occur in culture medium prepared from normotensive PG in a similar manner. This biologically active peak occurred in the same position on molecular exclusion and reverse-phase HPLC as PHF purified from SHR plasma using similar procedures. Incubation of PGCM with trypsin inactivates the biological activity of PHF. The UV spectrum of PGCM PHF is identical to that obtained from purified plasma PHF. These results are consistent with the presence of a peptide moiety in PHF, and support the parathyroid origin of plasma PHF.

Animals↗
PubMed1993

The occurrence of parathyroid hypertensive factor (PHF) in Dahl rats.

Parathyroid hypertensive factor (PHF) is a newly described circulating hypertensive factor which is present in genetic hypertensive rat models, and which has been associated with salt sensitivity in essential hypertensive patients. To determine if Dahl-S or -R rats differentially express PHF-like activity, and whether such PHF levels might be affected by salt intake, we placed 5-week-old Dahl-S and Dahl-R rats on one of three diets: low salt (< 0.04%), normal salt (0.7%), or high salt (8%). After 8 weeks on the respective diets, mean arterial pressure was measured and plasma obtained for PHF analysis. Mean arterial pressures of Dahl-R rats were not different despite varying salt intakes. Mean arterial pressures of Dahl-S rats on normal and high salt diets, but not on the low salt diet, were significantly higher than those of Dahl-R rats on the same diet. PHF-like activity was not detectable in Dahl-R rats at any level of salt intake. In Dahl-S rats, no PHF activity was detectable in rats on the low salt diet, but in rats on the normal and high salt diets, significant PHF-like activity was detectable (9.5 +/- 2 mm Hg and 14.2 +/- 2 mm Hg, respectively, P < .001 in both cases). For all Dahl-S rats together, PHF levels correlated with mean arterial pressure (r = 0.50, P = .0077). These results show that Dahl-S rats are capable of expressing PHF-like activity, which is induced by increasing dietary salt intakes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗