Calcium antagonists and cancer: limitations of pros and cons.
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Aged↗
Biomedical subjects
P Hamet
Publications and source records attributed to P Hamet.
Na+/H+ exchange in vascular smooth muscle cells is controlled by GTP-binding proteins.
This study examines the involvement of GTP-binding proteins (Gps) in the regulation of Na+/H+ exchange and Ca2+ influx, which are increased in vascular smooth muscle cells from spontaneously hypertensive rats. Gp activity was modulated by fluoride, GTPgammaS, GDPbetaS, and antisense oligodeoxynucleotides complementary to conserved regions of the alpha- and beta-subunits of Gps (alpha-comm and beta-comm, respectively). Beta-adrenergic-induced Gs-mediated cAMP production was used as a positive control to estimate the efficiency of these compounds. Na+/H+ exchange, measured as ethylisopropyl amiloride-sensitive 22Na influx, was activated by 5- to 6-fold by a 30-minute preincubation of cells with 10 mmol/L NaF with a K0.5 for NaF of approximately 13 mmol/L. In contrast, no activation of 45Ca influx was observed under preincubation of vascular smooth muscle cells with NaF in Ca2+-free medium, whereas at [Ca2+]o >0.5 mmol/L, simultaneous addition of 45Ca and 10 mmol/L NaF led to sharply increased isotope uptake. NaF-induced 45Ca influx did not reach saturation up to 3 mmol/L [Ca2+]o and 20 mmol/L NaF and was correlated with the formation of calcium-fluoride complexes measured by light scattering. GTPgammaS increased basal cAMP production and Na+/H+ exchange, whereas GDPbetaS decreased isoproterenol-induced cAMP production and Na+/H+ exchange. Alpha-comm reduced whereas beta-comm augmented isoproterenol-induced cAMP production by 70%. Both oligodeoxynucleotides decreased basal Na+/H+ exchange by 40% to 50%. NaF-induced Na+/H+ exchange was not sensitive to alpha-comm but was inhibited by 60% in beta-comm-loaded cells. Neither basal nor NaF-induced 45Ca uptake was affected by GTPgammaS, GDPbetaS, and the oligodeoxynucleotides. Our results show that 45Ca uptake is activated by NaF in vascular smooth muscle cells by nonspecific accumulation of calcium-fluoride complexes and is not related to modification of Gps. On the contrary, the Na+/H+ exchanger is controlled by Gps, and Gp beta-subunits are involved in [Ca2+]o-independent activation of this carrier by NaF.
Aluminum Chloride↗
Adrenocortical overexpression of gastric inhibitory polypeptide receptor underlies food-dependent Cushing's syndrome.
Abnormal responsiveness of adrenocortical cells to gastric inhibitory polypeptide (GIP) in food-dependent Cushing's syndrome suggested that adrenal expression of ectopic, overexpressed, or mutated GIP receptor (GIPR) underlies this syndrome. The expression of GIPR was studied by RT-PCR in human adrenal tissues from two patients with GIP-dependent Cushing's syndrome (adenoma, bilateral hyperplasia), five fetal or adult controls, one patient with Cushing's disease, and four patients with non-food-dependent cortisol-secreting adenomas or bilateral hyperplasias and compared to that in normal pancreas. Hybridization of the RT-PCR-amplified ribonucleic acids with the human GIPR complementary DNA showed an overexpression of GIPR in the adrenals of the two GIP-dependent Cushing's syndrome patients compared to that in normal adrenal tissues (2-3 orders of magnitude) or pancreas (10-fold); no signal could be seen in adrenal adenomas or macronodular hyperplasia from cases of non-food-dependent Cushing's syndrome. No mutation of the GIPR was identified by sequencing the full-length receptor in GIP-dependent adrenal tissue. New alternative spliced isoforms of the GIPR were found, but are identical in GIP-dependent and normal adrenal tissues. Incubation of adrenal cells with GIP stimulates cortisol secretion in GIP-dependent, but not in normal fetal, adult, or non-food-dependent Cushing's syndrome, adrenals. We conclude that the GIPR overexpression and its coupling to steroidogenesis underlie GIP-dependent Cushing's syndrome.
Adrenal Cortex↗
Propranolol therapy for ectopic beta-adrenergic receptors in adrenal Cushing's syndrome.
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Adrenal Glands↗
Hypertension in pregnancy: new recommendations for management.
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Female↗
Awareness, treatment, and control of hypertension in Canada.
The Canadian Heart Health Surveys are cross-sectional, population-based cardiovascular disease risk factor surveys that took place in each of the 10 Canadian provinces between 1986 and 1992. Hypertension awareness, treatment, and control status are examined. Of 23,129 randomly selected, noninstitutionalized respondents aged 18 to 74 years, 85% had four blood pressure (BP) measurements taken under standardized conditions, two at home during a home interview and two at a following clinic visit. The mean of all available measurements was used to determine hypertension status. Estimates are weighted and represent population values. Only 2% of respondents had never had their BP checked, and 73% had had their BP checked in the last 12 months. A systolic or diastolic BP > or = 140/90 mm Hg was found in 22% of participants (26% of men, 18% of women), representing 4.1 million Canadians. Overall, 16% of participants were treated and controlled; 23% were treated and not controlled; 19% were not treated and not controlled; and 42% were unaware of their hypertension (47% of men and 35% of women). Among hypertensives 18 to 34 years old, 64% of men and 19% of women were unaware of their hypertension. Among treated and not controlled hypertensives 63% had a mean systolic BP > or = 150 mm Hg, and 29% a diastolic BP > or = 95 mm Hg, suggesting that an important number of Canadians treated for hypertension are still at increased risk. Despite frequent interactions with the health care system, too many Canadians are still not well controlled or are unaware of their hypertension.
Adolescent↗
A prospective comparison of four study designs used in assessing safety and effectiveness of drug therapy in hypertension management.
The objective of the study was to compare prospectively the impact of study design on drug therapy safety and effectiveness data obtained in hypertension management. The main study was a randomized controlled clinical trial of four different prospective study designs used in postmarketing assessment involving 1008 primary care practices in nine Canadian provinces. Two thousand nine hundred sixty-four patients with mild to moderate hypertension received an angiotensin converting enzyme (ACE) inhibitor daily for 14 weeks in one of four postmarketing studies--a randomized double-blind clinical trial (RCT) (10 to 40 mg fosinopril daily v 5 to 20 mg enalapril daily), two structured open label trials of 10 to 40 mg fosinopril daily (one with free drugs), or an unstructured open label trial of 10 to 40 mg fosinopril daily. Patient demographic and baseline characteristics, systolic and diastolic blood pressures, adverse events reported, and data quality were recorded as the outcome measures. The results showed that the RCT patients were titrated to higher doses of ACE inhibitor than patients in the open studies, P < .008; patients in the open studies were more likely to receive adjuvant diuretic therapy, P < .008. The decrease in blood pressure was similar for patients in all four studies, mean decrease in systolic BP was between 18 and 20 mm Hg, mean decrease in diastolic BP was between 11 and 13 mm Hg. Fewer patients in the unstructured open trial reported adverse events than patients in the RCT; a 55% relative reduction in reported adverse events (P < .008) was associated with the unstructured trial. There were also fewer drug-related adverse events per patient reported in the unstructured study (17 per 100 patients) than in the other studies (27 to 41 per 100 patients), P < .008. Physician preference for rounding off blood pressure measurements to 0 or 5 occurred most often in the unstructured open trial (P < .008). In conclusion, despite differences in dose titration and in the use of adjuvant therapy, antihypertensive drug therapy effectiveness observed in an RCT may be similar to uncontrolled postmarketing studies. Open trials with scheduled follow-up visits are as effective in detecting severe adverse events as RCT, but postmarketing studies with unstructured schedules of follow-up are insufficient in identifying drug-related adverse events and have poorer quality data.
Antihypertensive Agents↗
Cancer and hypertension: a potential for crosstalk?
Epidemiological evidence, particularly from prospective studies, points to the possibility that there is a weak but significantly increased risk of cancer in hypertension. Many classes of drugs have been accused of increasing the risk of cancer yet these studies were case-controlled and did not withstand prospective randomized evaluation. As our understanding of cellular biology and our capacity to dissect genetic components of complex diseases progress, we realize that many pathophysiological pathways are actually quite similar in distinct disorders such as cancer and hypertension. A question can therefore be asked: are the increased risks of cancer and hypertension not related to fundamentally shared pathways, since both disorders reflect proliferative abnormalities? We propose a search for such shared pathways.
Animals↗
Smooth muscle apoptosis during vascular regression in spontaneously hypertensive rats.
We previously reported that apoptosis is increased in smooth muscle cells cultured from the aorta of spontaneously hypertensive rats versus normotensive controls. As an initial in vivo exploration, we now examined smooth muscle cell apoptosis regulation during the regression of vascular hypertrophy in the thoracic aorta media of spontaneously hypertensive rats receiving the antihypertensive drug enalapril (30 mg.kg-1.d-1), losartan (30 mg.kg-1.d-1), nifedipine (35 mg.kg-1.d-1), hydralazine (40 mg.kg-1.d-1), propranolol (50 mg.kg-1.d-1), or hydrochlorothiazide (75 mg.kg-1.d-1) for 1 to 4 weeks starting at 10 to 11 weeks of age. Three criteria were used to evaluate smooth muscle cell apoptosis: (1) oligonucleosomal fragmentation of the extracted aortic DNA, (2) reduction in aortic DNA content, and (3) depletion of smooth muscle cells in the arterial media. Arterial DNA synthesis was evaluated by [3H]thymidine incorporation in vivo. After 4 weeks of treatment, systolic blood pressure was reduced significantly by > 42% with losartan, enalapril, and hydralazine, and by 23% with nifedipine, versus control values of 220 +/- 5 mm Hg. However these agents affected vascular growth and apoptosis differently. Losartan, enalapril, and nifedipine stimulated smooth muscle cell apoptosis threefold to fivefold before there was a significant reduction in DNA synthesis (> 25%), vascular mass (> 19%), or vascular DNA content (> 38%), and these treatments markedly reduced (by 38% to 50%) medial cell number as measured at 4 weeks by the three-dimensional disector method. Losartan and nifedipine stimulated smooth muscle cell apoptosis before reducing blood pressure. In contrast, hydralazine did not affect vascular mass, apoptosis, or DNA synthesis, although blood pressure was lowered. Propranolol or hydrochlorothiazide failed to affect hypertension or vascular growth. Thus, smooth muscle cell apoptosis represents a novel therapeutic target for the control of hypertensive vessel remodeling in response to therapeutic agents.
Animals↗
Altered balance between cell replication and apoptosis in hearts and kidneys of newborn SHR.
Apoptosis is involved in neonatal remodeling of organs of the cardiovascular system. Since we previously reported hyperplasia of these organs at birth in several forms of genetic hypertension, the aim of this study was to determine whether alterations of the apoptotic process could explain our findings. The heart, aorta, and kidneys of newborn Wistar-Kyoto and spontaneously hypertensive rats were harvested 24 hours after an injection of [3H]thymidine. DNA was extracted to measure its specific activity (index of DNA synthesis) and DNA fragmentation as an estimation of apoptosis. All organs studied showed an increased weight to body weight ratio in spontaneously hypertensive rats. Twenty-four hours after birth, DNA synthesis in all organs of spontaneously hypertensive rats was comparable to that in normotensive rats. However, apoptosis was markedly decreased in the heart and kidneys of newborn spontaneously hypertensive rats compared with their normotensive controls. In the aorta, apoptosis was reduced, but not significantly. Calculation of a proliferation index (DNA synthesis/fragmentation) revealed a significant increase of heart proliferation, with a similar trend in the aorta and kidneys. In addition, we found a negative correlation between heart weight and DNA fragmentation. Although other factors may influence hyperplasia of the aorta, we propose that a reduction of apoptotic activity is responsible, at least in part, for heart and kidney hyperplasia in newborn spontaneously hypertensive rats.
Animals↗
Abnormal adrenal and vascular responses to vasopressin mediated by a V1-vasopressin receptor in a patient with adrenocorticotropin-independent macronodular adrenal hyperplasia, Cushing's syndrome, and orthostatic hypotension.
The elucidation of gastric inhibitory polypeptide-dependent Cushing's syndrome suggested that ectopic expression or increased responsiveness of other adrenal hormone receptors may underlie ACTH-independent macronodular adrenal hyperplasia (AIMAH) or adrenocortical tumors. We studied a 36-yr-old woman with Cushing's syndrome, AIMAH, and orthostatic hypotension. During upright posture, cortisol and aldosterone were stimulated despite suppression of ACTH and renin. Arginine vasopressin (AVP, 10 U im), under dexamethasone suppression, increased plasma cortisol (3.4-fold), aldosterone (67-fold), and androgens in this patient but not in controls. ACTH 1-24, but not desmopressin acetate, angiotensin II, isoproterenol, or other hormones stimulated steroidogenesis in vivo. Plasma AVP was undetectable initially and increased suboptimally during posture tests after bilateral adrenalectomy. AVP stimulated cortisol production more in dispersed cells from the AIMAH than from a normal adult adrenal (424 vs. 135% at 10 nmol/L). Adrenal V1-AVP receptor presence and mediation of response were shown by RT-PCR and by binding and [Ca+2]i studies. Post adrenalectomy, orthostatic hypotension persisted; a prolonged vasoconstrictive response to AVP was found in vitro in the patient's sc small arteries. We propose that altered adrenal and vascular responses of the V1-AVP receptor-effector pathway underlie this new syndrome.
Adrenal Glands↗
Apoptosis in pressure overload-induced heart hypertrophy in the rat.
Pressure overload induces cardiac growth in the rat, which implies the hypertrophy of cardiac muscle cells and proliferation of nonmuscle cells. The cardiac cell loss observed in parallel has generally been attributed to necrosis. Using an in situ assay, we demonstrated a phase of apoptosis or programmed cell death during the first 7 d after pressure overload with a peak at day 4 while cardiac growth continued for over 30 d. The increase in apoptosis was confirmed by quantification of 180-1500-bp DNA oligonucleosomes with agarose gel electrophoresis and in situ labeling via 3'-terminal deoxynucleotidyl transferase assay. While some apoptosis was observed in the basal state in nonmuscle cells, pressure overload induced apoptosis mainly in cardiomyocytes. These data suggest that cardiac hypertrophy is initiated by a wave of apoptosis of cardiomyocytes. Thus, apoptosis may be involved in the pathogenesis of heart remodeling.
Adaptation, Physiological↗
Apoptosis in vascular smooth muscle cells: role of cell shrinkage.
Cell volume decrease is known to be one of the earliest steps of apoptosis in immune system cells. In this study, we compared the kinetics of apoptosis and cell volume adjustment in cultured vascular smooth muscle cells (VSMC) from the aorta of normotensive Brown-Norway (BN.1x) as well as spontaneously hypertensive (SHR) rats and in Mardin-Darby canine kidney (MDCK) cells. The transfer of VSMC to serum-deprived medium led to a transient cell volume decrease and to increased apoptosis. Both the cell volume decrease and apoptosis displayed faster kinetics in SHR than in BN.1x VSMC. Increased tonicity of serum-deprived medium by the addition of 200 mM mannitol augmented apoptosis in VSMC by 2.5- to 3-fold. In contrast to VSMC, neither apoptosis nor the cell volume of MDCK cells was affected by serum deprivation. Apoptosis in MDCK cells was also insensitive to tonicity of serum-deprived medium. There results demonstrate an initial volume decrease in VSMC undergoing apoptosis and suggest that this phenomenon is involved in triggering the apoptotic process.
Animals↗
Bumetanide-sensitive ion fluxes in vascular smooth muscle cells: lack of functional Na+, K+, 2 Cl- cotransport.
To examine the involvement of Na+,K+,2Cl- cotransport in monovalent ion fluxes in vascular smooth muscle cells (VSMC), we compared the effect of bumetanide on 86Rb, 36Cl and 22Na uptake by quiescent cultures of VSMC from rat aorta. Under basal conditions, the values of bumetanide-sensitive (BS) inward and outward 86Rb fluxes were not different. Bumetanide decreased basal 86Rb uptake by 70-75% with a Ki of approximately 0.2-0.3 microM. At concentrations ranging up to 1 microM, bumetanide did not affect 36Cl influx and reduced it by 20-30% in the range from 3 to 100 microM. In contrast to 86Rb and 36Cl influx, bumetanide did not inhibit 22Na uptake by VSMC. BS 86Rb uptake was completely abolished in Na(+)- or Cl(-)-free media. In contrast to 86Rb, basal BS 36Cl influx was not affected by Nao+ and Ko+. Hyperosmotic and isosmotic shrinkage of VSMC increased 86Rb and 36Cl influx to the same extent. Shrinkage-induced increments of 86Rb and 36Cl uptake were completely abolished by bumetanide with a Ki or approximately 0.3 microM. Shrinkage did not induce BS 86Rb and 36Cl influx in (Na+ or Cl-)- and (Na+ or K+)-depleted media, respectively. In the presence of an inhibitor of Na+/H+ exchange (EIPA), neither hyperosmotic nor isosmotic shrinkage activated 22Na influx. Bumetanide (1 microM) did not modify basal VSMC volume and intracellular content of sodium, potassium and chloride but abolished the regulatory volume increase in isosmotically-shrunken VSMC. These data demonstrate the absence of the functional Na+,K+,2Cl- cotransporter in VSMC and suggest that in these cells basal and shrinkage-induced BS K+ influx is mediated by (Nao+ + Clo-)-dependent K+/K+ exchange and Nao(+)-dependent K+,Cl- cotransport, respectively.
Animals↗
Antihypertensive therapy debate: contribution from the Shanghai Trial Of Nifedipine in the Elderly (STONE).
BACKGROUND: In 1993, a number of influential bodies reported the results of consensus conferences on the management of hypertension, including the World Health Organization/International Society of Hypertension, the fifth United States Joint National Committee (JNC-V), the British Hypertension Society, the Canadian Hypertension Society (CHS) and the New Zealand National Advisory Committee. Most of these guidelines were in general agreement. The most significant difference was in the choice of first-line agents, whether to use only beta-blockers or thiazides (JNC-V/CHS) or to use any of the five major classes of antihypertensive agents. EVIDENCE FROM THE SHANGHAL TRIAL OF NIFEDIPINE IN THE ELDERLY (STONE): At present, this is the only placebo-controlled trial on newer classes of medications for which results are available. The trial has both strengths and weaknesses. Among the strengths of this trial is the comparability of the subjects in both arms and the robustness of the results. STONE does at least suggest that outcomes with newer agents like long-acting nifedipine are comparable to outcomes in major clinical trials in the elderly using diuretics and beta-blockers.
Age Factors↗
Chinese contribution to trials on antihypertensive therapy.
LACK OF TRIAL DATA ON NEW ANTIHYPERTENSIVE AGENTS: The present debate concerning the use of new classes of antihypertensive agents in general and calcium antagonists in particular, is due to the fact that for most of the agents, there is a lack of data from major clinical trials with cardiovascular outcomes. CONTRIBUTION OF CHINESE CLINICAL TRIAL DATA: The present review summarizes and qualifies the prospective clinical trial data obtained in China which were performed with calcium antagonists and indapamide. These results need to be reviewed critically for their weaknesses as well as strengths, so that the data can be used to improve present knowledge of antihypertensive therapy.
Antihypertensive Agents↗
Shanghai trial of nifedipine in the elderly (STONE).
OBJECTIVE: To assess the effectiveness of nifedipine treatment in elderly hypertensives. METHODS: A single-blind trial was conducted under the direction of the Shanghai Institute of Hypertension in 1632 subjects aged 60-79 years alternatively allocated to either nifedipine or placebo after a 4-week placebo run-in period between 1987 and 1990 with mean follow-up of 30 months. Clinical events and risk modification were analysed in collaboration with the University of Montreal. Seventy-four patients with severe hypertension were reallocated to active nifedipine treatment after placebo run-in. RESULTS: Cox's proportional hazards model accounting for covariates demonstrated a highly significant decrease in the probability of events: 'original treatment assignment' analysis indicated that 77 events occurred in the placebo and 32 in the nifedipine group. Similar significances were achieved with 'actual treatment' or 'changes excluded' (excluding reallocated subjects) analyses. A significant reduction in relative risk was observed for strokes and severe arrhythmia with an overall decrease from 1.0 to 0.41 (95% confidence interval 0.27-0.61). CONCLUSION: Nifedipine treatment diminished the number of severe clinical outcomes in elderly hypertensives significantly.
Aged↗