Clinical relationships of cyclic GMP.
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Cyclic GMP↗
Biomedical subjects
P Hamet
Publications and source records attributed to P Hamet.
Renal effects of immersion in essential hypertension. Carvedilol Study Group.
Plasma concentrations of atrial natriuretic factor (ANF) have been reported to be unchanged or increased in patients with essential hypertension. Head out of water immersion (HOI) in a thermoneutral bath induces diuresis and natriuresis, an increase in plasma ANF, and reductions in plasma renin activity and aldosterone concentrations. HOI was used in this study to stimulate the secretion of ANF, and compare its release in patients with essential hypertension (EH) (n = 14) and normotensive subjects (n = 13). Renal function changes induced by HOI were also monitored. HOI that lasted 2 h was compared with a control-seated period in each subject. Blood pressure was significantly reduced (P < .05) in normotensive controls from 112 +/- 3/74 +/- 2 to 100 +/- 3/61 +/- 2 mm Hg, and in patients with EH from 137 +/- 4/93 +/- 3 to 123 +/- 3/78 +/- 2 mm Hg. Plasma levels of ANF increased significantly (P < .05) in both groups from 5.9 +/- 1.3 to 16.3 +/- 3 pmol/L in normotensive controls and from 6.0 +/- 0.9 to 13.2 +/- 2.5 pmol/L in patients with EH. Plasma cyclic guanosine monophosphate concentrations increased more (P < .05) in the patients with EH (3.9 +/- 0.4 to 6.1 +/- 0.5 nmol/L) than in controls (3.4 +/- 0.3 to 4.8 +/- 0.4 nmol/L), whereas plasma renin activity levels decreased in controls (2.29 +/- 0.58 to 1.63 +/- 0.55 ng/mL/h) and to a greater degree in patients with EH (1.62 +/- 0.52 to 0.77 +/- 0.19 ng/mL/h, P < .05) by HOI.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Genes of stress in experimental hypertension.
1. A significant portion of blood pressure variance is modified by the environment. 2. The present report summarizes evidence that: (i) the environmental response is genetically determined; (ii) various stressors can evoke a differential response in hypertensive animals and constitute its intermediate phenotypes; (iii) the response to heat stress can be assigned to a single 'thermosensitivity' locus; (iv) candidate genes of susceptibility to environmental stresses are member(s) of the heat stress gene (HSP) gene families; (v) a restriction fragment length polymorphism of hsp70 and a single base mutation in the 3'-untranslated region of hsp27 are associated with hypertension in recombinant inbred strains. 3. In conclusion, HSP gene variants may be causative in susceptibility to hypertension.
Animals↗
Biochemical characteristics of a calmodulin-phosphodiesterase activator increased in spontaneously hypertensive mice and rats.
The biochemical characteristics of calmodulin-phosphodiesterase (CaM-PDE) are described. It is a cytosolic, hydrophobic, and heat-, acid-, and base-stable compound sensitive to proteases. It is optimally extracted from neutral supernatants by CHCl3/MeOH (2:1 or 1:1). It partitions into the organic fraction of CHCl3/MeOH extracts, whereas the aqueous fraction contains a component that potentiates the activator's capacity to stimulate CaM-PDE. The activator interacts with PDE by increasing its apparent affinity for CaM. Size partition chromatography of CHCl3/MeOH extracts from spontaneously hypertensive rats produces two activity peaks, one eluting at void volume with the second eluting at a position corresponding to a 4-kDa peptide. The compound at void volume can be converted to the 4-kDa entity by sonication. The CaM-PDE activator behaves as a lipopeptide that shares several characteristics with parathyroid hypertensive factor.
Acid-Base Equilibrium↗
Stress modulation by electrolytes in salt-sensitive spontaneously hypertensive rats.
Dietary calcium (Ca) has been proposed for the nonpharmacologic treatment of hypertension. However, its effect on blood pressure (BP) is debatable, and clinical intervention studies have not yet established a clear trend. The authors studied literature results on the effect of nutritional Ca on BP in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) controls, using the meta-analysis technique. Analysis of the data on inbred animals showed a clear effect of dietary Ca on BP: Ca supplementation produced a significant decrease in SHR and WKY rats, whereas Ca deprivation induced a significant increase in SHR. Furthermore, the hypotensive action of dietary Ca was maximal in salt-sensitive SHR (SHR-S), especially when given a high sodium (Na)/high Ca diet. Because the SHR-S may be more sensitive to stress than the salt-resistant SHR, the possible modulation of stress sensitivity by dietary Na and Ca in SHR-S was examined. High Ca regimens prevented salt-sensitive hypertension in SHR-S, with the high Na/high Ca diet being most potent in lowering BP. This BP reduction by Ca was paralleled by an attenuation of stress sensitivity, as measured by increased body temperature during immobilization stress. Therefore, stress sensitivity was heightened by dietary Na and diminished by dietary Ca (p < 0.05). It was concluded that salt and stress sensitivity in hypertension may be related phenotypes that are both modulated in parallel by dietary ions.
Animals↗
Receptor imaging with atrial natriuretic peptide. Part 1: High specific activity iodine-123-atrial natriuretic peptide.
METHODS: Atrial natriuretic peptide (ANP) was labeled in high specific activity using 123I (p,2n). The biodistribution of 123I-ANP was studied in green vervet monkeys by gamma scintigraphy and in rats by dissection and gamma counting. Iodine-125-ANP was also studied in monkeys by in vitro autoradiography. RESULTS: Iodine-123-ANP showed rapid blood clearance with localization to ANP receptors in the kidneys and lungs, which accounted for 35% of total uptake. In vivo competition imaging studies using cold ANP99-126 and C-ANP102-121 proved that uptake is receptor mediated and allowed imaging of the differential biodistribution of A/B and C-ANP receptor families. Thus, it was possible through the use of selective receptor occupation to prevent uptake in certain organs and to effectively steer the labeled ANP to others. The observed biodistribution patterns were confirmed by an in vitro study using 125I-ANP in the same monkeys, which correlated the scintigraphic images with receptor distribution. An in vivo biodistribution study in rats showed a profound effect of specific activity on biodistribution, with a cutoff for receptor uptake at less than 3000 Ci/mmole. CONCLUSION: Gamma scintigraphy with 123I-ANP permits the imaging of ANP receptors in vivo. In contrast to receptor imaging with either organic molecules or antibodies, ANP provides rapid first-pass uptake and substantial accumulation (%dose/organ approximately 20% or greater) in receptors. The key to receptor imaging with peptides is high specific activity. Labeled ANP offers potential as a diagnostic tool for diabetic nephropathy, particularly for quantifying the involvement of glomerular disease.
Animals↗
Report of the Canadian Hypertension Society Consensus Conference: 5. Hypertension and diabetes.
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Diabetes Complications↗
Increased cyclic guanosine monophosphate production and overexpression of atrial natriuretic peptide A-receptor mRNA in spontaneously hypertensive rats.
Atrial natriuretic peptide (ANP) specifically stimulates particulate guanylate cyclase, and cyclic guanosine monophosphate (cGMP) has been recognized as its second messenger. Spontaneously hypertensive rats (SHR) have elevated plasma ANP levels, but manifest an exaggerated natriuretic and diuretic response to exogenous ANP when compared to normotensive strains. In isolated glomeruli, the maximal cGMP response to ANP corresponds to a 12- to 14-fold increase over basal levels in normotensive strains (Wistar 13 +/- 2; Wistar-Kyoto 12 +/- 2; Sprague-Dawley 14 +/- 2) while a maximal 33 +/- 3-fold elevation occurs in SHR (P < 0.001). This hyperresponsiveness of cGMP is reproducible in intact glomeruli from SHR from various commercial sources. Furthermore, this abnormality develops early in life, even before hypertension is clearly established, and persists despite pharmacological modulation of blood pressure, indicating that it is a primary event in hypertension. In vitro studies have revealed a higher particulate guanylate cyclase activity in membranes from glomeruli and other tissues from SHR. This increase is not accounted for by different patterns of ANP binding to its receptor subtypes between normotensive and hypertensive strains, as assessed by competitive displacement with C-ANP102-121, an analog which selectively binds to one ANP receptor subtype. The hyperactivity of particulate guanylate cyclase in SHR and its behavior under basal, ligand (ANP), and detergent-enhanced conditions could be attributed either to increased expression or augmented sensitivity of the enzyme. Radiation-inactivation analysis does not evoke a disturbance in the size of regulatory elements normally repressing enzymatic activity, while the expression of particulate guanylate cyclase gene using mutated standard of A- and B-receptors partial cDNAs, quantified by polymerase chain reaction (PCR) transcript titration assay, manifests a selective increase of one guanylate cyclase subtype. Our data suggest that in hypertension, genetic overexpression of the ANP A-receptor subtype is related to the exaggerated biological response to ANP in this disease.
Affinity Labels↗
The 1993 guidelines for the management of mild hypertension: memorandum from a WHO/ISH meeting.
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Blood Pressure↗
Hypertension and diabetes.
Co-presentation of hypertension and diabetes leads to a significantly greater increase of cardiovascular mortality than each disease separately. Hypertension appears to be not only a complication of diabetes but apparently also shares a common pathogenetic mechanism, particularly in non-insulin dependent diabetes. Recent data suggest alterations in the nocturnal decline of blood pressure in diabetics, which together with microalbuminuria, may prove to be a predictor of nephropathy and hypertension. When hypertension occurs in diabetics, it requires a vigorous therapeutic approach. Nevertheless, the presence of diabetes modifies the requirement for first line therapy, particularly with respect to potential alterations of metabolic homeostasis in order to effectively prevent cardiovascular complications.
Antihypertensive Agents↗
Platelets, growth factors, and vascular smooth-muscle cells in hypertension and diabetes.
Inappropriate vascular smooth-muscle cell (VSMC) growth is the hallmark of vascular pathology in essential hypertension and diabetic macroangiopathy, whereas platelets constitute an important regulator of vessel wall homeostasis because of their content of various growth factors. Numerous abnormalities exist in platelet functions in diabetes and hypertension, such as enhanced activity and altered adhesion and aggregation. Increased thromboxane (TX2) production is characteristic of diabetes, and an elevation of intracellular free Ca2+ is found in platelets of hypertensive patients. By studying the growth patterns of VSMC from spontaneously hypertensive rats (SHRs) vs. those obtained from their normotensive counterparts, Wistar-Kyoto (WKY) rats, we have demonstrated that VSMC from SHRs exhibited a higher specific growth rate, abnormal contact inhibition, and accelerated entry into the S phase of the cell cycle. Moreover, they were hyperresponsive to many growth factors such as calf serum, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor beta 1 (TGF beta 1), and insulin. Additive effects were observed for EGF and PDGF or EGF and insulin. These intrinsic growth anomalies in cells of hypertensive origin persist in culture indicating their putative primary role in the pathogenesis of hypertension. Endogenous TGF beta 1 revealed an augmented expression of its message levels in SHR VSMC, the difference in mRNA between both strains being more pronounced at high cell density. Further, TGF beta 1 protein synthesis and secretion in VSMC culture were confirmed by immunoprecipitation of de novo labeled TGF beta 1. At high cell density, which most likely represents the physiological state of VSMC, plasmin, an activator of TGF beta 1, significantly stimulated DNA synthesis of VSMC in both strains. The reverse effect was obtained at low cell density. Yet, the fold stimulation was higher in WKY rats, suggesting that TGF beta 1 may be partially activated in SHR VSMC. This is supported by the inhibition of baseline DNA synthesis by TGF beta 1 neutralizing antibody in VSMC of hypertensive origin and not of normotensive controls. TGF beta 1 antisense oligodeoxynucleotide (ODN) nearly normalized the increased proliferation of SHR VSMC in culture. On the other hand, growth-promoting activity (GPA) in platelets of either diabetic or hypertensive patients was higher than in platelets of healthy controls and was found to be normalized by intensive insulin therapy in insulin-dependent diabetic patients. In hypertensive patients, however, hydrochlorothiazide (HCTZ)--even in low doses (25 mg/day)--enhanced the GPA in platelets, whereas other antihypertensive agents such as indapamide, atenolol, and captopril, had neutral effects.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Early experience with laparoscopic approach for adrenalectomy.
BACKGROUND: Adrenalectomy performed by a posterior or transabdominal approach causes substantial postoperative pain. The purpose of this study was to evaluate laparoscopy as a potential approach for adrenalectomy. METHODS: We performed 25 consecutive laparoscopic adrenalectomies on 22 patients from April 1, 1992, to March 30, 1993. Laparoscopic surgery was performed by using a lateral decubitus flank approach with four 11 mm trocars. RESULTS: Twelve right and 13 left adrenal glands were removed in a mean time of 2.3 hours. Three patients underwent bilateral adrenalectomies in a mean time of 5.3 hours. The 15 women and 7 men range in age from 31 to 60 years (mean, 42 years). The adrenal gland diseases were nonfunctional adenoma (seven), pheochromocytoma (five), Cushing's disease (four), Cushing's adenoma (four), primary aldosteronism (two), dehydroepiandrostenedione sulfate hypersecretion (one), angiomyolipoma (one), and medullary cyst (one). Average tumor size was 4.1 cm (range, 1 to 15 cm). Laparoscopic adrenalectomy was successful in 96% of patients, with one patient requiring a laparotomy because of inadequate exposure. The median postoperative stay was 4 days (range, 2 to 19), with a mean of five narcotic injections. There were no deaths, and morbidity was minor. CONCLUSIONS: Laparoscopy can be used successfully for adrenalectomy. It produces less postoperative pain and rapid return to normal activity. It may be the preferred method for removing most adrenal gland lesions that require operation.
Adrenal Gland Diseases↗
Prevalence, control and awareness of high blood pressure among Canadian adults. Canadian Heart Health Surveys Research Group.
OBJECTIVE: To estimate the prevalence and distribution of elevated blood pressure (BP) among Canadian adults and to determine the level of control, treatment, awareness and prevalence of other risk factors among adults with high BP. DESIGN: Population-based cross-sectional surveys. SETTING: Nine Canadian provinces, from 1986 to 1990. PARTICIPANTS: A probability sample of 26,293 men and women aged 18 to 74 years was selected from the health insurance registers in each province. For 20,582 subjects, BP was measured at least twice. Nurses administered a standard questionnaire and recorded two BP measurements using a standardized technique. Two further BP readings, anthropometric measurements and a blood specimen for lipid analysis were obtained from those subjects who attended a clinic. OUTCOME MEASURES: Mean values of systolic and diastolic BP, prevalence of elevated BP using different criteria, and prevalence of smoking, elevated blood cholesterol, body mass index, physical activity and presence of diabetes by high BP status are reported. MAIN RESULTS: Sixteen percent of men and 13% of women had diastolic BP of 90 mm Hg or greater or were on treatment (or both). About 26% of these subjects were unaware of their hypertension, 42% were being treated and their condition controlled, 16% were treated and not controlled, and 16% were neither treated nor controlled. Use of non-pharmacologic treatment of high BP with or without medication was low (22%). Hypertensive subjects showed a higher prevalence of elevated total cholesterol, high body mass index, diabetes and sedentary lifestyle than normotensive subjects. Most people with elevated BP were in the 90 to 95 mm Hg range for diastolic pressure and 140 to 160 mm Hg range for systolic pressure. Prevalence of high isolated systolic BP sharply increased in men (40%) and women (49%) 65 to 74 years old. CONCLUSIONS: The relatively low level of control of elevated BP calls for population and individual strategies, stressing a non-pharmacologic approach and addressing isolated systolic hypertension in the elderly.
Adult↗
In vivo measurement of atrial natriuretic peptide receptors using nuclear imaging.
We have successfully visualized atrial natriuretic peptide (ANP) receptors in vivo using nuclear imaging. 123I-Labelled ANP, injected in green vervet monkeys, was rapidly bound to ANP receptors in the kidneys and lungs. That the observed uptake was receptor mediated was demonstrated with competition studies using simultaneous injection of unlabelled ANP 99-126. It was possible to distinguish between the ANP receptor subtypes by the use of selective antagonists. Thus coinjection of ANP 102-121-des[Gln, Ser, Gly, Leu, Gly] (C-ANP), an ANP analog that selectively binds to the ANP C-receptor, decreased uptake in the kidneys by 50% but increased relative uptake in the lungs and soft tissues. This method permits for the first time, the dynamic in vivo analysis of ANP receptors and their interaction with endogenous ligand. Differences and changes in local ANP receptor concentrations and occupancy could be detected. Since ANP receptor density and affinity are influenced by various physiological and pathological conditions, clinical and diagnostic applications seem possible.
Animals↗
Epidemiological evidence of an interaction between calcium and sodium intake impacting on blood pressure. A Montréal study.
Nutritional calcium and sodium are considered to be important regulators of blood pressure. This study was performed on 182 randomly selected Canadians from Montréal to test the relative contribution of these ions to systolic and diastolic blood pressure, as well as their interaction with other demographic indices. Multiple analysis of the total study population revealed that 28% (P less than .001) of systolic blood pressure was predicted by gender sodium, and calcium interaction (P = .003), weight, and the additive effect of age and weight. The same characteristics contributed to 37% (P less than .001) of diastolic blood pressure with an additional contribution of alcohol intake. Analysis by terciles of sodium and calcium intake indicated that the positive effect of sodium on blood pressure occurred only in subjects given a low calcium diet, whereas blood pressure was lowest in the tercile of both high calcium and sodium intake. The impact of the sodium and calcium interaction on blood pressure represented as much as a 10 mm Hg decrement of systolic blood pressure with 400 mg calcium/1000 kcal intake at the highest level of sodium consumption and a 6 mm Hg decrease for diastolic blood pressure. In subjects without a family history of hypertension, the same indices contributed up to 53% of systolic and 55% of diastolic blood pressure with a synergetic effect of sodium and calcium, indicating that blood pressure was lowest in subjects given a high calcium and sodium diet. For subjects with a family history of hypertension, there was no significant impact of sodium, whereas calcium intake contributed negatively to both systolic and diastolic blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Expression of hsp70 gene in lymphocytes from normotensive and hypertensive humans.
The impact of environmental factors on hypertension depends to a certain extent on the individual's genetic background. Environmental temperature is one of the known modulators of blood pressure. We have previously demonstrated abnormal expression of a major environmentally-controlled gene, hsp70, in hypertensive mice and rats. We have developed a simple ex vivo method for the evaluation of hsp genes expression in humans. In the present study, we investigated the accumulation of hsp70 mRNA in lymphocytes from normotensive and hypertensive humans. The data showed a higher accumulation of hsp70 mRNA in lymphocytes from hypertensives vs normotensives (2.04 +/- 0.35 vs 1.48 +/- 0.29 OD mm2, P < 0.05) submitted to heat stress (15 min at 42 degrees C). Basal levels were the same in both groups (0.11 +/- 0.01 vs 0.10 +/- 0.01 OD mm2, respectively). These results support our hypothesis that alterations in the expression of a major environmentally-controlled gene, hsp70, may be involved in enhanced environmental responses even in human hypertension.
Female↗
Accelerated entry of aortic smooth muscle cells from spontaneously hypertensive rats into the S phase of the cell cycle.
The present study was designed to characterize the growth kinetics of the exaggerated proliferative response to mitogens of vascular smooth muscle cells from spontaneously hypertensive rats compared with cells from normotensive Wistar-Kyoto controls. Cellular DNA content, analyzed by flow cytometry, demonstrated a 4-h accelerated entry into the S phase of the cell cycle of vascular smooth muscle cells from spontaneously hypertensive rats; the significant (4.5-fold) increase in the percentage of cells in the S phase occurred between 8 and 12 h after calf serum stimulation. A 3.9-fold increase of cells in the S phase was seen in the normotensive controls only between 12 and 16 h. Transit through the cell cycle was quantitated by flow cytometry using the Hoechst 33,342--bromodeoxyuridine substitution technique. Vascular smooth muscle cells from spontaneously hypertensive rats went through the cell cycle 4 h ahead of cells from normotensive Wistar-Kyoto rats. This accelerated transit of spontaneously hypertensive rat cells was mostly due to an earlier entry into the S phase. Persistence of this new intermediate phenotype in cell culture suggests its primary pathogenetic role in spontaneous hypertension.
Animals↗
Enhanced growth-dependent expression of TGF beta 1 and hsp70 genes in aortic smooth muscle cells from spontaneously hypertensive rats.
Enhanced proliferation of vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) as compared with Wistar-Kyoto rats (WKY) persists in long-term culture and is characterized by an accelerated entry of these cells into the synthetic S phase of the cell cycle and a higher specific growth rate, particularly evident at high cell density. In the present study, we investigated by Northern blot experiments the expression of genes putatively involved in the regulation of VSMC growth. One of them is the transforming growth factor beta 1 gene (TGF beta 1), a bifunctional modulator of cell growth whose action is dependent on cell density. The accumulation of TGF beta 1 mRNA was enhanced in growing SHR cells at every density studied as early as 24 h after inoculation with a further increase at later times. Protooncogenes c-fos and c-myc, which have been implicated in G1/S phase transition, have also been investigated in VSMC by Northern blot analysis. At low cell density, calf serum stimulated c-fos and c-myc mRNA expression was comparable in WKY and SHR cells whereas at high cell density, c-fos induction was higher in VSMC from SHR. SHR VSMC respond more to mitogenic stimulation and to environmental (e.g., heat) stress, particularly when growing near saturation density. hsp70 constitutes a gene family responsive to environmental stimuli (heat) and to mitogenic stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗