Biomedical subjects

M Barbagallo

Publications and source records attributed to M Barbagallo.

At least 37 records · Page 2Linked to original sources

PubMed1997

Hypertension, diabetes mellitus, and insulin resistance: the role of intracellular magnesium.

Magnesium is one of the most abundant ions present in living cells and its plasma concentration is remarkably constant in healthy subjects. Plasma and intracellular magnesium concentrations are tightly regulated by several factors. Among them, insulin seems to be one of the most important. In fact, in vitro and in vivo studies have demonstrated that insulin may modulate the shift of magnesium from extracellular to intracellular space. Intracellular magnesium concentration has also been shown to be effective on modulating insulin action (mainly oxidative glucose metabolism), offset calcium-related excitation-contraction coupling, and decrease smooth cell responsiveness to depolarizing stimuli, by stimulating Ca2+-dependent K+ channels. A poor intracellular magnesium concentration, as found in non-insulin-dependent diabetes mellitus (NIDDM) and in hypertensive (HP) patients, may result in a defective tyrosine-kinase activity at the insulin receptor level and exaggerated intracellular calcium concentration. Both events are responsible for the impairment in insulin action and a worsening of insulin resistance in non-insulin-dependent diabetic and hypertensive patients. By contrast, in NIDDM patients daily magnesium administration, restoring a more appropriate intracellular magnesium concentration, contributes to improve insulin-mediated glucose uptake. Similarly, in HP patients magnesium administration may be useful in decreasing arterial blood pressure and improving insulin-mediated glucose uptake. The benefits deriving from daily magnesium supplementation in NIDDM and HP patients are further supported by epidemiological studies showing that high daily magnesium intake to be predictive of a lower incidence of NIDDM and HP. In conclusion, a growing body of studies suggest that intracellular magnesium may play a key role on modulating insulin-mediated glucose uptake and vascular tone. We further suggest that a reduced intracellular magnesium concentration might be the missing link helping to explain the epidemiological association between NIDDM and hypertension.

Animals↗

PubMed1997

Increased prevalence of cardiac arrhythmias and transient episodes of myocardial ischemia in hypertensives with left ventricular hypertrophy but without clinical history of coronary heart disease.

To evaluate the behavior of cardiac arrhythmias (CA) and transient episodes of myocardial ischemia (TEMI), in relation to the circadian pattern of blood pressure in patients suffering from arterial hypertension, with or without echocardiographically ascertained left ventricular hypertrophy (LVH), we studied 128 patients, 87 men (M) and 41 women (F), aging from 21 to 76 years, subdivided into two groups: Group I, including 66 patients with LVH (45 M and 21 F; mean age of 53.7 +/- 9.1 years; Group II, including 62 patients without LVH (42 M and 20 F; mean age of 49.7 +/- 9.5 years). Office blood pressure (OBP) as well as nighttime ambulatory blood pressure (ABP) were higher in patients with LVH (P < .05 and P < .01). CA were present in a higher number of patients of Group I (P < .001): premature supraventricular beats (PSVB) 22.7 v 4.8%, supraventricular couplets (SVC) 36.4 v 16.1%, supraventricular tachycardia runs (SVT runs) 27.3 v 12.9%, ventricular ectopic beats (VEB) 25.6 v 8.0%, ventricular couplets (VC) 30.3 v 12.9%, ventricular tachycardia runs (VT runs) 12.1 v 3.2%. The absolute number of ectopic beats was also significantly higher in patients of Group I. Ventricular arrhythmias were significantly related to ASBP (r = 0.83, P < .01), to ADBP (r = 0.74, P < .01) and to heart rate (r = 0.87, P < .01) in patients of Group I. TEMI were more frequent in patients of Group I (73 v 41 episodes, 39.39% v 25.8% of patients, P < .01) and were related to ABP peaks. In fact, in both groups of patients all TEMI without heart rate increase and most TEMI with heart rate increase were registered between 6:00 and midnight, hours in which ABP values were higher. We conclude that hypertensives with LVH, but without clinical history of coronary heart disease, have a higher prevalence of ventricular arrhythmias and of transient episodes of myocardial ischemia in relation to the circadian pattern of ABP.

Adult↗

PubMed1997

Bisoprolol and captopril effects on insulin receptor tyrosine kinase activity in essential hypertension.

Angiotension converting enzyme (ACE) inhibitors and beta-blockers have been reported to possess disparate effects on insulin sensitivity. The aim of this study was to study the effects of the selective beta-1 blocker bisoprolol and of the ACE inhibitor captopril on cellular insulin action in hypertensive individuals. After washout, 12 mild to moderate essential hypertensives were randomized in a double-blind manner to 5 mg bisoprolol daily or 25 mg captopril twice daily for 8 weeks. Erythrocyte insulin binding and insulin-stimulated tyrosine kinase (TK) activity were measured before and after therapy. Both agents decreased diastolic blood pressure significantly (bisoprolol 96.5+/-0.9 to 87.8+/-3.1 mm Hg; captopril 96.5+/-0.9 to 91.5+/-1.8 mm Hg; P < .05). Fasting plasma glucose, insulin, and insulin/glucose indices remained unchanged after both therapies, as did lipid profiles. Maximal insulin-stimulated TK activity, assessed by phosphorylation of the exogenous substrate poly-Glu80Tyr20, was significantly higher (P < .05) after bisoprolol treatment, but not after captopril treatment, when compared to placebo (bisoprolol 8.5+/-1.8; captopril 7.3+/-1.5; placebo: 6.4+/-1.3 pmol 32P-ATP/fmol bound insulin). However, captopril, but not bisoprolol, increased the sensitivity of the receptor TK activity, as measured by the half-maximal activity concentration (ED50). Specific insulin binding was not affected by these two agents. Thus, both captopril and bisoprolol may have favorable but different effects on TK activity and insulin action at the cellular level.

Adrenergic beta-Antagonists↗

PubMed1997

Mechanism of action of human calcitonin gene-related peptide in rabbit heart and in human mammary arteries.

We investigated the effects of human calcitonin gene-related peptide (CGRP) on isolated rabbit hearts to evaluate the mechanisms responsible for the vasodilatory action of the peptide on the coronary district, monitoring contemporaneously the effects on left ventricular pressure (LVP) and heart rate (HR). We also evaluated the reactivity of the human internal mammary artery (IMA) to excitatory drugs acting with different mechanisms and the inhibitory response to CGRP in comparison with the commonly used vasodilatory agents. The peptide induced a slight inhibitory effect on the basal coronary perfusion pressure (CPP), whereas it was ineffective on the inotropism and chronotropism. A more detectable coronary vasodilation was evident when CPP was increased by spasmogenic agents [vasopressin, methoxamine, Bay K 8644, and prostaglandin F2 alpha (PGF2 alpha)]. This inhibitory effect was dose dependent (10(-11)-10(-8) M) and apparently not specific, occurring to the same extent on different stimuli. Forskolin (10(-8) M), an adenylate-cyclase activator, and indomethacin (1.4 x 10(-5) M), a cyclooxygenase inhibitor, did not modify the spasmolytic activity of CGRP on precontracted coronary smooth muscle. The experiments performed on the segments of IMA, used for myocardial revascularization of patients affected by coronary diseases, have shown an evident spasmolytic action of CGRP on increased vascular tone induced by KCl (90 mM), noradrenaline (10(-5) M), serotonin (10(-6) M), and angiotensin II (10(-6) M). These inhibitory responses of CGRP on the spasmogenic compounds disappeared when the endothelial function of IMA, validated by the acetylcholine test, was abolished by mechanical ablation. A series of IMA segments was incubated (30 min) with N(G)-monomethil-L-arginine (L-NMMA), which inhibits nitric oxide (NO) synthase. In these experiments, the peptide failed to induce the vasodilation, suggesting that its action may be related to synthesis of NO. All these results show that CGRP is able to induce a potent vasodilatory action on different vessels of humans (internal mammary artery) and animals (rabbit coronary arteries). In particular the data obtained from IMA demonstrated that the vasorelaxant effect was related to synthesis of NO, one of the most studied endothelium-derived relaxing factors (EDRFs).

Adult↗

PubMed1997

Altered ionic effects of insulin in hypertension: role of basal ion levels in determining cellular responsiveness.

To investigate the ionic actions of insulin in hypertension, 19F- and 31P-nuclear magnetic resonance spectroscopy were used to measure cytosolic free calcium (Ca(i)) and intracellular free magnesium (Mg(i)) levels in red blood cells from normal (n = 9) and hypertensive (n = 9) subjects before and 30, 60, 120, and 180 min after in vitro incubation with insulin. In hypertensive patients, basal Ca(i) levels were significantly higher (30.0 +/- 2.2 vs. 19.8 +/- 2.5 nmol/L; P < 0.05), and basal Mg(i) levels were significantly lower (170 +/- 10.9 vs. 209 +/- 8 micromol/L; P < 0.05) than in normotensive subjects. In normal cells, insulin significantly elevated Ca(i) to 39.8 +/- 8.0, 50.1 +/- 8.2, 69.3 +/- 11.1, and 50.9 +/- 13.4 nmol/L at 30, 60, 120, and 180 min and Mg(i) to 238 +/- 10,264 +/- 14,226 +/- 11, and 216 +/- 10 micromol/L at 30, 60, 120, and 180 min. In hypertensive subjects, the insulin-dependent Ca(i) elevation was blunted, and Mg(i) accumulation was completely suppressed. Continuous relationships were observed between basal values of each ion and insulin responses; the greater the Ca(i), the less the Ca(i) rose (r = -0.574; P = 0.013), and the lower the Mg(i), the less Mg(i) rose (r = 0.524; P = 0.025). Furthermore, a blunting of Mg(i) responses to insulin could be reproduced in normal cells that were magnesium depleted by prior treatment either with A23187 in a calcium-free medium or with high glucose concentrations (15 mmol/L). Once again, insulin responsiveness followed basal Mg(i) levels (r = 0.637; P < 0.001). Together, these data demonstrate ionic aspects of insulin resistance in hypertension and suggest that Ca(i) and Mg(i) levels may regulate cellular responsiveness to insulin. This may help to explain the different vascular actions attributed to insulin in normal compared with insulin-resistant states such as hypertension.

Adult↗

PubMed1997

Diabetes mellitus, hypertension and ageing: the ionic hypothesis of ageing and cardiovascular-metabolic diseases.

Ageing in industrialised societies is associated with an increasing prevalence of hypertension, atherosclerotic vascular diseases, reduced insulin sensitivity and non-insulin-dependent diabetes mellitus (NIDDM). It has been suggested that hyperinsulinaemia/insulin resistance and/or hyperglycaemia could play a role in determining and/or exacerbating the hypertension and vascular disease associated with diabetes mellitus and ageing. Insulin-resistant states, such as essential hypertension and NIDDM, as well as "normal" ageing, are characterised by similar intracellular ionic defects, i.e. accumulation of cytosolic free calcium and depletion of free magnesium. The importance of calcium and magnesium ions in regulating cell functions is well-known. A rise in cellular free calcium and a depletion in cellular magnesium may induce cellular insulin resistance and vasoconstriction. Ionic levels quantitatively predict the extent of elevated blood pressure, fasting blood glucose, HBA1c and hyperinsulinaemic response to oral glucose challenge. We suggest that ionic disturbance might be the missing link responsible for the frequent clinical coexistence of hypertension, atherosclerosis and metabolic disorders. Ageing cells may become more vulnerable to ion disturbances, leading to possible elevation of intracellular free calcium and concurrent magnesium depletion. The "ionic hypothesis" of ageing supposes that an alteration in the cellular mechanisms which maintain the homeostasis of cytosolic calcium concentrations may play a key role in the ageing process, and that a sustained accumulation of cellular calcium and/or the depletion of cellular magnesium may also provide the final common pathway for many ageing-associated diseases, including hypertension and NIDDM.

Aging↗

PubMed1996

Altered cellular calcium responsiveness to insulin in normal and hypertensive pregnancy.

OBJECTIVE: To investigate the glucose-independent calcium-related effects of insulin from subjects with normal and hypertensive pregnancies. METHOD: We used lndo-l fluorescence spectroscopy to measure cytosolic free calcium levels (Cai) in peripheral blood mononuclear cells (PBM) from 17 women (aged 20-40 years), six nonpregnant controls (NPC), five pregnant normotensive (PNT) women and six pregnant hypertensive (PHT) women, before and 5, 30, 60, 120 and 180 min after in vitro incubation with 200 microU/ml insulin. RESULTS: Basal Cai levels were significantly higher in PHT women (175.2 +/- 18.8 nmol/l) than they were in NPC women (122.8 +/- 2.8 nmol/l) and PNT women (123.9 +/- 3.5 nmol/l). The initial insulin-induced rise in Cai was similar in NPC (delta Cai 13.5 +/- 5.6 nmol/l) and PNT women (delta Cai 14.6 +/- 3.7 nmol/l), but appeared blunted in PHT women (delta Cai 8.2 +/- 3.5 nmol/l), and, for all pregnant subjects, was closely and inversely related to basal Cai. Over time, in PNT women, delta Cai did not increase from the initial response (maximal delta Cai 20.5 +/- 2.3 nmol/l) compared to NPC. The total cellular calcium response to insulin was also blunted in PNT women (the area under the calcium-responses curve was 86 +/- 3.4 versus 97.4 +/- 6.5 nmol/l), but was excessive in PHT women (115.5 +/- 6 nmol/l, P = 0.05). CONCLUSIONS: Hypertension in pregnancy is associated with excess Cai, insulin raises Cai in PBM, and different alterations of Cai responsiveness to insulin occur both in normal and in hypertensive pregnancy. These cellular calcium alterations may help to explain altered tissue responsiveness to insulin and other hormones in pregnancy.

Adult↗

PubMed1996

Cellular ions in NIDDM: relation of calcium to hyperglycemia and cardiac mass.

OBJECTIVE: To investigate the role of hyperglycemia in mediating the clinical association of NIDDM with hypertension and left ventricular dysfunction and hypertrophy. RESEARCH DESIGN AND METHODS: Since hyperglycemia elevates cytosolic free calcium (Cai) both in myocardial and vascular smooth muscle cells, we utilized nuclear magnetic resonance (NMR) spectroscopy to measure erythrocyte Cai levels and compared them with serum ionized calcium (Caio), glucose, and insulin values before and following an oral glucose tolerance test (OGTT) and with previously obtained cardiac structural indexes in normotensive and hypertensive NIDDM (n = 32) and normal control subjects (n = 35). RESULTS: Compared with control subjects, normotensive NIDDM subjects had higher Cai (31.5 +/- 2.3 vs. 24.3 +/- 1.9 nmol/l, P = 0.05), lower intracellular free magnesium (Mgi) (200 +/- 10 vs. 225 +/- 7 mumol/l, P = 0.05), and greater posterior wall thickness (0.98 +/- 0.04 vs. 0.86 +/- 0.03 cm, P = 0.05). Hypertensive NIDDM subjects exhibited a further increase in Cai (43.1 +/- 4.4 nmol/l, P = 0.05 vs. control subjects) and left ventricular mass (LVM) (201.5 +/- 12.2 vs. 155.8 +/- 7.7 g, P = 0.05 vs. control subjects). For all subjects, significant relationships were observed between Cai and fasting blood glucose (r = 0.510, P < 0.01), HbAic (r = 0.389, P < 0.05), and the glycemic response to OGTT (the area under the curve [AUC] for glucose; r = 0.519, P < 0.01) and to systolic (r = 0.504, P < 0.01) and diastolic (r = 0.624, P < 0.01) blood pressure. Left ventricular mass index (LVMI) was related to fasting glucose levels (r = 0.406, P < 0.01) and the AUC for glucose (r = 0.380, P < 0.01), but not to fasting insulin or insulin responses to an OGTT. The LVMI was best related to Cai (r = 0.516, P < 0.01), while being inversely related to Caio (r = -0.486, P < 0.01). Multivariate regression indicated the contribution of glucose to LVMI was independent of age, BMI, insulin, and blood pressure but demonstrated a significant interaction with Cai. CONCLUSIONS: Altogether, these data suggest that glucose-related excess Cai is a fundamental lesion in diabetes that contributes to the elevated blood pressure and cardiac mass in this disease.

Blood Glucose↗

PubMed1995

Doxazosin lowers blood pressure and improves insulin responses to a glucose load with no changes in tyrosine kinase activity or insulin binding.

alpha-Adrenergic blockers have shown favorable metabolic effects. We evaluated the glucose and insulin responses to a glucose load and lipid profiles in 36 diabetic hypertensive patients before and after 8 weeks of doxazosin administration. To evaluate insulin action at the cellular level, erythrocyte insulin binding and tyrosine kinase (TK) activity were measured in 12 of these patients. Systolic and diastolic blood pressures decreased significantly (P < .0001) after 8 weeks of doxazosin therapy. Doxazosin administration significantly reduced the integrated insulin response (area under the curve [AUC]-insulin: 6093 +/- 894 to 5260 +/- 807; P = .04) and the insulin/glucose index (I/G) at 90 and 120 min after a glucose load (at 90 min, 0.230 +/- 0.055 v 0.180 +/- 0.04, P < .05; at 120 min, 0.275 +/- 0.071 v 0.173 +/- 0.036, P < .05). HDL3 level increased from 31.1 +/- 1.5 mg% to 34 +/- 1.6 mg% (P < .05) after doxazosin. Erythrocyte insulin binding and tyrosine kinase activity were not significantly altered after doxazosin. No significant correlation was found between the insulin or glucose responses and the insulin receptor binding or tyrosine kinase activity before and after treatment.

Blood Glucose↗

PubMed1995

Quinapril reduces microalbuminuria in essential hypertensive and in diabetic hypertensive subjects.

To investigate the metabolic and renal effects of the nonsulfhydryl, tissue-active ACE inhibitor quinapril in diabetes and in hypertension, we studied 30 essential hypertensives and 24 non-insulin-dependent (type II) diabetic (NIDDM) subjects with hypertension. Systolic and diastolic blood pressures, plasma glucose, and insulin responses to an oral glucose load (75 g), lipid profile, and urinary albumin excretion were evaluated before and after 8 weeks' administration of quinapril (10 to 40 mg/day). Quinapril produced a significant and comparable reduction of arterial blood pressure in both groups. Mean arterial pressure decreased from 114.8 +/- 0.9 to 94.2 +/- 1.1 (-17.9 +/- 1.5%) in the essential hypertensive group and from 118.4 +/- 1.6 to 96.2 +/- 1.4 (-18.4 +/- 1.6%) in the diabetic hypertensive group. In both essential hypertensives and diabetic-hypertensive subjects with microalbuminuria, quinapril significantly and comparably reduced the urinary albumin excretion rate (UAE); UAE decreased from 32.5 +/- 5.5 micrograms/min to 14.7 +/- 3.7 micrograms/min (P < .05 v baseline) in the diabetic-hypertensive group and from 27.5 +/- 3.0 micrograms/min to 11.6 +/- 2.7 micrograms/min (P < .05 v baseline) in the essential hypertensives. Altogether, a direct correlation was found between the initial level of UAE and the UAE reduction after quinapril (delta UAE) (r = 0.706, p < .05). Insulin and glucose responses to an oral glucose tolerance test and the lipid profiles were not modified by quinapril treatment. The results confirm that quinapril is an effective antihypertensive agent that additionally reduces microalbuminuria in both hypertensive diabetics and in patients with essential hypertension, without altering insulin sensitivity and lipid profiles.

Albuminuria↗

PubMed1995

Effects of dehydroepiandrosterone sulfate on cellular calcium responsiveness and vascular contractility.

Dehydroepiandrosterone sulfate (DHEAS) is an endogenous steroid having a wide variety of biological effects, but its physiological role remains undefined. Since an age-related decline of DHEAS corresponds to the progressive onset of atherosclerosis, cardiovascular diseases, and overall mortality, we investigated a possible protective role of DHEAS in vascular disease by studying the effects of this hormone (10(-7) to 10(-5) mol/L) on cytosolic free calcium and contractility in different in vitro vascular tissue preparations. DHEAS produced a significant, dose-dependent relaxation of isolated helical strips of rat tail artery precontracted with KCl (60 mmol/L) (89.7 +/- 18.7%, P < .01), arginine vasopressin (3 nmol/L) (27.3 +/- 7.1%, P < .01), and norepinephrine (0.1 mumol/L) (49.2 +/- 18.2%, P < .01). In isolated vascular smooth muscle cells DHEAS reversibly inhibited KCl (30 mmol/L)-induced elevations of cytosolic free calcium to 69.8 +/- 8.4% and 43.8 +/- 7.4% of the control response at 5 x 10(-7) and 5 x 10(-6) mol/L, respectively (P < .05 at both doses). These results provide evidence of a direct vascular action of DHEAS, in doses reflecting circulating levels in vivo, and suggest the possibility that these effects are mediated by modulation of intracellular calcium metabolism. We hypothesize that physiologically, DHEAS may serve to buffer vascular responsiveness to a wide variety of depolarizing and constrictor hormonal stimuli.

Analysis of Variance↗

PubMed1995

Glucose-induced alterations of cytosolic free calcium in cultured rat tail artery vascular smooth muscle cells.

We have previously suggested that hyperglycemia per se may contribute to diabetic hypertensive and vascular disease by altering cellular ion content. To more directly investigate the potential role of glucose in this process, we measured cytosolic free calcium in primary cultures of vascular smooth muscle cells isolated from Sprague-Dawley rat tail artery before and after incubation with 5 (basal), 10, 15, and 20 mM glucose. Glucose significantly elevated cytosolic free calcium in a dose- and time-dependent manner, from 110.0 +/- 5.4 to 124.5 +/- 9.0, 192.7 +/- 20.4, and 228.4 +/- 21.9 nM at 5, 10, 15, and 20 mM glucose concentrations, respectively. This glucose-induced cytosolic free calcium elevation was also specific, no change being observed after incubation with equivalent concentrations of L-glucose or mannitol. This glucose effect was also dependent on extracellular calcium and pH, since these calcium changes were inhibited in an acidotic or a calcium-free medium, or by the competitive calcium antagonist lanthanum. We conclude that ambient glucose concentrations within clinically observed limits may alter cellular calcium ion homeostasis in vascular smooth muscle cells. We suggest that these cellular ionic effects of hyperglycemia may underlie the predisposition to hypertension and vascular diseases among diabetic subjects and/or those with impaired glucose tolerance.

Animals↗

PubMed1994

alpha-Glycerophosphocholine in the mental recovery of cerebral ischemic attacks. An Italian multicenter clinical trial.

The clinical efficacy and the tolerability of alpha-glycerophosphocholine (alpha-GPC), a drug able to provide high levels of choline for the nervous cells of the brain and to protect their cell walls, have been tested in a clinical open multicenter trial on 2044 patients suffering from recent stroke or transient ischemic attacks. alpha-GPC was administered after the attack at the daily dose of 1000 mg im for 28 days and orally at the dose of 400 mg tid during the following 5 months after the first phase. The evaluation of the efficacy on the psychic recovery was done by the Mathew Scale (MS) during the period of im drug administration, and using the Mini Mental State Test (MMST), the Crichton Rating Scale (CRS), and the Global Deterioration Scale (GDS) during the following period of oral administration. The MS mean increased 15.9 points in 28 days in a statistically significant way (p < 0.001) from 58.7 to 74.6. At the end of the 5 month oral administration, the CRS mean significantly decreased 4.3 points, from 20.2 to 15.9 (p < 0.001); the MMST mean significantly increased (p < 0.001) from 21 to 24.3 at the end of the trial, reaching the "normality" score at the 3rd month assessment. The GDS score at the end of the trial corresponded to "no cognitive decline" or "forgetfulness" in 71% of the patients. Adverse events were complained of by 44 patients (2.14%); in 14 (0.7%) the investigator preferred to discontinue therapy. The most frequent complaints were heartburn (0.7%), nausea-vomit (0.5%), insomnia-excitation (0.4%), and headache (0.2%). The trial confirms the therapeutic role of alpha-GPC on the cognitive recovery of patients with acute stroke or TIA, and the low percentage of adverse events confirms its excellent tolerability.

Aged↗

PubMed1994

Vascular effects of 17 beta-estradiol in male Sprague-Dawley rats.

Bolus intravenous injections of 100 micrograms/kg 17 beta-estradiol significantly decreased the pressor responses to norepinephrine (NE; 0.3 microgram/kg) at the fourth, fifth, and sixth hour in anesthetized male Sprague-Dawley rats. At doses of 10(-6) to 3 x 10(-5) M, 17 beta-estradiol relaxed the sustained phase of contraction in male Sprague-Dawley rat tail artery helical strips precontracted in vitro by [Arg8]vasopressin (AVP), KCl, or NE. The effect was dose dependent. At doses of 3 x 10(-6) to 3 x 10(-5) M, it also decreased the initial phase of tension generation and extracellular Ca(2+)-dependent vasoconstriction induced by NE, AVP, or KCl in a dose-dependent manner in male Sprague-Dawley rat tail artery helical strips. 17 beta-Estradiol (2 x 10(-8) to 2 x 10(-6) M) decreased the voltage-dependent inward Ca2+ current and the intracellular free Ca2+ concentration ([Ca2+]i) increment induced by 15 mM KCl in a dose-dependent manner (3.6 x 10(-8) to 3.6 x 10(-6) M) in vascular smooth muscle cells (VSMC) isolated from male Sprague-Dawley rat tail arteries. We suggest that, at pharmacological doses, estrogen has a direct vasodilating effect on the rat tail artery that is mediated by its inhibitory effect on Ca2+ influx through voltage-dependent Ca2+ channels. The inhibitory effect of estrogen on the pressor responses to NE or AVP may be correlated with its modulation of VSMC [Ca2+]i through its actions on membrane Ca2+ channels.

Animals↗

PubMed1994

Intracellular ionic consequences of dietary salt loading in essential hypertension. Relation to blood pressure and effects of calcium channel blockade.

To study the ionic basis of salt sensitivity in hypertension, 19F-, 13P-, and 23Na-nuclear magnetic resonance techniques were used to measure cytosolic free calcium (Cai), pH (pHi), free magnesium (Mgi), and sodium (Nai) in erythrocytes of essential hypertensive subjects (n = 19). Individuals were studied for 2 mo each on low- (UNaV < 50 meq/d) and high- (UNaV > 200 meq/d) salt diets, with the concomitant administration of nifedipine (10 mg t.i.d.) or placebo tablets for 1 mo of each diet. Salt loading elevated Cai and Nai while suppressing Mgi and pHi; these changes occurred predominantly in salt-sensitive subjects (n = 9). Nifedipine blunted the pressor response to salt loading > 50% (delta diastolic BP [high-low salt vs placebo] = 5 +/- 2 vs 14 +/- 2 mmHg, P < 0.05) and reversed salt-induced ionic changes, lowering Cai and elevating Mgi and pHi. Regardless of the definition of salt sensitivity, continuous relationships were observed between the pressure response to salt loading, the levels of Cai (r = 0.726, P < 0.001), Nai (r = 0.747, P < 0.001), and pHi (r = -0.754, P < 0.001), and the salt-induced change in Mgi (r = -0.757, P < 0.001). Altogether, these results emphasize the reciprocal and coordinate nature of intracellular ionic changes in response to dietary salt loading and calcium channel blockade in essential hypertension. They suggest that salt sensitivity is mediated by cellular calcium accumulation from the extracellular space, in association with magnesium depletion and acidification. Lastly, interpretation of intracellular ion measurements in the future will require concurrent assessment of dietary salt intake.

Analysis of Variance↗

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

The role of glucose in diabetic hypertension: effects on intracellular cation metabolism.

The clinical association of hypertension, obesity, noninsulin-dependent diabetes mellitus (NIDDM), and other cardiovascular risk factors has long been recognized. The recent finding that essential hypertension is also an insulin-resistant state associated with hyperinsulinemia led some authors to attribute a role in mediating this association and in the pathogenesis of hypertension itself to insulin. However, evidence also exists independently of insulin per se that alterations in glucose metabolism in general, and of hyperglycemia in particular, may also contribute to the hypertensive process, especially in the hypertension of diabetes. The authors attempted to understand the relationship between glucose and insulin metabolism, diabetes, and hypertension from a cellular ionic point of view. In vitro it was shown that glucose, in a specific, dose- and time-dependent manner, can directly and coordinately alter intracellular ions, increasing cytosolic free calcium, while suppressing intracellular free magnesium and pH levels. These glucose-induced changes exactly parallel those ionic lesions previously observed in vivo in the fasting hyperglycemia of hypertension associated with NIDDM. These and other data led to the hypothesis that circulating blood glucose, independently of insulin and even at normal levels, is a physiologic determinant of cellular ion homeostasis. Furthermore, the cellular ionic consequences of hyperglycemia may contribute to the increased risk of hypertension and vascular diseases present among subjects with NIDDM, impaired glucose tolerance, or both.

Animals↗

PubMed1994

Is the higher incidence of ischemic disease in patients with hypertension and diabetes related to intracellular depletion of high energy metabolites?

To study mechanisms underlying ischemia in hypertension and non-insulin dependent diabetes mellitus (NIDDM), 31P-magnetic resonance spectroscopy was used to evaluate adenosine triphosphate and 2,3 diphosphoglycerate (2,3 DPG) levels in erythrocytes of control (n = 21), hypertensive (n = 22), and NIDDM (n = 10) subjects. Compared to adenosine triphosphate levels in controls (2.22 +/- 0.10 mM), both hypertensive (1.89 +/- 0.10 mM, sig = 0.05 versus normal) and NIDDM subjects (1.57 +/- 0.13 mM, sig = 0.05 versus normal) exhibited lower values. NIDDM subjects also displayed suppressed levels of 2,3 DPG (6.84 +/- 0.48 mM, sig = 0.05 versus normal and EH), compared to hypertensives (8.34 +/- 0.27 mM). These data suggest cellular energy metabolism is disrupted in hypertension and NIDDM. Both conditions may thereby sensitize tissues to ischemic damage, lower adenosine triphosphate levels by decreasing energy reserves, and lower 2,3 DPG levels by inhibiting hemoglobin-oxygen dissociation.

2,3-Diphosphoglycerate↗