Magnesium decreases arterial pressure and inhibits cardiovascular responses induced by N-methyl-D-aspartate and metabotropic glutamate receptors stimulation in rostral ventrolateral medulla.

OBJECTIVE: Magnesium sulfate (MgSO4) is widely used for the treatment of eclampsia. However, effects of Mg2+ in central cardiovascular regulation remain unclear. In the present study, the role of Mg2+ on cardiovascular regulation in the rostral ventrolateral medulla (RVLM) of rats was examined. METHODS: Adult male Wistar rats were anesthetized with urethane, and artificially ventilated. The ventral surface of the medulla was exposed, and the RVLM was identified by microinjection (50 nl) of l-glutamate (l-Glu; 2 nmol). Then, MgSO4 (1, 3, 10 nmol, n = 7 for each dose) and magnesium chloride (MgCl2; 10 nmol, n = 7) were microinjected into the RVLM. l-Glu (2 nmol), N-methyl-D-aspartate (NMDA; 20 pmol), alpha-amino-3-hydroxy-5-methyl isoxazole-4-propionic acid (AMPA; 5 pmol) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD, metabotropic glutamate receptor agonist; 1 nmol] were also microinjected with or without pretreatment of MgSO4 (10 nmol; n = 7 for each drug). RESULTS: MgSO4 dose-dependently decreased mean arterial pressure (MAP) and heart rate (HR). The high dose of MgSO4 (10 nmol) significantly decreased MAP and HR (-25 +/- 4 mmHg and -43 +/- 6 bpm). Similarly, MgCl2 decreased MAP and HR (-27 +/- 4 mmHg and -30 +/- 6 bpm). The pressor response evoked by NMDA or (1S,3R)-ACPD was significantly attenuated by the pretreatment with MgSO4. In contrast, pressor response caused by l-Glu or AMPA was not affected by pretreatment with MgSO4. CONCLUSIONS: These results suggest that Mg2+ has an inhibitory role on the RVLM neurons, and inhibits cardiovascular responses induced by NMDA and metabotropic glutamate receptor agonists.

Cardiovascular and sympathetic responses to dental surgery with local anesthesia.

We investigated changes in blood pressure and blood variables, including plasma catecholamines, serum glucose and insulin concentrations, during dental surgery. The study included 11 normotensive patients (age, 22.5+/-0.7 years) who underwent tooth extraction at Kyushu Dental College Hospital. Three to 7 days prior to dental surgery, blood pressure, pulse rate, and heart rate variability were measured every 30 min over 24 h. The low frequency (LF: 0.05 to 0.15 Hz) and high frequency (HF: 0.15 to 0.40 Hz) powers were calculated, and the ratio of LF to HF (LF/HF) and HF were used as indexes of sympathetic and parasympathetic activities, respectively. Lidocaine, 2% with epinephrine (1:80,000), was used as the local anesthetic for all patients. Systolic blood pressures significantly increased during dental surgery (+10.8+/-3.5 mmHg); however, this increase failed to correlate not only with baseline systolic blood pressure but with 24-h averaged blood pressures, LF/HF or HF. On the other hand, plasma epinephrine and norepinephrine concentrations increased during dental surgery, and peak values of these variables were obtained after local anesthesia and during tooth extraction, respectively. Serum glucose level increased after local anesthesia (control vs. local anesthesia: 5.16+/-0.11 vs. 5.62+/-0.10 mmol/l; p<0.01); however, plasma insulin concentrations did not change significantly. These results suggest that 1) ambulatory measurements of blood pressure and heart rate variability over 24 h cannot predict the responses of blood pressure during dental surgery, and that 2) administration of local anesthetic and tooth extraction activate sympathoadrenal outflow, resulting in an increase in serum glucose level in normotensive subjects.

Benzalacetone synthase. A novel polyketide synthase that plays a crucial role in the biosynthesis of phenylbutanones in Rheum palmatum.

Benzalacetone synthase (BSA) is a novel plant-specific polyketide synthase that catalyzes a one step decarboxylative condensation of 4-coumaroyl-CoA with malonyl-CoA to produce the C6-C4 skeleton of phenylbutanoids in higher plants. A cDNA encoding BAS was for the first time cloned and sequenced from rhubarb (Rheum palmatum), a medicinal plant rich in phenylbutanoids including pharmaceutically important phenylbutanone glucoside, lindleyin. The cDNA encoded a 42-kDa protein that shares 60-75% amino-acid sequence identity with other members of the CHS-superfamily enzymes. Interestingly, R. palmatum BAS lacks the active-site Phe215 residue (numbering in CHS) which has been proposed to help orient substrates and intermediates during the sequential condensation of 4-coumaroyl-CoA with malonyl-CoA in CHS. On the other hand, the catalytic cysteine-histidine dyad (Cys164-His303) in CHS is well conserved in BAS. A recombinant enzyme expressed in Escherichia coli efficiently afforded benzalacetone as a single product from 4-coumaroyl-CoA and malonyl-CoA. Further, in contrast with CHS that showed broad substrate specificity toward aliphatic CoA esters, BAS did not accept hexanoyl-CoA, isobutyryl-CoA, isovaleryl-CoA, and acetyl-CoA as a substrate. Finally, besides the phenylbutanones in rhubarb, BAS has been proposed to play a crucial role for the construction of the C6-C4 moiety of a variety of natural products such as medicinally important gingerols in ginger plant.

Green tea polyphenols as potent enhancers of glucocorticoid-induced mouse mammary tumor virus gene expression.

The effect of natural and synthetic galloyl esters on glucocorticoid-induced gene expression was evaluated by using rat fibroblast 3Y1 cells stably transfected with a luciferase reporter gene under the transcriptional regulation of the mouse mammary tumor virus promoter. The glucocorticoid-induced gene transcription was strongly suppressed by synthetic alkyl esters; n-dodecyl gallate showed the most potent inhibition (66% inhibition at 10 microM), which was far more potent than that of crude tannic acid. n-Octyl and n-cetyl gallate also showed good inhibition, while gallic acid itself was not so active, suggesting that the presence of hydrophobic side chain is important for the suppressive effect. On the other hand, surprisingly, green tea gallocatechins, (-)-epigallocatechin-3-O-gallate and theasinensin A, potently enhanced the promoter activity (182 and 247% activity at 1 microM, respectively). The regulation of the level of the glucocorticoid-induced gene expression by the antioxidative gallates is of great interest from a therapeutic point of view.

Green tea polyphenols: novel and potent inhibitors of squalene epoxidase.

The green tea gallocatechins, (-)-epigallocatechin-3-O-gallate (EGCG) (IC(50) = 0.69 microM), (-)-gallocatechin-3-O-gallate (GCG) (IC(50) = 0.67 microM), (-)-epicatechin-3-O-gallate (ECG) (IC(50) = 1.3 microM), and theasinensin A (IC(50) = 0.13 microM), were found to be potent and selective inhibitors of rat squalene epoxidase (SE), a rate-limiting enzyme of cholesterol biogenesis. On the other hand, flavan-3-ols without galloyl group at C-3 did not show significant enzyme inhibition. It was demonstrated for the first time that the cholesterol lowering effect of green tea may be attributed to their potent SE inhibition activities. Inhibition kinetics revealed that EGCG inhibited SE in noncompetitive (K(I) = 0.74 microM), and non-time-dependent manner. The potent enzyme inhibition would be caused by specific binding to the enzyme, and by scavenging reactive oxygen species required for the monooxygenase reaction.

Galloyl esters from rhubarb are potent inhibitors of squalene epoxidase, a key enzyme in cholesterol biosynthesis.

Galloyl glucoses and galloyl proanthocyanidins obtained from rhubarb (Rhei Rhizoma, Rheum palmatum L., Polygonaceae); e.g. 1,2,6-tri-O-galloyl-beta-D-glucose (IC50 = 0.63 microM), 1,6-di-O-galloyl-2-O-cinnamoyl-beta-D-glucose (IC50 = 0.58 microM), procyanidin B-2 3,3'-di-O-gallate (IC50 = 0.54 microM), and procyanidin B-5 3,3'-di-O-gallate (IC50 = 0.55 microM), were found to be potent inhibitors of rat squalene epoxidase (SE). The inhibition at submicromolar level was far more potent than that of chemically synthesized substrate analogs. It was demonstrated for the first time that the cholesterol-lowering effect of rhubarb may be attributed to the potent inhibition activities of SE, a rate-limiting enzyme of cholesterol biogenesis.

Comparative efficacies of a calcium antagonist and an alpha1 blocker in elderly hypertensive patients with stroke.

We compared the effects of nilvadipine, a calcium antagonist, and terazosin. an alpha1 blocker, on the hemodynamics and quality of life (QOL) in 12 elderly hypertensive patients with stroke. Following a washout period of 2 weeks. nilvadipine or terazosin was administered for 2 weeks in a randomized crossover manner. At the end of control and treatment periods, we measured the 24-hour-ambulatory blood pressure (BP) and postural change of BP, and interviewed QOL. Terazosin treatment did not show consistent decrease of casual BP, but was associated with a transient decrease of systolic BP and an increase of pulse rate after standing, and enhanced postprandial decrease in BP. Nilvadipine decreased casual BP in a dose-dependent manner, but showed neither postural nor postprandial change of BP. There was no difference in QOL scores with either treatment. Results suggest that nilvadipine is preferable to terazosin for the treatment of elderly hypertensive patients with stroke.

Central and peripheral mechanisms involved in hypertension induced by chronic inhibition of nitric oxide synthase in rats.

OBJECTIVE: To study the possible central and peripheral mechanisms involved in hypertension induced by chronic inhibition of nitric oxide synthase. METHODS: We evaluated neurohormonal and renal responses of Wistar rats to chronic oral administration of 20 and 100 mg/kg per day NG-nitro-L-arginine methyl ester (L-NAME). Effects of intracerebroventricular and intravenous injections of NO donors (NOC-18 and FK-409) and an angiotensin II type 1 receptor antagonist CV-11974, and intravenous injection of alpha-adrenergic receptor antagonist phentolamine after chronic treatment with 100 mg/kg per day L-NAME were also studied. RESULTS: The chronic treatment with L-NAME induced a sustained dose-dependent hypertension with a decrease in heart rate. Urinary levels of norepinephrine and epinephrine decreased with no changes in plasma catecholamine levels, renin activity, and vasopressin level. Serum nitrate/nitrite levels in the rats treated with the high dose of L-NAME decreased. The intracerebroventricular and intravenous injections of the NO donors reduced arterial pressure in L-NAME-treated rats to a significantly greater extent than they did that in control rats. The intravenous but not intracerebroventricular injection of CV-11974 produced a sustained decrease in arterial pressure of L-NAME-treated rats. The depressor responses to intravenous injection of phentolamine of L-NAME-treated and control rats were similar. CONCLUSIONS: Results indicate that L-NAME-induced hypertension is associated with a deficiency of nitric oxide, both peripherally and centrally. Circulating angiotensin II could contribute to the maintenance of hypertension via angiotensin II type 1 receptor while the sympathetic nervous system seems to be suppressed.

[Guidelines on treatment of hypertension in the elderly, 1995--a tentative plan for comprehensive research projects on aging and health-- Members of the Research Group for "Guidelines on Treatment of Hypertension in the Elderly", Comprehensive Research Projects on Aging and Health, the Ministry of Health and Welfare of Japan].

We propose the following guidelines for treatment of hypertension in the elderly. 1. Indications for Treatment. 1) Age: Lifestyle modification is recommended for patients aged 85 years and older. Antihypertensive therapy should be limited to patients in whom the merit of the treatment is obvious. 2) Blood pressure: Systolic BP > 160 mmHg, diastolic BP > 90 approximately 10 mmHg. Systolic BP < age + 100 mmHg for those aged 70 years and older. Patients with mild hypertension (140-160/ 90-95 mmHg) associated with cardiovascular disease should be considered for antihypertensive drug therapy. 2. Goal of Therapy for BP: The goal BP in elderly patients is higher than that in younger patients (BP reduction of 10-20 mmHg for systolic BP and 5-10 mmHg for diastolic BP). In general, 140-160/< 90 mmHg is recommended as the goal. However, lowering the BP below 150/85 should be done with caution. 3. Rate of Lowering BP: Start with half the usual dose, observe at the same dose for at least four weeks, and reach the target BP over two months. Increasing the dose of antihypertensive drugs should be done very slowly. 4. Lifestyle Modification: 1) Dietary modification: (1) Reduction of sodium intake is highly effective in elderly patients due to their high salt-sensitivity. NaCl intake of less than 10 g/day is recommended. Serum Na+ should be occasionally measured. (2) Potassium supplementation is recommended, but with caution in patients with renal insufficiency. (3) Sufficient intake of calcium and magnesium is recommended. (4) Reduce saturated fatty acids. Intake of fish is recommended. (2) Regular physical activity: Recommended exercise for patients aged 60 years and older: peak heart rate 110/minute, for 30-40 minutes a day, 3-5 days a week. (3) Weight reduction. (4) Moderation of alcohol intake, smoking cessation. 5. Pharmacologic Treatment: 1) Initial drug therapy. First choice: Long-acting (once or twice a day) Ca antagonists or ACE inhibitors. Second choice: Thiazide diuretics (combined with potassium-sparing diuretic). 2) Combination therapy. (1) For patients without complications, either of the following is recommended. i) Ca antagoinst + ACE inhibitor, ii) ACE inhibitor + Ca antagonist (or low-dose diuretics), iii) diuretic + Ca antagonist (or ACE inhibitor), iv) beta-blockers, alpha 1-blockers, alpha + beta blockers can be used according to the patho-physiological state of the patient. (2) For patients with complications. Drug(s) should be selected according to each complication. 3) Relatively contraindicated drugs. beta-Blockers and alpha 1-blockers are relatively contraindicated in elderly patients with hypertension in Japan. Centrally acting agents such as reserpine, methyldopa and clonidine are also relatively contraindicated beta-Blockers are contraindicated in patients with congestive heart failure, arteriosclerosis obliterans, chronic obstructive pulmonary disease, diabetes mellitus (or glucose intolerance), or bradycardia. These conditions are often present in elderly subjects. Elderly subjects are susceptible to alpha 1-blocker-induced orthostatic hypotension, since their baroreceptor reflex is diminished. Orthostatic hypotension may cause falls and bone fractures in the elderly.

Peroxidase-catalyzed generation of catechin oligomers that inhibit glucosyltransferase from Streptococcus sobrinus.

Oolong tea extract (OTE) and the purified polymeric polyphenols from OTE have been found to inhibit glucosyltransferase (GTase) of mutans streptococci. In view of the partial fermentation characteristic of oolong tea, we describe here an in vitro model reaction system to produce partially fermented products of D-(+)-catechin or green tea extract (GTE) using horseradish peroxidase. A dimeric catechin molecule was identified as dehydro-dicatechin A by instrumental analyses. The molecular size of some oligomeric catechins was estimated by the elution profile with HPLC. These catechin oligomers markedly inhibited GTase from Streptococcus sobrinus 6715. As the degree of polymerization of catechin or GTE increased, GTase was inhibited more effectively. These results suggest that polymeric polyphenols found in OTE are synthesized by partial fermentation due to oxidases/peroxidases present in tea leaves.

Ambulatory blood pressure monitoring in elderly hypertensives treated with the new calcium antagonist, nilvadipine.

A newly developed calcium antagonist, nilvadipine, was administered to 7 hypertensive patients aged 75.6 y. Nilvadipine 4 mg b.d. decreased the average 24-h blood pressure significantly from 169/89 mmHg to 152/81 mmHg after 7 to 14 days without any change in the pulse rate. The circadian patterns of blood pressure and pulse rate were not affected by nilvadipine. Although the present study was a preliminary one done over a short period in a small number of patients, the results suggest that nilvadipine exerts an antihypertensive effect without altering the circadian pattern or the variability of blood pressure in elderly hypertensive patients.