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An expanded concept of "insurance"
supplementation--broad-spectrum protection from cardiovascular
disease.
McCarty MF
Med Hypotheses (England) Oct 1981, 7 (10)
p1287-1302
The preventive merits of "nutritional insurance"
supplementation can be considerably broadened if meaningful
doses of nutrients such as mitochondrial "metavitamins"
(coenzyme Q, lipoic acid, carnitine), lipotropes, and key
essential fatty acids, are included in insurance supplements.
From the standpoint of cardiovascular protection, these
nutrients, as well as magnesium, selenium, and GTF-chromium,
appear to have particular value. Sophisticated insurance
supplementation would likely have a favorable impact on many
parameters which govern cardiovascular risk--serum lipid
profiles, blood pressure, platelet stability, glucose
tolerance, bioenergetics, action potential regulation--and as
a life-long preventive health strategy might confer
substantial benefit. (111 Refs.)
Italian multicenter study on the safety and
efficacy of coenzyme Q10 as adjunctive therapy in heart
failure (interim analysis)
Baggio E, Gandini R, Plancher AC, Passeri M, Carmosino
G
Department of Internal Medicine, V. Buzzi Hospital,
Milan.
Clin Investig (Germany) 1993, 71 (8 Suppl)
pS145-9
Digitalis, diuretics, and vasodilators are considered
standard therapy for patients with congestive heart failure,
for which treatment is tailored according to the severity of
the syndrome and the patient profile. Apart from the clinical
seriousness, heart failure is always characterized by an
energy depletion status, as indicated by low intramyocardial
ATP and coenzyme Q10 levels. We investigated safety and
clinical efficacy of coenzyme Q10 (CoQ10) adjunctive treatment
in congestive heart failure, whi ch had been diagnosed at
least 6 months previously and treated with standard therapy. A
total of 2500 patients in NYHA classes II and III were
enrolled in this open noncomparative 3-month postmarketing
drug surveillance study in 173 Italian centers. The daily dose
of CoQ10 was 50-150 mg orally, with the majority of patients
(78%) receiving 100 mg/day. Clinical and laboratory parameters
were evaluated at the entry into the study and on day 90; the
assessment of clinical signs and symptoms was made using from
two- to seven-point scales. Preliminary results on 1113
patients (mean age 69.5 years) show a low incidence of side
effects: 10 adverse reactions were reported in 8 (0.8%)
patients, of which only 5 reactions were considered as
correlated to the test treatment. After 3 months of test
treatment the proportions of patients with improvement in
clinical signs and symptoms were as follows: cyanosis 81%,
edema 76.9%, pulmonary rales 78.4%, enlargement of the liver
area 49.3%, jugular reflux 81.5%, dyspnea 54.2%, palpitations
75.7%, sweating 82.4%, arrhythmia 62%, insomnia 60.2%, vertigo
73%, and nocturia 50.7%.
Isolated diastolic dysfunction of the myocardium
and its response to CoQ10 treatment.
Langsjoen PH, Langsjoen PH, Folkers K
Clin Investig (Germany) 1993, 71 (8 Suppl)
pS140-4
Symptoms of fatigue and activity impairment, atypical
precordial pain, and cardiac arrhythmia frequently precede by
years the development of congestive heart failure. Of 115
patients with these symptoms, 60 were diagnosed as having
hypertensive cardiovascular disease, 27 mitral valve prolapse
syndrome, and 28 chronic fatigue syndrome. These symptoms are
common with diastolic dysfunction, and diastolic function is
energy dependent. All patients had blood pressure, clinical
status, coenzyme Q10 (CoQ10) blood levels and
echocardiographic measurement of diastolic function, systolic
function, and myocardial thickness recorded before and after
CoQ10 replacement. At control, 63 patients were functional
class III and 54 class II; all showed diastolic dysfunction;
the mean CoQ10 blood level was 0.855 micrograms/ml; 65%, 15%,
and 7% showed significant myocardial hypertrophy, and 87%,
30%, and 11% had elevated blood pressure readings in
hypertensive disease, mitral valve prolapse and chronic
fatigue syndrome respectively. Except for higher blood
pressure levels and more myocardial thickening in the
hypertensive patients, there was little difference between the
three groups. CoQ10 administration resulted in improvement in
all; reduction in high blood pressure in 80%, and improvement
in diastolic function in all patients with follow-up
echocardiograms to date; a reduction in myocardial thickness
in 53% of hypertensives and 36% of the combined prolapse and
fatigue syndrome groups; and a reduced fractional shortening
in those high at control and an increase in those initially
low.(ABSTRACT TRUNCATED AT 250 WORDS)
Protective effects of propionyl-L-carnitine during
ischemia and reperfusion.
Shug A, Paulson D, Subramanian R, Regitz V
University of Wisconsin Medical School, Madison.
Cardiovasc Drugs Ther (United States) Feb 1991, 5 Suppl 1
p77-83
When cardiac function in isolated rat hearts was impaired
by subjecting them to ischemia, subsequent perfusion with
propionyl-L-carnitine and related compounds increased their
rate of recovery. Thus at 11 mM, both propionyl-L-carnitine
and, to a lesser extent, its taurine amide, and also
acetyl-L-carnitine, significantly restored cardiac function in
15 minutes after 90 minutes of either low-flow or intermittent
no-flow ischemia. Carnitine itself was ineffective.
Propionyl-L-carnitine also increased tis sue ATP and creatine
phosphate compared with controls, but did not affect the
levels of long-chain acyl carnitine and coenzyme. These esters
also depleted fatty acid peroxidation, as shown with
malonaldehyde, and were more effective than carnitine in
preventing the production of superoxide. In myocytes,
propionyl-L-carnitine alone stimulated palmitate oxidation,
but in rat heart homogenates, both L-carnitine and
propionyl-L-carnitine did so, while acetyl-L-carnitine was
actually inhibitory. Possible mechanisms for the protective
action of propionyl-L-carnitine against ischemia include an
increased rate of cellular transport, stimulation of fatty
acid oxidation, and a reduction of free radical formation.
Consequences of magnesium deficiency on the
enhancement of stress reactions; preventive and therapeutic
implications (a review).
Seelig MS
Department of Nutrition, School of Public Health, University
of North Carolina, Chapel Hill.
J Am Coll Nutr 1994 Oct;13(5):429-46
Stress intensifies release of catecholamines and
corticosteroids that increase survival of normal animals when
their lives are threatened. When magnesium (Mg) deficiency
exists, stress paradoxically increases risk of cardiovascular
damage including hypertension, cerebrovascular and coronary
constriction and occlusion, arrhythmias and sudden cardiac
death (SCD). In affluent societies, severe dietary Mg
deficiency is uncommon, but dietary imbalances such as high
intakes of fat and/or calcium (Ca) can intensify Mg
inadequacy, especially under conditions of stress. Adrenergic
stimulation of lipolysis can intensify its deficiency by
complexing Mg with liberated fatty acids (FA), A low Mg/Ca
ratio increases release of catecholamines, which lowers tissue
(i.e. myocardial) Mg levels. It also favors excess release or
formation of factors (derived both from FA metabolism and the
endothelium), that are vasoconstrictive and platelet
aggregating; a high Ca/Mg ratio also directly favors blood
coagulation, which is also favored by excess fat and its
mobilization during adrenergic lipolysis. Auto-oxidation of
catecholamines yields free radicals, which explains the
enhancement of the protective effect of Mg by anti-oxidant
nutrients against cardiac damage caused by
beta-catecholamines. Thus, stress, whether physical (i.e.
exertion, heat, cold, trauma--accidental or surgical, burns),
or emotional (i.e. pain, anxiety, excitement or depression)
and dyspnea as in asthma increases need for Mg. Genetic
differences in Mg utilization may account for differences in
vulnerability to Mg deficiency and differences in body
responses to stress.
Community-based prevention of stroke: nutritional
improvement in Japan
Yamori Y, Horie R
Kyoto University, Japan.
Health Rep 1994;6(1):181-8
OBJECTIVES: (1) To demonstrate the importance of nutrition,
especially sodium restriction and increased potassium and
protein intakes, in the prevention of hypertension and stroke
in a pilot study involving senior citizens. (2) To design a
population-based intervention in the Shimane Prefecture of
Japan concerning dietary factors such as low sodium and high
potassium, protein, magnesium, calcium and dietary fibre in
the prevention of stroke.
DESIGN AND METHODS: The intervention study was carried out
at a senior citizens' residence and included general health
education along with a reduction of dietary salt intake and
increases in vegetable and protein, especially from seafood.
Sixty-three healthy senior citizens (average age: 74.8 +/- 7.7
years) had their daily meals modified to a low
sodium/potassium ratio for four weeks without their knowledge
by the use of a potassium chloride substitute for salt, soy
sauce and bean paste, which contains much less sodium and more
potassium. Monosodium L-glutamate monohydrate used for cooking
was changed to monopotassium L-glutamate monohydrate. Blood
pressure was measured with the patient in the sitting
position. Daily dietary sodium and potassium intakes were
assessed by flame photometry from 24-hour urine specimens.
Extensive intervention programs were introduced into the
Shimane Prefecture, which has a population of 750,000, through
health education classes for housewives, home visits by health
nurses and an educational TV program for dietary improvement.
The mortality from stroke was monitored for 10 years and
compared with the average in Japan.
RESULTS: The blood pressure lowering effect of reducing the
dietary sodium/potassium ratio was confirmed through a pilot
intervention study at the senior citizens' resid ence. The
mortality rates for stroke in the middle-aged population from
the Shimane Prefecture during the 10 years after the
introduction of dietary improvement had a steeper decline in
hemorrhagic, ischemic and all strokes than the average for
Japan.
Effect of dietary magnesium supplementation on
intralymphocytic free calcium and magnesium in stroke-prone
spontaneously hypertensive rats.
Adachi M; Nara Y; Mano M; Yamori Y
Department of Pathology, Shimane Medical University, Izumo,
Japan.
Clin Exp Hypertens 1994 May;16(3):317-26
The effects of dietary magnesium (Mg) supplementation on
intralymphocytic free Ca2+ ([Ca2+]i) and Mg2+ ([Mg2+]i) were
examined in the stroke-prone spontaneously hypertensive rats
(SHRSP) at the age of 10 weeks. After 40 day Mg
supplementation (0.8% Mg in the diet), systolic blood pressure
(SBP) was significantly lower in Mg supplemented group (Mg
group) than the control group (0.2% Mg). [Ca2+]i was
significantly lower and [Mg2+]i was significantly higher in Mg
group than in the control group. Further, [Ca2+]i was
positively and [Mg2+]i was negatively correlated with SBP.
These results suggest that dietary Mg supplementation modifies
[Ca2+]i and [Mg2+]i, and modulates the development of
hypertension.
Clinical study of cardiac arrhythmias using a
24-hour continuous electrocardiographic recorder (5th
report)--antiarrhythmic action of coenzyme Q10 in
diabetics.
Fujioka T, Sakamoto Y, Mimura G
Tohoku J Exp Med (Japan) Dec 1983, 141 Suppl
p453-63
An investigation was undertaken to evaluate the
antiarrhythmic effect of CoQ10 on VPBs using the Holter ECG,
in 27 patients with no clinical findings of organic
cardiopathies. As a result, the effect of CoQ10 on VPBs was
considered beneficial in 6 (22%) of 27 cases, consisting of 1
patient with hypertension and 5 patients with DM. Even in the
remaining 2 patients with DM, the frequency of VPBs was
reduced by 50% or more during treatment with CoQ10. The mean
reduction of VPBs frequency in the 5 responders plus these 2
patients with DM was 85.7%. These findings suggest that CoQ10
exhibits an effective antiarrhythmic action not merely on
organic heart disease but also on VPBs supervening on DM.
Usefulness of coenzyme Q10 in clinical cardiology:
a long-term study.
Langsjoen H, Langsjoen P, Langsjoen P, Willis R, Folkers
K
University of Texas Medical Branch, Galveston 77551,
USA.
Mol Aspects Med 1994;15 Suppl:s165-75
Over an eight year period (1985-1993), we treated 424
patients with various forms of cardiovascular disease by
adding coenzyme Q10 (CoQ10) to their medical regimens. Doses
of CoQ10 ranged from 75 to 600 mg/day by mouth (average 242
mg). Treatment was primarily guided by the patient's clinical
response. In many instances, CoQ10 levels were employed with
the aim of producing a whole blood level greater than or equal
to 2.10 micrograms/ml (average 2.92 micrograms/ml, n = 297).
Patients were followed for an average of 17.8 months, with a
total accumulation of 632 patient years. Eleven patients were
omitted from this study: 10 due to non-compliance and one who
experienced nausea. Eighteen deaths occurred during the study
period with 10 attributable to cardiac causes. Patients were
divided into six diagnostic categories: ischemic
cardiomyopathy (ICM), dilated cardiomyopathy (DCM), primary
diastolic dysfunction (PDD), hypertension (HTN), mitral valve
prolapse (MVP) and valvular heart disease (VHD). For the
entire group and for each diagnostic category, we evaluated
clinical response according to the New York Heart Association
(NYHA) functional scale, and found significant improvement. Of
424 patients, 58 per cent improved by one NYHA class, 28% by
two classes and 1.2% by three classes. A statistically
significant improvement in myocardial function was documented
using the following echocardiographic parameters: left
ventricular wall thickness, mitral valve inflow slope and
fractional shortening. Before treatment with CoQ10, most
patients were taking from one to five cardiac medications.
During this study, overall medication requirements dropped
considerably: 43% stopped between one and three drugs. Only 6%
of the patients required the addition of one drug. No apparent
side effects from CoQ10 treatment were noted other than a
single case of transient nausea. In conclusion, CoQ10 is a
safe and effective adjunctive treatment for a broad range of
cardiovascular diseases, producing gratifying clinical
responses while easing the medical and financial burden of
multidrug therapy.
Effect of coenzyme Q10 on structural alterations in
the renal membrane of stroke-prone spontaneously hypertensive
rats.
Okamoto H, Kawaguchi H, Togashi H, Minami M, Saito H, Yasuda
H
Department of Cardiovascular, Hokkaido University,
Japan.
Biochem Med Metab Biol 1991 Apr;45(2):216-26
To test the hypothesis that structural abnormalities exist
in the kidney membrane of spontaneously hypertensive rats, we
examined the effect of long-term administration of coenzyme
Q10 on membrane lipid alterations in the kidney of
stroke-prone spontaneously hypertensive rats (SHRSP). As
compared with normotensive Wistar-Kyoto rats, renal membrane
phospholipids, especially phosphatidylcholine and
phosphatidylethanolamine, decreased and renal phospholipase A2
activity was enhanced with age in untreated SHRSP. Treatment
with coenzyme Q10 attenuated the elevation of blood pressure,
the membranous phospholipid degradation, and the enhanced
phospholipase A2 activity. These results suggest that one
factor contributing to the progress of hypertension is a
structural membrane abnormality that alters the physical and
functional properties of the cell membrane, and coenzyme Q10
might protect the renal membrane from damage due to
hypertension in SHRSP.
Co-enzyme Q10: a new drug for cardiovascular
disease.
Greenberg S, Frishman WH
Department of Medicine, Mt. Sinai Hospital and Medical
Center, New York, New York.
J Clin Pharmacol 1990 Jul;30(7):596-608
Co-enzyme Q10 (ubiquinone) is a naturally occurring
substance which has properties potentially beneficial for
preventing cellular damage during myocardial ischemia and
reperfusion. It plays a role in oxidative phosphorylation and
has membrane stabilizing activity. The substance has been used
in oral form to treat various cardiovascular disorders
including angina pectoris, hypertension, and congestive heart
failure. Its clinical importance is now being established in
clinical trails worldwide.
[Effects of
2,3-dimethoxy-5-methyl-6-(10'-hydroxydecyl)-1,4-benzoquinone
(CV-2619) on adriamycin-induced ECG abnormalities and
myocardial energy metabolism in spontaneously hypertensive
rats]
Shimamoto N, Tanabe M, Hirata M
Nippon Yakurigaku Zasshi 1982 Oct;80(4):307-15
Antidote actions of CV-2619 and ubiquinone-10 (Q-10)
against adriamycin (ADM) cardiotoxicity were studied in
spontaneously hypertensive rats. ADM (1 mg/kg/day, i.p.)
elicited widening of the QRS complex in the ECG. The widening
of the QRS complex was counteracted by a 10-day treatment with
CV-2619 (10 and 30 mg/kg/day, p.o.) or Q-10 (10 mg/kg/day,
p.o.), which was started on the 15th day of the ADM treatment.
CV-2619 or Q-10, however, did not influence ADM-induced
decrease in body and heart ventricular weights. Systemic
hypotension caused by adriamycin was accelerated by CV-2619 or
Q-10. The ADM treatment significantly decreased myocardial
glycogen and glucose contents, while it did not affect the
lactate content. Furthermore, ADM did not affect the
myocardial content of adenine nucleotides, but significantly
increased that of creatine phosphate. CV-2619 or Q-10
medication did not counteract changes in these contents by
ADM. On the contrary, both agents decreased the lactate
content and increased the phosphorylation potential, an index
of myocardial energy state. In conclusion, CV-2619 might be as
effective as Q-10 to protect the heart against ADM
cardiotoxicity, and both test agents improved the myocardial
energy state.
Bioenergetics in clinical medicine. III. Inhibition
of coenzyme Q10-enzymes by clinically used anti-hypertensive
drugs.
Kishi H, Kishi T, Folkers K
Res Commun Chem Pathol Pharmacol 1975
Nov;12(3):533-40
Background data revealed that some American and Japanese
patients with essential hypertension, including many who were
not being treated with any anti-hypertensive drug, had a
deficiency of coenzyme Q10. Eight clinically used
anti-hypertensive drugs have now been tested for inhibition of
two mitochondrial coenzyme Q10-enzymes of heart tissue,
succinoxidase and NADH-oxidase. Diazoxide and propranolol
significantly inhibited the CoQ10-succinoxidase and
CoQ10-NADH-oxidase, respectively. Metoprolol did not inhibit
succinoxidase, and was one-fourth as active as propranolol for
inhibition of NADH-oxidase. Hydrochlorothiazide, hydralazine,
ans clonidine also inhibited CoQ10-NADH-oxidase. Reserpine did
not inhibit either CoQ10-enzyme, and methyldopa was a very eak
inhibitor of succinoxidase. The internationally recognized
clinical side-effects of propranolol may be due, in part, to
inhibition of CoQ10-enzymes which are indispensable in the
bioenergetics of cardiac function. A pre-existing deficiency
of coenzyme Q10 in the myocardium of hypertensive patients
could be augmented by subsequent treatment with propranolol,
possibly to the "life-threatening" state described by
others.
Bioenergetics in clinical medicine. Studies on
coenzyme Q10 and essential hypertension.
Yamagami T, Shibata N, Folkers K
Res Commun Chem Pathol Pharmacol 1975
Jun;11(2):273-88
The specific activities (S.A.) of the succinate
dehydrogenase-coenzyme Q10 (CoQ10) reductase of a control
group of 65 Japanese adults and 59 patients having essential
hypertension were determined. The mean S.A. of the
hypertensive group was significantly lower (p less than 0.001)
and the mean % deficiency of enzyme activity was significantly
higher (p less than 0.001) than the values for the control
group. These data on Japanese in Osaka agree with data on
Americans in Dallas. Some patients showed no CoQ10-deficiency,
and others showed definite deficiencies. Emphasizing the
CoQ10-enzyme for patient selection, CoQ10 was administered to
hypertensive patients. Four individuals showed significant but
partial reductions of blood pressure. Monitoring the
CoQ10-enzyme before, during, and after administration of CoQ10
indicated responses. The maintenance of high blood pressure
could be primarily due to contraction of the arterial wall.
Contraction or relaxation of an arterial wall is dependent
upon bioenergetics, which also provide the energy for
biosynthesis of angiotensin II, renin, aldosterone, and the
energy for sodium and potassium transport. A clinical benefit
from administration of CoQ10 to patients with essential
hypertension could be based upon correcting a deficiency in
bioenergetics, and point to possible combination treatments
with a form of CoQ and anti-hypertensive drugs.
[Prevention of cerebrovascular insults]
Stahelin HB, Evison J, Seiler WO
Geriatrische Universitatsklinik, Kantonsspital Basel.
Schweiz Med Wochenschr 1994 Nov
12;124(45):1995-2004
Cerebrovascular infarction is the third leading cause of
mortality following coronary heart disease and malignancies.
WHO studies show that more than half of patients admitted for
cerebrovascular infarction were not treated for hypertension.
The risk factors for coronary heart disease and
cerebrovascular infarction are not identical. Patients with
systolic and diastolic hypertension, atrial fibrillation,
stenosis of the carotid artery, and smoking, have a
significantly elevated risk for cerebrovascular accidents.
Hypercholesterolemia and diabetes are less important risk
factors. Risk factors amendable by adequate nutritional intake
are low supply of carotene and vitamin C. Homocysteineemia
appears to be a risk factor that may be influenced by
appropriate nutrition. Antihypertensive therapy is the most
important primary and secondary preventive measure. No smoking
and adequate dietary intake are also important. Primary
prevention with low dose salicylic acid (ASA) is recommended
in the presence of additional cardiovascular risk factors. The
benefit of low dose anticoagulant therapy in atrial
fibrillation without symptoms is not fully established. In
subjects with atrial fibrillation with cerebrovascular events
anticoagulants are superior to ASA. Surgical treatment of
significant stenosis of the carotid artery is indicated. In
secondary prevention of thromboembolic events, low dose ASA is
recommended. A valuable alternative in case of side effects is
available in ticlopidine.
[Essential antioxidants in cardiovascular
diseases--lessons for Europe]
Gey KF, Stahelin HB, Ballmer PE
Vitamin-Einheit, Institut fur Biochemie und
Molekularbiologie, Universitat Bern.
Ther Umsch 1994 Jul;51(7):475-82
Complementary epidemiological studies consistently reveal a
substantially increased risk of cardiovascular disease (CVD)
at suboptimal plasma levels of essential antioxidants in
comparison with optimum ranges of vitamin C (> 50 mumol/l),
of lipid-standardized vitamin E (> 30 mumol/l or a
tocopherol/cholesterol ratio > 5.2 mumol/mmol),
beta-carotene (> 0.4 mumol/l). The poor level of any single
essential antioxidant can increase the risk, and the
combination of suboptimal levels has additive or even
overmultiplicative effects on the risk for CVD. Suboptimal
antioxidant levels are stronger predictors of the severalfold
regional differences of CVD in Europe than classical risk
factor such as hypercholesterolemia, hypertension, etc.
Scotsmen and Fins tend to suboptimal levels of essential
antioxidants, whereas German-speaking regions may mostly
reveal a fair vitamin E status, but at least one out of four
subjects can reveal suboptimal levels of vitamin C and
carotene, particularly in smokers. This deficit can be avoided
by 'prudent diets' rich in fruits and vegetables as practiced
by Frenchmen, Italians and Spaniards. The simultaneous
correction of all suboptimal antioxidant levels appears to be
a promising new means for CVD prevention, particularly in the
northern parts of Europe. In the USA the risk of CVD could
substantially be reduced without dietary modifications by
voluntary daily supplements as follows: vitamin C > 140 mg,
vitamin E > 100 IU (100 mg d,l- or 74 mg
d-alpha-tocopherylacetate), and in current smokers by
gamma-carotene > 8.6 mg. Hence, these antioxidants may be
crucial constituents of diets rich in fruits and vegetables,
which are by consensus associated with a lower risk of
premature death from CVD (and cancer as well).
Antioxidant vitamin intake and coronary mortality
in a longitudinal population study.
Knekt P, Reunanen A, Jarvinen R, Seppanen R, Heliovaara M,
Aromaa A
Social Insurance Institution, Helsinki, Finland.
Am J Epidemiol 1994 Jun 15;139(12):1180-9
Oxidation of lipoproteins is hypothesized to promote
atherosclerosis and, thus, a high intake of antioxidant
nutrients may protect against coronary heart disease. The
relation between the intakes of dietary carotene, vitamin C,
and vitamin E and the subsequent coronary mortality was
studied in a cohort of 5,133 Finnish men and women aged 30-69
years and initially free from heart disease. Food consumption
was estimated by the dietary history method covering the total
habitual diet during the previous year. Altogether, 244 new
fatal coronary heart disease cases occurred during a mean
follow-up of 14 years beginning in 1966-1972. An inverse
association was observed between dietary vitamin E intake and
coronary mortality in both men and women with relative risks
of 0.68 (p for trend = 0.01) and 0.35 (p for trend < 0.01),
respectively, between the highest and lowest tertiles of the
intake. Similar associations were observed for the dietary
intake of vitamin C and carotenoids among women and for the
intake of important food sources of these micronutrients,
i.e., of vegetables and fruits, among both men and women. The
associations were not attributable to confounding by major
nondietary risk factors of coronary heart disease, i.e., age,
smoking, serum cholesterol, hypertension, or relative weight.
The results support the hypothesis that antioxidant vitamins
protect against coronary heart disease, but it cannot be
excluded that foods rich in these micronutrients also contain
other constituents that provide the protection.
The decline in stroke mortality. An epidemiologic
perspective.
Klag MJ, Whelton PK
Department of Medicine, Johns Hopkins University School of
Medicine, Baltimore, MD.
Ann Epidemiol 1993 Sep;3(5):571-5
The evidence that treatment of hypertension prevents stroke
is incontrovertible. Several observations, however, suggest
that improvements in the prevalence of antihypertensive
treatment cannot explain all of the recent decline in stroke
mortality. Changes in nutritional patterns may explain some of
the observed decline. Prospective studies have demonstrated
conclusively an independent, increasing risk of hemorrhagic,
but not thrombotic, stroke at higher levels of alcohol use.
Stroke mortality is associated inversely with fat and protein
intake. Dietary sodium has been linked to stroke in ecologic
studies but not in prospective studies. Ecologic studies have
suggested that foods high in vitamin C and potassium protect
against stroke; an inverse association of potassium intake
with fatal stroke has been demonstrated in cohort studies. Two
studies in humans also suggest a protective effect of serum
selenium against subsequent stroke. Determination of the
influence of nutrients on stroke incidence offers tantalizing
opportunities for future research and possibly,
intervention.
Can antioxidants prevent ischemic heart
disease?
Maxwell SR
Queen Elizabeth Hospital, Edgbaston, Birmingham, U.K.
J Clin Pharm Ther 1993 Apr;18(2):85-95
Ischemic heart disease remains a major cause of mortality
in developed countries. A number of important risk factors for
the development of coronary atherosclerosis have been
identified including hypertension, hypercholesterolaemia,
insulin resistance and smoking. However, these factors can
only partly explain variations in the incidence of ischaemic
heart disease either between populations or within populations
over time. In addition, population interventions based upon
these factors have had little impact in the primary prevention
of heart disease. Recent evidence suggests that one of the
important mechanisms predisposing to the development of
atherosclerosis is oxidation of the cholesterol-rich
low-density lipoprotein particle. This modification
accelerates its uptake into macrophages, thereby leading to
the formation of the cholesterol-laden 'foam cell'. In vitro,
low-density lipoprotein oxidation can be prevented by
naturally occurring antioxidants such as vitamin C, vitamin E
and beta-carotene. This article explores the evidence that
these dietary anti-oxidants may influence the rate of
progression of coronary atherosclerosis in vivo and discusses
the need for formal clinical trials of antioxidant
therapy.
Antioxidant therapy in the aging process.
Deucher GP
Clinica Guilherme Paulo Deucher, Sao Paulo, Brazil.
EXS 1992;62:428-37
A total of 1,265 patients with age-related diseases such as
diabetes, arthritis, vascular disease and hypertension as well
as 1,100 persons in diminished health without apparent
disease, were treated with the metal chelator EDTA and
antioxidants such as vitamin C, E, beta-carotene, selenium,
zinc and chromium. Good results were observed in the majority
of patients. This is encouraging for the initiation of
controlled clinical trials.
Effect of flosequinan on ischaemia-induced
arrhythmias and on ventricular cyclic nucleotide content in
the anaesthetized rat.
Jones RB, Frodsham G, Dickinson K, Foster GA
Boots Pharmaceuticals, Research Department, Nottingham.
Br J Pharmacol (England) Apr 1993, 108 (4)
p1111-6
1. Flosequinan, milrinone, isoprenaline and forskolin given
intravenously at similarly hypotensive doses have been
evaluated in separate studies for their effect on
ischaemia-induced arrhythmias and on ventricular cyclic
nucleotide content following coronary artery ligation in the
pentobarbitone anaesthetized rat.
2. Flosequinan did not affect mortality or arrhythmias
following coronary artery ligation in either study and no
change in ventricular cyclic nucleotide content was
observed.
3. Isoprenaline caused a significant increase in mortality
(P < 0.05) in both studies whereas milrinone and forskolin
caused a significant increase in mortality in only one of the
two studies conducted. All three agents caused significant
increases in cyclic AMP which were associated with increased
incidence of arrhythmias.
4. When compared at similarly hypotensive doses,
flosequinan, in contrast to milrinone, isoprenaline and
forskolin, did not influence ischaemia-induced arrhythmias or
raise ventricular cyclic nucleotide levels in the anesthetized
rat.
What do the newer inotropic drugs have to
offer?
Sasayama S
Second Department of Internal Medicine, Toyama Medical and
Pharmaceutical University, Japan.
Cardiovasc Drugs Ther 1992 Feb;6(1):15-8
Intensive interest and passion have been generated in the
search for orally effective inotropes over the past few
decades. Several extensive clinical evaluations of these
agents have now been completed. Both beta- adrenergic agonists
and phosphodiesterase inhibitors that exert cardiotonic action
by increasing intracellular cyclic adenosine monophosphate
produced dramatic short-term therapy hemodynamic benefits in
patients with advanced heart failure. However, patients who
received long-term treatment with these agents had unfavorable
outcomes, including a higher mortality and morbidity rate, and
deleterious side effects. The principal mechanisms responsible
for the limitations in its usefulness in long-term therapy may
be related to increased energy expenditure and potential
arrhythmogenic effects. In contrast to these pessimistic
views, one quinolinone derivative has been shown to exert a
positive inotropic action without a chronotropic effect.
Patients with mild heart failure responded favorably to this
agent in long- term therapy. The lack of an increase in heart
rate might be the cause of this salutary effect. Concerns
regarding the possible improvement in the prognosis of
patients with heart failure due to the use of positive
inotropic therapy still continue.
Arrhythmogenic effect of forskolin in the isolated
perfused rat heart: Influence of nifedipine reduction of
external calcium
Huang XD, Wong TM
Department of Physiology, Faculty of Medicine, University of
Hong Kong.
Clin. Exp. Pharmacol. Physiol. (Australia), 1989, 16/10
(751-757)
This study investigated first the effects of forskolin on
cardiac rhythm, and second the roles of calcium in cardiac
arrhythmogenesis by cAMP. Two series of experiments were
performed. In the first series, forskolin was administered
into the isolated perfused rat heart. In the second series,
forskolin administration was preceded by administration of
nifedipine, a calcium channel blocker, or infusion of a low
concentration calcium solution. In both experiments, the
myocardial cAMP level and electrocardiogram were determined.
It was found that forskolin increased cAMP level as well as
inducing arrhythmia. Pretreatment with nifedipine or a
reduction of external calcium, that either maintained or
further enhanced the forskolin-induced increase in the cAMP
level, abolished the forskolin-induced arrhythmia. The results
of the present study support the hypothesis that myocardial
cAMP mediates cardiac arrhythmia, and provide evidence that
calcium is essential in arrhythmia mediated by cAMP.
Hormone secretagogues increase cytosolic calcium by
increasing cAMP in corticotropin-secreting cells
Luini A, Lewis D, Guild S, Corda D, Axelrod J
Proc. Natl Acad. Sci. U.S.A. (USA), 1985, 82/23
(8034-8038)
Corticotropin (ACTH)-releasing factor, vasoactive
intestinal peptide, and catecholamines - hormones that
stimulate ACTH secretion and cAMP generation - increased
cytosolic calcium in AtT-20 cells. The increase in
intracellular calcium is presumably a consequence of the
stimulated cAMP synthesis, since forskolin, an activator of
the catalytic unit of adenylate cyclase, and the cAMP analog
8-bromoadenosine 3',5'-cyclic monophosphate (8Br-cAMP) also
increased the cytosolic levels of this ion. Pretreatment with
somatostatin, a neuropeptide that inhibits stimulation of the
adenylate cyclase system and the secretion of ACTH blocked the
increase of cytosolic calcium. The effect of 8Br-cAMP, which
bypasses the cyclase, was not inhibited by somatostatin
pretreatment. The source of the increased calcium appears to
be mainly extracellular. This is indicated by the inability of
the secretagogues to increase cytosolic calcium in a medium
deprived of this ion or in the presence of blockers of
voltage-gated calcium channels. The involvement of calcium
channels in the calcium rise evoked by the secretagogues was
supported by experiments using the whole-cell patch-clamp
technique. In these experiments 8Br-cAMP increased
voltage-dependent calcium currents. These results suggest the
following chain of events in the receptor-mediated elevation
of cytosolic calcium and the concomitant release of ACTH from
AtT-20 cells: hormone-receptor binding > or = cAMP
synthesis > or = protein kinase activation > or =
calcium channel activation > or = increase in cytosolic
calcium > or = many steps > or = ACTH release. Phorbol
myristate acetate, a compound which does not stimulate cAMP
generation but enhances the release of ACTH in AtT-20 cells,
decreased the cytosolic calcium level.
The genesis of arrhythmias during myocardial
ischemia. Dissociation between changes in cyclic adenosine
monophosphate and electrical instability in the rat
Manning AS, Kinoshita K, Buschmans E, Coltart DJ, Hearse
DJ
Circ. Res. (USA), 1985, 57/5 (668-675)
It has been proposed that increases in tissue cyclic
adenosine monophosphate during ischemia may be responsible for
the induction of arrhythmias that occur during the early
minutes of ischemia. We have tested this hypothesis using the
isolated perfused rat heart with coronary artery occlusion for
30 minutes. In control hearts, after a transient small rise,
cyclic adenosine monophosphate content remained close to its
preischemic value (3.0 + or - 0.1 nM/g dry weight) throughout
the period of occlusion. Eight percent (1/12) of the hearts
fibrillated. Ninety-two percent (11/12) of the hearts
exhibited ventricular tachycardia, and the mean total number
of premature ventricular complexes was 528 + or - 121.
Inclusion of epinephrine (1.0 muM) in the perfusion fluid
elevated cyclic adenosine monophosphate prior to coronary
occlusion (to 10.7 + or - 0.6 nM/g dry weight) and also
throughout the ischemic period. It also increased arrhythmias
such that 83% (20/24) of hearts fibrillated, 100% exhibited
ventricular tachycardia, and the mean number of premature
ventricular complexes increased to 747 + or - 86. Inclusion of
forskolin (0.2 muM), which stimulates adenyl cyclase
independently of the beta-receptor, increased cyclic adenosine
monophosphate content to a greater extent than epinephrine, to
14.1 + or - 0.9 nM/g dry weight before the onset of ischemia
and to 8.2 + or - 0.4 nM/g dry weight after 30 minutes of
ischemia. Despite the large increases in cyclic adenosine
monophosphate, there was no increase in rhythm disturbances
which were less than those seen in controls. Thus, no hearts
fibrillated, the incidence of ventricular tachycardia was
reduced to 58% (7/12), and the mean number of premature
ventricular complexes was greatly reduced (79 + or - 29,
P<0.001 compared to the number with drug carrier alone).
Higher concentrations of both epinephrine and forskolin caused
changes that were qualitatively similar to those seen with the
lower concentrations. In addition, when hearts were paced at
400 impulses/min, again only epinephrine increased the
severity of ischemia-induced arrhythmias. In conclusion,
despite its ability to increase cyclic adenosine monophosphate
content to a greater extent than epinephrine, forskolin exerts
an antiarrhythmic effect. This suggests that increased cyclic
adenosine monophosphate content is not necessarily involved in
the genesis of ischemia-induced arrhythmias, and that some
other facet of adrenoceptor stimulation or catecholamine
action may be involved.
Effects of high K on relaxation produced by drugs
in the guinea-pig tracheal muscle
Ito M, Baba K, Takagi K, Satake T, Tomita T
Respir. Physiol. (Netherlands), 1985, 61/1
(43-55)
In the guinea-pig tracheal smooth muscle, effects of
various relaxants were compared in normal (5.9 mM) and excess
(40 mM) K media. The relaxing efect of calcium-channel
blockers, nifedipine and verapamil (group I) was potentiated
by increasing the external K concentration. The effect of the
drugs which are supposed to increase intracellular cyclic AMP,
such as isoprenaline, forskolin, isobutylmethylxanthine,
theophylline, dibutyryl cyclic AMP (group II) was moderately
reduced by excess K. Nitroprusside, 8-bromo-cyclic GMP and
sodium nitrite (group III) are generally considered to
increase intracellular cyclic GMP and their effect was
markedly reduced by excess K. When the tension development was
made the same at 5.9 mM K and 40 mM K by adjusting the Ca
concentration, the relaxing effect was similar and independent
of the K concentration both for group II and group III drugs.
It seems that the group II drugs can better overcome a large
influx of Ca than group III drugs.
Forskolin inhibits ouabain-sensitive ATPase in the
medulla of rat kidney
Giesen E.M.; Grima M.; Imbs J.L.; et al.
Institut de Pharmacologie, INSERM U. 206 CNRS ERA 142,
Faculte de Medecine, 67000 Strasbourg France
IRCS Medical Science (United Kingdom) 1983, 11/11
(957-958)
The diterpene forskolin, a cardiotonic, vasodilatory and
hypotensive drug, is a potent activator of adenylate cyclase
but little is known about its effects on other membrane bound
enzymes. Total ATPase, in the absence of ouabain, and
ouabain-insensitive ATPase, in the presence of 1 mM ouabain,
were measured by the enzymatic technique of Fritz and Hamrick.
The difference between total and ouabain-insensitive ATPase
activity is referred to as Na+Ksup +-ATPase. The protein
content was determined according to Lowry. In cortex
homogenates, no significant modification of total,
ouabain-insensitive and Nasup +Ksup +-ATPase activities
occurred in the presence of 10sup -sup 4 M forskolin. In
medulla homogenates, forskolin (10sup -sup 4 M) caused a
significant 55% decrease of Nasup +Ksup +-ATPase activity. The
inhibition is dose-dependent but not complete at 10sup -sup 4
M forskolin, higher concentrations of the drug could, however,
not be prepared because of its limited solubility. It would be
interesting to correlate this result with a physiological
difference of the cortical and medullary Nasup +Ksup
+-ATPase.
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