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.)

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%.

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)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.