Pharmacological Toxicological Effects 51 Cardiovascular Effects

Hawthorn extracts purportedly dilate coronary blood vessels, decrease blood pressure, increase myocardial contractility, and lower serum cholesterol (9). Benefits have been demonstrated in patients with heart failure (10). In patients with stage II New York Heart Association (NYHA) heart failure, doses of 160-900 mg/day of the aqueous-alcoholic extract for up to 56 days showed an increase in exercise tolerance, decrease in rate/pressure product, and increased ejection fraction (11). Degenring and colleagues, in a randomized, double-blind, placebo-controlled trial, studied a standardized extract of fresh Crataegus berries (Crataegisan®) for the treatment of patients with

NYHA II heart failure (12). Using an intent-to-treat analysis, these investigators found that the hawthorn preparation significantly increased exercise tolerance as compared to placebo, but subjective symptoms of heart failure were unchanged. In a meta-analysis of 13 randomized trials of hawthorn extract in the treatment of heart failure, investigators noted that hawthorn produced a statistically significant increase in exercise tolerance over placebo (13). In addition, symptoms such as dyspnea and fatigue improved significantly with hawthorn treatment. Adverse events were infrequent. These investigators concluded that hawthorn provides a significant benefit in the treatment of heart failure. The active principles are thought to be flavonoids, including hyperoside, vitexin, vitexin-rhamnose, rutin, and oligomeric procyanidins (dehydrocatechins, catechins, and/or epicatechins) (4-6,11).

Two clinical trials have also been conducted to evaluate the ability of hawthorn to reduce blood pressure and treat hypertension. Asgary et al. studied the effect of Iranian Crataegus curvisepala hydroalcoholic extract in 92 men and women with primary mild hypertension (14). These investigators found that treatment with the hawthorn extract for 4 months reduced both systolic (~13 mmHg decrease) and diastolic (~8 mmHg decrease) blood pressure as compared with placebo. The effect was progressive over the 4-month treatment period. In a similar study, a hawthorn extract was investigated for its ability to treat mild, essential hypertension (15). Studying 36 subjects, these investigators found no difference in blood-pressure-lowering between hawthorn and placebo treatments (though both treatments did reduce blood pressure somewhat). Thus, results of hawthorn use in the treatment of hypertension are mixed.

Investigators attempted to elucidate the mechanism of action of the flavonoids hyperoside, luteolin-7-glucoside, rutin, vitexin, vitexin-rhamnoside, and monoacetyl-vitexin-rhamnoside in spontaneous-beating Langenhoff preparations of guinea pig hearts (16). Dose-dependent effects on contractility, heart rate, and coronary blood flow similar to that of theophylline were exhibited by luteolin-7-glucoside, hyperoside, and rutin, whereas vitexin and its derivatives were less potent. These results were different from those of previous investigators, who found a decrease in coronary blood flow, contractility, and heart rate with hyperoside, whereas vitexin decreased contractility and increased heart rate and coronary blood flow. Vitexin-rhamnoside increased coronary blood flow, heart rate, and contractility in the previous study. These differences were attributed to differences in the experimental device. The investigators concluded that the mechanism behind the cardiac effects of these flavonoids involved phosphodiesterase inhibition, causing an increase in cyclic adenosine monophosphate concentration, as well as inhibition of thromboxane synthesis and enhancement of prostacyclin synthesis, as described by previous researchers. The authors also concluded that despite previous studies showing that vitexin-rhamnoside protected cultured heart cells from oxygen and glucose deprivation, the role of antioxidant activity as a mechanism behind the anti-ischemic effect of these flavonoids requires further study, given that vitexin-rhamnoside exhibited only minor effects in their study.

Because reactive oxygen species may play a role in the pathogenesis of atherosclerosis, angina, and cerebral ischemia, the antioxidant activity of dried hawthorn flowers and flowering tops, fluid extract, tincture, freeze-dried powder, and fresh plant extracts was investigated (8). Antioxidant activity, determined by the ability of the preparations to scavenge hydrogen peroxide, superoxide anion, and hypochlorous acid, was provided by all preparations, but was highest with the fresh young leaf, fresh floral buds, and dried flowers. The antioxidant activity was correlated to total phenolic proanthocyanidin and flavonoid content.

The effects of hawthorn extract LI 132 standardized to 2.2% flavonoids (Faros® 300, Lichtwer Pharma GmbH, Berlin, Germany) on contractility, oxygen consumption, and effective refractory period of isolated rat cardiac myocytes were studied (17). In addition, the effect of partially purified oligo-meric procyanidins on contractility was also studied. The concentrations used in their study were chosen for their physiological plausibility, based on the assumption that the volume of distribution of both hawthorn extract and procyanidins in humans is 5 L, and that the daily dose is 900 mg and 5 mg, respectively. At concentrations of 30-180 ^g/mL, the hawthorn extract increased myocardial contractility with a more favorable effect on oxygen consumption than P-1 agonists or cardiac glycosides. Hawthorn also prolonged the effective refractory period, indicating that it might be an effective antiar-rhythmic agent. Oligomeric procyanidins at concentrations of 0.1-30 ^g/mL had no detectable effect on contractility, suggesting that they are not responsible for the positive inotropic effect of hawthorn.

Tincture of Crataegus (TCR), made from hawthorn berries, was shown to have a hypocholesterolemic effect on rats fed 0.5 mL/100 g body weight for 6 weeks. These findings prompted a study that examined the ability of TCR to increase low-density lipoprotein (LDL) binding to liver plasma membranes in rats fed an atherogenic diet (18). The hypocholesterolemic effect of TCR appears to be caused by a 25% increase in LDL receptor activity, resulting in greater LDL uptake by the liver. This was caused by an increased number of receptors, not an increase in receptor binding affinity. In addition, TCR

suppressed de novo cholesterol synthesis in the liver, and enhanced the use of liver cholesterol to make bile acids. Despite LDL receptor upregulation, the atherogenic diet fed to the rats offset the beneficial effects; LDL levels increased 104% and liver cholesterol increased by 231%. The investigators did not attempt to determine which TCR constituent was responsible for the hypocholesterolemic effect, but hypothesized that all contribute in some manner.

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