Coenzyme Q10 in essential hypertension

Molec.AspectsMed.Vol. 15 (Supplement),pp. s257-s263, 1994

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Coenzyme Qlo in Essential Hypertension V. Digiesi*, F. Cantinit, A. Oradei~:, G. Bisi§, G. C. Guarino*, A. Brocchi§, F. Bellandit, M. Mancini* and G. P. Littarrull

*Third Institute of Clinical Medicine and Medical Therapy, and §Department of Clinical Physiopathology, University of Florence Medical School, Florence ?Second Division of Internal Medicine, Chief Hospital of Prate, Prate .1:Institute of Physiology, Catholic University Medical School, Rome I]lnstitute of Biochemistry, University of Ancona Medical School, Ancona, Italy

Abstract--This study was undertaken to clarify the mechanism of the antihypertensive effect of coenzyme Q10 (CoQlo). Twenty-six patients with essential arterial hypertension were treated with oral COQlo, 50 mg twice daily for 10 weeks. Plasma CoQl0, serum total and high-density lipoprotein (HDL) cholesterol, and blood pressure were determined in all patients before and at the end of the 10-week period. At the end of the treatment, systolic blood pressure (SBP) decreased from 164.5 + 3.1 to 146.7 _+ 4.1 mmHg and diastolic blood pressure (DBP) decreased from 98.1 + 1.7 to 86.1 + 1.3 mmHg (P < 0.001). Plasma COQlo values increased from 0.64 + 0.1 i~g/ml to 1.61 + 0.3 txg/ml (P < 0.02). Serum total cholesterol decreased from 222.9 +_ 13 mg/dl to 213.3 _+ 12 mg/dl (P < 0.005) and serum H D L cholesterol increased from 41.1 _+ 1.5 mg/dl to 43.1 +_ 1.5 mg/dl (P < 0.01). In a first group of 10 patients serum sodium and potassium, plasma clinostatic and orthostatic renin activity, urinary aldosterone, 24-hour sodium and potassium were determined before and at the end of the 10-week period. In five of these patients peripheral resistances were evaluated with radionuclide angiocardiography. Total peripheral resistances were 2,283 + 88 dyne.s-cm -5 before treatment and 1,627 + 158 dyne-s-cm-5 after treatment (P < 0.02). Plasma renin activity, serum and urinary sodium and potassium, and urinary aldosterone did not change. In a second group of 11 patients, plasma endothelin, electrocardiogram, two-dimensional echocardiogram and 24-hour automatic blood pressure monitoring were determined. Plasma endothelin, electrocardiographic and echocardiographic findings did not change after therapy. Mean 24-hour blood pressure recordings showed a statistically significant reduction of both SBP and DBP after therapy. SBP changed from 167 + 2.7 to 148.9 _ 2.2 m m H g (P < 0.001) and DBP from 98.9 + 1.5 to 88.6 + 1.1 m m H g (P < 0.001). In eight of 26 patients group (30%) plasma baseline values of CoQlo were below normal and returned to normal or higher levels after therapy. This research confirms the antihypertensive effect of CoQlo. The antihypertensive effect of the drug is probably based on a diminution of peripheral resistances. CoQloS slight effect on blood cholesterol is useful since hypercholesterolemia is a risk factor for arterial hypertension.

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Introduction Coenzyme Qlo (CoQlo) is an essential component of human cells and probably has multiple roles in the cell, acting as a membrane stabilizer and a free radical scavenger. As a cofactor of the respiratory chain, CoQ~0 is indispensable to oxidative phosphorylation. Thus the substance provides energy and has a key role in the contraction and relaxation of the myocyte. Several experimental studies on animals with induced arterial hypertension (Igarashi et al., 1972; Yamagami et al., 1974a; Okamoto et al., 1991) and on patients with essential arterial hypertension (Yamagami et al., 1974b, 1975, 1976; Folkers et al., 1981; Digiesi et al., 1990, 1992) have shown a beneficial therapeutic effect of CoQ10 on systolic blood pressure (SBP) and diastolic blood pressure (DBP). It should be pointed out that a deficiency of CoQ10 has been observed in some hypertensive rats (Iwamoto et al., 1974) and in some men (Yamagami et al., 1975, 1986; Digiesi et al., 1992). The mechanism of the antihypertensive effect of the drug is not clear. The purpose of this investigation was to evaluate plasma CoQ10 levels in patients with essential arterial hypertension and to inquire the mechanism of the antihypertensive effect of CoQ10. The effect of CoQ10 on blood cholesterol was also studied because CoQx0 shares with cholesterol the first steps of its biosynthesis.

Patients and Methods The study group consisted of 26 patients, 13 men and 13 women, with an average age of 61.3 years (they ranged in age from 21 to 75 years), affected by essential arterial hypertension, World Health Organisation stages 1 and 2. Patients who had other significant diseases, particularly renal failure, who were older than age 75, or who weighted more than 90 kg were excluded from the trial. All patients gave informed consent before participating in the study. After a 2-week washout period, all patients received oral CoQ10, 50 mg twice daily for 10 weeks. Their diet remained unchanged. Basic hematologic and urinary examinations, including blood crasis, renal and liver function, plasma CoQ10, serum total and high-density lipoprotein (HDL) cholesterol and blood pressure were determined in all patients before and at the end of the 10-week period. In a first group of 10 patients, serum sodium and potassium, plasma clinostatic and orthostatic renin activity, urinary aldosterone, 24-hour sodium and potassium were also determined before and at the end of the 10-week period. In five of these patients peripheral resistances were evaluated with radionuclide angiocardiography. In a second group of 11 patients, plasma endothelin, electrocardiogram, two-dimensional echocardiogram and 24-hour automatic blood pressure monitoring were also determined.

Coenzyme Qlo in Essential Hypertension

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Plasma CoQ10 was determined by HPLC (Lippa e t a l . , 1985), and plasma renin activity, plasma endothelin and urinary aldosterone were evaluated by radioimmunoassay. Arterial pressure readings were measured with a Riva-Rocci sphygmomanometer regularly at the same time of the morning, by the same examiner, and on the same arm, after the patient had rested for 10 min in a reclining position. The actual pressure reading was obtained by calculating the mean of five successive readings at 1-min intervals. Student's test for dependent samples was used for the statistical evaluation of the data; P < 0.05 was accepted as showing statistical significance.

Results Initial blood pressure values were 164.5 + 3.1 mmHg (mean + SE) for systolic blood pressure and 98.1 + 1.7 mmHg for diastolic blood pressure. At the end of the trial, systolic blood pressure was 146.7 + 4.1 mmHg and diastolic blood pressure was 86.1 + 1.3 mmHg (Fig. 1). Both systolic and diastolic blood pressures decreased significantly compared with baseline values (P < 0.001). Plasma COQlo increased from 0.64 +_ 0.1 p.g/ml to 1.61 _+ 0.3 p.g/ml (P < 0.002) (Table 1). In eight patients (30%) plasma baseline values of CoQ10 were below normal but returned to normal levels after therapy. Serum total cholesterol decreased from 222.9 +_ 13 mg/dl to 213.3 +_ 12 mg/dl (P < 0.005) and serum HDL cholesterol increased from 41.1 _+ 1.5 mg/dl to 43.1 +_ 1.5 mg/dl (P < 0.01).

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B.T,: BEFORETHERAPY SBP : P < 0.001 ; DBP : P < 0.001 A.T.: AFTER THERAPY Fig. 1. CoQ10 in essential hypertension. Effects on systolic (SBP) and diastolic (DBP) blood pressure before and after therapy in 26 patients.

V. Digiesi et aL

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Table 1. CoQlo in essential hypertension metabolic and hormonal changes before and after ten weeks of treatment with CoQlo in patients with hypertension

Plasma CoQlo (p.g/ml) Serum cholesterol (mg/dl) Serum high-density-lipoprotein cholesterol (mg/dl) Serum sodium (mEq/L) Serum potassium (mEq/L) Urinary sodium (mEq/24 hr) Urinary potassium (mEq/24 hr) Urinary aldosterone (nmol/24 hr) Plasma clinostatic renin activity (ng/ml/hr) Plasma orthostatic renin activity (ng/ml/hr) Plasma endothelin (pg/ml)

Before

After

P Value

0.64 + 0.1 222.9 ___ 13

1.61 _+ 0.3 213.3 + 12

< 0.002 < 0.005

41.1 136 3.8 102.5 41.8 27.3

43.1 137 3.9 101.7 44.1 31.8

1.5 1.5 2.1 6.3 3.8 5.5

< 0.01 NS NS NS NS NS

+ + + + + _+

1.5 2.0 1.8 9.0 2.7 5.1

+ + _+ _+ + +

0.61 +

0.16

0.44 +

0.10

NS

1.23 + 2.74 +

0.36 0.29

1.30 + 3.37 +

0.39 0.37

NS NS

Plasma renin activity, serum and urinary sodium and potassium, and urinary aldosterone did not change significantly.

Plasma levels of endothelin, electrocardiographic and echocardiographic findings did not change after therapy. Mean 24-hour blood pressure values showed a statistically significant reduction of both SBP and D B P after therapy. SBP c h a n g e d from 167 _+ 2.7 to 148 __ 2.2 m m H g (P < 0.001) and D B P f r o m 98.9 _ 1.5 to 88.6 ___ 1.1 m m H g ( P < 0.001) (Fig. 2).

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B.T.

A.T.

B.T.: BEFORE THERAPY A.T.: AFTER THERAPY

B.T.

A.T. SBP : P < 0.001 ; DBP : P < 0.001

Fig. 2. CoQlo in essential hypertension. Mean 24-hour systolic (SBP) and diastolic (DBP) blood pressure automatically recorded in 11 patients.

CoenzymeQloin EssentiaHypertensi l on

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Significant reduction of total peripheral resistances after CoQlo therapy : P < 0.02 B.T = Before therapy ; A.T = after therapy

Fig. 3. CoQ10in essential hypertension. Effects on total peripheral resistances (dyne.sec.cm-5) radionuclide angiocardiography.

Total peripheral resistances evaluated with radionuclide angiocardiography in five patients were 2,283 + 88 dyne.s.cm-5 before treatment and 1,627 + 158 dyne.s.cm -5 after treatment (P < 0.02) (Fig. 3). Discussion

and Conclusions

In conclusion, CoQ10 induced a significant decrease in both systolic and diastolic blood pressures, thus confirming its therapeutic utility in patients with essential arterial hypertension. Plasma CoQ10levels increased after therapy, as expected. This increase, which was observed in all patients, both those with normal baseline values of COQlo and those with levels below normal, shows that oral CoQ10 is effectively absorbed. Why plasma levels of CoQ10 are below normal levels in some patients (30%) with essential hypertension is not known. Common causes of low CoQ10 plasma levels are total parenteral nutrition, aerobic training, hyperthyroidism, organ transplant and therapeutic use of HMG-CoA reductase inhibitors. None of these conditions was present in our patients. Some patients with essential hypertension may have an acquired or genetically impaired biosynthesis or an increased metabolic demand for CoQ10 of unknown origin. The mechanism of the antihypertensive effect of CoQ10 is not known precisely. In our study, no effect was observed on plasma renin activity, urinary aldosterone, or serum and urinary sodium and potassium, indicating that CoQlo does not have an antialdosteronic effect. Moreover, plasma levels of endothelin, electrocardiographic and echocardiographic findings did not change after therapy. From the results showing a decrease in total peripheral resistances, CoQ10s mechanism of action is probably based on a diminution of peripheral resistances. In stroke-prone, spontaneously hypertensive rats, treatment with CoQ~o attenuated the elevation of blood pressure, the degradation of membrane phospholipids, and the enhanced phospholipase A 2 activity in the renal membrane (Okamoto et al., 1991). Thus CoQ10 could have membrane-stabilizing activity.

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The increase of vascular resistances in essential arterial hypertension is caused by arteriolar vasoconstriction, that determines ischemia of tissues with consequent metabolic alterations. Another hypothesis is based on the antioxidant effect of CoQ10. Oxygen-derived free radicals (Bolli, 1988) could interact and inactivate endothelium-derived relaxing factor (Ignarro, 1989) with consequent arteriolar vasoconstriction; moreover, oxygen-derived free radicals could stimulate proliferation and fibrosis of smooth muscle cells of arterioles. Also, the exogenous COQlo could compensate for diminution of CoQlo of muscle fibers in patients with hypertension (Karlsson et al., 1991). The decrease in serum total cholesterol after therapy might be attributed to a negative feedback mechanism of exogenously supplied CoQ10 in the metabolic pathway of mevalonate, which is implicated in the synthesis of cholesterol and CoQ10. Moreover, some ubiquinones inhibit cholesterogenesis in rat thymocytes (Noselova, 1989). We conclude that CoQ10 has an antihypertensive effect that is probably based on a diminution of peripheral resistances. CoQ10 administration leads to a slight, though significant, decrease of total blood cholesterol, a useful effect since hypercholesterolemia is a risk factor for arterial hypertension.

References Bolli, R. (1988). Oxygen-derived free radicals and postischemic myocardial dysfunction. J. Am. Coll. Card. 12, 239-249. Digiesi, V., Cantini, F. and Brodbeck, B. (1990). Effect of coenzyme Q10 on essential arterial hypertension. Curr. Ther. Res. 5, 841-845. Digiesi, V., Cantini, F., Bisi, G., Guarino, G. C., Oradei, A. and Littarru, G. P. (1992). Mechanism of action of coenzyme Q10 in essential hypertension. Curr. Ther. Res. 5, 668-672. Folkers, K., Drzewoski, J., Richardson, P. C., Ellis, J., Shizukulshi, S. and Baker, L. (1981). Bioenergetics in clinical medicine. XVI. Reduction of hypertension in patients by therapy with coenzyme Qlo. Res. Commun. Chem. Pathol. Pharmacol. 31, 129-140. Igarashi, T., Tanabe, Y., Nakajima, Y., Kobayashi, M., Tanaka, M. and Ohtake, S. (1972). Effect of coenzyme Qlo on experimental hypertension in the desoxycorticosterone acetate-saline loaded rats. Folia Pharmacol. Jpn. 68, 460--472. Ignarro, L. J. (1989) Biological actions and properties of endothelium-derived nitric oxide formed from arteries and veins. Circ. Res. 65, 1-21. Iwamoto, Y., Yamaguchi, T., Folkers, K. and Blomquist, C. G. (1974). Deficiency of coenzyme Qlo in hypertensive rats and reduction of deficiency by treatment with coenzyme Qlo. Biochem. Biophys. Res. Commun. 58, 734-748.

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Karlsson, J., Diamant, B., Folkers, K. and Lund, B. (1991). Muscle fibre types, ubiquinone content and exercise capacity in hypertension and effort angina. Ann. Med. 23, 339-344. Lippa, S., Littaru, G. and Oradei, A. (1985). Determinazione routinaria del coenzima Qlo mediante HPLC in campioni biologici. Ist conferenza nazionale "La cromatografia liquida ad alta risoluzione ed analitica clinica: situazione attuale e prospettive". (abstract) Verona, Italy, 51. Noselova, E. (1989). The role of ubiquinones in the regulation of lipid metabolism in rat thymocytes. FEBS. Lett. 249, 371-374. Okamoto, H., Kawaguchi, H., Togashi, H., Minami, M., Saito, H. and Yasuda, H. (1991). Effect of coenzyme Qlo on structural alterations in the renal membrane of stroke-prone spontaneously hypertensive rats. Biochem. Metab. Biol. 45, 216-226. Yamagami, T., Iwamoto, Y., Folkers, K. and Blomquist, C. G. (1974a). Reduction by coenzyme Q10 of hypertension induced by desoxycorticosterone and saline in rats. Int. J. Vitam. Nutr. Res. 4, 487-496. Yamagami, T., Iwamoto, Y., Folkers, K. and Blomquist, C. G. (1974b). Deficiency of activity of succinate dehydrogenase-coenzyme Q~o reductase in leucocytes from patients with essential hypertension. Int. J. Vitam. Nutr. Res. 44, 404-414. Yamagami, T., Shibata, N. and Folkers, K. (1975). Bioenergetics in clinical medicine. Studies on coenzyme Qlo and essential hypertension. Res. Comm. Chem. Pathol. Pharmacol. 11, 273-288. Yamagami, T., Shibata, N. and Folkers, K. (1976). Bioenergetics in clinical medicine. VIII. Administration of coenzyme Q~o to patients with essential hypertension. Res. Commun. Chem. Pathol. Pharmacol. 14, 721-728. Yamagami, T., Takagi, M., Akagami, H., Kubo, H., Toyama, S., Okamoto, T., Kishi, T. and Folkers, K. (1986). Effect of coenzyme Qlo on essential hypertension: a double-blind controlled study. In: Biomedical and Clinical Aspects on Coenzyme Q., Vol. 5, Folkers, K. and Yamamura, Y. (eds.), pp, 337-343. Elsevier, Amsterdam.