Survival of cancer patients on therapy with coenzyme Q10.

Over ca. 25 years, assays in animal models established the hematopoietic activities of coenzyme Q's in rhesus monkeys, rabbits, poultry, and children having kwashiorkor. Surprisingly, a virus was found to cause a deficiency of CoQ9. Patients with AIDS showed a-"striking"-clinical response to therapy with CoQ10. The macrophage potentiating activity of CoQ10 was recorded by the carbon clearance method. CoQ10 significantly increased the levels of IgG in patients. Eight new case histories of cancer patients plus two reported cases support the statement that therapy of cancer patients with CoQ10, which has no significant side effect, has allowed survival on an exploratory basis for periods of 5-15 years. These results now justify systematic protocols.

Myocardial preservation by therapy with coenzyme Q10 during heart surgery.

Coenzyme Q10 (CoQ10) is a natural and essential cofactor in the heart. It is the primary redox coupler in the respiratory chain, a potent free radical scavenger, and a superoxide inhibitor. In this study the myocardial protective effects of CoQ10 were determined in high-risk (n = 10) patients during heart surgery compared to that found in placebo controls (n = 10). In both groups, there was a blood CoQ10 deficiency (< 0.6 microgram/ml), low cardiac index (CI < 2.4 l/m2 per minute), and low left ventricular ejection fraction (LVEF < 35%) before treatment. CoQ10 (100 mg per day) was given orally for 14 days before and 30 days after surgery. Presurgical CoQ10 treatment significantly (P < 0.01) improved blood and myocardial CoQ10 and myocardial ATP compared to that found in the control group. Cardiac functions (CI and LVEF) were improved but not significantly. After cardiac cooling, rewarming, and reperfusion; blood and tissue CoQ10 and tissue ATP levels were maintained in the normal ranges in the CoQ10 patients. Cardiac pumping (CI) and LVEF were significantly (P < 0.01) improved. The recovery course was short (3-5 days) and uncomplicated. In the control group blood and tissue CoQ10, tissue ATP levels, and cardiac functions were depressed after surgery. The recovery course was long (15-30 days) and complicated. Positive relationships between blood and myocardial CoQ10, myocardial ATP, cardiac function, and the postoperative recovery time and course found in both study groups show the therapeutic benefits of CoQ10 in preserving the myocardium during heart surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the effects of pindolol and atenolol on hemodynamic function in systemic hypertension.

A randomized double-blind study was performed on a group of mild hypertensive patients (WHO class I) to compare the hemodynamic effects of pindolol and atenolol. Blood pressure (BP) was monitored with a mercury gauge sphygmomanometer, while cardiac function and peripheral arterial flows were measured by the noninvasive technique of bioelectric impedance. After a 2-week washout period, patients with a diastolic BP greater than 95 mm Hg but less than 114 mm Hg were randomized into the pindolol (29 patients) or atenolol (28) treatment groups. Patients were treated with 1 of the 2 drugs in an incremental fashion for 12 weeks. Cardiovascular function was measured after the washout period and at the end of the 12-week treatment period. Baseline hemodynamics were similar in both groups. The 2 drugs were equally effective in lowering both systolic and diastolic BP. Hemodynamically, pindolol lowered BP by decreasing total peripheral resistance (-406 +/- 145 dynes.s.cm-5) while atenolol decreased cardiac index (-0.2 +/- 0.1 liters/min/m2) associated with a decrease in heart rate (-12 +/- 2 beats/min). Regarding peripheral vascular beds, pindolol lowered arm vascular resistance (-198 +/- 72 mm Hg/liter/min) and leg vascular resistance (-73 +/- 25 mm Hg/liter/min), especially when subjects who did not respond to pindolol were excluded from the analysis. Both arm (5.5 +/- 5.4% increase above baseline) and leg (1.2 +/- 4.4% increase above baseline) arterial flow indexes were maintained with pindolol. Conversely, atenolol decreased the arm arterial flow index (-9,8 +/- 5.6% decrease below baseline), but not significantly and with no change in resistance (+54 +/- 62 mm Hg/liter/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of naloxone on hemorrhagic shock in the beagle.

Naloxone reverses the hypotension in various types of hemorrhagic shock models. What has yet to be firmly established is the mechanism by which naloxone reverses the hypotension. In a canine hemorrhagic shock model, impedance cardiography and invasive methods were used to measure various cardiovascular parameters. All dogs (beagles, 10-15 kg) were bled to and maintained at a mean arterial blood pressure (MAP) of 60 mmHg for 90 min and were then given either naloxone (2 mg/kg; n = 6) or an equivalent volume of saline (n = 6) intravenously (IV). After another 90 min observation period, the shed blood was reinfused. No significant differences in the preshock and shock cardiodynamics were noted between the naloxone and the control animals. During the treatment period, MAP was significantly increased in the naloxone group. There was no increase in cardiac output (CO), stroke volume (SV), end diastolic volume (EDV), dP/dt max, dP/dt/P, or HI (the impedance contractility index) over control animals. The most significant parameter improvement was total peripheral resistance (TPR). The data suggest that naloxone in this hemorrhagic shock model improves hemodynamics primarily by increasing vascular resistance.

Benoxaprofen attenuation of lethal canine endotoxic shock.

Our prior work demonstrated in a canine endotoxic shock model (LD100) that the cyclooxygenase inhibitor ibuprofen given 60 minutes after endotoxin administration could improve hemodynamics but not survival over control animals. The present study was designed to examine the effect of benoxaprofen, a dual lipoxygenase and cyclooxygenase inhibitor, in the same canine endotoxic model (LD100) and compare it to ibuprofen treatment. After thiopental anesthesia (25 mg/kg IV), animals were instrumented to measure various cardiovascular parameters. Endotoxic shock was induced by injecting Escherichia coli (0111:B4) endotoxin (1 mg/kg IV). Benoxaprofen (10 mg/kg IV; N = 13), ibuprofen (12.5 mg/kg; N = 6), or saline (N = 12) was injected 60 minutes after endotoxin administration. During the treatment period, both benoxaprofen and ibuprofen increased mean arterial pressure, heart rate, and vascular resistance to the same degree over the control animals. Benoxaprofen did increase dP/dtmax while ibuprofen did not. Twenty-four-hour survival was 0% for the control animals (N = 12), 0% for the ibuprofen group (N = 6), and 61.5% for the benoxaprofen group (N = 13). In an additional set of experiments, benoxaprofen (N = 8) was given 120 minutes after endotoxin administration and demonstrated similar improvements in hemodynamics and survival. These data demonstrate that benoxaprofen could improve survival in an otherwise lethal endotoxic model and suggest that the products of the lipoxygenase pathway may contribute to the lethality of an LD100 endotoxic shock model.

The effects of vasoactive mediator antagonists on endotoxic shock in dogs. I.

Many vasoactive mediators have been implicated in causing or maintaining the hypotension of endotoxic shock. What has yet to be firmly established is the relative importance of each of these mediators in a given shock model. In a canine endotoxic shock model (LD100), we studied the effects of opiate and prostaglandin inhibition 60 min after endotoxin administration. After thiopental anesthesia, the animals were instrumented to measure various cardiovascular parameters. Endotoxic shock was induced by injecting E. coli endotoxin (0111:B4) (1 mg/kg i.v.). Drug intervention occurred 60 min after endotoxin administration. Naloxone (2 mg/kg i.v.) improved mean arterial pressure (MAP) transiently. A more significant increase of MAP (85% of preshock levels) was attained after ibuprofen (12.5 mg/kg i.v.) administration secondary to an increase in total peripheral resistance (TPR). All groups had 0% 24-hour survival. These data suggest that the endogenous opioids, presumably inhibited by naloxone, seem to contribute little to this lethal canine endotoxic shock model. By contrast, the prostanoids which are inhibited by ibuprofen appear to be more hemodynamically significant in this model.

Reproducibility of haemodynamic measurements by impedance cardiography.

Impedance cardiography was used to measure heart rate (HR), stroke index (SI), cardiac index (CI) and left ventricular ejection time (t) in four subjects at rest and in eight subjects anticipating exercise and working at loads of 49, 98 and 147 watts on a bicycle ergometer. The resting measurements were repeated five times over a 2 week period and the exercise measurements were repeated three times at weekly intervals. Analysis of variance testing indicated that none of the variables changed significantly from day to day (P greater than 0.1). All variables changed with exercise and all but t changed from subject to subject (P less than 0.01). Coefficients of variation for CI, SI, HR and t were 10, 12, 8 and 1% respectively at rest and rose to 16, 13, 5 and 6% during exercise. There was a high linear correlation between work load and CI (r = 0.96). The data indicate that noninvasive impedance cardiography can be used to obtain reproducible measurements of CI, SI, HR and t during rest and immediately after exercise.

Reduced stroke volume related to pleural pressure in obstructive sleep apnea.

Left ventricular stroke volume (LVSV) falls during obstructed inspiration in animals and normal human subjects through mechanisms that may be closely related to pleural pressure. In this study we postulated that a similar reduction in LVSV should occur in patients with obstructive sleep apnea (OSA). Daytime polysomnograms were performed in 10 patients with OSA. A noninvasive electrical impedance method was used to determine LVSV. Pleural pressure was measured by esophageal balloon. In comparison with awake values, during OSA we found reductions in LVSV, cardiac output, and heart rate of 18, 27, and 11%, respectively (P less than 0.01). We observed that systolic pleural pressure did not have a significant effect on LVSV (P greater than 0.05). However, at pleural pressures lower than 10 cmH2O below resting expiratory level, there was a linear relationship between falls in LVSV and falls in middiastolic pleural pressure (P less than 0.0001). We concluded that reduced LVSV shown in patients with OSA was significantly related to diastolic pleural pressure level. Our findings suggested reduced preload as the most likely mechanism for decreased cardiac output in OSA.

Arterial baroreceptor reflex control of sympathetic nerve activity in the spontaneously hypertensive rat.

The combined and individual carotid sinus and aortic baroreceptor control of sympathetic nerve activity (SNA) and mean arterial pressure (MAP) were studied by direct measurement in groups of spontaneously hypertensive rats (SHR) and normotensive Kyoto Wistar rats (WKY) of 5 to 40 weeks of age. The SHR showed a significantly greater SNA and resultant MAP increase as a function of age compared to that of the WKY rats. Both SHR and WKY rats showed a significant rise in SNA and MAP with ablation of all four major baroreceptors. The proportionate change of SNA and MAP after ablation was greater in the younger SHR than in the younger WKY groups and the change in these decreased as a function of age in the SHR. The reflex inhibition of SNA via baroreceptor stimulation also decreased as a function of age in the SHR, due to a 43% loss of aortic inhibitory function; no significant loss of carotid sinus function was found in either the SHR or WKY. The decrement in aortic function occurred after the rapid phase of blood pressure development; therefore baroreceptor dysfunction cannot be the cause of the high SNA and MAP observed in young SHR. An upward resetting of central sympathetic centers was evaluated via the baroreceptor deafferentation; and it appears that the hyperactive sympathetic nervous system and resultant hypertension in the SHR is due to central resetting of sympathetic centers rather than baroreceptor dysfunction.

Sympathetic nerve activity and blood pressure in normotensive backcross rats genetically related to the spontaneously hypertensive rat.

The genetic basis of hyperactivity of the sympathetic nervous system (SNA) in spontaneously hypertensive rats (SHR) was assessed by measuring SNA in animals derived from a backcross (BC) breeding program designed to isolate single gene differences causing changes in blood pressure. Selective breeding of the male hypertensive rats with inbred normotensive female Wistar/Lewis rats yielded progeny with a range of blood pressures, but whose group mean pressures were lower than the group mean pressures of the original SHR. Progressive generations had progressively lower group mean pressures. There was a positive correlation between SNA and mean arterial pressure in BC rats. These results indicate that the genetic defect in SHR may be abnormality in SNA, and the hypertension in these animals is a secondary result of this primary defect. Baroreceptor function was also assessed in SHR and in BC rats. In young (8 to 24 weeks old) SHR, baroreceptor function was similar to that in BC rats, whereas SNA was markedly increased. Only in older (24 to 40 weeks old) SHR was there an abnormality in the gain of baroreceptors. The development of hypertension in SHR therefore appears to be due to increased SNA resulting from a defect in the central nervous system. Changes in baroreceptor function are secondary to the hypertension and occur after the hypertension is established.

Effect of l-dopa on sympathetic nerve activity and blood pressure in the spontaneously hypertensive rat.

We examined the effect of L-Dopa, after peripheral L-amino acid decarboxylase inhibition, on sympathetic nerve activity (SNA) and blood pressure in spontaneously hypertensive rats (SHR) and in normotensive control rats. L-Dopa reduced SNA in both groups of animals. The SHRs were significantly more sensitive to the depressor effect of L-dopa than were the control animals, the threshold dose for reduction of SNA being 3 mg/kg in the SHR and 15 mg/kg in control rats. Similarly, the magnitude of inhibition of SNA was substantially greater in the SHR than in normotensive rats. The reduction in SNA in the SHR accompanied by a parallel fall in blood pressure. In contrast, blood pressure in control rats did not change significantly, even though SNA was diminished. Studies of the penetration of L-dopa into the cerebral parenchyma revealed that equivalent amounts of the amino acid entered the brains of the two groups of rats. These results suggest that the SHRs are more sensitive to the SNA-inhibiting effects of L-dopa than are normotensive rats. In addition, they confirm our previous suggestion that excessive SNA plays a causative role in the hypertension of the SHR.

Sympathetic nerve activity: role in regulation of blood pressure in the spontaenously hypertensive rat.

Sympathetic nerve activity (SNA) and high pressure baroreceptor regulation of SNA were studied in the Okamoto strain of spontaneously hypertensive rat (SHR). Mean arterial pressure (MAP) and SNA were not significantly affected by anesthesia with low doses of pentobarbital (20-25 mg/kg). Thus, most of these studies were performed in anesthetized rats. SNA in visceral sympathetic nerves increased rapidly with age up to 24 weeks and slowly thereafter. MAP increased with SNA, following the same time course. Both SNA and MAP in SHR were significantly greater than that found in normotensive Wistar control rats of comparable ages. Abolition of ganglionic transmission with hexamethonium in both SHR and normotensive controls reduced postganglionic SNA and MAP to comparable levels. In SHR less than 16 weeks old, increased baroreceptor stimulation effectively inhibited SNA with the same sensitivity as found in Wistar control rats. However, older SHR appeared to lose their ability to completely inhibit SNA during induced hypertension, whereas in Wistar control rats as old as 52 weeks, elevation of blood pressure to 165.3 +/- 2.3 mm Hg completely suppressed SNA. These results suggest that SNA may play an important role in the development and maintenance of hypertension in SHR, and that central sympathetic centers, uninhibited by baroreceptor afferents, become active during the development of hypertension in the SHR.