Percutaneous transluminal mitral valvuloplasty improves cardiopulmonary baroreflex sensitivity in patients with mitral stenosis.

Patients with heart failure frequently have increased sympathetic tone, which could result in part from impairment of the inhibitory influence of cardiopulmonary baroreflexes. Percutaneous transluminal mitral valvuloplasty (PTMV) provides a unique model for evaluating functional changes in cardiopulmonary baroreflexes without open-heart surgical manipulation. We examined the effects of PTMV on cardiopulmonary baroreflexes and sympathetic nerve activity in 10 patients with mitral stenosis. We measured muscle sympathetic nerve activity using microneurography. Cardiopulmonary baroreflex provocation was performed by applying a lower body negative pressure of -10 mm Hg, and its sensitivity was determined by dividing the percent change in muscle sympathetic nerve activity by the change in central venous pressure. Response to isometric exercise was assessed by handgrip at 30% of maximal voluntary contraction for 3 min. PTMV significantly increased mitral valve area and cardiac index and decreased mean left atrial pressure. PTMV significantly decreased burst rate from 25.1+/-2.5 to 15.6+/-2.6 bursts/min (p < 0.01) and burst incidence from 37.1+/-3.7 to 23.6+/-3.3 bursts/100 heart beats (p < 0.01). After PTMV, cardiopulmonary baroreflex sensitivities measured using burst rate and burst incidence were -39.9+/-4.9%/mm Hg and -38.7+/-6.2%/mm Hg, respectively, which were significantly steeper than those before PTMV (-9.2+/-1.1%/mm Hg and -8.4+/-1.1%/mm Hg; p < 0.01). There were significant correlations between muscle sympathetic nerve activity at rest and cardiopulmonary baroreflex sensitivity. PTMV did not affect muscle sympathetic responses to handgrip exercise. These results suggest that patients with mitral stenosis have baseline sympathetic nerve activation, which could result in part from impaired cardiopulmonary baroreflexes.

Neutrophil elastase inhibition reduces cerebral ischemic damage in the middle cerebral artery occlusion.

It has been reported that activated neutrophils are involved in the development of cerebral damage induced by ischemia. Activated neutrophils release a lot of mediators including toxic oxygen metabolites, elastase and cytokines which damage brain tissue. Therefore, we investigated roles of neutrophil elastase in the development of cerebral damage using an elastase inhibitor, ONO-5046. The rat middle cerebral artery (MCA) was occluded by a thrombus induced by photochemical reaction between green light and the photosensitizer dye, Rose Bengal. Photochemical reaction causes endothelial injury followed by formation of a platelet and fibrin-rich thrombus at the site of the irradiation. Photochemical reaction is routinely used in our laboratory to produce arterial occlusion in experimental animals. Twenty-four hours after the MCA occlusion, the size of cerebral damage was measured by histochemical technique. Water content in the brain was measured and neuronal deficits were examined 24 h after the MCA occlusion. ONO-5046 was administered at various doses as continuous infusion for 24 h, starting just after the MCA occlusion or from 3 h after. ONO-5046 at doses of 10 and 30 mg/kg/h significantly (p<0.05 and p<0.01, respectively) reduced the size of cerebral damage and water content (p<0.05, p<0.01, respectively) in different eight rats. Further, ONO-5046 at a dose of 30 mg/kg/h significantly (p=0.01) improved neuronal deficits. ONO-5046 which was administered starting from 3 h after the MCA occlusion, also reduced the size of cerebral damage. Neutropenia by anti-neutrophil antibody injection significantly (p<0. 01) reduced the size of cerebral damage. Elastase released from activated neutrophils may play a key role in the development of cerebral damage.

Enhanced insulin response to oral glucose load in patients with angina pectoris associated with ST segment elevation in the absence of epicardial coronary arterial obstruction.

The authors treated 10 patients with microvascular angina (MVA) manifesting angina pectoris, ST segment elevation suggestive of transmural myocardial ischemia, and no epicardial arterial obstruction. Since such patients frequently showed abnormal responses to oral glucose loading, the authors investigated the glucose and insulin responses to glucose loading in 10 MVA patients, 25 patients with vasospastic angina (VAP), 25 patients with effort angina (EAP), and 25 control subjects. Insulinogenic index, peripheral insulin activity [= 10(4)/(peak glucose x insulin at glucose peak)], glucose area, and insulin area were calculated. The MVA group included two patients with impaired glucose tolerance and two newly diagnosed diabetic patients. These proportions were similar to those in the VAP and EAP groups. Glucose levels at 30 to 180 min and insulin levels at 90 to 120 min in the MVA group were higher than in the control group. Peak glucose, glucose area, peak insulin, and insulin area were higher in the MVA group than in the control group (p<0.01). Those in the VAP and EAP groups were also higher. Insulin/glucose ratio at 120 min was higher, peripheral insulin activity, lower, in the disease groups than in the control group (p<0.05). The MVA patients showed a hyperglycemic and hyperinsulinemic response to oral glucose loading, as did the patients with EAP and VAP. Enhanced insulin response to oral glucose loading may also contribute to the pathogenesis of MVA.

Spectral analysis of heart rate, arterial pressure, and muscle sympathetic nerve activity in normal humans.

We investigated the frequency components of fluctuations in heart rate, arterial pressure, respiration, and muscle sympathetic nerve activity (MSNA) in 11 healthy women using an autoregressive model and examined the relation among variables using Akaike's relative power contribution analysis with multivariate autoregressive model fitting. Power spectral analysis of MSNA revealed two peaks, with low-frequency (LF) and high-frequency (HF) components. The LF component of MSNA was a major determinant of the LF component of arterial pressure and R-R interval variability (0.70 +/- 0.07 and 0.18 +/- 0.05, respectively). The effect of the LF component of MSNA on arterial pressure showed no change in response to propranolol but was diminished (0.35 +/- 0.08) by phentolamine (P < 0.02). The effect of the LF component of MSNA on R-R interval was not altered by pharmacological sympathetic nerve blockade. The HF component of MSNA did not influence other variables but was influenced by R-R interval, arterial pressure, and respiration. These findings indicate that the LF component of MSNA reflects autonomic oscillations, whereas the HF component is passive and influenced by other cardiovascular variables.

Neuroprotective effect of a novel AMPA receptor antagonist, YM90K, in rat focal cerebral ischaemia.

It has been reported that delayed treatment with alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor antagonists was able to more completely inhibit glutamate neurotoxicity than N-methyl-D-aspartate (NMDA) receptor antagonists. Therefore, we investigated the neuroprotective effect of YM90K, an AMPA receptor antagonist, on focal cerebral lesions induced by thrombotic middle cerebral artery (MCA) occlusion in rats, particularly in the early phase of the cerebral ischaemic lesions. The MCA was occluded by photochemical reaction between transmural green light and systemically administered Rose Bengal, which causes endothelial injury followed by platelet adhesion, aggregation and formation of a platelet and fibrin-rich thrombus at the site of photochemical reaction. The infarct size was measured at 24 and 72 h after the MCA occlusion by a histochemical technique. YM90K was administered at various doses as a continuous infusion for 4 h, beginning 0 to 3 h after the MCA occlusion. YM90K (10 and 20 mg/kg per h for 4 h continuous infusion), starting immediately after the MCA occlusion significantly (P < 0.05) reduced the infarct size at 24 h after MCA occlusion in a dose-dependent manner. Further, the agent showed the same efficacy at 72 h after. The inhibitory effect of YM90K (20 mg/kg per h) on the infarct size was the same when the drug was started immediately, 1, 2 and 3 h after MCA occlusion. In conclusion, the novel AMPA receptor antagonist YM90K was effective in the treatment of focal cerebral ischaemic lesions. Activation of AMPA receptor may play a key role in the development of cerebral infarct in the early phase of ischaemia in rats.

Primary antiphospholipid syndrome and pulmonary hypertension with prolonged survival. A case report.

The outcome of patients with pulmonary hypertension (PHT) and antiphospholipid syndrome (APS) is usually fatal. The authors report the rare case of a patient with primary APS and nonthrombotic PHT who has survived for twenty years after the onset of PHT. In this case, the patient's PHT resembled the primary idiopathic variety with clear lung fields and normal perfusion on the lung scan, and the combination therapy with nitrate, digoxin, and diuretics had been performed. During her clinical course over twenty years, she had not experienced any critical pulmonary thrombosis that influenced the progression of nonthrombotic PHT or any other severe systemic involvement of APS.

Compensatory enlargement of angiographically normal coronary segments in patients with coronary artery disease. In vivo documentation using intravascular ultrasound.

Intravascular ultrasound (IVUS) frequently reveals plaque formation at sites with a normal angiographic appearance. However, whether angiographically normal coronary arteries undergo adaptive expansion in vivo remains uncertain. The authors studied 12 patients (11 men, 1 woman; mean age fifty-three +/- ten years [mean +/- SD]) with focal coronary stenosis. Sixty IVUS images from angiographically normal coronary segments were analyzed (14 left main, 44 left anterior descending, and 2 left circumflex coronary arteries). The mean percent area stenosis was 36 +/- 5% and the circular shape factor of the lumen cross section averaged 0.97 +/- 0.02. Both total arterial area and internal elastic lamina area increased as the plaque area expanded (y = 2.13x + 8.07, r = 0.87, P = 0.0001; y = 2.06x + 4.57, r = 0.87, P = 0.0001, respectively), suggesting that for every 1 mm2 increase in plaque area, the total arterial area increased by approximately 2.13 mm2 and the internal elastic lamina area increased by approximately 2.06 mm2. The lumen area also increased as the plaque area expanded (y = 1.06x + 4.57, r = 0.68, P = 0.0001), suggesting that for every 1 mm2 increase in plaque area, the lumen area increased by approximately 1.06 mm2. The medial area did not correlate with the plaque area (r = 0.15, P = 0.26). Thus, compensatory enlargement precedes development of angiographically, detectable coronary atherosclerosis. Furthermore, in early stages of atherosclerosis, arterial enlargement may overcompensate for plaque area. The reduction of the total medial mass does not appear to contribute to the mechanism of compensatory enlargement.

Localization of the active center of nitroxide radical reduction in rat liver microsomes: its relation to cytochrome P-450 and membrane fluidity.

The properties and localization of the active center of NADPH-dependent nitroxide radical reduction in rat liver microsomes were investigated with the following five spin-probes as substrates; tetramethylpiperidinol-N-oxyl (TEMPOL) and four spin-labeled stearic acid derivatives with a nitroxide radical at the 5th, 7th, 12th, or 16th position of the hydrocarbon chain (abbreviated as 5SLS, 7SLS, 12SLS, and 16SLS, respectively). The ESR signals of these spin-probes in microsomes decreased on the addition of NADPH, and the decay was inhibited by pretreatment with SKF-525A. Experiments with various microsomal preparations induced by phenobarbital (PB), polychlorinated biphenyls (PCB), or 3-methylcholanthrene (3-MC) revealed that the reduction rate was correlated to the concentration of cytochrome P-450 but not to that of NADPH reductase. Thus, the nitroxide radicals of the SLSs and TEMPOL seem to be reduced by the combined action of NADPH-cytochrome P-450 reductase and cytochrome P-450. The decay showed a lag time, but no distinct correlation was observed between the lag time and the spin-probe species. On the other hand, the initial velocity of the nitroxide reduction depended strongly on the spin-probe species. Among the five spin-probes, 7SLS was reduced most quickly, followed by 5SLS, 12SLS, TEMPOL, and 16SLS in that order. The reduction rate varied from 0.18/min for 7SLS to 0.08/min for 16SLS. There was a linear relation between the cytochrome P-450 content and the reduction rate.(ABSTRACT TRUNCATED AT 250 WORDS)