Restoration of flow-dependent coronary dilation by ACE inhibition improves papaverine-induced maximal coronary blood flow in hypertensive patients: demonstration that large epicardial coronary arteries are more than conductance vessels.

Restoration of flow-dependent coronary artery dilation by angiotensin-converting enzyme inhibition (ACEI) has been demonstrated in patients with hypertension. The aim of the present study was to evaluate whether dilation of conductance coronary arteries may alter maximal coronary blood flow (CBFmax) and minimal coronary resistance (CRmin) in hypertensive patients with reversible impairment of flow-dependent coronary artery dilation. Thirteen hypertensive patients with angiographically normal coronary arteries and no other risk factors were studied. Cross-sectional areas (CSAs) of proximal and distal left anterior descending (LAD) coronary arteries were determined by quantitative angiography. Coronary flow velocity was recorded in the distal LAD with an intracoronary Doppler catheter. Estimates of coronary blood flow and resistance were calculated at rest and during maximal increase in blood flow induced by papaverine injected in the midportion of the LAD, both before and after ACEI. Flow-dependent dilation of the proximal LAD, abolished before ACEI, was restored after (26.7 +/- 11.2%; p < 0.001). The increase in CSA of the distal LAD exposed to papaverine was significantly higher after ACEI than before (from 33.4 +/- 20.5% to 51.5 +/- 23.4%; p < 0.001). After restoration of proximal LAD flow-dependent dilation, CBFmax was increased by +21.0 +/- 10.3% (p < 0.001), and CRmin was reduced by 19.3 +/- 9.5% (p < 0.001). Thus, dilation of epicardial coronary arteries participates substantially in the coronary resistance in hypertensive patients. Restoration of flow-dependent coronary artery dilation by ACEI may improve the ability of coronary circulation to deliver its maximal myocardial blood flow in hypertensive patients.

Improvement of endothelial function by chronic angiotensin-converting enzyme inhibition in heart failure : role of nitric oxide, prostanoids, oxidant stress, and bradykinin.

BACKGROUND-Chronic heart failure (CHF) impairs the endothelium-dependent, flow-mediated dilation (FMD) of small arteries. However, whether chronic angiotensin-converting enzyme (ACE) inhibition affects the impairment of FMD in CHF is unknown. We investigated the effects of long-term ACE inhibition on the FMD of peripheral arteries in rats with CHF and the mechanism(s) involved. METHODS AND RESULTS-FMD was assessed in isolated, perfused gracilis muscle arteries from sham-operated, and untreated or ACE inhibitor-treated (perindopril 2 mg. kg(-1). day(-1) for 10 weeks) rats with CHF (coronary artery ligation). The role of nitric oxide (NO), prostaglandins, and free radicals was assessed by pretreating the vessels with the NO synthase inhibitor N(W)-nitro-L-arginine, the cyclooxygenase inhibitor diclofenac, or the free radical scavenger N-2-mercaptopropionyl-glycine (MPG). Endothelial NO synthase mRNA expression was determined by reverse transcriptase polymerase chain reaction. In animals with hemodynamic and echographic signs of CHF, FMD was converted into vasoconstriction, and this was prevented by ACE inhibition. FMD of arteries from sham-operated or ACE inhibitor-treated CHF rats was abolished by N(W)-nitro-L-arginine. In untreated CHF rats, FMD was increased by diclofenac and MPG. In contrast, in arteries from ACE inhibitor-treated rats, neither diclofenac nor MPG affected FMD. In parallel, ACE inhibition prevented the reduction of endothelial NO synthase mRNA by CHF. CONCLUSIONS-In CHF, ACE inhibition normalized NO-dependent dilatation and suppressed the production of vasoconstrictor prostanoid(s), resulting in improved FMD. The improvement of FMD might contribute to the beneficial effects of ACE inhibition during CHF.

[Survey of infant mortality in Mirebalais, Haiti]. / Enquête sur la mortalité infantile à Mirebalais, Haïti.

Infant mortality remains high in Haiti, at 74 deaths per 1,000 live births. In this study, we aimed to assess infant mortality in Mirebalais and to identify the associated risk factors. We carried out a census of pregnant women in Mirebalais, at the beginning of the study, over a three-week period. Twelve researchers visited the homes of the newborns to enroll the families in the study and to collect demographic data. Further visits were scheduled for two, four, six, nine and twelve months after birth. If the child died during this time, the investigator asked the mother about all the steps taken to prevent the death of the child, and an autopsy was carried out. The survey began on July 12 1994 and ended on December 31 1995. During that time, about 2,151 pregnant women were enrolled. Seven of these women died and 16 had abortions. In total, 2,069 children were born to the enrolled women. We enrolled 515 other children after birth or following referral by health workers or midwives. We therefore followed 2,584 children. We found that 10% of the mothers were aged between 15 and 19 years, 66.3% had had one to three pregnancies and 73% were entirely uneducated. The early neonatal mortality rate was 4.64 per 1,000 live births, late neonatal mortality was 6.96 per thousand and post-neonatal mortality was 45.6 per thousand live births. Diarrhea was responsible for 60% of the deaths and acute respiratory infections for 11%, these two causes accounting for 71% of the deaths of children aged 1 to 12 months. Thus, although infant mortality has decreased it remains high in Mirebalais, largely due to diarrhea and acute respiratory infections in the post-neonatal period.

Impaired skeletal muscle performance in the early stage of cardiac pressure overload in rabbits: beneficial effects of angiotensin-converting enzyme inhibition.

Abnormalities of skeletal muscles are frequently observed in patients with congestive heart failure. In these patients, angiotensin-converting enzyme (ACE) inhibitors improve exercise performance. The present study was designed to assess whether skeletal muscle dysfunction develops in the early stage of cardiac overload and if so, whether such functional alterations can be prevented by ACE inhibition. Mechanical performance, cross-bridge (CB) properties, and myosin heavy chain composition were investigated in respiratory and limb skeletal muscles of rabbits with moderate cardiac hypertrophy, and after single therapy with the ACE inhibitor perindopril (PE). After constriction of the aorta, the rabbits were treated during a 10-week period with either PE (1 mg/kg/day; n = 9) or a placebo (PL; n = 15). A third group of sham-operated animals received PL (n = 10). Analyses were performed on isolated diaphragm and soleus strips. Compared with sham-operated animals (shams), peak tetanic tension in PL fell by 40% in diaphragm and 34% in soleus. There were no significant differences in peak tetanic tension and the maximum shortening velocity between PE and shams. In both muscles, the total number of CBs was significantly lower in PL than in shams, but did not differ between shams and PE. The elementary force per CB did not differ between groups. In both muscles, the myosin heavy chain composition did not differ between groups. The study demonstrated that intrinsic performance of diaphragm and soleus muscles was affected early in the development of chronic pressure overload. Single therapy with PE tended to preserve muscle strength, essentially by limiting the loss of CBs.

Exercise improves flow-mediated vasodilatation of skeletal muscle arteries in rats with chronic heart failure. Role of nitric oxide, prostanoids, and oxidant stress.

BACKGROUND: Flow-mediated dilatation (FMD) of the peripheral arteries may be impaired in chronic heart failure (CHF), and this could contribute to the increased peripheral resistance and exercise intolerance that occur with this disease. Physical exercise improves the FMD of large conduit arteries in CHF, but whether a similar impairment also occurs in smaller arteries is unknown. The mechanisms of the changes in FMD after CHF or exercise are also unknown. METHODS AND RESULTS: FMD was assessed in isolated, perfused, and preconstricted gracilis muscle arteries from sham-operated rats or CHF rats (coronary artery ligation) who were either sedentary or exercised (30-minute swimming period twice a day for 10 weeks, starting 7 days after ligation). In animals with hemodynamic and echographic signs of CHF, FMD was abolished and converted into vasoconstriction (percent change in diameter after 370 microL/min flow: sham, 42+/-5%; CHF, -4+/-3%; P<0.05). Exercise partially restored FMD (18+/-3%; P<0.05 versus CHF). In sham rats, FMD was abolished by the nitric oxide-synthase inhibitor Nomega-nitro-L-arginine (L-NA) but unaffected by the cyclooxygenase inhibitor diclofenac or the free radical scavenger N-(2-mercaptopropionyl)-glycine (MPG). In arteries from sedentary CHF rats, FMD was not modified by L-NA, but it was partially restored by diclofenac or MPG. In exercised CHF rats, FMD was abolished by L-NA and only moderately improved by diclofenac or MPG. Likewise, endothelial nitric oxide synthase mRNA expression (determined by reverse transcription polymerase chain reaction at the level of the gracilis muscle) was reduced by CHF, and this was prevented by exercise. CONCLUSIONS: CHF abolishes the FMD of small arteries by impairing the nitric oxide pathway, increasing oxidant stress, and releasing a prostanoid-contracting factor. Exercise partially restores FMD by increasing expression of endothelial nitric oxide synthase and preventing the production of vasoconstrictor prostanoids and free radicals. Such restoration of FMD might contribute to the increase in exercise capacity after physical exercise in CHF.

Relationships between heart rate and heart rate variability: study in conscious rats.

Heart rate (HR) and heart rate variability (HRV) are risk markers in cardiac disease. HRV is also an index of the sympathovagal modulation of heart rate. Their relations have been rarely analyzed. We aimed to study such relations in normal adult conscious rats by using a novel bradycardic agent, a sinus node inhibitor, S-16257. Placebo-drug crossover designs were used while monitoring HR with telemetry and analyzing HRV in both time and frequency domains. S-16257 (2 mg/kg; n = 10) decreased HR by 29% and markedly increased HRV in parallel. By using various combinations of S-16257, atropine (2 mg/kg), and propranolol (4 mg/kg), a positive relation was shown between RR interval and various indexes of HRV: the slower the HR, the greater the HRV. Nevertheless, there is one exception to this correlation. When S-16257 was associated with both atropine and propranolol, the deep bradycardia was accompanied by a reduction of HRV, which indicates that the physiologic negative correlation between HR and HRV is not an intrinsic property of the pacemaker but is highly dependent on the two components of the autonomic system.

Effects of angiotensin converting enzyme inhibition on crossbridge properties of diaphragm in cardiomyopathic hamsters of the dilated bio 53-58 strain.

Crossbridge properties of cardiomyopathic Syrian hamster (CSH) diaphragm from the dilated Bio 53-58 strain were analyzed after 5-mo of treatment with the angiotensin converting enzyme (ACE) inhibitor perindopril (1 mg/kg/d by oral gavage). Three groups were studied: control F1B hamsters (C; n = 14); CSH given placebo (PL; n = 11 ); and perindopril-treated CSH (PE; n = 11). Peak isometric tension was lower in PL than in C, in both twitch (21.4 +/- 1.5 versus 46.9 +/- 1.5 mN/mm2; p < 0.001) and tetanus (41.0 +/- 2.7 versus 90.5 +/- 3.3 mN/mm2; p < 0.001). In PE, peak isometric tension was intermediate between C and PL, and was significantly lower than in C and higher than in PL. The single force of one crossbridge (pi), the number (m) of crossbridges, the turnover rate of myosin adenosine triphosphatase (ATPase) (kcat), and peak mechanical efficiency (Effmax) were calculated from A.F. Huxley's equations; m was lower in PL than in C, in both twitch (3.4 +/- 0.2 versus 4.9 +/- 0.2 10(9)/mm2; p < 0.001) and tetanus (4.0 +/- 0.3 versus 8.9 +/- 0.7 10(9)/mm2; p < 0.001); m was higher in PE than in PL, in both twitch 4.3 +/- 0.5 versus 3.4 +/- 0.2 10(9)/mm2; NS) and tetanus (6.2 +/- 0.4 versus 4.0 +/- 0.3 10(9)/mm2; p < 0.01), with no change in pi. In the three groups, Effmax correlated linearly with kcat (r = 0.93; p = 0.001) and showed a negative linear correlation with pi (r = 0.996; p = 0.001). In conclusion, our results show that in experimental cardiomyopathy, ACE inhibitor mainly helps to prevent a decrease in the number of diaphragm muscle crossbridges, resulting in preserved peak isometric tension.

Angiotensin-converting enzyme inhibition restores flow-dependent and cold pressor test-induced dilations in coronary arteries of hypertensive patients.

BACKGROUND: Cold pressor test (CPT)-induced and flow-dependent epicardial coronary artery dilations are impaired in patients with hypertension. ACE inhibition can attenuate sympathetic coronary constriction and potentiate or restore endothelium-dependent relaxations. This study was designed to determine whether the ACE inhibitor perindoprilat can restore normal coronary dilative responses in hypertensive patients. METHODS AND RESULTS: Coronary vasomotor responses to CPT and to maximal increase of blood flow induced by papaverine were studied in 10 untreated patients with essential hypertension, no other risk factors, and angiographically normal coronary arteries before and after intravenous ACE inhibition by perindoprilat. Diameters of proximal and distal left anterior descending (LAD) and circumflex coronary arteries were measured by quantitative angiography. Estimates of coronary blood flow and resistance index were calculated with an intracoronary Doppler catheter in the distal LAD. Perindoprilat did not modify the hemodynamic responses to CPT and papaverine. In response to CPT, perindoprilat changed the epicardial coronary constriction (-8.4 +/- 5.8%, P < .001) into a significant dilation (+12.0 +/- 6.4%, P < .001). Perindoprilat significantly increased the coronary blood flow (from 33.7 +/- 10.0 to 57.9 +/- 20.5 mL/min, P < .01) and enhanced the decrease in coronary resistance (from 4.28 +/- 1.27 to 2.96 +/- 0.84 mm Hg.mL-1.min-1, P < .001) caused by CPT. Flow-dependent dilation of the proximal LAD was abolished in the control condition and was restored after perindoprilat (12.6 +/- 4.7%, P < .001). CONCLUSIONS: ACE inhibition restored CPT-induced and flow-mediated coronary artery dilations in patients with essential hypertension. These results indicate that impaired coronary vasomotor responses may be reversible in recently diagnosed hypertension.

[Restoration of normal coronary vasomotricity after intravenous infusion of angiotensin converting-enzyme inhibitor (perindoprilat) in hypertensive patients]. / Rétablissement d'une vasomotricité coronaire normale après injection intraveineuse d'un inhibiteur de l'enzyme de conversion (périndoprilate) chez les sujets hypertendus.

We have previously shown that in hypertensive patients, the response of normal coronary arteries to sympathetic stimulation evoked by the cold-pressor test (CPT), and the endothelial-mediated flow-dependent coronary vasodilation were impaired. The immediate effects of the converting-enzyme inhibitor perindoprilat (PER) have been evaluated in 10 untreated hypertensive patients with angiographically normal coronary arteries and results have been compared to the normal responses of 10 control subjects. Diameter changes of proximal left anterior descending coronary artery (pLAD) and coronary flow velocity in distal LAD have been measured at baseline, during CPT, during recontrol, and after 10 mg papaverine (PAP) injection in the mid portion of the LAD. Measures have been repeated after intravenous infusion of 1 mg PER, and at the end of the procedure after 2 mg intracoronary injection of isosorbide dinitrate (ISDN). Left ventricular dimensions and systolic function, total cholesterol, triglycerides, HDL and LDL-cholesterol were within the normal range. In hypertensive patients before PER, pLAD constricted in response to the CPT and no diameter change was observed after PAP, despite the increase in flow velocity in the 2 conditions (+63 +/- 27%, and +412 +/- 77%, respectively; all p < 0.001). In control subjects, pLAD dilated significantly in these 2 conditions. In hypertensive patients after PER, pLAD dilated similarly to control subjects in the 2 conditions. Endothelium-independent coronary dilation to ISDN was comparable in the 2 groups of patients. In conclusion, PER restores a normal coronary response both to sympathetic stimulation due to CPT and to flow increase in hypertensive patients with angiographically normal coronary arteries and without any other coronary risk factors.

Clinical acceptability of ACE inhibitor therapy in mild to moderate hypertension, a comparison between perindopril and enalapril.

The aim of this 3-month double-blind study was to assess the antihypertensive effect and acceptability of perindopril in comparison with enalapril in patients with mild to moderate essential hypertension. After a 4-week placebo run-in period, 161 patients with supine diastolic blood pressure (DBP) between 95 and 115 mmHg were randomized to receive perindopril 4 mg or enalapril 10 mg once daily. If supine DBP was higher than 90 mmHg, treatment was adjusted monthly, first by doubling the dose and then by addition of hydrochlorothiazide 12.5 mg. After 3 months of active treatment the decrease in supine and standing blood pressures was statistically significant within both groups but was not statistically different between groups. The percentage of patients (65%) who achieved supine DBP of < or = 90 mmHg in the perindopril group was not significantly different from the enalapril group (73%). Monotherapy resulted in control of supine DBP in 56% of the perindopril group and 58% of the enalapril group; the addition of hydrochlorothiazide resulted in control of supine DBP in 6% and 15% respectively. The number of withdrawals for adverse events was statistically significant between groups (0 in the perindopril group and 7 in the enalapril group, p = 0.01). During active treatment the most frequently reported complaints were headaches and cough; there was not statistically difference between groups. Changes in laboratory parameters were minor and not significantly different between the two groups except for serum glucose, potassium, and triglyceride levels. In conclusion, there was no significance between perindopril and enalapril in terms of efficacy. Clinical acceptability seems to be better in the perindopril group.(ABSTRACT TRUNCATED AT 250 WORDS)