RESUMEN
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.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Circulación Coronaria/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Indoles/uso terapéutico , Papaverina/uso terapéutico , Vasodilatación/efectos de los fármacos , Vasodilatadores/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Angiografía Coronaria/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Humanos , Indoles/farmacología , Papaverina/farmacología , Vasodilatadores/farmacologíaRESUMEN
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.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Gasto Cardíaco Bajo/tratamiento farmacológico , Gasto Cardíaco Bajo/fisiopatología , Endotelio Vascular/fisiopatología , Animales , Bradiquinina/fisiología , Gasto Cardíaco Bajo/diagnóstico , Gasto Cardíaco Bajo/patología , Ecocardiografía , Hemodinámica , Masculino , Miocardio/metabolismo , Miocardio/patología , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo III , Estrés Oxidativo/fisiología , Prostaglandinas/fisiología , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
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.
Asunto(s)
Mortalidad Infantil , Adolescente , Adulto , Causas de Muerte , Diarrea Infantil/mortalidad , Escolaridad , Femenino , Fertilidad , Haití/epidemiología , Humanos , Lactante , Mortalidad Infantil/tendencias , Recién Nacido , Edad Materna , Persona de Mediana Edad , Madres/educación , Paridad , Vigilancia de la Población , Infecciones del Sistema Respiratorio/mortalidad , Factores de Riesgo , Factores SocioeconómicosRESUMEN
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.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Cardiomegalia/tratamiento farmacológico , Indoles/farmacología , Músculo Esquelético/efectos de los fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Cardiomegalia/fisiopatología , Diafragma/efectos de los fármacos , Diafragma/fisiología , Femenino , Indoles/uso terapéutico , Complejo Mayor de Histocompatibilidad/fisiología , Contracción Muscular/efectos de los fármacos , Músculo Esquelético/enzimología , Músculo Esquelético/fisiología , Peptidil-Dipeptidasa A/sangre , Perindopril , Isoformas de Proteínas/metabolismo , ConejosRESUMEN
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.
Asunto(s)
Gasto Cardíaco Bajo/fisiopatología , Músculo Esquelético/irrigación sanguínea , Condicionamiento Físico Animal/fisiología , Vasodilatación/fisiología , Animales , Arterias/fisiopatología , Gasto Cardíaco Bajo/patología , Enfermedad Crónica , Ecocardiografía , Hemodinámica/fisiología , Masculino , Miocardio/patología , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo III , Estrés Oxidativo/fisiología , Prostaglandinas/fisiología , Ratas , Ratas Wistar , Flujo Sanguíneo Regional/fisiologíaRESUMEN
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.
Asunto(s)
Benzazepinas/farmacología , Cardiotónicos/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Animales , Antiarrítmicos/farmacología , Atropina/farmacología , Benzazepinas/administración & dosificación , Cardiotónicos/administración & dosificación , Interacciones Farmacológicas , Frecuencia Cardíaca/fisiología , Inyecciones Intraperitoneales , Ivabradina , Masculino , Propranolol/farmacología , Ratas , Ratas WistarRESUMEN
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.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Cardiomiopatías/fisiopatología , Diafragma/efectos de los fármacos , Indoles/farmacología , Animales , Fenómenos Biomecánicos , Cardiomiopatías/metabolismo , Cricetinae , Diafragma/metabolismo , Diafragma/fisiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Contracción Isométrica/efectos de los fármacos , Mesocricetus , Peptidil-Dipeptidasa A/sangre , PerindoprilRESUMEN
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.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Vasos Coronarios/fisiopatología , Hemodinámica/efectos de los fármacos , Hipertensión/fisiopatología , Indoles/farmacología , Papaverina/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Presión Sanguínea/efectos de los fármacos , Frío , Angiografía Coronaria , Circulación Coronaria/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Endotelio Vascular/fisiopatología , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Resistencia Vascular/efectos de los fármacosRESUMEN
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.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Vasos Coronarios/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Indoles/farmacología , Sistema Vasomotor/efectos de los fármacos , Adulto , Endotelio Vascular/fisiopatología , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Sistema Vasomotor/fisiopatologíaRESUMEN
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)
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Enalapril/uso terapéutico , Hipertensión/tratamiento farmacológico , Indoles/uso terapéutico , Administración Oral , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Antihipertensivos/farmacología , Método Doble Ciego , Sinergismo Farmacológico , Enalapril/farmacología , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hidroclorotiazida/administración & dosificación , Hidroclorotiazida/farmacología , Hidroclorotiazida/uso terapéutico , Indoles/farmacología , Masculino , Persona de Mediana Edad , PerindoprilRESUMEN
In normal coronary arteries, increased flow velocity induces endothelium-dependent dilation, and dilation in response to sympathetic stimulation evoked by the cold pressor test is partly due to increased flow velocity. In arterial hypertension, angiographically normal coronary arteries were constricted by acetylcholine, an endothelium-dependent vasodilator. To assess the epicardial coronary artery response to the increase blood flow velocity induced by the cold pressor test in hypertensive patients with angiographically normal coronary arteries, coronary artery diameters and flow velocity were measured during cold pressor test in 12 untreated hypertensive patients and in 10 control subjects. Diameters were determined by quantitative angiography on proximal and distal segments of the left anterior descending coronary artery, and flow velocity measurements were made by Doppler testing in the distal segment. In control subjects, the proximal and distal segments dilated during cold pressor test by 12.0 +/- 4.5% and 13.9 +/- 6.5%, respectively (both P < .001), when flow velocity increased by 46.7 +/- 26.1% (P > .05). In hypertensive patients, segments were constricted, respectively, by 10.3 +/- 8.5% (P < .001) and 7.9 +/- 8.6% (P < .01), when the flow velocity was increased by 68.3 +/- 48.2% (P < .001). Intracoronary injection of an endothelium-independent dilator resulted in similar dilation in control subjects (proximal: +30.0 +/- 12.9%; distal: +32.4 +/- 15.2%) and in hypertensive patients (proximal: +22.3 +/- 7.5%; distal: +28.8 +/- 15.4%). In conclusion, in hypertensive patients with angiographically normal coronary arteries and without any other coronary risk factors, endothelium-dependent flow-mediated coronary dilation evoked by the cold pressor test is impaired.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Velocidad del Flujo Sanguíneo/fisiología , Vasos Coronarios/fisiopatología , Hipertensión/fisiopatología , Vasodilatación/fisiología , Frío , Electrocardiografía , Endotelio Vascular/fisiopatología , Femenino , Hemodinámica/fisiología , Humanos , Dinitrato de Isosorbide , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Abnormal endothelium-dependent coronary response to acetylcholine has been shown in patients with essential hypertension. We tested the hypothesis that flow-dependent dilatation, which has been shown in normal human coronary arteries, is impaired in hypertensive patients. METHODS AND RESULTS: The coronary vasomotor response to maximal increase of blood flow induced by papaverine was studied in 10 control subjects and in 14 hypertensive patients with no other risk factors and angiographically normal coronary arteries. After the injection of papaverine in the midportion of the left anterior descending coronary artery (LAD), the diameter of the proximal LAD (LAD1) was measured by quantitative angiography, whereas that of the proximal circumflex artery (LCx) served as control segment. Estimates of coronary blood flow in the distal LAD (LAD2) were calculated by intracoronary Doppler flow velocity measurements. An increase in LAD2 blood flow of 521 +/- 41% (P < .001) in control subjects was associated with a 17.0 +/- 3.3% dilatation of the LAD1 (P < .001) and with no significant change in the diameter of the LCx. In hypertensive patients, despite a comparable increase in LAD2 blood flow of 406 +/- 32% (P < .001), the LAD1 failed to dilate (-0.4 +/- 0.6%, NS). The dilative response to isosorbide dinitrate was similar in control subjects and hypertensive patients (30.0 +/- 4.1%, P < .001 and 21.9 +/- 1.9%, P < .001, respectively). CONCLUSIONS: Thus, the flow-mediated coronary dilatation is lost in hypertensive patients, and this may impair normal dilatation observed in response to an increase in myocardial metabolic demand.
Asunto(s)
Vasos Coronarios/fisiopatología , Hipertensión/fisiopatología , Vasodilatación , Adulto , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Angiografía Coronaria , Vasos Coronarios/patología , Femenino , Humanos , Hipertensión/patología , Dinitrato de Isosorbide/farmacología , Masculino , Persona de Mediana Edad , Papaverina/farmacología , Vasodilatación/efectos de los fármacosRESUMEN
Perindopril is a long acting angiotensin-converting enzyme inhibitor with a perhydroindole group and no sulphydryl radical. Perindopril is a pro-drug that is hydrolyzed to the active metabolite perindoprilat. Perindopril is rapidly absorbed, reaching peak plasma concentrations about 1 h after a single oral dose. Its bioavailability is greater than 70% and is not influenced by meals. Perindoprilat reaches peak plasma concentrations 3 to 4 h after administration. The blood pressure lowering effect of perindopril has been shown in animal models with spontaneous and renovascular hypertension. In hypertensive patients dose response studies have shown a significant and linear relationship between the dose and the activity of perindopril. The antihypertensive efficacy of 4 and 8 mg doses is significantly greater than that of 2 mg or of placebo. The maximal response is attained about 4 to 6 h after the first dose. As demonstrated by 24 h blood pressure recordings in ambulatory patients, the antihypertensive activity of perindopril was still significant 24 h after the last dose. Clinical trials have indicated that perindopril is at least as effective as usual therapeutic doses of captopril, atenolol or a combination of hydrochlorothiazide plus amiloride in mild to moderate essential hypertension. Oral administration of 4 to 8 mg od significantly reduced supine and standing systolic and diastolic blood pressure, and adequate diastolic blood pressure control was attained in about 60 to 70% of patients with monotherapy. In the majority of patients, hypertension was controlled with a daily dose of 4 mg.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Indoles/uso terapéutico , Antihipertensivos/efectos adversos , Ensayos Clínicos como Asunto , Humanos , Indoles/efectos adversos , PerindoprilRESUMEN
In normal subjects, coronary arteries dilate in response to sympathetic stimulation evoked by the cold pressor test. Similarly, in normal coronary arteries the increase in blood flow velocity induced by papaverine results in flow-dependent coronary dilation. In order to assess the coronary responses to both stimuli in hypertensive patients, variations of proximal left anterior descending coronary artery diameters and coronary blood flow velocity have been measured using quantitative coronary angiography and intracoronary Doppler in 10 control subjects and in 12 hypertensive patients. All the patients had angiographically normal coronary arteries. Total serum cholesterol, triglycerides, HDL- and LDL-cholesterol were within normal range in all patients. All patients were nonsmokers and none of them had diabetes mellitus. During the cold pressor test (hands immersed in ice water for 120 s), the rate-pressure product and coronary blood flow velocity increased respectively by 33 +/- 9% (p < 0.001) and 51 +/- 26% (p < 0.05) in control subjects, by 28 +/- 18% (p < 0.001) and 68 +/- 52% (p < 0.05) in hypertensive patients. In control subjects, coronary arteries dilated by + 12.0 +/- 4.4% (p < 0.001), and constricted by -10.3 +/- 8.5% (p < 0.001) in hypertensive patients. After injection of 10 mg of papaverine into the distal left anterior descending coronary artery, proximal left anterior descending coronary artery dilated by + 17.0 +/- 10.6% (p < 0.001) in control subjects, and did not vary (-0.7% +/- 10.6%) in hypertensive patients, when blood flow velocity was increased respectively by 449 +/- 97% and 383 +/- 103% (p < 0.001 in both groups).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Vasos Coronarios/fisiopatología , Hipertensión/complicaciones , Vasodilatación , Adulto , Velocidad del Flujo Sanguíneo , Frío , Angiografía Coronaria , Enfermedad Coronaria/fisiopatología , Femenino , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
Hypertensive patients with angiographically normal coronary arteries may have myocardial ischemia when metabolic demand increases. Abnormal epicardial coronary artery vasomotion in response to sympathetic stimulation may contribute to ischemia in such patients. We studied the vasomotor response of smooth coronary arteries to a cold pressor test in 10 hypertensive patients without other risk factors and in 9 control subjects. Vessel dimensions were measured by quantitative angiography, and blood flow was calculated using an intracoronary Doppler catheter in the left anterior descending coronary artery. In response to cold pressor stimulation, arteries of control subjects dilated 13.0 +/- 5.9% (P < .001), and they constricted 8.2 +/- 8.5% in hypertensive patients (P < .001). Rate-pressure product increased from 9466 +/- 1677 to 12,547 +/- 2367 beats per minute (bpm).mm Hg in control subjects (P < .001) and from 13,720 +/- 1823 to 17,353 +/- 2037 bpm.mm Hg in hypertensive patients (P < .001). Coronary blood flow velocity and blood flow increased 51 +/- 26% (P < .05) and 87 +/- 27% (P < .001), respectively, in control subjects and 68 +/- 52% (P < .05) and 36 +/- 33% (P < .01) in hypertensive patients. At peak cold pressor test, despite a significant higher rate-pressure product in hypertensive patients, blood flow was similar in both groups, suggesting an uncoupling between myocardial metabolic demand and supply. Thus, hypertension impairs the vasodilator response of angiographically normal coronary arteries to a cold pressor test. This abnormal response may be due to enhanced catecholamine reactivity and/or impairment of endothelial flow-mediated vasodilator response.
Asunto(s)
Vasos Coronarios/fisiopatología , Hipertensión/fisiopatología , Vasoconstricción , Adulto , Frío , Angiografía Coronaria , Circulación Coronaria/efectos de los fármacos , Endotelio Vascular/fisiología , Femenino , Humanos , Dinitrato de Isosorbide/farmacología , Masculino , Persona de Mediana Edad , Sistema Nervioso Simpático/fisiología , Vasoconstricción/efectos de los fármacosRESUMEN
We wished to test (a) whether single-drug therapy with a low dose of the angiotensin-converting enzyme (ACE) inhibitor perindopril has the capacity to improve early survival of the cardiomyopathic Syrian hamster (CSH); (b) whether early treatment with perindopril modifies CSH survival to a greater extent than perindopril treatment initiated later in the course of the disease; and (c) the effects of early and late perindopril therapy on the intrinsic contractility of left ventricular (LV) papillary muscle. We studied CSH from the Bio 53.58 dilated strain (n = 76), in which myocardial necrosis is known to develop from age 30 days, whereas congestive heart failure (CHF) is observed only after age 6 months. Animals were randomly assigned to three groups. In early-treated animals, perindopril (1 mg/kg body weight once daily in distilled water) was administered by force-feeding from age 1 month to 9 months (PE1, n = 21). Animals receiving delayed treatment received distilled water from age 1 month to 6 months, followed by 1 mg/kg body weight from age 6 to 9 months (PE2, n = 34). Controls received distilled water from age 1 month to 9 months (C, n = 21). At endpoint (9 months), mechanical properties of LV papillary muscles and serum ACE activity were studied in a subgroup of 32 CSH (C, n = 8; PE1, n = 10; and PE2, n = 14). Maximum unloaded shortening velocity, maximum extent of systolic shortening in twitch with preload only, and normalized peak of isometric active force were measured.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Cardiomiopatía Dilatada/tratamiento farmacológico , Indoles/uso terapéutico , Contracción Miocárdica/efectos de los fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Animales , Peso Corporal , Cardiomiopatía Dilatada/mortalidad , Cricetinae , Modelos Animales de Enfermedad , Masculino , Mesocricetus , Peptidil-Dipeptidasa A/sangre , Perindopril , Análisis de SupervivenciaRESUMEN
There is uncertainty over whether vitamin A supplementation reduces morbidity among children with subclinical deficiency of the vitamin. Hence a double-blind, placebo-controlled trial of the effect of vitamin A supplementation on childhood morbidity was conducted among 11,124 children aged 6-83 months in the northwest of Haiti. After a random start, children were sequentially assigned by household units to receive either megadose vitamin A or placebo in three distribution cycles 4 months apart. 2 to 8 weeks after each administration of the vitamin A and placebo capsules, indicators of childhood morbidity were reassessed through interviews conducted in the homes of participating families. The vitamin A group was found to have an increased 2-week prevalence of all symptoms and signs of childhood morbidity assessed, including diarrhoea (rate ratio [RR] = 1.09, 95% confidence interval 1.05-1.14), rhinitis (RR = 1.02, 95% confidence interval 1.00-1.04), cold/flu symptoms (RR = 1.04, 95% confidence interval 1.01-1.06), cough (RR = 1.07, 95% confidence interval 1.03-1.11), and rapid breathing (RR = 1.18, 95% confidence interval 1.09-1.27). The study shows an increased 2-week prevalence of diarrhoea and the symptoms of respiratory infections after vitamin A supplementation.
PIP: In the late 1980s, 11,124 children 6-83 months old, living in the sparsely populated northwest of Haiti participated in a double-blind, placebo-controlled trial of the effect of vitamin A supplementation on child morbidity. An ophthalmic assistant and a supervising ophthalmologist examined all children 2 years old. 30 children had vitamin A deficient related corneal disease (20 with corneal xerosis and 10 with corneal ulceration, keratomalacia, and/or corneal scarring). The children received either a capsule containing 200,000 IU of vitamin A and 40.6 mg vitamin E or a capsule containing only 40.6 mg vitamin E (placebo) every 4 months. Field workers interviewed caretakers 2-8 weeks after the children received their capsules to gather data on signs and symptoms of illness. Children in the vitamin A group were more likely to have a higher prevalence of diarrhea and of respiratory infections than the placebo group (e.g., 1st cycle, 42 vs. 36% for diarrhea and 18 vs. 15% for rapid breathing, rate ratios = 1.6 and 1.19, respectively). The risk of morbidity was highest 8-17 weeks after receiving the megadose of vitamin A. These findings indicate that prevalence of diarrhea and respiratory infections increased 2 weeks after vitamin A supplementation. Mortality rates of the 2 groups were essentially the same. The mortality rate of nonparticipants was higher than that of participants (52/1000 vs. 23/1000), however, suggesting that the supplements may have had some benefit.
Asunto(s)
Diarrea/epidemiología , Terapia Ortomolecular , Infecciones del Sistema Respiratorio/epidemiología , Deficiencia de Vitamina A/tratamiento farmacológico , Vitamina A/uso terapéutico , Enfermedad Aguda , Niño , Preescolar , Intervalos de Confianza , Método Doble Ciego , Femenino , Haití , Humanos , Lactante , Masculino , Terapia Ortomolecular/efectos adversos , Prevalencia , Estudios Prospectivos , Vitamina A/efectos adversosRESUMEN
The long-term acceptability of perindopril in mild-to-moderate chronic heart failure (CHF) was evaluated in a multicenter open study. A total of 320 patients with a mean age of 62 +/- 1 years and CHF of New York Heart Association (NYHA) class I (2 patients), II (204 patients), or III (114 patients) were included after a 2-week run-in period during which time vasodilators were stopped and diuretic and/or digoxin therapy stabilized. Perindopril treatment was started at 2 mg, increasing to 4 mg once daily after 2 weeks if supine systolic blood pressure remained > 100 mm Hg. After this dose titration period, follow-up visits were scheduled at monthly intervals for the first 3 months, then at 3-month intervals with a maximum period of follow-up being 30 months. At the time of analysis, mean duration of treatment was 276 days and 208 patients were treated > or = 6 months. Of the 320 patients, 10 (3.1%) died, 9 (2.8%) were withdrawn for worsening heart failure, and 38 (11.9%) for nonfatal adverse events, including cough (2.8%), dizziness or orthostatic discomfort (1.9%), angina pectoris (1.6%), and cutaneous signs (1.3%). Exercise test duration increased from 516 +/- 14 to 659 +/- 19 sec after 6 months of treatment (p < 0.01). At 6 months, 55.6% of patients improved by at least 1 NYHA class. Supine systolic blood pressure decreased slightly from 137 +/- 2 to 132 +/- 1 mm Hg (p < 0.01) and plasma creatinine levels remained stable from 100 +/- 2 to 102 +/- 2 mumol/liter after 6 months of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Indoles/uso terapéutico , Adulto , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Enfermedad Crónica , Prueba de Esfuerzo/efectos de los fármacos , Femenino , Humanos , Indoles/efectos adversos , Indoles/farmacología , Masculino , Persona de Mediana Edad , Perindopril , Resultado del TratamientoRESUMEN
Twelve patients, intubated for acute exacerbation of chronic obstructive pulmonary disease, received six intravenous doses of 400 mg of pefloxacin at 12-h intervals. Samples of blood and bronchial secretions were taken simultaneously, before the injection and at 0.5, 3, 6, 9, and 12 h after the end of the sixth infusion. There was a large variation in pefloxacin levels in both serum and bronchial secretions. The mean concentrations of pefloxacin in bronchial secretions ranged from 6.51 to 11.1 micrograms/ml and were higher than the corresponding concentrations in serum at all times. Of 61 bronchial specimens, 48 (79%) contained more than 8 micrograms of the antibiotic per ml.