Arterial hypertension, myocardial hypertrophy and disorders of cardiac rhythm induced by ligation of the left coronary artery in the rat

Cardiac hypertrophy and hypertension are major elements in sudden cardiac death in patients with coronary artery disease. To investigate in animals the hypothesis that left ventricular hypertrophy (LVH) and/or hypertension increase the incidence of severe ventricular arrhythmias, we have undertaken a 30 min period of coronary artery ligation in anaesthetized spontaneously hypertensive rats (SHR), normotensive (NT) Wistar Kyoto (WKY) and Wistar (W) rats. Mean systolic blood pressure (SBP) was 190 +/- 4 mmHg in SHR vs 123 +/- 5 mmHg in WKY and 116 +/- 4 mmHg in W (p less than 0.001). LVH index was 2.81 +/- 0.04 in SHR vs 196 +/- 0.03 in WKY and 1.65 +/- 0.05 in W (p less than 0.01). Incidence (IVF) and duration (DVF) of ventricular fibrillation were significantly more elevated in SHR than in NT rats. IVF was 100 p. 100 in SHR vs 36 p. 100 in WKY and 27 p. 100 in W (p less than 0.001); DVF was 61 +/- 17 s in SHR vs 6 +/- 6 s in WKY and W (p less than 0.001). In addition the calcium channel blocker nicardipine (N) has been administered orally to SHR either chronically during eight weeks (20 mg/kg-1 per os twice daily) or acutely as a single dose of 20 mg/kg. After long term treatment (LT) with N the LVH index and SBP were significantly reduced when compared to vehicle treated (VT) SHR; whereas a single administration of N (AT) only decreased SBP without affecting LVH.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of the renin-angiotensin and cardiac sympathetic nervous systems in the development of hypertension and left ventricular hypertrophy in spontaneously hypertensive rats.

To elucidate the relationship between the development of left ventricular hypertrophy (LVH) in hypertension and the development of both the cardiac sympathetic nervous and renin-angiotensin systems, as measured by norepinephrine and angiotensin II levels, respectively. In this longitudinal study, we compared blood pressure (BP), left ventricular weight, and norepinephrine (NE) and angiotensin II (Ang II) concentrations, in Spontaneously Hypertensive Rats (SHR) and age-matched Wistar-Kyoto (WKY) rats at 5, 10, 15, 20, and 28 wk of age. Blood pressure, plasma and ventricular Ang II and tissue NE were measured by the tail-cuff method, radioimmunoassay, and high-performance liquid chromatography (HPLC), respectively. At 5 wk, systolic blood pressure was the same in both strains. But the left ventricular plus septum weight to body weight (LVSW/BW) ratio was higher in SHR than in WKY rats (p < 0.01), which finding may have been related to the increased cardiac tissue NE concentration, and this increase tended to parallel the rise in blood pressure. Both left ventricle and forelimb muscle NE concentrations were significantly higher in SHR than in WKY rats at 5, 10, and 15 wk of age (p < 0.01, respectively), and were similar at 20 and 28 wk of age. The heart and plasma Ang II levels decreased with age, which results were in keeping with the known developmental tendencies of the biological aging progress. There was no significant difference in plasma Ang II levels between the two strains from 5 to 20 wk, whereas these levels were remarkably higher in WKY than in SHR rats at 28 wk (p< 0.01). Otherwise, the left ventricular tissue Ang II concentrations were significantly higher in SHR than in WKY rats at the late stage (from 15 to 28 wk), which may have contributed to the late-stage cardiac hypertrophy. These results suggested that the sympathetic nervous system (SNS) and the renin-angiotensin-system (RAS) in SHR may contribute to the pathogenesis of hypertension and LVH at the early and late stages, respectively.     

Chronic l-arginine treatment increases cardiac cyclic guanosine 5′-monophosphate in rats with aortic stenosis: effects on left ventricular mass and beta-adrenergic contractile reserve

Objectives. We tested the hypothesis that nitric oxide (NO) cyclic guanosine 5′-monophosphate (GMP) signaling is deficient in pressure overload hypertrophy due to ascending aortic stenosis, and that long-term l-arginine treatment will increase cardiac cyclic GMP production and modify left ventricular (LV) pressure overload hypertrophy and beta-adrenergic contractile response.Background. Nitric oxide cyclic GMP signaling is postulated to depress vascular growth, but its effects on cardiac hypertrophic growth are controversial.Methods. Forty control rats and 40 rats with aortic stenosis left ventricular hypertrophy ([LVH] group) were randomized to receive either l-arginine (0.40 g/kg/day) or no drug for 6 weeks.Results. The dose of l-arginine did not alter systemic blood pressure. Animals with LVH had similar LV constitutive nitric oxide synthase (cNOS) mRNA and protein levels, and LV cyclic GMP levels as compared with age-matched controls. In rats with LVH l-arginine treatment led to a 35% increase in cNOS protein levels (p = 0.09 vs untreated animals with LVH) and a 1.7-fold increase in LV cyclic GMP levels (p < 0.05 vs untreated animals with LVH). However, l-arginine treatment did not suppress LVH in the animals with aortic stenosis. In contrast, in vivo LV systolic pressure was depressed in l-arginine treated versus untreated rats with LVH (163 ± 16 vs 198 ± 10 mm Hg, p < 0.05). In addition, the contractile response to isoproterenol was blunted in both isolated intact hearts and isolated myocytes from l-arginine treated rats with LVH compared with untreated rats with LVH. This effect was mediated by a blunted increase in peak systolic intracellular calcium in response to beta-adrenergic stimulation.Conclusions. Left ventricular hypertrophy due to chronic mechanical systolic pressure overload is not characterized by a deficiency of LV cNOS and cyclic GMP levels. In rats with aortic stenosis, l-arginine treatment increased cardiac levels of cyclic GMP, but it did not modify cardiac mass in rats with aortic stenosis. However, long-term stimulation of NO-cyclic GMP signaling depressed in vivo LV systolic function in LVH rats and markedly blunted the contractile response to beta-adrenergic stimulation.     

Cardiac hypertrophy and antihypertensive therapy.

Biochemical (myocardial DNA, RNA, and hydroxyproline) and humoral (plasma [PRA] and kidney [KRA] renin activity) factors were determined in spontaneously hypertensive rats (SHR) and normotensive Wistar controls (NR) before and following treatment with minoxidil or propranolol. Minoxidil (150 mg.litre-1 drinking water) effectively controlled blood pressure (17.3 kPa vs 24.9 kPa [130 mmHg vs 187 mmHg], P less than 0.001) despite marked and sustained increases in both PRA and KRA ventricular weight which were not reduced and myocardial DNA, RNA, and hyperdroxyproline which were increased by minoxidil (P less than 0.01). In contrast propranolol did not reduce blood pressure in SHR but ventricular weight was reduced somewhat (3.1 +/- 0.4 mg.g-1 vs 3.4 +/- 0.09 mg.g-1, P less than 0.05); in both SHR and NR, KRA, and PRA were lowered by pranolol. Methyldopa which controlled blood pressure and lowered PRA led to a reversal of hypertrophy. Thus, although blood pressure control is obviously important for reversing cardiac hypertrophy, it may not be the sole factor for the development and reversal of cardiac hypertrophy.     

Nifedipine in congestive heart failure: effects on resting and exercise hemodynamics and regional blood flow

Ten patients with moderate to severe congestive heart failure (CHF) underwent central and regional hemodynamic measurements at rest and central hemodynamic measurements during exercise before and after the oral administration of nifedipine (0.2 mg/kg). Nifedipine significantly decreased systemic blood pressure, systemic vascular resistance, pulmonary artery pressure, pulmonary vascular resistance, and pulmonary capillary wedge pressure. Stroke volume and cardiac output increased after nifedipine. The measured parameters of left ventricular inotropy did not change significantly for this calcium channel blocker. While blood flow to renal, hepatic, and limb vascular beds increased (p less than 0.05 for renal and limb) after nifedipine, only limb blood flow increased in proportion to the increase in cardiac output, suggesting preferential dilatation of limb vasculature. Although initial-dose nifedipine did not increase exercise duration, it elicited an improvement in exercise hemodynamics by reducing systemic vascular resistance and pulmonary capillary wedge pressure and increasing stroke volume and cardiac output. The calcium channel blocker, nifedipine, can be administered safely in the setting of ventricular failure and appears to favorably alter resting and exercise hemodynamics. A select number of patients with CHF may benefit from its long-term administration.     

Hemodynamic effects of nifedipine during upright exercise in stable angina pectoris and either normal or severely impaired left ventricular function

The immediate effects of sublingual nifedipine (20 mg) were evaluated in 18 men with stable, exercise-related angina pectoris and angiographically confirmed coronary artery obstructions, stratified at the time of left ventricular (LV) angiography according to the degree of LV dysfunction supine at rest (Group 1: n = 9, left ventricular end-diastolic pressure [LVEDP] less than 20 mm Hg; Group 2: n = 9, LVEDP greater than 20 mm Hg). At rest, in the upright posture in both groups, nifedipine reduced the systemic vascular resistance (p less than 0.01). The systemic arterial mean (p less than 0.05) and diastolic (p less than 0.01) pressures were reduced despite an increase in the cardiac output (p less than 0.05). Heart rate was increased only in Group 1 (p less than 0.05). Pulmonary artery occluded pressure was unchanged in both groups. During upright bicycle exercise in all patients, compared to control measurements, systemic arterial pressure (p less than 0.01) and vascular resistance (p less than 0.05) were similarly reduced, while exercise cardiac output response and LV filling pressure did not change after nifedipine. Heart rate was increased in Group 1 (p less than 0.05) and decreased in Group 2 (p less than 0.05). Stroke volume during exercise after nifedipine decreased 1 ml/m2 in Group 1 (p greater than 0.05) and increased 2 ml/m2 in Group 2 (p greater than 0.05) compared to control measurements; the between-group difference in the exercise heart rate and stroke volume responses after nifedipine were significant at the 5% level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of lisinopril upon cardiac hypertrophy, central and peripheral hemodynamics and neurohumoral factors in spontaneously hypertensive rats.

OBJECTIVE: Left ventricular function (LVF) after reversal of left ventricular hypertrophy (LVH) with antihypertensive therapy is still controversial. The present study was undertaken in spontaneously hypertensive rats (SHR) to determine whether LVF of the regressed heart with lisinopril is normally maintained. DESIGN: We compared cardiac function of SHR after reversal of LVH induced by lisinopril with that observed in control SHR and also with effects after a 4-week washout period. METHODS: Administration of lisinopril began at 15 weeks of age and continued for 20 weeks. Cardiac index, renal blood flow, leg muscle blood flow, plasma renin activity, atrial natriuretic peptide level, and norepinephrine concentration were determined. RESULTS: Lisinopril decreased body weight, blood pressure and left ventricular weight and increased leg muscle blood flow; cardiac index and renal blood flow were unaltered. Although norepinephrine concentration was unchanged, plasma renin activity increased and atrial natriuretic peptide decreased in treated SHR. Peak left ventricular pumping ability during volume loading was comparable in the two groups. After a 4-week washout period, left ventricular mass and blood pressure increased but remained lower than controls; cardiac index at rest and during volume loading was similar in the two groups. CONCLUSIONS: These data indicate that LVF of the regressed heart induced by lisinopril was well preserved at rest, during volume loading and also after spontaneous recurrence of hypertension in SHR.     

Evaluation of the effects of a new calcium antagonist, diltiazem, in patients with stable effort angina and a therapeutic comparison with nifedipine

The comparative efficacy of diltiazem, a new calcium-antagonist drug, and nifedipine were evaluated with computerized treadmill exercise test in 12 patients with stable effort angina. The drugs were administered in a random single-blind fashion in divided doses (diltiazem 60 mg three times daily and nifedipine 10 mg four times daily) over 3 weeks. Maximal exercise tests were performed before and at the end of each 3-week treatment period. Both diltiazem and nifedipine increased the total duration of exercise (p less than 0.001) and the time to appearance of 1.5 mm of ST depression (p less than 0.001). Both drugs reduced resting systolic and diastolic blood pressure; however the effect was greater with nifedipine. Nifedipine, but not diltiazem, caused a significant increase of resting heart rate (p less than 0.05). Both drugs blunted the blood pressure and heart rate response to exercise: nifedipine had a greater effect on the former (p less than 0.001), diltiazem on the latter (p less than 0.05). The rate-pressure product was significantly reduced at rest (p less than 0.01) and submaximal (p less than 0.001), but not maximal exercise with both drugs. The reduction of rate-pressure product is possible as the mechanism by which calcium-antagonist drugs enhance the duration of exercise in the coronary patients. Our results documented a comparable therapeutic efficacy of the two drugs, but side effects were more common with nifedipine.     

Acute electrophysiologic, hemodynamic and left ventricular effects of nifedipine and beta-blocker interactions. Maintenance of global and regional left ventricular wall motion

To assess potential cardiac effects of nifedipine and beta-blocker interactions, 10 men receiving chronic beta-blocker therapy for angina underwent hemodynamic, electrophysiologic and left ventricular (LV) functional analyses at the time of cardiac catheterization before and after buccal administration of 10 mg of nifedipine. Although this combination is usually well tolerated, there have been occasional reports suggesting that the combination of nifedipine and beta-blocking agents may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina. All patients had class II or III stable angina pectoris and were receiving at least 160 to 240 mg/day of propranolol or equivalent doses of beta-blocker therapy. Nifedipine produced no acute electrophysiologic changes, including heart rate, PR interval, AH interval, HV interval, sinus node recovery time or heart rate at which atrioventricular nodal block occurred. Hemodynamic effects included no significant change in mean right atrial pressure (7 +/- 1 vs 5 +/- 1 mm Hg), while mean pulmonary artery pressure decreased significantly (20 +/- 2 vs 17 +/- 1 mm Hg, p less than or equal to 0.05). In addition, LV end-diastolic pressure decreased significantly from 16 +/- 2 to 10 +/- 1 mm Hg (p less than or equal to 0.05), with a nonsignificant decrease in mean aortic pressure from 93 +/- 5 to 86 +/- 4 mm Hg. Likewise, no significant change occurred in cardiac index (3.2 +/- 0.4 vs 3.0 +/- 0.4 liters/min/m2) or systemic vascular resistance (1,157 +/- 247 vs 1,170 +/- 236 dynes/s/cm-5). Left ventricular ejection fraction (EF) was the same before and after nifedipine (73 +/- 2% vs 74 +/- 2%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of nifedipine controlled release on blood pressure and heart rate of spontaneously hypertensive rats. Comparison with nifedipine standard and with amlodipine]

BACKGROUND: Antihypertensive therapy aims to reduce long-term morbidity and mortality. Drugs characterized by controlled release show a better pharmacokinetic and pharmacodynamic profile compared to standard formulations. METHODS: The present study evaluated the effects of nifedipine controlled release (0.33, 0.66 and 1.32 mg/kg per os), nifedipine standard (0.08, 0.165 and 0.33 mg/kg per os) and amlodipine (0.08, 0.165 and 0.33 mg/kg per os) on mean arterial blood pressure, heart rate and pressure rate index of spontaneously hypertensive rats (SHR). These were treated by gastric gavage, and analyzed after 30 min, 1, 3, 6, 12, and 24 hours. Moreover, plasma levels of nifedipine and amlodipine were also assayed by high-performance liquid chromatography. RESULTS: Nifedipine controlled release showed a longer antihypertensive effect when compared with standard formulation and with amlodipine. The highest dose of nifedipine controlled release decreased blood pressure soon after 1 hour with a maximum decrease (-20 mmHg) at 3 hours. The effect was still significant 24 hours later (p < 0.05). Amlodipine antihypertensive effect lasted 12 hours with a maximum decrease of 18 mmHg at 6 hours. The treatment of SHR rats with nifedipine controlled release, at each of the tested doses, did not cause any significant alterations in heart rate recorded at the beginning of the experiments. Nifedipine standard (0.165 and 0.33 mg/kg) and amlodipine (0.33 mg/kg) increased heart rate in SHR rats. Interestingly enough, pressure rate index was slightly affected by nifedipine standard release and amlodipine whereas it was remarkably reduced by nifedipine controlled release (p < 0.01 vs vehicle until 9 hours). All the compounds showed maximum plasma concentrations paralleled by maximum antihypertensive effects, as evidenced at high-performance liquid chromatography method. CONCLUSIONS: Nifedipine controlled release showed more pronounced antihypertensive effects and longer pharmacokinetic properties with respect to nifedipine standard release and amlodipine.     

Changes in plasma renin activity induced by acute administration of nifedipine in hypertensive patients (author's transl)]

In the present study we assessed plasma renin activity (PRA) variations induced by Ca++ antagonist antihypertensive drug Nifedipine in 8 normoreninaemic or hyporeninaemic hypertensive patients. On two successive days three venous blood samples were sampled, two in clinostatic position and the last one 120 min later in orthostatic position; on the second day 20 mg of nifedipine were administered sublingually. Nifedipine increases significantly PRA after orthostatic position compared with starting conditions (p < 0.01) and compared with the values recorded without the drug at the same times (p < 0.01). Both systolic and diastolic blood pressure decreased 15 and 120 min after nifedipine administration while heart rate increased at the same times. Acute nifedipine administration augments PRA in hypertensive subjects; explanatory hypoteses are proposed.     

A comparative study of cardiac function in transgenic hypertensive rats, in spontaneously hypertensive rats and in normotensive rats

Left ventricular hypertrophy (LVH) entails numerous functional and molecular changes that ultimately lead to cardiac insufficiency. The renin-angiotensin system and adrenergic receptor signalling pathway have both been implicated in LVH progression and interactions between these factors may precipitate contractile dysfunction. We therefore investigated cardiac function in hypertensive rats transgenic for the human renin and angiotensinogen genes (TGR) having a genetic activation of the renin-angiotensin system, stroke-prone spontaneously hypertensive rats (SHR) and normotensive controls (CTR) aged 6 weeks. The isolated perfused heart model was used and the effect of isoproterenol (0.1-1000 nmol/L on cardiac function was studied. Cardiac protein and gene expression was studied by Western blot and RNase protection assay. TGR had 75 mmHg higher blood pressure and a 24% higher cardiac/body weight ratio than CTR; blood pressure in SHR was 17 mmHg higher without heart weight difference (p < 0.05). Basal Pmax, +dP/dt and -dP/dt were higher in TGR and SHR compared with CTR hearts. Isoproterenol stimulated these parameters by a maximum factor 6-8 in CTR and SHR but had almost no effect in TGR (p < 0.05). Basal CF per g heart weight was similar in all experimental groups. Isoproterenol produced a significantly smaller vasodilation in TGR compared with CTR or SHR. beta 1 and beta 2 receptor and Gs alpha proteins were similar in TGR, SHR and CTR. Gi alpha was increased in TGR hearts (p < 0.05). Converting enzyme and atrial natriuretic factor mRNA expression was increased (p < 0.01) while beta 1 receptor, adenylyl-cyclase V, SERCA2a and phospholamban mRNA expression was unchanged in TGR compared with CTR. Thus, LVH in TGR is characterised by early adrenergic dysfunction and beta 1 receptor signalling abnormalities indicating progressive functional deterioration. The data may serve as support for an early preventive intervention in angiotensin-II dependent cardiac hypertrophy and may have also implications for patients with genetic alterations of the renin-angiotensin system.     

Effects of nifedipine on baroreflex modulation of vascular resistance in man

Studies in animals have demonstrated that, in addition to their vascular effects, calcium channel blockers have important effects on baroreceptor function. We performed a series of experiments to determine if nifedipine, in doses employed clinically, alters baroreflex control of vascular resistance in normal humans. Forearm vasoconstrictor responses of 14 normal subjects to unloading of baroreceptors with lower body negative pressure (LBNP), to a cold pressor test and during intra-arterial infusions of norepinephrine were studied in the control state and following administration of nifedipine. Nifedipine had no effect on baseline mean arterial pressure or central venous pressure. Heart rate and forearm blood flow (FBF) increased significantly following nifedipine: heart rate = 59.7 +/- 2.4 bpm before and 72.6 +/- 4.4 bpm after nifedipine (mean +/- SE, p less than 0.001, n = 14); FBF = 4.6 +/- 0.4 ml X min-1 X 100 ml-1 before and 6.7 +/- 1.0 ml X min1 X 100 ml-1 after nifedipine (p less than 0.02, n = 14). Forearm vascular resistance (FVR) tended to decrease following nifedipine but the difference was not significant: FVR = 21.1 +/- 1.4 units before and 17.8 +/- 2.3 units after nifedipine (p = 0.07, n = 14). Nifedipine attenuated forearm vasoconstrictor responses to cold pressor stimulus: delta FVR during cold pressor test = +10.3 +/- 2.4 units before and +4.7 +/- 1.4 units after nifedipine (p less than 0.02, n = 14). Likewise, nifedipine depressed vasoconstrictor responses to intra-arterial infusion of norepinephrine: delta FVR during norepinephrine = +15.5 +/- 3.4 units before and +10.2 +/- 2.9 units after nifedipine (p less than 0.05, n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)     

Neurohumoral factors in hypertensive patients with and without left ventricular hypertrophy

Increased pressure load and neurohumoral activation are main factors involved in pathomechanism of left ventricular hypertrophy (LVH) in hypertension (HT). To gain insight into the involvement of neurohumoral factors responsible for cardiac hypertrophy, plasma level of aldosterone (Aldo), plasma renin activity (PRA), insulin-like growth factor-1 (IGF-1), pro-endothelin-1 (pro-ET) and atrial natriuretic peptide (ANP) were measured in HT patients (pts) and compared between pts with and without LVH. Also relationships between neurohormones and LV mass index (LVMI), mean blood pressure (MBP) were assessed separately in HT pts with and without LVH. 121 HT patients (pts) of age 17-79 (mean 48 +/- 15.3) were divided into three groups: 1-53 pts with mild HT, 2-44 pts with moderate HT and 3-24 pts with severe HT. Each of the group was divided into pts with and without LVH further all HT pts were divided into two groups; with and without LVH. Control group consisted of 39 healthy normotensives. LV mass was assessed echocardiographically and plasma levels of IGF-1, PRA, Aldo, pro-ET, and ANP were measured by radioimmunoassay in each pts and controls. LVH was found in 35.8% pts with mild HT, in 68.18% pts with moderate HT and in 100% pts with severe HT. The level of all measured neurohormones were significantly higher in pts with LVH compared to pts without LVH (p < 0.001). In pts with LVH there was significant correlation between LVMI and IGF-1, PRA, Aldo, pro-ET-1 and ANP, contrary to pts without LVH in which such correlations was not found. In pts with LVH there was also significant correlation between MBP and IGF-1, PRA, ANP and pro-ET-1. Increased plasma level of PRA, Aldo, IGF-1, pro-ET-1 and ANP in HT pts with LVH and significant correlation between measured neurohormones and LVMI suggests their contribution to LVH in HT pts. Significant correlation between LVMI, MBP and IGF-1 level, PRA and ANP indicate interplay between hemodynamic and neuroendocrine factors in pathomechanism of LVH.     

Effects of nifedipine on transmitral Doppler blood flow velocity profile in patients with concentric left ventricular hypertrophy

To examine the effects of calcium channel blockade on left ventricular diastolic function, transmitral blood flow was evaluated by Doppler echocardiography following administration of sublingual nitroglycerin and nifedipine in 10 younger normal subjects and in 10 subjects with concentric left ventricular hypertrophy (LVH) and abnormal Doppler transmitral flow patterns. Nitroglycerin decreased peak early filling velocity (E velocity) in both normal (p less than 0.01) and LVH subjects (p less than 0.05) but did not significantly alter peak late filling velocity (A velocity), early filling velocity time integral (VTI E), or late velocity time integral (VTI A). In normal subjects, nifedipine decreased E velocity (p less than 0.01) but did not significantly change A velocity, VTI E, or VTI A. In LVH subjects nifedipine increased E velocity (p less than 0.05) as well as VTI E (p less than 0.05) and the ratio of VTI E/VTI A (p less than 0.05). Thus nifedipine, unlike nitroglycerin, improves the transmitral Doppler flow profile in patients with concentric LVH.     

Comparative effects of calcium-channel blocking agents on left ventricular function during acute ischemia in dogs with and without congestive heart failure

To examine the relative potencies of verapamil, nifedipine and diltiazem on left ventricular (LV) function under ischemic conditions, 20 conscious closed-chest dogs that had partial occlusion of their circumflex coronary arteries were studied. Myocardial blood flow was measured by microspheres, LV function by radionuclide angiography. Drug effects were compared at doses causing equal decreases in mean arterial pressure (MAP) and in coronary vascular resistance of the nonischemic zone. Global ejection fraction (EF) and EF of the ischemic region were significantly decreased by verapamil (p less than 0.002) and increased by nifedipine (p less than 0.001); diltiazem caused no significant changes. Verapamil significantly increased peak diastolic filling rate (p less than 0.001); nifedipine also increased diastolic filling rate but only at doses that markedly decreased MAP and coronary vascular resistance. Diltiazem was not significantly different from placebo. For doses causing an equal decrease in MAP, verapamil decreased heart rate (p less than 0.001), and diltiazem and nifedipine increased heart rate (p less than 0.05). Myocardial ischemic zone flow remained unchanged during placebo, verapamil, diltiazem or nifedipine infusion. To study the influence of heart failure on the hemodynamic effects of the calcium-channel blocking agents, 6 foxhounds underwent total occlusions of the left anterior descending coronary artery, resulting in myocardial infarction, volume loading to increase left atrial pressure and partial occlusion of the circumflex coronary artery. Verapamil depressed global left ventricular ejection fraction and increased left atrial pressure to as high as 40 to 45 mm Hg. In contrast, nifedipine decreased left atrial pressure and increased global EF.(ABSTRACT TRUNCATED AT 250 WORDS)     

潜阳通络方对肝阳上亢证自发性高血压大鼠左室肥厚及儿茶酚胺的影响

目的观察潜阳通络方对肝阳上亢证自发性高血压大鼠(SHR)左室肥厚(LVH)及儿茶酚胺(CA)的影响。方法用32只14周龄SHR大鼠,随机分为模型组、潜阳通络方低剂量组、潜阳通络方高剂量组和卡托普利。另购8只14周龄雄性Wistar大鼠,为空白对照组。参照相关文献,将SHR大鼠加灌附子汤法造肝阳上亢模型,实验期间每周末测量血压,实验结束后取材,测量左室重量及CA含量。结果对治疗结束后,与模型组血压相比,其余各治疗组血压均有显著下降(P<0.01),且三组之间相比较,也均有显著性差异(P<0.01)与模型组左室重量指数(LVMI)比较,潜阳通络方高、低剂量组LVMI均有显著性降低(P<0.05),卡托普利组与模型组比较,无显著变化(P>0.05)。与模型组肾上腺素(AD)比较,其余各治疗组AD含量均明显降低(P<0.05),但三组之间差异不显著。与模型组去甲肾上腺素(NE)比较,其余各治疗组NE含量均明显降低(P<0.05),且潜阳通络方高、低剂量组与卡托普利组差异显著(P<0.05),潜阳通络方低、高剂量两组之间无差异。结论潜阳通络方的降血压和逆转左室肥厚机制,初步认为与其降低体内CA的含量相关。     

高血压左心室肥厚与血管紧张素Ⅱ受体的关系

目的探讨自发性高血压大鼠(SHR)左心室肥厚和血管紧张素Ⅱ(AngⅡ)受体的关系。 方法雄性SHR自10周龄始,给予依那普利［enalapril20mg/(kg     

Sublingual nifedipine: acute effects in severe chronic congestive heart failure secondary to idiopathic dilated cardiomyopathy

Nine patients with chronic, severe (New York Heart Association class III to IV) congestive heart failure were studied to determine the acute effects of 10 mg of sublingual nifedipine on left ventricular (LV) function. Hemodynamic and echocardiographic data were obtained at rest and 30 minutes, 1, 2, 4 and 6 hours after nifedipine. Measurements at rest reflected LV dysfunction with elevation of end-diastolic volume index (102 +/- 46 ml/m2), pulmonary capillary wedge pressure (17 +/- 8 mm Hg), systemic vascular resistance (1,547 +/- 439 dynes s cm-5) and reduction of cardiac index (2.8 +/- 0.5 liters/min/m2). There were no adverse effects noted with administration of sublingual nifedipine. Initial changes through 1 hour reflected an unloading effect of nifedipine with reduction in pulmonary capillary wedge pressure (11 +/- 5 mm Hg) (p less than 0.05), systemic vascular resistance (1,179 +/- 289 dynes s cm-5) (p less than 0.01), end-diastolic volume index (91 +/- 37 ml/m2 [difference not significant]) and an increase in cardiac index (3.6 +/- 0.7 ml liters/min/m2) (p less than 0.01). Subsequently the cardiac index, systemic vascular resistance and end-diastolic volume index returned toward baseline. Only the pulmonary capillary wedge and pulmonary artery pressures demonstrated a sustained reduction through the 6-hour study period suggesting an effect of nifedipine on LV relaxation. Thus, sublingual nifedipine administered acutely to patients with clinical congestive heart failure is a safe and efficacious vasodilator.     

Aldosterone receptor blockade prevents the transition to cardiac pump dysfunction induced by beta-adrenoreceptor activation

The transition from compensated to decompensated left ventricular hypertrophy (LVH) in hypertension involves excessive beta-adrenoreceptor (beta-AR) stimulation. To explore whether aldosterone receptor activation contributes toward beta-AR-induced left ventricular (LV) decompensation in hypertensive LVH, the effect of spironolactone (SPIRO; 80 mg x kg(-1) x day(-1)) on LV cavity dimensions, function, and chamber remodeling mechanisms was evaluated in spontaneously hypertensive rats (SHR) receiving a low dose of the beta-AR agonist isoproterenol (ISO) at 0.02 to 0.04 mg x kg(-1) . day for 4.5 months. ISO administered to SHR resulted in an increased 24-hour urinary aldosterone excretion and LV cavity dimensions, a right shift in LV diastolic pressure-volume relations, a decreased LV relative wall thickness, and increased total, noncross-linked, type I and type III myocardial collagen concentrations without further enhancing increased myocardial norepinephrine (NE) release. ISO reduced pump function without modifying intrinsic myocardial systolic function or inducing further myocyte necrosis or apoptosis. ISO only increased LV cavity volumes after prolonged periods of administration. SPIRO abolished ISO-induced chamber dilatation, wall thinning, and pump dysfunction and reduced total, noncross-linked, type I and type III myocardial collagen concentrations but failed to modify blood pressure, volume preloads, intrinsic myocardial systolic function, myocardial NE release, or the degree of necrosis or apoptosis. In conclusion, these results suggest that aldosterone receptor blockade, through load-independent effects, may be useful in preventing the transition from compensated LVH to dilatation and pump dysfunction mediated by chronic beta-AR activation.