Administration Of Antihypertensive Drugs Research Articles

Does dosing antihypertensive drugs at night alter renal or cardiovascular outcome: do we have the evidence?

Recent evidence suggests that blood pressure during nighttime and the early morning hours is associated with increased cardiovascular risk independently of the average 24 h blood pressure. The review aims to investigate whether nighttime administration of antihypertensive drugs alters the circadian blood pressure variation and prevents hypertension-induced target organ damage and cardiovascular or renal disease. Several studies showed that nighttime administration of antihypertensive drugs has a larger blood pressure lowering effect during nighttime and the early morning hours. Some studies of intermediate endpoints, such as albuminuria, ventricular hypertrophy and carotid thickness suggested beneficial effects of nighttime administration of drugs. Few long-term outcome studies showed impressive cardiovascular protection using nighttime administration of antihypertensive drugs. Owing to methodological issues, however, these studies cannot prove whether, for the same 24 h blood pressure reduction, nighttime dosing provides greater cardiovascular and renal protection than the conventional morning dosing. Whether nighttime dosing is superior to the conventional morning dosing in improving cardiovascular or renal outcome remains unclear. Randomized outcome studies comparing the same treatment administered in the morning versus at nighttime are needed. Until these data become available nighttime dosing of antihypertensive drugs cannot be recommended.

The Appropriateness of Renal Angioplasty. The ANPARIA Software: A Multidisciplinary Expert Panel Approach

Percutaneous transluminal renal angioplasty (PTRA) is an invasive technique that is costly and involves the risk of complications and renal failure. The ability of PTRA to reduce the administration of antihypertensive drugs has been demonstrated. A potentially greater benefit, which nevertheless remains to be proven, is the deferral of the need for chronic dialysis. The aim of the study (ANPARIA) was to assess the appropriateness of PTRA to impact on the evolution of renal function. A standardized expert panel method was used to assess the appropriateness of medical treatment alone or medical treatment with revascularization in various clinical situations. The choice of revascularization by either PTRA or surgery was examined for each clinical situation. Analysis was based on a detailed literature review and on systematically elicited expert opinion, which were obtained during a two-round modified Delphi process. The study provides detailed responses on the appropriateness of PTRA for 1848 distinct clinical scenarios. Depending on the major clinical presentation, appropriateness of revascularization varied from 32% to 75% for individual scenarios (overal 48%). Uncertainty as to revascularization was 41% overall. When revascularization was appropriate, PTRA was favored over surgery in 94% of the scenarios, except in certain cases of aortic atheroma where sugery was the preferred choice. Kidney size [7 cm, absence of coexisting disease, acute renal failure, a high degree of stenosis (C70%), and absence of multiple arteries were identified as predictive variables of favorable appropriateness ratings. Situations such as cardiac failure with pulmonary edema or acute thrombosis of the renal artery were defined as indications for PTRA. This study identified clinical situations in which PTRA or surgery are appropriate for renal artery disease. We built a decision tree which can be used via Internet: the ANPARIA software (http://www.chu-clermontferrand.fr/anparia/). In numerous clinical situations uncertainty remains as to whether PTRA prevents deterioration of renal function.

Effects of sibutramine plus verapamil sustained release/trandolapril combination on blood pressure and metabolic variables in obese hypertensive patients

Objective: The management of obese hypertensive subjects may require the administration of anti-obesity and antihypertensive drugs. Sibutramine use has raised concerns regarding a potential increase in subjects' blood pressure and heart rate. The primary end-points of this study were an evaluation of the effect of sibutramine together with a verapamil sustained release/trandolapril combination tablet versus verapamil sustained release/trandolapril alone on the blood pressure and heart rate in obese hypertensive patients. Research design/methods: Patients received a low-fat low-calorie diet and were randomly allocated to open-label verapamil sustained release/trandolapril 180/2 mg (n = 26) or sibutramine 10 mg together with verapamil sustained release/trandolapril 180/2 mg (n = 28) daily for 6 months. Results: Significant reductions in the subjects' systolic blood pressure and diastolic blood pressure were observed in both groups (p < 0.01 versus baseline). At 6 months a greater fall in blood pressure was observed in the sibutramine/verapamil sustained release/trandolapril group compared with the verapamil sustained release/trandolapril group (systolic blood pressure 21.9 ± 8.1 versus 15.9 ± 12.3 mmHg and diastolic blood pressure 15.7 ± 8.1 versus 9.1 ± 9.9 mmHg) but this was only significant (p = 0.03) for diastolic blood pressure. The subjects' heart rate did not change significantly in any group. No significant sibutramine-associated attenuation of blood pressure reduction was observed during the study. The sibutramine/verapamil sustained release/trandolapril treatment resulted in significantly greater improvement in the subjects' anthropometric variables, homeostasis model assessment and lipid profiles compared with verapamil sustained release/trandolapril administration. The subjects' small dense low-density lipoprotein cholesterol, high-sensitivity C-reactive protein and visfatin plasma levels were only measured in the sibutramine/verapamil sustained release/trandolapril group (all decreased by p < 0.05 versus baseline). Conclusions: The sibutramine/verapamil sustained release/trandolapril combination in obese hypertensive patients significantly reduced their blood pressure and improved their anthropometric and metabolic variables without affecting the heart rate.

Kidney and Circadian Blood Pressure Rhythm

Association between nondipper pattern of circadian rhythm of blood pressure (BP) and impaired renal capacity to excrete sodium into urine was confirmed by Bankir et al1 in this issue of Hypertension based on a large number of subjects. Although this association has been observed in small studies,2,3 their study1 is the first to show it in a large-scale setting, and, therefore, is highly welcomed. Because there is a tight link between kidney and hypertension, renal dysfunction causes hypertension, whereas hypertension accelerates renal damage. It is well appreciated that the kidneys play an important role in the long-term regulation of BP. Usually it takes almost 1 week for kidneys to achieve a new steady-state balance of sodium, when sodium intake is altered. Therefore, renal participation in the short-term BP regulation, such as circadian rhythm, has been overlooked. However, the findings of Bankir et al1 strongly suggest that nocturnal hypertension and nondipper pattern of circadian BP rhythm are because of impaired renal capacity to excrete sodium, and circadian BP rhythm is at least in part regulated by kidneys. Sodium sensitivity of BP is also determined by renal capacity to excrete sodium and is regulated by glomerulotubular balance between glomerular ultrafiltration capability and rate of tubular sodium reabsorption.4 Thus, sodium sensitivity is increased in chronic kidney disease (CKD) where glomerular filtration rate (GFR) is reduced and also in disorders with enhanced tubular sodium reabsorption, including primary aldosteronism, diabetes mellitus, and metabolic syndrome, where GFR is augmented. When sodium sensitivity is increased, glomerular capillary pressure is usually elevated, resulting in albuminuria and renal damage. It becomes evident that, in patients with high-sodium sensitivity, the nocturnal dip in …

Participation of nitric oxide in different models of experimental hypertension

This review concerns the role of nitric oxide (NO) in the pathogenesis of different models of experimental hypertension (NO-deficient, genetic, salt-dependent), which are characterized by a wide range of etiology. Although the contribution of NO may vary between different models of hypertension, a unifying characteristic of these models is the presence of oxidative stress that participates in the maintenance of elevated arterial pressure and seems to be a common denominator underlying endothelial dysfunction in various forms of experimental hypertension. Besides the imbalance between the endothelial production of vasorelaxing and vasoconstricting compounds as well as the relative insufficiency of vasodilator systems to compensate augmented vasoconstrictor systems, there were found numerous structural and functional abnormalities in blood vessels and heart of hypertensive animals. The administration of antihypertensive drugs, antioxidants and NO donors is capable to attenuate blood pressure elevation and to improve morphological and functional changes of cardiovascular system in some but not all hypertensive models. The failure to correct spontaneous hypertension by NO donor administration reflects the fact that sympathetic overactivity plays a key role in this form of hypertension, while NO production in spontaneously hypertensive rats might be enhanced to compensate increased blood pressure. A special attention should be paid to the modulation of sympathetic nervous activity in central and peripheral nervous system. These results extend our knowledge on the control of the balance between NO and reactive oxygen species production and are likely to be a basis for the development of new approaches to the therapy of diseases associated with NO deficiency.

Decreased Expression of Angiotensin II Type 1 and Type 2 Receptors in the Brain After Long-Term Administration of Antihypertensive Drugs in Stroke-Prone Spontaneously Hypertensive Rat

The present study examined the levels of Angiotensin II type 1 receptor (AT1) and type 2 receptor (AT2) in the brain stem and cerebral cortex of the stroke-prone spontaneously hypertensive rat (SHR-sp) after long-term treatment with three types of antihypertensive drugs: valsartan, enalapril, and amlodipine. In both tissues, expression of the AT1was decreased by administration of each drug. Expression of the AT2was decreased in the cerebral cortex by drug administration, but did not change in the brain stem. This study may contribute to elucidating the relationship between AT1and AT2expressions and the effect of antihypertensive drugs in SHR-sp brain.

Abstract 2742: The Comparison Of Direct Measurement Of Central Blood Pressure And Noninvasive Evaluation By Radial Artery Tonometry.

Background and objectives: New devices including radial applanation tonometer have been developed for central blood pressure measurement. The devices can noninvasively calculate the central blood pressure. To investigate the accuracy of estimated central blood pressure, this study demonstrates the comparison of catheter based central blood pressure and radial applatnation tonometer based central blood pressure. Materials and Methods: Seventy two patients (64 ± 10 years old) underwent cardiac catheterization were recruited for this study. Ascending aortic pressure was measured using a pressure guide wire (RADI Medical Systems), and recorded on a laptop personal computer through a SEIREG polygraph (Siemens). Radial arterial pulse waves were simultaneously measured noninvasively using applanation tonometry technique by HEM-9000AI (Omron Healthcare Co.,Ltd.) and SphygmoCor (AtCor Medical Pty Ltd.). The measurements were performed before and after administration of vasodilator (nicorandil or glycerol trinitrate) or antihypertensive (nicardipine hydrochloride) drugs. The central blood pressure calculated by HEM-9000AI (cSBP) and SphygmoCor (aSBP Sphy) was compared respectively with that by catheter (aSBP). Results: cSBP and aSBP Sphy indicated significant correlation with aSBP (r=0.94, 0.93, respectively, p=0.001). The regression line slope of cSBP to aSBP was 0.92 and that of aSBP Sphy to aSBP was 0.76. A significant difference was observed between aSBP and aSBP Sphy, but was not observed between aSBP and cSBP. Bland-Altman test showed that the difference of cSBP to aSBP was - 0.4 ± 9.6 mmHg and that of aSBP Sphy to aSBP was -9.0 ± 10.3 mmHg. It shows significant difference between cSBP to aSBP error and aSBP Sphy to aSBP error (p&lt;0.05). Conclusion: The central blood pressure measured by HEM-9000AI is very close to that by catheter. These findings indicate that noninvasive central blood pressure measurement by radial applanation tonometry is accurate enough for clinical applications.

The effects of losartan on signal-averaged P wave in patients with atrial fibrillation

Background Losartan has recently been reported to suppress atrial structural remodeling. However, few reports exist on signal-averaged electrocardiography (ECG) for preventing atrial electrical remodeling. We examined the effect of losartan on atrial electricity by using signal-averaged ECG of P waves. Methods The subjects comprised 40 patients with essential hypertension complicated with symptomatic paroxysmal atrial fibrillation. The patients received pilsicainide for the complication; they were defibrillated and divided into two subgroups for antihypertensive therapy: calcium antagonist-administrated (CB) and losartan-administrated (LOS) groups. We recorded the signal-averaged electrocardiography of P waves and calculated (1) filtered P wave duration (PD), (2) the voltage integral for the entire P wave (integral-p), and (3) the root mean square voltages of the terminal 40, 30, and 20 ms (RMS-40, RMS-30, and RMS-20). Procollagen C propeptide type I (PIP) and A- and B-type natriuretic peptide (ANP and BNP, respectively) levels in the groups were measured before and after antihypertensive agent administration. Results RMS-20 increased significantly and PD decreased significantly in the LOS group 24 weeks after antihypertensive drug administration; however, they remained unchanged in the CB group. Integral-p decreased significantly in both groups, and the decrease rate was significantly higher in the LOS group. Serum BNP levels decreased significantly only in the LOS group. Conclusions Losartan inhibits atrial remodeling by inhibiting left atrial fibrosis as indicated by the procollagen C propeptide type I, ANP, and BNP levels. Signal-averaged ECG demonstrated that losartan suppresses atrial fibrillation recurrence by improving atrial conduction disturbance.

Blood pressure management in patients with acute stroke: Pathophysiology and treatment strategies

Hypertension is one of the key risk factors for development of various forms of vascular disease including ischemic and hemorrlmgic stroke, coronary artery disease, and peripheral vascular disease. Blood pressure (BP) elevation and its treatment have implications for both primary ~md secondary prevention [1] and in the acute management of cardiovascular diseases. In acute myocardial infarction, administration of antihypertensive drugs, especially ~3-blockers and angiotensin-com~erting enzyme (ACE) inhibitors, are incorporated into the treatment algorithms [2-41. In patients with cerebrovascular events, best management strategies remain somewhat tmcertain. Contributing to this uncertainty are the heterogeneity of these conditions, complex interaction between systemic and cerebral circulation, differential involvement of vascular distributions, and limited data from clinical trials.

Incidence and Predictors of Angioedema in Elderly Hypertensive Patients at High Risk for Cardiovascular Disease: A Report From the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

Angioedema is a rare, potentially life-threatening condition that has been associated with angiotensin-converting enzyme inhibitors since their introduction in the 1980s. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the largest antihypertensive study conducted to date, randomized 42,418 participants to a diuretic (chlorthalidone), a calcium channel blocker (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), or an alpha-blocker (doxazosin). Patients who developed angioedema were compared for baseline characteristics and changes in antihypertensive drug administration. Fifty-three participants developed angioedema during active follow-up: 55% were black, 60% men, and 70% were assigned to lisinopril (including 62% of black participants with angioedema), 15% to chlorthalidone, 9% to doxazosin, and 6% to amlodipine. Six percent occurred within a day of randomization and 23% within the first week. Over half did not have an increase in their assigned (blinded) antihypertensive drug before angioedema onset; 3 (6%) had a dose increase within a week before onset. One patient died following an angioedema episode. The occurrence of angioedema in the angiotensin-converting enzyme inhibitor arm corresponds with previously reported angioedema-angiotensin-converting enzyme inhibitor associations.

Hypertension in the intensive care unit

The severity of hypertensive crises is determined by the presence of target organ damage rather than the level of blood pressure. Hypertensive urgencies with no signs of organ dysfunction can therefore be distinguished from hypertensive emergencies in which the presence of severe end-organ damage requires prompt therapy. Hypertensive emergencies include acute aortic dissection, hypertensive encephalopathy, acute myocardial ischaemia, severe pulmonary oedema, eclampsia, and acute renal failure. Malignant hypertension is a severe form of hypertensive emergency demanding special consideration because of the risks of permanent blindness and renal failure. Catecholamine excess and postoperative hypertension may also sometimes require urgent treatment. The management of patients with hypertensive emergencies must be ensured in an intensive care unit, and must include the parenteral administration of antihypertensive drugs and accurate blood pressure monitoring. Except for acute aortic dissection, the recommended goals of treatment are a reduction of mean arterial pressure by no more than 20% during the first few hours, because an abrupt fall in blood pressure in patients with preexisting hypertension may induce severe ischaemic injury in major organs as a result of the chronic adaptation of autoregulation mechanisms. Hypertension in the context of acute stroke should be treated only rarely and cautiously because of the presence of impaired autoregulation.

Angioedema in the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT)

ALLHAT, the largest antihypertensive study conducted to date, randomized 42,418 participants to one of four antihypertensive drug classes/drugs (diuretic/chlorthalidone, calcium-channel blocker/amlodipine, angiotensin-converting enzyme (ACE) inhibitor/lisinopril, and alpha-blocker/doxazosin), with 9054 participants assigned to lisinopril. This large patient sample, combined with the double-blind design of ALLHAT, provides a large and diverse population in which to further examine the occurrence of angioedema, a rare but potentially life-threatening side effect of ACE-inhibitors. The purpose of this presentation is to describe the characteristics, both within and between treatment groups, of treated hypertensive participants with angioedema. Patients who developed angioedema during ALLHAT were compared for baseline characteristics and for the temporal relationship of changes in antihypertensive drug administration to the onset of angioedema. Results were as follows: Fifty-three ALLHAT participants developed angioedema during active follow-up in ALLHAT. Of these, 55% were black, 60% male, 70% were assigned to the ACE-inhibitor lisinopril (0.83 events per 1000 person-years), 15% to chlorthalidone (0.11 events per 1000 person-years), 9% to doxazosin (0.17 events per 1000 person-years), and 6% to amlodipine (0.07 events per 1000 person-years). Three cases (6%) occurred within a day of randomization, 22% within the first week, 34% within the first month, and 68% within the first year. In addition, 3 patients (6%) had a dose increase of their assigned medication within a week prior to onset, but over half (51%) had no prior dose increase. One patient died following the angioedema onset. The occurrence of angioedema cases in the ACE-inhibitor arm of ALLHAT corresponds with the previously reported association of angioedema and ACE-inhibitor use.

Cyclosporin A-Associated Changes in Red Blood Cell Membrane Composition, Deformability, Blood and Plasma Viscosity in Rats

Most of the studies concerning the effects of cyclosporin A (Cs A) on red blood cell (RBC) rheology were carried out in human transplant recipients who may still have residual insufficiency and concomitant administration of other immunosuppressive and antihypertensive drugs. The aim of this study is to evaluate the effects of Cs A on red cell rheology and membrane composition in nontransplant healthy rats. Female Wistar albino rats were divided into two groups of 10 animals each. Rats received 10 mg/kg Cs A, i.p. or saline for 4 weeks. Cs A administration significantly increased the RBC deformability, and plasma and blood viscosity (p < 0.001, p < 0.01 and p < 0.01, respectively). Cs A administration to the rats increased RBC membrane cholesterol (CHO) levels and the CHO/phospholipid (PL) ratio significantly (p < 0.01 and p < 0.05, respectively) but did not change RBC membrane proteins and membrane PL levels. These results suggest that Cs A changes the rheological functions of RBC and lipid content of RBC membrane in healthy rats and thereby it may play an important role in the regulation of microcirculation.

Ambulatory blood pressure monitoring in renal transplant patients: modifiable parameters after active antihypertensive treatment

Background Hypertension (HT) accounts for nearly 60% to 80% of renal transplant patients (RT). It is one of the most important risk factors for cardiovascular diseases and may cause chronic graft dysfunction. Therefore, it is important to accurately detect and treat HT. We aimed to evaluate the changes in ambulatory blood pressure monitoring (ABPM) parameters among hypertensive RT after active treatment compared with baseline values. Methods Thirty seven RT (25 men, 12 women, aged 49.4 ± 11.2 year) diagnosed with mild to moderate HT underwent 24-hour ABPM after a 4-week washout period (W 0). For the 23 RT with confirmed HT of a second 24-hour ABPM was recorded after 4 weeks of treatment with doxazosin GITS (−4 mg once daily in the morning), a new formulation of an α 1-receptor inhibitor (W 4). Nondippers were considered when mean blood pressure (BP) showed a ≤10% reduction during sleep. Statistical analyses included Saphiro-Wilks test, Student t test, and ANOVA. Results After active treatment systolic, diastolic, and mean BP (SBP, DBP, MBP) significantly decreased during diurnal and 24 hours but not the nocturnal period. No significant change was observed for heart rate nor for pulse pressure during any period. The prevalence dippers increased from 0% to 17% after treatment. After placebo administration 8 among 37 RT with HT diagnosed according to casual BP remained hypertensive at nighttime (but not at daytime) according to 24-hour ABPM. Conclusions Diurnal and 24-hour periods of ABPM showed significant changes in SBP, DBP, and MBP after active treatment with doxazosin GITS. No significant BP changes were observed in the nocturnal period or in dipper status. Further studies using ABPM must be undertaken to determine the optimal dosage and time of administration of antihypertensive drugs in RT.

Administration of Nifedipine CR Immediately after Awakening Prevents a Morning Surge in Hypertensive Patients. Case Report of Three Cases

Although the blood pressure-lowering action of some long-acting calcium antagonists may last more than 24 h, some patients taking this drug still experience a morning surge, i.e. an early morning increase in blood pressure. We evaluated this morning surge in three hypertensive patients with morning surge after administration of antihypertensive drugs including nifedipine CR. Nifedipine CR is one of the once-a-day formulations of nifedipine, which after administration, results in two peaks in the plasma concentration of nifedipine. The first concentration peak of occurs 3 h after administration and the second around 12 h after intake. When the time of intake of nifedipine CR was changed from after breakfast to immediately after awakening, the morning surge was suppressed in these patients without the use of other drugs such as alpha- or beta-blockers. Administration of nifedipine CR immediately after awakening is one option that can be used to prevent morning surge as well as to control blood pressure throughout the day.

Hypertension in chronic renal failure and end-stage renal disease patients treated with haemodialysis or peritoneal dialysis.

Guidelines should be used for clinical decisions about although it remains debatable whether ‘dry weight’ individual patients. However, most of the available was really achieved in all of these patients [4,5]. guidelines are based on randomized clinical trials which only provide a statistical prediction of the likely effect of an intervention, usually based on the ‘average’ Effect of hypertension on survival outcome, aggregated across all the heterogeneous patients participating in the trial. Heterogeneity due to The well established concept that hypertension is a the stage of the disease, its severity, organ complica- risk factor for death both in the general population tion, comorbid conditions etc., together with exclusion and in dialysis patients has recently been questioned of the patients with major complications from the trial, by independent studies [4–9] showing that low prelimit the information generated by such trials for a dialysis systolic BP is associated with increased precise prediction of outcome for an individual patient. adjusted mortality risk. No association with elevated Although these limitations may be partially circum- mortality risk has been observed for pre-dialysis sysvented by the clinical experience and pathophysiolog- tolic hypertension. A number of explanations may be ical knowledge of clinicians or experts (in the case of offered for this rather unexpected finding: (i) it may a guideline), personal bias is almost inevitable. A be an iatrogenic effect due to overmedication; (ii) all comprehensive approach to the issue of hypertension the studies were carried out in the USA on patients has recently been published [1]. The present review with an overall poor prognosis. The influence of summarizes the most important aspects discussed in expected survival is indeed crucial. The beneficial effect that review and, in particular, addresses some specific of BP reduction may need several years to become topics whcih, in the opinion of the Medical Expert visible, and this may not be detectable if life expectancy Group, are rather relevant. is only 2–3 years; (iii) older malnourished patients have lower BP and shorter survival; and (iv) the presence of overt or not fully developed heart failure Prevalence or disease may lower BP and survival. The Cox proportional hazard used in some of these studies may be The prevalence of hypertension varies according to the inadequate to correct for all these confounding factors. degree and the cause of renal failure in chronic renal insufficiency (CRI ) or according to the type of dialytic treatment, haemodialysis ( HD) or peritoneal dialysis Pathophysiological basis for management (PD). However, the prevalence of hypertension is much greater in the CRI population (60–100%) than in the In these clinical conditions, it is still not known if general population. With the remarkable exception of hypertension is caused by inappropriate secretion of Tassin, France, where >90% of patients achieve norm- renin for the status of body sodium and water, or if otension without anti-hypertensive medication [2], the other renal or extra-renal factors are involved. A control of hypertension in HD patients is rather poor correct answer to this question is crucial not only for despite administration of anti-hypertensive drugs. This the understanding of the pathogenesis of hypertension poor control has also been documented with 24 h but also for a correct therapeutical approach. ambulatory blood pressure (BP) monitoring where a There are close interrelationships among the various feedback loops regulating BP (renal, hormonal, haemo

Long–Term Effect on Blood Pressure of Early Brief Treatment by Different Antihypertensive Agents: A Study in the Prague Hypertensive Rat

In the Prague hypertensive rat (PHR), a strain of genetic hypertension derived from Wistar, administration of various antihypertensive drugs (AHD) during the developmental phase of hypertension (weeks 5–9 of life) prevents the rise of blood pressure. However, only drugs blocking the renin–angiotensin system (RAS, i.e. AT1–antagonist losartan and ACE inhibitor perindopril) have a long–term effect on blood pressure leading to values of systolic blood pressure (SBP) of 174.5±14.5 and 169.8±15.3 mmHg, respectively, at week 30. At this time, control, untreated PHR have a SBP of 222.0±16.6 mmHg (p<0.01 for both groups); age–matched PNR (Prague normotensive rat, bred in parallel with PHR from the same parent pair) exhibit values as low as 123.3±11.7 mmHg (p<0.01 from all other values). When losartan was administered to another group of PHR not only at weeks 5–9 but once more at weeks of 15–19 of age, the values of their SBP at week 30 were 156.8±12.64 mmHg, i.e., values significantly (p<0.01) different not only from 239.7±17.59 mmHg (value of the untreated PHR group) but also from 174.5±14.5 mmHg (value of PHR to which losartan was administered only once, at weeks 5–9). Thus, twice repeated administration of losartan in young age almost normalizes blood pressure deep into adult age. Proteinuria, a common finding in adult PHR, is also significantly lower in adult age in both groups receiving at weeks 5–9 drugs blocking RAS; the values at week 30 are 4.0±0.26 mg/24 h/rat in the losartan and 3.87±0.27 in the perindopril group, in contrast to 12.8±1.08 (p<0.01 for both groups) in control PHR. In conclusion, early brief administration (weeks 5–9 of life) of RAS–blocking agents to PHR led to long–term antihypertensive and antiproteinuric effects. These effects were significantly intensified by a second brief administration at weeks 15–19.

Therapeutic implications of the epidemiology and timing of myocardial infarction and other cardiovascular diseases.

Cardiovascular diseases (CVD) account for almost 50% of the 2 million deaths annually in the United States. Coronary heart disease (CHD) (ie, myocardial infarction, sudden death) account for the largest proportion (32%) of this mortality. Over the last 3 decades both CVD and age-adjusted coronary death rates have fallen dramatically. However, crude CVD (and CHD) incidence is actually increasing, almost exclusively as a function of rising CVD incidence amongst older Americans. Population groups at highest for premature CVD complications include African-Americans, diabetics, men, smokers, and those with high levels of single risk factors (ie, stage III hypertension). Individuals with multiple CVD risk factors as well as those with manifestations of blood pressure (BP)-related target-organ damage (TOD) (ie, left ventricular hypertrophy, hypercreatinemia) are at an inordinately high risk for clinical events. CVD events do not randomly occur throughout the 24-h time period. The peak incidence of myocardial infarction (MI), thrombotic stroke, sudden cardiac death, and transient myocardial ischemia is between 6 am and 12 noon. During the morning hours coinciding with the peak incidence of CVD events, coronary vasomotor tone, plasma catecholamines, and platelet aggregability are at their highest levels while coronary blood flow and plasma fibrinolytic activity are at their lowest levels of the day. Moreover, BP rapidly rises from its nocturnal nadir during the early morning hours. Prevention of pressure-related CVD events in hypertensive patients over the long term can be best accomplished by controlling BP throughout the 24 h time period with drugs that do not adversely impact (or favorably affect) other metabolic, neurohormonal, and hemostatic parameters. BP control (minimally to <140/90 mm Hg) may be particularly important in the early morning hours since elevated BP and/or rapidly rising BP is a plausible biological trigger for the aforementioned CVD events. One effective strategy for achieving this goal is to utilize antihypertensive drugs with long therapeutic half-lives. Such agents will provide smooth whole-day BP control and also will minimize the loss of BP control during time period(s) between missed medication doses in the setting of therapeutic non-compliance. Practitioners should give due consideration to nocturnal administration of antihypertensive drugs prescribed once-daily as a means of achieving more effective morning BP control.

Histological Ophthalmic Changes in M-SHRSP after Administration of Antihypertensive Drugs

Histological Ophthalmic Changes in M-SHRSP after Administration of Antihypertensive Drugs

Timing for administration of an antihypertensive drug in the treatment of essential hypertension.

To find the best timing for administration of long-acting antihypertensive drugs, we gave nitrendipine, a calcium antagonist of the dihydropyridine group, once a day to six hospitalized and drug-free patients with essential hypertension, changing the time of administration and studying the effects on the circadian rhythm of blood pressure. After control values of 24-hour blood pressure variations were taken with patients on placebo, a 10-mg tablet of nitrendipine was given for 3 days on three occasions--at 6 AM on awakening, at 8:30 AM after breakfast, and at 6 PM after supper; 24-hour blood pressure values for each period were recorded on the third day. The 24-hour blood pressure values during the control period showed a biphasic circadian rhythm, with higher values during wakefulness and lower values during sleep. The control period was also characterized by a rapid rise in blood pressure on awakening, the so-called morning surge of blood pressure, and a gradual decline during sleep at night. Although the morning surge was not completely suppressed by nitrendipine given after breakfast, it was diminished by the drug given on awakening or after supper; the latter brought a deeper decline in blood pressure during sleep compared with other times. The average of 24-hour blood pressure values obtained by nitrendipine given on awakening was the lowest among the three occasions. Thus, administration of long-acting calcium antagonists with a rapid onset of action on awakening in the early morning seems to be a more rational and beneficial alternative than the conventional administration after breakfast.(ABSTRACT TRUNCATED AT 250 WORDS)