Maximal Blood Pressure Reduction Research Articles

One peptide derived from hen ovotransferrin as pro-drug to inhibit angiotensin converting enzyme

Angiotensin I-converting enzyme (ACE) inhibitory peptide was derived from hen ovotransferrin and identified as Lys-Val-Arg-Glu-Gly-Thr-Thr-Tyr. It produced a concentration-dependent inhibition of ACE activity in vitro with an IC50 value of 102.8 μM. After hydrolysis by ACE, the product (Lys-Val-Arg-Glu-Gly-Thr) has an IC50 value of 9.1 μM that was about 11-fold lower of the parent peptide. Thus, Lys-Val-Arg-Glu-Gly-Thr-Thr-Tyr can be considered as a pro-drug. Moreover, Lys-Val-Arg-Glu-Gly-Thr-Thr-Tyr and Lys-Val-Arg-Glu-Gly-Thr were intravenously administered into spontaneously hypertensive rats (SHR) to monitor the time-course change of systolic blood pressure. We found that Lys-Val-Arg-Glu-Gly-Thr-Thr-Tyr and its hydrolyzed product produced the maximal reduction of systolic blood pressure at 40 min and 20 min after injection, respectively. This 20 min delay might be considered as the time required for conversion of prodrug into Lys-Val-Arg-Glu-Gly-Thr, the true ACE inhibitor. In conclusion, the obtained results suggest that Lys-Val-Arg-Glu-Gly-Thr-Thr-Tyr works as the pro-drug of Lys-Val-Arg-Glu-Gly-Thr to inhibit ACE activity in vivo.

Paucity of high-quality studies reporting on salt and health outcomes from the science of salt: A regularly updated systematic review of salt and health outcomes (April 2017 to March 2018).

The purpose of this review is to identify, summarize, and critically appraise studies on dietary salt and health outcomes that were published from April 2017 to March 2018. The search strategy was adapted from a previous systematic review on dietary salt and health. Identified studies were screened based on a priori defined criteria to identify publications eligible for detailed critical appraisals. Overall, 6747 citations were identified by the search strategy, and 42 health outcome studies were identified. Three of the 42 studies met the criteria for methodological quality and health outcomes and underwent detailed critical appraisals and commentary. In addition, a systematic review and meta-analysis was critically appraised, although it did not strictly meet our methodological criteria. All four of the studies critically appraised found that sodium reduction improved blood pressure, especially in individuals with hypertension. In addition, sodium reduction reduced albuminuria in patients with stage 1-3 chronic kidney disease. Examination of the time course of blood pressure responses to sodium reduction revealed lowering sodium in the context of an average American diet may not produce maximal blood pressure reductions within a 4-week intervention period. This review provides further evidence of the benefit of sodium reduction for blood pressure lowering and gives insights into the subgroups of the population that may derive the greatest benefit from sodium reduction and the time course required to see benefit. Only three high-quality studies were identified during this 12-month review period, highlighting the critical need for more well-conducted rigorous studies in this area.

Angiotensin-I Converting Enzyme (ACE) Inhibitory and Anti-Hypertensive Effect of Protein Hydrolysate from Actinopyga lecanora (Sea Cucumber) in Rats.

Food protein hydrolysates are known to exhibit angiotensin converting enzyme (ACE) inhibitory properties and can be used as a novel functional food for prevention of hypertension. This study evaluated the ACE inhibitory potentials of Actinopyga lecanora proteolysate (ALP) in vivo. The pre-fed rats with ALP at various doses (200, 400, 800 mg/kg body weight) exhibited a significant (p ≤ 0.05) suppression effect after inducing hypertension. To determine the optimum effective dose that will produce maximal reduction in blood pressure, ALP at three doses was fed to the rats after inducing hypertension. The results showed that the 800 mg/kg body weight dose significantly reduced blood pressure without noticeable negative physiological effect. In addition, there were no observable changes in the rats’ heart rate after oral administration of the ALP. It was concluded that Actinopyga lecanora proteolysate could potentially be used for the development of functional foods and nutraceuticals for prevention and treatment of hypertension.

Renal sympathetic denervation for treatment of resistant hypertension: a systematic review.

Catheter-based renal sympathetic denervation (RSD) is a novel technique that is being investigated as treatment for resistant hypertension. To systematically evaluate the existing literature on the safety and efficacy of RSD in persons with resistant hypertension, online searches of Medline and the Cochrane Library Database (up to June 2012) were performed. Randomized controlled trials, observational studies, and conference proceedings published in English language were included. Nineteen studies (N=683 persons) were included. Follow-up duration ranged from 1 to 24 months. All studies reported significant reductions in systolic and diastolic pressures. Maximal reduction of blood pressure ranged from 18 mm Hg to 36 mm Hg (systolic) and 9 mm Hg to 15 mm Hg (diastolic). Sustained benefit of blood pressure reduction at 12 months was seen in 5 studies. No worsening of renal function was reported and there were few procedure-related adverse events such as pseudoaneurysm formation, hypotension, and bradycardia. Data from short-term studies suggest that RSD is a safe and effective therapeutic option in carefully selected patients with resistant hypertension. Long-term studies with large patient populations are needed to study whether this benefit is sustained with a demonstrable difference in cardiovascular disease event rates.

Intravenous fentanyl during shoulder arthroscopic surgery in the sitting position after interscalene block increases the incidence of episodes of bradycardia hypotension

BackgroundEpisodes of bradycardia hypotension (BH) or vasovagal syncope have a reported incidence of 13-29% during arthroscopic shoulder surgery in the sitting position after an interscalene block (ISB). This study was designed to investigate whether intravenous fentanyl during shoulder arthroscopy in the sitting position after ISB would increase or worsen the incidence of BH episodes.MethodsIn this prospective study, 20 minutes after being in a sitting position, 160 patients who underwent ISB were randomized to receive saline (S, n = 40), 50 µg of fentanyl (F-50, n = 40), 100 µg of fentanyl (F-100, n = 40) or 30 mg of ketorolac (K-30, n = 40) randomly. We assessed the incidence of BH episodes during the operation and the degree of maximal reduction (Rmax) of blood pressure (BP) and heart rate (HR).ResultsThe incidence of BH episodes was 10%, 15%, 27.5% and 5% in the S, F-50, F-100 and K-30 groups, respectively. Mean Rmax of systolic BP in the F-100 group was significantly decreased as compared to the S group (-20.0 ± 4.5 versus -6.3 ± 1.6%, P = 0.004). Similarly, mean Rmax of diastolic BP in the F-100 group was also significantly decreased (P = 0.008) as compared to the S group.ConclusionsThese results suggest that fentanyl can increase the incidence of BH episodes during shoulder arthroscopic surgery in the sitting position after ISB.

Olmesartan/amlodipine: a review of its use in the management of hypertension

Combination therapy is an effective strategy to increase antihypertensive efficacy in those patients with poor blood pressure (BP) control. In order to achieve BP targets, at least 75% of patients may require combination therapy, and European guidelines advocate this approach, particularly in those patients with a high cardiovascular risk. Evidence from large, randomized controlled trials, and the European hypertension treatment guidelines is supportive of the use of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB). Fixed-dose combination formulations of olmesartan medoxomil, an ARB, and the CCB amlodipine are approved in several European countries for patients with essential hypertension. The olmesartan/amlodipine combination has demonstrated greater efficacy than its component monotherapies in reducing BP in patients with mild-to-severe hypertension. Significantly greater reductions in seated diastolic BP were observed between baseline and after eight weeks of treatment with olmesartan/amlodipine, compared with equivalent doses of olmesartan or amolodipine monotherapy (P < 0.001), in the factorial Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure (COACH) trial. About 85% of the maximal BP reductions after the 8-week treatment period were already observed after two weeks. Uptitration as necessary, with or without hydrochlorothiazide, allowed the majority of patients to achieve BP control in a 44-week open-label extension treatment period to the COACH trial. The use of olmesartan/amlodipine allowed up to 54% of patients, with previously inadequate responses to amlodipine or olmesartan monotherapy, to achieve their BP goals. Data from post-registration studies using tight BP control and forced titration regimens have further demonstrated the high efficacy of olmesartan/amlodipine in achieving BP goal rates. Moreover, consistent reductions in BP were observed over the 24-hour dosing interval using ambulatory measurements. Olmesartan/amlodipine was generally well tolerated over the short- and long-term, with a lower frequency of peripheral edema with olmesartan/amlodipine 40/10 mg than with amlodipine 10 mg monotherapy.

A study of orthostatic hypotension, heart rate variability and baroreflex sensitivity in late-life depression

BackgroundTo determine if subjects with late-life depression have significant cardiovascular autonomic abnormalities (orthostatic blood pressure drop, heart rate variability and baroreflex sensitivity). MethodsA case–control study, in secondary care facilities, of forty two older (>60years) individuals with lifetime history of major depression and 31 age and sex matched comparison subjects. Autonomic function was assessed by measuring postural blood pressure, heart rate variability and baroreflex sensitivity using non-invasive beat-to-beat blood pressure and continuous ECG monitoring (Task Force® Monitor, CNSystems, Graz, Austria). The main outcome measures were maximal reduction in systolic blood pressure with active stand, low frequency and high frequency heart rate variability and baroreflex sensitivity using the sequence method. ResultsParticipants with depression had a significantly larger drop in systolic blood pressure on standing from a supine position. Depression was an independent predictor for developing systolic orthostatic hypotension. Depressed participants also had lower low frequency heart rate variability and lower baroreflex sensitivity. LimitationsThis was a cross-sectional and observational study; longitudinal effects or causality cannot be inferred from the findings and we could not distinguish state from trait related changes. ConclusionsLate-life depression has been associated with vascular disease but previous studies examining vascular risk factors have been inconsistent. Brain MRI white matter hyperintensities are ischemic and increased in late-life depression and associated with orthostatic blood pressure drops in animals. The presence of autonomic abnormalities in late-life depression may partly explain these inconsistencies and be associated with the development of brain white matter hyperintensities.

Inhaled nitric oxide versus aerosolized iloprost for the treatment of pulmonary hypertension with left heart disease*

To determine the effects of inhaled nitric oxide (NO) and aerosolized iloprost on pulmonary hemodynamics and lung edema formation in a rat model of pulmonary hypertension due to congestive heart failure (CHF). Prospective, randomized, controlled study. Research laboratory. One hundred sixty male Sprague-Dawley rats. CHF was induced by supracoronary aortic banding whereas sham-operated rats served as controls. CHF rats or controls inhaled NO, aerosolized iloprost, or 0.9% NaCl for 3 minutes each. Additional CHF groups received intravenous infusions of iloprost, sodium nitroprusside, or 0.9% NaCl. For prolonged drug administration over 150 minutes, NO was inhaled continuously whereas aerosolized iloprost was administered for 3 minutes each at 45-minute intervals. Dose-response relations in rats with CHF showed a maximal pulmonary-selective reduction in blood pressure at 20 ppm NO and 2.5 microg/mL aerosolized iloprost, with iloprost therapy resulting in a greater decrease in pulmonary arterial pressure (PAP). At these doses, both vasodilators decreased pulmonary vascular resistance and increased venous oxygen saturation (Svo2) in the absence of systemic hemodynamic effects. No pulmonary or systemic effects were detected in rats with CHF inhaling 0.9% NaCl or in control rats inhaling NO or iloprost. Intravenous infusion of iloprost or sodium nitroprusside not only reduced pulmonary but also systemic vascular resistance. During prolonged inhalation, NO caused a stable reduction in PAP, whereas PAP decreased even further during repetitive iloprost inhalations. After 150 minutes, iloprost-treated rats had a higher Svo2 and lesser edema as compared with animals with CHF inhaling NO or untreated rats with CHF, although differences in wet/dry weight ratio did not reach statistical significance (p < 0.06). Inhaled vasodilators may offer an effective, safe, and pulmonary-selective strategy for the treatment of pulmonary hypertension in left heart disease, and inhaled iloprost may be superior to NO in this condition.

Kallikrein kinin system activation in post-exercise hypotension in water running of hypertensive volunteers

Previous studies demonstrated a reduction in blood pressure level immediately after different types of exercises, like running, cycling and resistance training, a phenomenon called post-exercise hypotension (PEH). Since PEH can persist for hours it could be suggested as a non-pharmacological therapy for hypertensive individuals. Unfortunately, usually running is not recommended due to the high impact caused by its practice. Therefore running in water treadmill should be a better option, since the environment is completely different and causes lower impact. However it is not known whether PEH occurs in this situation. The objective of this work was to evaluate the existence of PEH after water running and to compare PEH promoted by running in two different environments. In addition, changes in plasmatic concentrations of the kallikrein kinin system (KKS) components were also evaluated. Sixteen hypertensive subjects were submitted to two exercise sessions, conventional running and water running, in two different occasions. The pattern of heart rate, blood pressure and plasmatic concentrations of KKS components immediately after and one hour after exercise were investigated. Results showed a maximal reduction in systolic and diastolic blood pressure 30 min after both exercise models (P<0.001), indicating that moderate water running promotes PEH with similar magnitude as compared to conventional running. Plasma kallikrein activity and bradykinin concentration increased immediately after exercise (P<0.05), but these parameters were not different in both exercise models. In conclusion, our findings show that water running, similarly to conventional running, can also provoke PEH and alterations in the KKS components.

Peptide with Angiotensin I-Converting Enzyme Inhibitory Activity from Hydrolyzed Corn Gluten Meal

Corn gluten meal (CGM) was hydrolyzed by Alcalase after starch removal of CGM was applied as a pretreatment. A new inhibitory peptide for angiotensin I-converting enzyme (ACE) was isolated from the hydrolysate of CGM with the use of Bio-Rad P-2 gel filtration and followed by reverse-phase high-performance liquid chromatography (RP-HPLC). The sequence of the active peptide was determined to be Ala-Tyr after the application of amino acid analysis and HPLC/MS. The IC50 of the peptide was 14.2 microM, and it was not affected by preincubation with 30 mU of ACE at 37 degrees C for 3 h. Ala-Tyr also exerted antihypertensive effects after oral administration to spontaneously hypertensive rats. A maximal reduction of systolic blood pressure of 9.5 mmHg was observed 2 h after oral administration of Ala-Tyr at doses of 50 mg/kg.

Heart and Kidney: Fatal Twins?

The importance of renal function as both a marker of and risk factor for cardiovascular disease is increasingly recognized. This link is apparent even in the earliest stages of renal dysfunction, at levels that are conventionally considered “normal.” These findings are of considerable importance, given the prevalence of high-normal levels of albuminuria (i.e., 10 to 20 mg/L) in the general population. There is also a close link between the progression of albuminuria and the development of insulin resistance and type 2 diabetes mellitus, such that kidney disease—far from being simply a consequence of the metabolic syndrome—may be considered a component of it. It may be hypothesized that minor derangements of renal function, such as microalbuminuria or reduced glomerular filtration rate, can lead to dysfunction of the endothelium, with the consequence of sensitizing the vasculature to the injurious effects of hypertension, dyslipidemia, and other risk factors. The renin-angiotensin system (RAS) is highly activated in patients with the metabolic syndrome, and this presumably is also true for the intrarenal RAS systems. Both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are known to reduce the progression of renal damage. Still to be resolved, however, is the optimal dosage; several recent studies indicate that the dosage required for maximal blood pressure reduction is insufficient to provide maximal renoprotection.

Anti-hypertensive Effect of Chunghyul-dan (Qingxue-dan) on Stroke Patients with Essential Hypertension

Hypertension is one of the modifiable risk factors for stroke. Lowering blood pressure is helpful for primary and secondary prevention of stroke. This study is aimed to assess the efficacy of Chunghyul-dan on stroke patients with stage 1 hypertension using 24 hours ambulatory blood pressure monitoring (24ABPM). Forty hospitalized stroke patients with stage 1 hypertension were included in the study and they were randomly assigned into two groups: group A was treated with Chunghyul-dan 1200 mg once a day for 2 weeks, while group B was not. Twelve subjects were dropped out because of unexpected early discharge or data errors, thus the remaining 28 subjects were included in the final analysis (15 in group A and 13 in group B). Blood pressure was monitored every 30 minutes for 24 hours at baseline and 2 weeks after medication. Blood pressure, pulse rate, trough/peak ratio (TPR) [the value calculated by dividing the blood pressure change at trough (22 to 24 hours after drug intake) by the change at peak (2 adjacent hours with a maximal blood pressure reduction between the second and eighth hour after drug intake)] and smoothness index (SI) (the value calculated as the ratio between the average of the 24 hours, treatment-induced blood pressure changes and its standard deviation) were compared to assess the efficacy of Chunghyul-dan. To assess the safety of Chunghyul-dan, any adverse effects during medication period were monitored. There was no significant difference in the baseline assessment between the two groups. Systolic blood pressure was lower in group A than in group B (141.37+/-8.96 mmHg versus 132.28+/-9.46 mmHg, P = 0.03), while diastolic blood pressure and pulse rate had no significant difference between the two groups. Systolic TPR and SI was 0.87 and 1.04 in group A, respectively. This suggests that Chunghyul-dan have anti-hypertensive effect on stroke patients with stage 1 hypertension.

Treatments of Hemodynamic Maladjustment and Oxidative Stress Prevent Renal Disease Progression in Chronically Severe Glomerulonephritides

Hemodynamic maladjustment is a unique observation in chronically severe glomerulonephritides. It is characterized by a markedly elevated efferent arteriolar resistance (RE), an elevated intraglomerular hydrostatic pressure (PG) and a markedly decreased renal plasma flow (RPF), and peritubular capillary flow (PTCF). A correction of such hemodynamic maladjustment can be accomplished by administering a combination of vasodilators (angiotensin receptor antagonist, angiotensin converting enzyme inhibitor, and calcium channel blocker) in 14 chronic glomerulonephritides with severe renal function impairment (mean serum creatinine 3.6 + 1.3 mg/dL). Doses titration aim for maximal renal perfusion effect (increased RPF, PTCF) or maximal renal function improvement (increased CCr, reduced FE Mg) usually higher than needed for maximal blood pressure reduction. Evidence of oxidative stress is also corrected with high doses of vitamins C and E. After a mean period of treatment for 13.5 months, improvements in CCr (pre Rx 22 ± 10 vs. post Rx 32 ± 13 mL/min/1.73 m2), and FE Mg (pre Rx 11.9 ± 4% vs. post Rx 10 ± 3%) were observed in conjunction with the improvement in intrarenal hemodynamics namely RPF (pre Rx 201 ± 71 vs. post Rx 288 ± 99 mL/min/1.73 m2), PTCF (pre Rx 161 ± 57 vs. post Rx 242 ± 90 mL/min/1.73 m2), PG (pre Rx 56.7 ± 0.5 vs. post Rx 51 ± 0.1 mm Hg), and RE (pre Rx 12085 ± 6503 vs. post Rx 6550 ± 1872 dyne.s.cm−5).

Protection of the cardiovascular system by imidapril, a versatile angiotensin-converting enzyme inhibitor.

Imidapril hydrochloride (imidapril) is a long-acting, non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor, which has been used clinically in the treatment of hypertension, chronic congestive heart failure (CHF), acute myocardial infarction (AMI), and diabetic nephropathy. It has the unique advantage over other ACE inhibitors in causing a lower incidence of dry cough. After oral administration, imidapril is rapidly converted in the liver to its active metabolite imidaprilat. The plasma levels of imidaprilat gradually increase in proportion to the dose, and decline slowly. The time to reach the maximum plasma concentration (T(max)) is 2.0 h for imidapril and 9.3 h for imidaprilat. The elimination half-lives (t(1/2)) of imidapril and imidaprilat is 1.7 and 14.8 h, respectively. Imidapril and its metabolites are excreted chiefly in the urine. As an ACE inhibitor, imidaprilat is as potent as enalaprilat, an active metabolite of enalapril, and about twice as potent as captopril. In patients with hypertension, blood pressure was still decreased at 24 h after imidapril administration. The antihypertensive effect of imidapril was dose-dependent. The maximal reduction of blood pressure and plasma ACE was achieved with imidapril, 10 mg once daily, and the additional effect was not prominent with higher doses. When administered to patients with AMI, imidapril improved left ventricular ejection fraction and reduced plasma brain natriuretic peptide (BNP) levels. In patients with mild-to-moderate CHF [New York Heart Association (NYHA) functional class II-III], imidapril increased exercise time and physical working capacity and decreased plasma atrial natriuretic peptide (ANP) and BNP levels in a dose-related manner. In patients with diabetic nephropathy, imidapril decreased urinary albumin excretion. Interestingly, imidapril improved asymptomatic dysphagia in patients with a history of stroke. In the same patients it increased serum substance P levels, while the angiotensin II receptor antagonist losartan was ineffective. These studies indicate that imidapril is a versatile ACE inhibitor. In addition to its effectiveness in the treatment of hypertension, CHF, and AMI, imidapril has beneficial effects in the treatment of diabetic nephropathy and asymptomatic dysphagia. Good tissue penetration and inhibition of tissue ACE by imidapril contributes to its effectiveness in preventing cardiovascular complications of hypertension. The major advantages of imidapril are its activity in the treatment of various cardiovascular diseases and lower incidence of cough compared with some of the older ACE inhibitors.

Verapamil revisited: a transition in novel drug delivery systems and outcomes.

Verapamil, the oldest calcium-channel blocker, is now being rediscovered and reevaluated in the light of new novel drug delivery systems and new evidence-based trials. Verapamil, a phenylalkylamine, is useful in the treatment of hypertension, stable angina, and narrow QRS supraventricular arrhythmias. This calcium antagonist is effective in both young and old, and both black and white hypertensive patients, and is free of metabolic side effects. Verapamil has a well-documented history as an effective antianginal agent when directly compared with a beta-blocker, and is more effective in reducing myocardial ischemia compared with amlodipine monotherapy. Because of the short half-life of verapamil, drug delivery systems are used to prolong the duration of action. Novel drug delivery systems using encapsulated beads or a modified osmotic pump have been designed to be taken at nighttime to provide maximal blood pressure reduction in the early morning hours and effective 24-hour blood pressure control, and to avoid excessive blood pressure reduction during sleep. The Verapamil in Hypertension and Atherosclerosis Study has documented equivalent effectiveness of verapamil compared with chlorthalidone, but showed superior plaque regression and reduced events in subjects with the greatest plaques with verapamil treatment. The Angina Prognosis Study in Stockholm, comparing verapamil and metoprolol for stable angina, found no difference in total cardiovascular mortality or combined cardiovascular events. Other large ongoing randomized, multicenter trials, including Controlled-Onset Verapamil Investigation of Cardiovascular Endpoints and the International Verapamil-Trandolapril Study, will expand our knowledge of the role of verapamil in the treatment of hypertension.

Human tissue kallikrein gene delivery attenuates hypertension, renal injury, and cardiac remodeling in chronic renal failure

Tissue kallikrein cleaves kininogen substrate to produce the potent vasodilating peptide kinin, which plays important roles in cardiovascular and renal function. To explore cardiac and renal potential protective effects of kallikrein gene delivery in chronic renal failure, we delivered adenovirus carrying the human tissue kallikrein cDNA (cHK) into rats with 5/6 reduction of renal mass. Expression of human tissue kallikrein in rats was assessed by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR)/Southern blotting. Physiological parameters monitored in rats included systolic blood pressure, heart rate, and urinary excretion of protein, albumin, kinin, cGMP, cAMP, and nitrate/nitrites. Systemic and regional hemodynamics were measured by fluorescent-labeled microspheres. Heart weight and myocyte diameter were used to assess left ventricular hypertrophy. Quantitative and qualitative morphological analyses were used to evaluate histologic changes in kidney and heart sections. Active tissue kallikrein reached a peak serum level of 463 +/- 76 ng/mL following gene delivery and returned to control levels within 21 days. A maximal blood pressure reduction of 37 mm Hg was observed within one week in rats receiving kallikrein gene delivery as compared with control rats receiving adenovirus containing the luciferase gene (159 +/- 5 vs. 196 +/- 6 mm Hg, N = 15, P < 0.001), and a significant blood pressure difference continued for five weeks postgene delivery. Kallikrein gene delivery significantly decreased total urinary protein and albumin excretion and increased levels of urinary kinin, nitrite/nitrate, and cGMP levels. Cardiac output and regional blood flow were also increased, while peripheral vascular resistance decreased. Kallikrein gene transfer reduced glomerular sclerotic lesions, tubular damage, lumenal protein cast accumulation, and interstitial inflammation in the kidney. Myocardial hypertrophy and fibrosis were also attenuated in rats receiving kallikrein gene delivery. These findings indicated that kallikrein gene delivery attenuates hypertension and protects against renal injury and cardiac remodeling in the rat remnant kidney model of chronic renal failure.

Usefulness of Carvedilol in unstable angina pectoris

The safety and efficacy of adding oral carvedilol (25 mg twice daily) to standardized treatment of unstable angina was assessed in a multicenter, randomized, double-blind, placebo- controlled trial on 116 patients with acute unstable angina. Patients were monitored in an intensive care unit and underwent 48-hour Holter monitoring to assess transient ischemia. Carvedilol as adjunctive therapy resulted in a significant reduction of median heart rate (65 vs 75 beats/min, p <0.05), mean systolic blood pressure (133 vs 130 mm Hg, p <0.05), and mean rate-pressure product (8,337 vs 10,042, p <0.05). Carvedilol reduced the ischemic burden during 48 hours of treatment by 75% (49 vs 204 minutes), including a 36% reduction of patients with ischemic episodes (p <0.05), a 66% reduction of the mean number of ischemic episodes (8 vs 24, p <0.05), and a 76% reduction in the mean duration of ischemic episodes (50 vs 205 minutes, p <0.05). Side effects occurred in 8 of 59 patients (13.6%) in the carvedilol group and in 5 of 54 patients (8.8%) given placebo. Although not significant, the early onset of maximal blood pressure reduction and the delayed effect on heart rate were closely correlated to drug-induced hypotension and bradycardia in the carvedilol group. Thus, carvedilol as an adjunctive to standardized treatment effectively reduces heart rate and blood pressure, and thus the ischemic burden in patients with unstable angina pectoris, but requires close monitoring of patients at risk for bradycardia or hypotension.

Sildenafil/nitrate interaction.

To the Editor: The ACC/AHA consensus document on sildenafil (Viagra)1 takes a very cautious approach to interaction between organic nitrates and sildenafil, suggesting that neither should be used within 24 hours of the other in any dose and by any route of administration. While justifiable on the basis of current information (Pfizer studies 148/230 and 148/231, which show approximate doubling of maximal blood pressure reduction by nitrate after sildenafil), this approach could result …

LKPNM: a prodrug-type ACE-inhibitory peptide derived from fish protein

It has been previously documented that the thermolysin-digest of “Katsuo-bushi”, a Japanese traditional food processed from dried bonito possesses potent inhibitory activity against angiotensin I-converting enzyme (ACE). The present authors isolated eight kinds of ACE-inhibitory peptides from it. Of these isolated peptides, LKPNM (IC50=2.4 μM) was found to be hydrolyzed by ACE to produce LKP (IC50=0.32 μM) with 8-fold higher ACE-inhibitory activity relative to the parent peptide or LKPNM, suggesting that LKPNM can be regarded as a prodrug-type ACE-inhibitory peptide. For assessment of relative antihypertensive activities of LKPNM and LKP to that of captopril, they were orally administered to SHR rats to monitor time-course changes of blood pressures, whereby it was evidenced that both LKPNM and captopril showed maximal decrease of blood pressure 4 h after oral administration and their efficacies lasted until 6 h post-administration. In sharp contrast, however, maximal reduction of blood pressure occurred as early as 2 h after administration of LKP. Minimum effective doses of LKPNM, LKP and captopril were 8, 2.25 and 1.25 mg/kg, respectively. When compared on molar basis, antihypertensive activities of LKPNM and LKP accounted for 66% and 91% relative to that of captopril, respectively, whereas in vitro ACE-inhibitory activities of LKPNM and LKP were no more than 0.92% and 7.73% compared with that of captopril (IC50=0.022 μM). It is of interest to note that both of these peptides exert remarkably higher antihypertensive activities in vivo despite weaker in vitro ACE-inhibitory effects, which was ascertained by using captopril as the reference drug.

Adenovirus-mediated kallikrein gene delivery attenuates hypertension and protects against renal injury in deoxycorticosterone-salt rats

To demonstrate potential therapeutic effects of kallikrein gene delivery in salt-induced hypertension and renal diseases, we delivered adenovirus carrying the human tissue kallikrein gene (Ad.CMV-cHK) into deoxycorticosterone acetate (DOCA)-salt hypertensive rats. A single intravenous injection of Ad.CMV-cHK caused a delay in the rise of blood pressure that began 2 days post gene delivery and lasted for more than 23 days. A maximal blood pressure reduction of 50 mm Hg was observed in rats receiving kallikrein gene delivery, as compared to rats receiving adenovirus containing the luciferase gene (Ad.CMV-Luc) (172±5 vs. 222±13 mm Hg, n=6, P<0.01). Throughout the experimental period, a blood pressure reduction of at least 32 mm Hg was observed in the DOCA-salt rats injected with Ad.CMV-cHK as compared to DOCA-salt rats receiving control adenovirus. Immunoreactive human tissue kallikrein levels were detected in rat serum and urine post gene delivery. Adenovirus-mediated kallikrein gene delivery caused a significant reduction in urinary excretion, urinary protein levels and body weight. Morphological examination of the kidney showed that kallikrein gene transfer significantly reduced DOCA-salt-induced glomerular sclerotic lesions, brush border disruption of proximal tubules, tubular dilatation and protein cast accumulation. These findings showed that the expression of human tissue kallikrein via gene delivery has protective effects against hypertension and renal injury in DOCA-salt hypertensive rats.