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Background: The benefits of treating isolated systolic hypertension (ISH) are well established, but the most appropriate drug choice is still uncertain.Objective: The purpose of this study was to compare amlodipine, a calcium channel blocker, with enalapril, an angiotensin-converting enzyme inhibitor, in the treatment of ISH in a cohort of elderly patients (60 years of age).Methods: Ambulatory patients with ISH (seated systolic blood pressure [SBP] >160 mm Hg and <220 mm Hg; diastolic blood pressure [DBP] <95 mm Hg) who had not been treated previously or who had stopped their medication at least 4 weeks before the study were enrolled. Patients were randomized to receive amlodipine 5 mg/d or enalapril 10 mg/d. After 4 weeks of treatment, the dose was doubled for those patients whose sitting SBP had not decreased to <150 mm Hg or by>20 mm Hg, and treatment was continued for an additional 4 weeks.Results: A total of 89 patients were randomized to treatment, 46 to amlodipine and 43 to enalapril; 1 patient in the enalapril group died due to ischemic stroke despite adequate blood pressure control. The absolute reductions in seated and standing SBP/DBP were similar with both drugs after 8 weeks: 27 mm Hg/4.6 mm Hg with amlodipine and 23.9 mm Hg/3.9 mm Hg with enalapril (sitting) and 25.1 mm Hg/4.1 mm Hg and 21.3 mm Hg/4.2 mm Hg (standing) with amlodipine and enalapril, respectively (P = NS). At 4 weeks, 24 patients (52.2%) in the amlodipine group and 33 patients (76.7%) in the enalapril group had their medication dose doubled because their SBP was not adequately controlled with the initial dose (P < 0.01). At the end of the study, 24 patients were taking 10 mg amlodipine and 22 patients were taking 5 mg (mean dose 7.6 +/- 2.5 mg); 33 patients were taking 20 mg enalapril and 10 patients were taking 10 mg (mean dose 17.8 +/- 4.1 mg). Side effects occurred significantly more frequently in the amlodipine group (P = 0.01).Conclusion: The results of this study suggest that amlodipine and enalapril are similarly effective in treating ISH in elderly patients, with few side effects. [ABSTRACT FROM AUTHOR]

Background: Self-measurement of blood pressure (BP) has been increasingly encouraged as a supplement to measurements in the clinic., Objective: The main objective of this study is to clinically evaluate a new device for self-measurement of BP according to the International Protocol of the European Society of Hypertension (2002)., Methods: Measurements of systolic and diastolic BP in 33 volunteers (15 for phase 1 and a further 18 for phase 2 providing 99 measurements) were obtained using the mercury sphygmomanometer (HgS; Baumanometer) and the Braun BP VitalScan Plus 1650 device. Nine sequential same-arm measurements between the test device and the standard HgS were carried out according to the International Protocol of the European Society of Hypertension in two phases (phase 1, phase 2.1 and phase 2.2)., Results: The device passed phase 1 as 30 systolic and 33 diastolic readings fell within 5 mmHg exceeding the 25 required. In addition, the equipment also passed phase 2.1 as 74 systolic and 77 diastolic readings fell within 5 mmHg exceeding the 65 required for being approved. Finally, it also passed the phase 2.2 as 25 volunteers for systolic and 28 for diastolic had at least 2/3 of their comparisons falling within 5 mmHg (exceeding the 22 required) and only two of the 33 volunteers had their three comparisons over 5 mmHg apart (at the most three are required). The difference-against-mean plots showed that the disagreement between the HgS and the device was -2.57+/-4.36 mmHg for systolic BP and +0.83+/-4.97 mmHg for diastolic BP, respectively., Conclusion: The equipment passed the different phases satisfactorily and the study suggests that it can be used for self-BP monitoring. The device, however, needs to be used with care by the patients following the instructions, because even when it may be accurate in a laboratory setting, there is potential for them to be used inaccurately in the home setting.

Background: Home blood pressure monitoring has been increasingly encouraged as a supplement to measurements in the clinic in the 2003 European Society of Hypertension-European Society of Cardiology and in the Seventh Joint National Committee guidelines. Before marketing, however, blood pressure measuring devices for self-blood pressure monitoring should be independently validated., Objective: The main objective of the present study was to examine the clinical accuracy of the Braun BP 3000 (Braun GmbH, Kronberg, Germany) wrist blood pressure measurement device., Methods: Measurements of systolic and diastolic blood pressure in normotensive and hypertensive individuals were obtained using the mercury sphygmomanometer and the Braun BP 3000 equipment. Repeated sequential blood pressure single-arm measurements comparing the test device and the standard mercury sphygmomanometer were completed according to the American National Standard Institution (ANSI)/Association for the Advancement of Medical Instrumentation (AAMI) SP 10:2002 Protocol Guidelines on 90 study participants (270 measurements with each pressurometer)., Results: The equipment passed the test of systolic blood pressure measurements for method 1 (270 measurements treated separately) and method 2 (mean values of three observations on 90 patients). The mean+/-SD value was -2.01+/-5.61 (upper limit 5+/-8) and -2.01+/-4.41 (upper limit 2.01+/-6.65), respectively. The device also passed the diastolic blood pressure measurement requirements as the mean+/-SD value for method 1 was -0.97+/-5.52 (upper limit 5+/-8) and for method 2 was -0.97+/-4.87 (upper limit 0.97+/-6.87), respectively., Conclusions: The data from this study show that the Braun BP 3000 successfully passed the ANSI/AAMI SP 10:2002 requirements.

Background: The Sixth Report of the Joint National Committee states that the 'measurement of blood pressure outside the clinician's office may provide valuable information for the initial evaluation of patients with hypertension and for monitoring the response to treatment'. Prior to their marketing, however, blood pressure measuring devices should be independently validated for safety and accuracy using standard guidelines., Objective: The main objective of the present study was the clinical evaluation of the Braun Precision Sensor 2550 upgrade (Braun BP 2550 (UG)) according to the International Protocol of the European Society of Hypertension (ESH)., Methods: Measurements of systolic and diastolic blood pressure in 33 subjects were obtained using the mercury sphygmomanometer (Baumanometer) and the device. The sizes of the cuffs used for different arm circumferences were 12 x 23 cm, 15 x 33 cm and 18 x 36 cm for the thin adult, adult and overweight adult, respectively. The adult size was mostly used. If the cuff of the sphygmomanometer did not fall between the two range lines, a larger or smaller cuff was required. The reproducibility of self-blood pressure measurement was compared in 33 subjects (99 measurements). Nine sequential same-arm measurements comparing the test device and the standard mercury sphygmomanometer were carried out according to the International Protocol of the ESH in three steps (phases 1, 2.1 and 2.2)., Results: The device passed phases 1 and 2.1 as 75 systolic and 78 diastolic readings fell within 5 mmHg, exceeding the total of 65 required for approval. It also passed phase 2.2 as 30 subjects for systolic and 29 for diastolic had at least two out of three comparisons within 5 mmHg, exceeding the 22 subjects required. The difference-against-mean plots showed that the device-sphygmomanometer disagreement was -1.58+/-4.84 for systolic pressure (the Braun being lower) and +2.23+/-3.84 for diastolic pressure (the Braun being higher), respectively., Conclusions: The equipment passed both phases of the International Protocol (subject measurements and subject accuracy). The difference of 0-5 mmHg between the sphygmomanometer and the device represents 'measurements considered to be very accurate and with no error of clinical relevance'. It can therefore be used at home as an adjunct to physicians' effort to control blood pressure in their hypertensive patients.

Objective: To study the renin-angiotensin-aldosterone and kallikrein-kinin systems in essential hypertensives and offspring of hypertensive parents during different sodium loads, and to explore their possible influence on renal hemodynamics., Methods: Forty-five essential hypertensives (35 +/- 4 years old, 25 males), 30 offspring of hypertensive parents (26 +/- 8 years old, 16 males) and 30 normotensive controls (28 +/- 5 years old, 20 males) were submitted to three different sodium loads (high, 250 mmol/l; normal, 140 mmol/l; and low, 20 mmol/l). Blood pressure, plasma renin activity, serum aldosterone, total kallikrein and urinary kallikrein-like activity were measured after each period. Effective renal plasma flow and glomerular filtration rate were also measured. In essential hypertensive subjects, renal hemodynamic and hormonal parameters were also measured after 3 days of 20 mg enalapril administration., Results: Plasma renin activity and serum aldosterone were higher in normotensives, essential hypertensives and offspring of hypertensive parents only during low sodium intake, whereas urinary kallikrein activity was lower in hypertensive offspring and essential hypertensives, compared with normotensives, during the three diet conditions. Effective renal plasma flow was found to be reduced in hypertensives and normotensive offspring, while the glomerular filtration rated was similar in the three groups. Angiotensin converting enzyme inhibitor (ACEI) administration to essential hypertensives for 3 days normalized effective renal plasma flow, increased plasma renin activity and decreased aldosterone and urinary kallikrein activity., Conclusions: Our observations confirmed the presence of a hormonal imbalance between the renin-angiotensin-aldosterone system and the kallikrein-kinin system, not only in essential hypertensives but also in the offspring of hypertensive parents. This imbalance probably affects the renal circulation and sodium homeostasis, since there was reduced effective renal plasma flow in both populations compared with normotensive subjects. The positive effect of ACEI, resulting in normalization of the effective renal plasma flow in essential hypertensive patients, suggests the involvement of both systems in impaired renal circulation.

The efficacy and tolerability of eplerenone, a selective aldosterone blocker, was assessed when added to existing antihypertensive therapy with an ACE inhibitor or an angiotensin II receptor blocker (ARB). Hypertensive patients (n=341) whose blood pressure (BP) was not controlled despite ACE inhibitor or ARB were randomized (double-blind) to receive 50 mg eplerenone (increasing to 100 mg if required) once daily or placebo for 8 weeks. Diastolic and systolic BP and adverse events were recorded. By study end (week 8), mean seated diastolic BP was significantly reduced from week 0 among patients receiving eplerenone/ARB (-12.7+/-0.81 mm Hg) compared with those receiving placebo/ARB (-9.3+/-0.83 mm Hg). The change in mean seated diastolic BP was -9.9+/-0.88 mm Hg in eplerenone/ACE inhibitor patients and -8.0+/-0.86 mm Hg in placebo/ACE inhibitor patients (P=NS). Systolic BP levels were also significantly lower at week 8 for eplerenone/ACE inhibitor (-13.4+/-1.35 mm Hg) and eplerenone/ARB (-16.0+/-1.37 mm Hg) patients, respectively, compared with placebo/ACE inhibitor (-7.5+/-1.31 mm Hg) and placebo/ARB patients (-9.2+/-1.41 mm Hg). Adverse events were generally nonsevere and not significantly different between eplerenone and placebo. This study demonstrated that in patients whose BP was not controlled with an ACE inhibitor or ARB, the addition of eplerenone over an 8-week period significantly lowered systolic BP in both groups and diastolic BP in ARB patients. Selective aldosterone blockade with eplerenone, therefore, may be useful add-on therapy in hypertensive patients inadequately controlled on ACE inhibitor or ARB alone.

Objective: The hypertensive state is often associated with metabolic abnormalities, including glucose intolerance. Tissue kallikrein, a potent kinin-generating enzyme, is present in the vascular wall and heart tissue. High dietary fructose consumption is reported to induce hyperinsulinemia, hypertriglyceridemia and hypertension. The objective of the present study was to examine the status of kallikrein in vascular and cardiac tissue from highly fructose-fed rats and to delineate the effect of kinins and the angiotensin converting enzyme inhibitor ramipril in this animal model of glucose intolerance., Design and Methods: Male Wistar rats (350 g body weight) were divided into four groups of 10 rats each: (1) controls; (2) oral ramipril at 500 microg/kg per day for the last 2 study weeks; (3) fructose in drinking water as a 10% (w/v) solution for 4 weeks; and (4) fructose + ramipril, with fructose administered as in group 3 plus the administration of ramipril for the last 2 study weeks. Systolic blood pressure (tail-cuff method), glucose tolerance (2 g/kg body weight intraperitoneally) and metabolic parameters were recorded. Kallikrein activity in tail artery and heart tissue homogenates was estimated at the end of the 4th study week from measurements of kininogenase activity and kinins generated by a radioimmunoassay., Results: The area under the curve for the glucose tolerance test increased from 1265 +/- 103 mmol/l after 120 min in the control and 1152 +/- 36 mmol/l in the ramipril group (NS) to 2628 +/- 143 mmol/l in the fructose group (P<0.01). The administration of ramipril to fructose-treated rats in group 4 improved glucose tolerance (2160 +/- 100 mmol/l; P<0.05 versus group 3). Blood pressure increased significantly in fructose-fed rats but fell markedly in fructose-fed rats treated with ramipril (P<0.01). Kallikrein activity measured in the heart and vessels increased as a consequence of fructose administration (P<0.05), but the administration of ramipril increased this parameter to a much greater extent (P<0.01 versus control group), which correlated closely with the decrease in blood pressure and the improvement in glucose tolerance observed in the fructose + ramipril group., Conclusions: The administration of fructose as a solution in the drinking water induced glucose intolerance and increased blood pressure. Treatment with the angiotensin converting enzyme inhibitor ramipril improved glucose tolerance and significantly diminished blood pressure. Cardiovascular kinin-generating capability increased in treated animals and this increase was even higher when rats were treated with ramipril, suggesting that kinins, acting as a paracrine hormonal system, can exert cardiovascular protection and contribute to the beneficial effects of angiotensin converting enzyme inhibitor.

The endothelial cell should be regarded as a highly active metabolic and endocrine organ interacting with the blood streak and the interstitium. Kinins are vasodepressor hormones that may participate in local blood flow regulation as part of an autocrine-paracrine system. We have previously reported that tissue kallikrein, its mRNA and kininogen are present in vascular tissue. The present study was undertaken to examine the release of the components of this system from isolated perfused rat vessels. These vessels were perfused at 4 ml/min with physiological saline solution containing 3% Ficoll and 0.1% BSA. Kallikrein was released into the perfusate at a rate of 75 +/- 5 ng Bk/100 g bw/30 min (n = 10). Kininogen was released at a rate of 55 +/- 5 pg Bk/100 g bw/30 min. Pre-treatment with puromycin, a protein synthesis inhibitor, significantly reduces kallikrein and kininogen release. Vascular derived kinins were released at a constant rate of 38 +/- 6 pg Bk/100 g bw/30 min for at least 120 min. This basal kinin release was increased 3-fold when perfused with the angiotensin converting enzyme inhibitor ramiprilat (p < 0.05). When purified kininogen was added to the physiological saline solution, immunoreactive kinins in the perfusate increased from 42 +/- 7 to 3140 +/- 210 pg Bk/100 g bw/30 min (n = 6; p < 0.002). Increase in flow rate (from 2 ml/min up to 4 ml/min and 8 ml/min) causes a parallel increase in the release of kinins (from 32 +/- 4 up to 48 +/- 6 and 62 +/- 8 pg Bk/100 g bw/30 min, respectively; p < 0.01); the increase may be due to the effect of shear stress upon the endothelial cells. The present data confirm that vascular tissue synthesizes and releases continuously kallikrein, kininogen and kinins. Vascular kinins induce potent vasodilatation through the release of prostacyclin, nitric oxide and endothelium-derived hyperpolarization factor, and some of the converting enzyme inhibitors effect may be explained by potentiation of vascular-derived kinins.

The main objective of this study was to determine if the components of the kallikrein-kinin system are released into the venous effluent from isolated perfused rat hearts. To assess the contribution of kinins and the vascular and cardioprotective effects of the ACE inhibitor ramipril, we determined the status of cardiac kallikrein (CKK), potent kinin-generating enzyme, in rats with right ventricular hypertrophy induced by chronic volume overload and left ventricular hypertrophy by aortic banding. CKK was measured as previously described (Nolly, H.L., Carbini, L., Carretero, O.A., Scicli, A.G., 1994). Kininogen by a modification of the technique of Dinitz and Carvalho (1963) and kinins were extracted with a Sep-Pak C18 cartridge and measured by RIA. CKK (169 +/- 9 pg Bk/30 min), kininogen (670 +/- 45 pg Bk/30 min) and immunoreactive kinins (62 +/- 10 pg Bk/30 min) were released into the perfusate. The release was almost constant over a 120 min period. Pretreatment with the protein synthesis inhibitor puromycin (10 mg i.p.) lowered the release of kallikrein (42 +/- 12 pg Bk/30 min, p < 0.001) and kininogen (128 +/- 56 pg Bk/30 min, p < 0.001). Addition of ramiprilat (10 micrograms/ml) increased kinin release from 54 +/- 18 to 204 +/- 76 pg Bk/30 min (p < 0.001). Aortic banding of rats increased their blood pressure (BP) (p < 0.001), relative heart weight (RHW) (p < 0.001) and CKK (p < 0.001). Ramipril treatment induced a reduction in BP (p < 0.05) and RHW (p < 0.005) while CKK remained elevated. Aortocaval shunts increased their ANF plasma levels (p < 0.05), RHW (p < 0.001) and CKK (p < 0.01). Ramipril treatment induced a reduction in RHW (p < 0.05), while CKK and ANF increased significantly (p < 0.05). The present data show that the components of the kallikrein-kinin system are continuously formed in the isolated rat heart and that ramipril reduces bradykinin breakdown with subsequent increase in bradykinin outflow. The experiments with aorta caval shunt and aortic banding show that cardiac tissues increase their kinin-generating activity and this was even higher in ramipril-treated animals. This may suggest that the actual level of kinins is finely tuned to the local metabolic demands. In this experimental model of cardiac hypertrophy. ACE inhibitors potentiate the actions of kinins and probably try to normalise endothelial cell function.

The vascular wall itself, through a complex interplay of endocrine, neurocrine and autoparacrine mechanisms, plays an active role in vascular homeostasis. The endothelial cell senses humoral and hemodynamic changes and responds by secreting a variety of metabolically active substances that act locally causing either vasodilatation or vasoconstriction. Kallikrein (KK) and the mRNA for KK are present in arteries and veins. Vascular KK releases kinins from kininogen which circulate in plasma and is also present in vascular tissue. Vascular-derived kinins induce vasodilatation through the release of endothelial compounds (prostacyclin, EDRFs and cytochrome P-450). Disturbance in the delicate balance between vasodilators and vasoconstrictors may play a role in the development of hypertension. Vascular kallikrein (VKK) was significantly (P < 0.05) elevated after 2 weeks of development of renovascular and mineralocorticoid hypertension, and blood pressure was only slightly elevated. However, VKK decreased in both experimental models when blood pressure was increased. It is possible that the increase in VKK in the early stages resulted in increased local vasodilatory activity, thus counteracting the rise in blood pressure. As hypertension developed, KK was significantly decreased in arteries. The decrease in arterial KK during established hypertension is most likely secondary to high blood pressure. When the endothelium is damaged by high blood pressure, diabetes, excessive LDL cholesterol or cigarette smoking, a net imbalance favoring vasoconstriction, proliferation and migration of cells and increased lipid deposition predisposes to specific vascular diseases. Converting enzyme inhibitors (CEI) blunt the proliferative response of vascular smooth muscle cells after endothelial injury. The cardiovascular protective effects of CEI are mediated in part by the antihypertrophic, antihyperplastic and antithrombotic effects of kinins. The vascular kallikrein-kinin system has a promising role in the regulation of vascular homeostasis and some of the CEI effects may be explained by potentiation of the vascular-derived kinins.

Kallikrein and minute amounts of kininogen have been found in rat cardiac tissue. The mRNA for kallikrein was also determined by the polymerase chain reaction using KK-specific probe. The existence of an intrinsic kallikrein-kinin system in the heart raises the possibility that the enzyme-peptide system is involved in local regulation of cardiac function and metabolism.

We have previously reported that vascular tissue contains kallikrein and kallikrein mRNA. We can now show that kallikrein is present throughout the vascular tree and is released from arterial and venous rings incubated "in vitro". Using the isolated perfused rat hindquarters as a model, we found that kallikrein appeared in the perfusate in concentrations that increased linearly with time. Treatment with puromycin inhibited kallikrein release by 87% (p < 0.01), these data suggest that kallikrein is synthesized and released by the vascular wall. Local generation of kinins (autocrine/paracrine system) may contribute to the regulation of vascular homeostasis.

SBTI-resistant kininogenase activity was found in nonpregnant and pregnant rat uterus, placenta, amniotic fluid and fetal membranes. After trypsin treatment the kininogenase activity increased 2-3 fold. Total kininogenase (active plus inactive) was completely blocked by kallikrein antibodies. The physiological role of these kallikrein-like enzymes is unknown. It is speculated that these enzymes play a local role, perhaps in the processing of polypeptide hormones of through the release of kinins in the regulation of uterine blood flow.

1. Administration of bradykinin caused dose-dependent vasoconstriction in rat isolated perfused mesenteric arteries precontracted with noradrenaline. 2. The vasoconstrictor response was not mediated by BK1-bradykinin receptors. 3. Inhibition of cyclo-oxygenase with indomethacin, aspirin or meclofenamate abolished the vasoconstrictor effect of bradykinin, showing that a member of the arachidonic acid cascade may be involved. 4. Inhibitors of thromboxane synthesis (imidazole and UK 38485) did not affect or only reduced the bradykinin-induced vasoconstriction. 5. The endoperoxide H2/thromboxane A2 receptor antagonist SQ 29548 significantly reduced the vasoconstrictor effect of bradykinin, but did not affect the vasoconstrictor response to noradrenaline, adrenaline, vasopressin, 5-hydroxytryptamine or prostaglandins. 6. The eicosanoid(s) that mediate bradykinin-induced vasoconstriction appear to be synthesized outside the arterial endothelium. 7. The data suggest that the vasoconstrictor effect of bradykinin in the rat isolated mesenteric artery is mediated by vasoconstrictor arachidonic acid metabolites including the cyclic endoperoxides and/or the thromboxanes.

The present study was undertaken to examine whether there is a kallikrein-like enzyme in vascular tissue. Isolated saline-perfused rat mesenteric arteries were used. A kallikrein-like enzyme and acid protease from saline-perfused mesenteric arteries were separated by CM-cellulose chromatography with a linear NaCl gradient. The separation made it possible to study the optimum pH of the kallikrein-like enzyme and acid protease. The kallikrein-like enzyme showed optimal activity in the range of pH 7-9 and the acid protease in the range of pH 4-5. Both enzymes when acting on a protein plasma substrate release an active peptide that has a similar chemical and pharmacological properties to bradykinin. Using antibodies that specifically inhibit kinins, the biological action was completely abolished. These results indicate that arterial tissue contains two enzymes which generate kinins, the characteristics of one of the enzymes are quite similar to those of a lysosomal protease of the cathepsin-like type of enzyme and the other differs clearly from the acid protease and plasma kallikreins and has physicochemical characteristics quite similar to those of the kallikreins of glandular origin.