Abstract-The aortic pulse wave contour in isolated systolic hypertension often shows a prominent reflection peak, which combines with the incident wave arising from cardiac ejection so as to widen pulse pressure. We investigated the effects of an extended-release nitrate preparation and of 2 angiotensin II (AII) inhibitors (an AII receptor antagonist and an ACE inhibitor) on the aortic pulse wave contour and systemic blood pressure in hypertensive subjects with high augmentation index caused by exaggerated pulse wave reflection. Two double-blind, randomized, placebo-controlled crossover studies were carried out in a total of 16 elderly patients with systolic hypertension resistant to conventional antihypertensive therapy. In 1 study, pharmacodynamic responses to single doses of placebo, isosorbide mononitrate, eprosartan, and captopril were determined; in the other, single-dose isosorbide mononitrate and placebo were compared in subjects treated with AII inhibitors at baseline. Blood pressure was measured by sphygmomanometry and pulse wave components by applanation tonometry at the radial artery. All 3 agents were shown to decrease brachial systolic blood pressure, aortic systolic blood pressure, and aortic pulse pressure. Qualitative effects on the aortic pulse wave contour differed: augmentation index was not significantly altered by either captopril or eprosartan but was decreased (PϽ0.0001) by Ϸ50% of the placebo value with isosorbide mononitrate in both study groups. We propose that isosorbide mononitrate corrected the magnified wave reflection in systolic hypertension of these elderly patients by an effect that was distinct from that exercised by either acute or chronic AII inhibition. Key Words: angiotensin antagonist Ⅲ antihypertensive therapy Ⅲ elderly Ⅲ hypertension, arterial Ⅲ isosorbide mononitrate Ⅲ pulse wave I solated systolic hypertension (ISH) and associated widening of pulse pressure have been identified as important risk factors for cardiovascular disease in the elderly 1-4 and may persist despite the use of conventional antihypertensive drugs. 5-7 A hierarchy of clinical responses to such therapy has been reported: Calcium antagonists produced the most significant antihypertensive effect, followed by diuretics, ACE inhibitors, and ␤-blockers. 5 A place for nitrates in this hierarchy has been surmised for more than a decade 8,9 but has not been clearly established. 10 The high pulse pressure of ISH is usually associated with the presence in the aortic pulse wave of a prominent reflection peak, long known to be nitrate-sensitive, 11 which combines with the tail of the incident peak arising from cardiac ejection to increase pulse pressure. 12,13 We showed in a previous study that the amplitude of this wave reflection, measured by applanation tonometry, could be decreased by the use of isosorbide mononitrate (ISMN) given as an adjunct to conventional combined antihypertensive therapy. 12 This effect was associated with sustained lowering of systolic blood pressure during continued once-daily admi...

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Hypertension in the elderly is associated with increased occurrence rates of sodium sensitivity, isolated systolic hypertension, and ‘white coat effect’. Arterial stiffness and endothelial dysfunction also increase with age. These factors should be considered in selecting antihypertensive therapy. The prime objective of this therapy is to prevent stroke. The findings of controlled trials show that there should be no cut-off age for treatment. A holistic program for controlling cardiovascular risks should be fully discussed with the patient, including evaluation to exclude underlying causes of secondary hypertension, and implementation of lifestyle measures. The choice of antihypertensive drug therapy is influenced by concomitant disease and previous medication history, but will typically include a thiazide diuretic as the first-line agent; to this will be added an angiotensin inhibitor and/or a calcium channel blocker. Beta blockers are not generally recommended, in part because they do not combat the effects of increased arterial stiffness. The hypertension–hypotension syndrome requires case-specific management. Drug-resistant hypertension is important to differentiate from faulty compliance with medication. Patients resistant to third-line drug therapy may benefit from treatment with extended-release isosorbide mononitrate. A trial of spironolactone may also be worthwhile.

A B S T R A C T Continuous 6-h infusions of the beta adrenergic blockers dl-propranolol or oxprenolol significantly reduced plasma renin activity (PRA) and mean blood pressure in the resting rabbit and prevented the stimulatory effects of isoproterenol on renin release and heart rate. These actions were due to blockade of beta receptors, for the inactive isomer, d-propranolol, had no effect. Despite sustained high plasma concentrations of dl-propranolol (0.2 Ag/ml) in the unstimulated animal, PRA did not fall below 36% of control values, suggesting that basal renin secretion is maintained partly by factors other than beta adrenergic mechanisms.Prindolol, another beta blocker, also abolished the effects of isoproterenol on renin and on the heart, and reduced blood pressure in the resting animal. However, prindolol increased resting PRA and heart rate, and in animals already receiving dl-propranolol, it raised PRA and heart rate without further altering blood pressure. This suggests that the effect on PRA of prindolol was due to its intrinsic sympathomimetic activity and not hypotension-mediated mechanisms. The observation that the blood pressure-lowering effect of prindolol was associated with a rise in PRA, while another beta antagonist, H 35/25, lowered PRA but had no effect on blood pressure, indicates that the hypotensive action of beta blockers is unrelated to their effects on renin release.In both unstimulated and isoproterenol-challenged animals, only blockers possessing beta-i receptor affinity (d,t-propranolol, oxprenolol, prindolol, practolol, and metoprolol) affected heart rate, while effects on PRA were more prominent with agents possessing beta-2 activity (dl-propranolol, oxprenolol, prindolol, and H 35/25). Thus, the changes in PRA caused by the beta adrenergic blockers appear to be dependent upon the summation of their direct effects, antagonistic or sympathomimetic, on beta-2 adrenergic receptors regulating renin release.

SummaryLong-term treatment with propranolol was shown to produce a sustained suppression of the renin-aldosterone system in hypertensive patients, despite concurrent diuretic treatment. However, the antihypertensive effect of this treatment correlated poorly with its effects on plasma renin activity and urinary aldosterone excretion. When prindolol, another p-adrenergic blocking drug, was substituted for propranolol, blood pressure control was retained, but there was a prompt rise in plasma renin activity, which was not attributable to changes in electrolyte balance. These observations suggest that the antihypertensive action of propranolol and other ,3-blockers does not result from their effects on plasma renin activity.

ISMN has a role as an adjunct in the anti-hypertensive therapy of patients with refractory systolic hypertension due to exaggerated pulse-wave reflectance.

EDITORIAL SYNOPSIS This paper describes the effect on the pH, ammonia, and urea content of the caecum in rabbits made uraemic by bilateral nephrectomy. The considerable quantities of free ammonia present are considered in relation to uraemic colitis in man.Urea is freely diffusible from the blood into the lumen of the alimentary tract, where it is converted by the enzyme urease into ammonia and CO2. Tracer studies indicate that at least 25 % of the urea in the body undergoes hydrolysis within the gut (Walser and Bodenlos, 1959), but a proportion of the ammonia produced is absorbed and re-synthesized to urea in the liver. The practical importance of this metabolic cycle, therefore, lies in the concentration of ammonia within the gut and its effect on the pH of the gastric and intestinal fluids.

I The effects of a 5-min period of sustained mental arithmetic upon blood pressure and heart rate were determined in several groups of healthy subjects and hypertensive patients. 2 The arithmetic produced significant increases in heart rate and blood pressure (both systolic and diastolic) in both normotensive and hypertensive subjects. 3 The blood pressure changes were neither attenuated nor enhanced by the prior administration of ,B-adrenergic receptor blocking drugs (alprenolol, propranolol or metoprolol) on an acute or chronic basis. 4 In subjects habituated to the test the heart rate increase was unaffected by the drugs, but in those less familiar with the test it was usually attenuated.S Although the fi1-adrenoceptor selective blocker, metoprolol, caused decreases in baseline values for blood pressure and heart rate similar to those observed with the use of the two non-selective blockers, it was shown in a double-blind crossover comparison with propranolol that the haemodynamic changes provoked by the mental arithmetic were not less in the presence offi -receptor blockade than when both pf-andfi2-receptors were blocked.6 These findings suggest that, during fi2-adrenoceptor blockade, the haemodynamic effects of minor mental stress are not exaggerated because of uncompensated a-receptor mediated vasoconstriction, such as occurs following adrenaline infusion.