Perindopril and reference antihypertensives.
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Adult↗
Biomedical subjects
H Thurston
Publications and source records attributed to H Thurston.
Structural and functional smooth muscle injury after surgical preparation of reversed and non-reversed (in situ) saphenous vein bypass grafts.
Intimal hyperplasia and isolated stenoses are major factors in determining the long-term patency of reversed and in situ vein grafts. Surgical handling causes functional endothelial damage in reversed vein grafts but the effects of valvulotome use are unknown. Saphenous vein samples were taken after minimal dissection (control), distension with saline, or after the passage of a valvulotome. Rectangular strips of vein were mounted in an organ bath and cumulative noradrenaline (10(-8)-10(-5) M) dose contraction curves were performed. Compared with controls there was a significant reduction in the contractile response of both the distended and valvulotome-prepared veins (P less than 0.05). Histological studies revealed partial endothelial cell loss in the distended group and total endothelial cell loss with patchy necrosis of the smooth muscle in the valvulotome group. These results suggest that the current use of a valvulotome not only renders the valves incompetent but also seriously damages the function of the smooth muscle layer.
Aged↗
Calcium dependent and independent endothelin-1-induced contraction of human omentum vessels.
Endothelin-1, an endothelium derived vasoconstrictor peptide, induced concentration-dependent contraction of isolated human omental resistance arteries. Pre-treatment with the calcium antagonist nicardipine or calcium depletion caused a significant reduction but did not abolish the contractile response. However, when calcium depletion was combined with pretreatment with the protein kinase C inhibitor (H7), endothelin-1 failed to produce a contraction. This study shows that a large component of endothelin-1 contraction is calcium-dependent, involving activation of dihydropyridine-sensitive voltage-dependent calcium channels but in addition there is a calcium-independent component produced by protein kinase C activation.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Assessment of antihypertensive efficacy of perindopril: results of double-blind multicenter studies versus reference drugs.
Perindopril (4 mg) was compared to atenolol (50 mg), captopril (25 mg b.i.d.), or a diuretic (hydrochlorothiazide 50 mg and amiloride 5 mg) in three studies involving a total of 503 hypertensive patients with diastolic blood pressure (DBP) of 95-125 mm Hg. A 4-week single-blind placebo period preceded 12 weeks of active treatment. Dose titration was at weeks 4 and 8 if the supine DBP was greater than 90 mm Hg. The dose was doubled and, if necessary, a diuretic was added in atenolol or captopril comparison and atenolol added in the diuretic study. The fall in supine blood pressure (BP) was 27/17 mm Hg with perindopril and 21/16 mm Hg for atenolol. Fifty-five percent on perindopril and 48% on atenolol were controlled on monotherapy, increasing to 78 and 58% with addition of hydrochlorothiazide. Captopril caused a BP fall of 19/12 mm Hg compared to 27/18 mm Hg for perindopril with 49% of both groups being controlled on monotherapy. Diuretic addition produced a greater antihypertensive effect with perindopril 75% compared to 57% of the captopril patients achieving control. Perindopril caused a comparable fall in supine BP to the diuretic combination 27/19 mm Hg and 31/18 mm Hg but the fall in erect systolic BP was significantly greater for the diuretic. At 3 months, 84% of the diuretic and 78% of the perindopril group achieved the target BP. There were no adverse effects on the blood count or blood chemistry with a low incidence of side effects and withdrawals from treatment. These studies show that perindopril compares favorably with the standard antihypertensive drugs.
Amiloride↗
A double blind comparison of perindopril and atenolol in essential hypertension.
A multicentre randomised double-blind trial was performed in order to compare the therapeutic efficacy and acceptability of the angiotensin converting enzyme (ACE) inhibitor perindopril with those of atenolol in mild to moderate hypertension. After one month of placebo, 173 patients with supine diastolic blood pressure (DBP) between 95 and 125 mmHg were randomised to receive perindopril 4 mg once daily or atenolol 50 mg once daily. Monthly assessments were made for three months. Treatment was adjusted at these visits if supine DBP was greater than 90 mmHg; the dose was first doubled (8 mg perindopril or 100 mg atenolol once daily) and then hydrochlorothiazide was added. The pretreatment blood pressure levels were similar in both groups. Supine DBP was 105.5 +/- 0.9 mmHg (n = 85) in the perindopril group and 106.9 +/- 0.9 mmHg (n = 88) in the atenolol group. At the end of the third month, the study target blood pressure (supine DBP less than or equal to 90 mmHg) was achieved in a significantly (P = 0.006) larger percentage of patients in the perindopril group (78%) than in the atenolol group (58%). This appeared to be due to a greater potentiation of the antihypertensive effect by the addition of diuretic to perindopril than to atenolol. The fall in systolic blood pressure was significantly greater in the perindopril group than in the atenolol group (supine: 26.5 +/- 2.0 mmHg vs. 20.6 +/- 2.0 mmHg; P = 0.042) although the fall in DBP was comparable (supine: perindopril 17.4 +/- 0.9 mmHg, atenolol 15.6 +/- 1.1 mmHg; P = 0.195).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Vasoconstrictor actions of endothelin-1 in human resistance vessels.
The contractile response to endothelin-1 was studied in isolated human resistance vessels in the presence and absence of extracellular calcium. Endothelin-1 was 1000-fold more potent than noradrenaline, with an ED50 of 6.5 +/- 1.26 x 10(-9) mol/l compared with 2.1 +/- 0.7 x 10(-6) mol/l. Calcium depletion by repeated stimulation with noradrenaline in a calcium-free medium attenuated but did not prevent a sustained contraction in response to endothelin-1 (30% of control). On re-adding calcium to the bath a full contraction immediately occurred. These experiments suggest that an endothelin-1-induced contraction is largely dependent on the presence of extracellular calcium, but a partial contraction can be induced in a calcium-free medium and this may be dependent on mobilization of intracellular calcium from a store not affected by repeated noradrenaline stimulation.
Adult↗
Endothelium-dependent relaxation in resistance vessels from the spontaneously hypertensive rats.
The endothelium-dependent vasodilator acetylcholine was used to observe relaxation responses of noradrenaline-contracted mesenteric resistance vessels from 3-, 6-, 12- and 18-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Relaxation responses were greater than normal in the 3-week-old SHR but the pattern of response was different in the 6-18-week-old SHR compared with the WKY. In these older animals, low concentrations of acetylcholine relaxed SHR and WKY vessels to a similar extent, but high concentrations (greater than 10(-7) mol/l) caused the partially relaxed vessels to contract again. Indomethacin enhanced relaxation in the 12-week-old SHR and reduced the difference between the SHR and WKY. The reduction in acetylcholine-induced, endothelium-dependent relaxation in SHR suggested that a functional change occurred, causing the vessels to release a vasoconstrictor factor that opposes the action of endothelium-derived relaxing factor.
Acetylcholine↗
The effect of dietary linoleic acid on blood pressure and erythrocyte sodium transport.
The influence of an increase in the polyunsaturated fat linoleic acid on blood pressure and erythrocyte membrane sodium transport was investigated in normotensive first degree relatives of hypertensive patients and controls by the double blind administration of safflower oil or paraffin oil (placebo) capsules for four weeks separated by a four week washout period. Systolic blood pressure fell in the controls with linoleic acid supplementation but there was no significant change in total sodium efflux rate constant. When the pattern of response was compared the changes in supine systolic blood pressure, plasma renin activity, total and ouabain-sensitive sodium efflux rate constant were significantly different in the controls compared to the relatives. These results show that dietary linoleic acid supplementation may have effects on ionic fluxes across cell membranes and cause a modest fall in blood pressure. In addition, since the response to the change in fat intake was different in the relatives and the controls, this provides further evidence of differences in the physicochemical structure of the plasma membrane in hypertensive subjects and their offspring.
Adult↗
Effects of changes in dietary sodium intake on aortic sodium pump activity in the rat.
Aortic smooth muscle sodium efflux was studied in normal rats undergoing salt restriction or salt loading. Sodium efflux rate constant was not changed by salt loading but fell significantly with salt restriction. This change was not associated with a fall in blood pressure. These studies show that smooth muscle sodium transport can be influenced by dietary salt intake but do not support the concept that salt loading leads to the inhibition of the vascular smooth muscle sodium pump.
Animals↗
Haemodynamic consequences of experimental papillary necrosis in the rat.
Experimental renal papillary necrosis induced by 2-bromoethylamine hydrobromide (BEA) results in hypertension in the rat. The haemodynamics of this increase in blood pressure were investigated with radiolabelled microspheres, thus enabling individual organ blood flows to be evaluated. Total peripheral resistance was raised in BEA-treated rats (3.6 +/- 0.3 mmHg ml-1 min X 100 g) compared with control rats (2.87 +/- SEM 0.2, P less than 0.05) whilst cardiac index remained similar (39.9 +/- 3.6 vs 39.2 +/- 3.1 ml min-1 100 g-1). Heart and brain from BEA rats demonstrated a significant rise in vascular resistance with a normal blood flow. In the kidneys vascular resistance increased still further and here there was a reduction in renal blood flow despite an increase in kidney size. These findings are compatible with a loss of renomedullary vasodepressor mechanisms acting directly or indirectly on the resistance vessels.
Animals↗
Reversal of renovascular hypertension: role of the renal medulla.
The fall in blood pressure, which occurs when renovascular hypertension is corrected surgically, offers a means of elucidating the factors responsible for blood pressure control. When Goldblatt two-kidney, one-clip hypertension in the rat is reversed by unclipping the renal artery, or by removal of the ischaemic kidney, restoration of normal blood pressure is due to a fall in peripheral resistance. This is associated with sodium retention and cannot be modified by inhibition of the renin-angiotensin system. The fall is, however, partially inhibited by chemical removal of the renal medulla by means of 2-bromo-ethylamine hydrobromide. When normal rats are chemically medullectomized, moderate hypertension is produced, which cannot be attributed to the renin-angiotensin system or sodium retention. It is concluded that a renomedullary vasodepressor system is ablated by chemical medullectomy: further, this system plays a role in the surgical correction of Goldblatt hypertension.
Animals↗
Endothelial-dependent relaxation in human subcutaneous resistance vessels.
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Acetylcholine↗
Effect of cold pressor test-induced stress on leukocyte sodium transport and norepinephrine.
The effects of stress on leukocyte membrane sodium efflux rate constant and plasma norepinephrine levels were studied before and during cold pressor test in normotensive subjects with and without a family history of hypertension. After 20 minutes of supine rest, no significant differences in total, ouabain-resistant or ouabain-sensitive sodium efflux rate constants were apparent between the two groups. In normotensive subjects with no family history, there was no significant change in any efflux rate constant during cold pressor test, although there was a highly significant negative correlation between change in total efflux rate constant and change in norepinephrine levels (r = -0.82, p less than 0.01, n = 12). During cold pressor test in subjects with a family history of hypertension, there was a significant rise in the ouabain-resistant efflux rate constant (1.5 +/- 0.1 vs 1.0 +/- 0.1 hr-1; p less than 0.01, n = 10); this level was also significantly higher than that in control subjects (p less than 0.002). In this group, the ouabain-sensitive efflux rate constant fell slightly but not significantly (1.8 +/- 0.2 vs 2.1 +/- 0.2 hr-1; n = 10). These results suggest that stress in the form of a cold stimulus produces qualitative differences in leukocyte cation transport in normotensive offspring of hypertensive patients as compared with subjects without such a family history.
Adult↗
Failure of naloxone to influence surgical reversal of two-kidney, one-clip hypertension in the rat.
The rapid fall in blood pressure after removal of the constricting clip in two-kidney one-clip (2K-1C) hypertension in the rat is not fully explained by inhibition of the renin-angiotensin system or change in sodium balance. It has been postulated that compounds released in the renal venous effluent following unclipping of 2K-1C rats have a central opiate-like action and endogenous opioids are recognized to have profound hypotensive properties. To investigate this, we removed the clip from, or performed a sham operation in, early phase (less than 6 weeks) 2K-1C hypertensive rats during an infusion of naloxone, an opioid antagonist, or vehicle alone. The infusion of naloxone did not affect the pattern of blood pressure fall in either unclipped or sham-operated rats. Both naloxone-treated and control groups were similarly normotensive at 24 hr postoperation, the MAP being significantly lower than in the sham-operated groups, which regained previously hypertensive levels. Heart rate was unchanged 24 hr postoperatively in all groups. Morphine-induced bradycardia and hypotension were significantly reduced by naloxone infusion. Thus, naloxone infusion had no effect on blood pressure or heart rate in either the sham-operated or the unclipped groups, indicating that endogenous opioids do not have a major role in the reversal of renovascular hypertension under these circumstances.
Animals↗
Nifedipine substituted for minoxidil in the treatment of refractory hypertension.
Nifedipine slow release tablets were substituted for minoxidil in the treatment of 13 patients with hypertension refractory to conventional therapy. In 12 patients substitution was associated with continuing control of blood pressure (BP), although 11 required maximum dose of 120 mg daily and one 80 mg daily. BP control remained satisfactory in nine patients for at least one year after substitution and in all, loop diuretics previously required with minoxidil to control fluid retention, were discontinued. Three patients (23%) however had to be withdrawn because of side effects; one within days of starting therapy and two after three months: one patient died after sustaining myocardial infarction. There was no evidence of deterioration in renal function in those patients continuing on nifedipine. This drug in combination with other antihypertensive agents provides an alternative approach to the management of patients with refractory hypertension, avoiding the severe side effects of the potent vasodilators.
Adrenergic beta-Antagonists↗
Hydralazine sensitivity: clinical features, autoantibody changes and HLA-DR phenotype.
The clinical features, autoantibody changes, acetylator and HLA-DR phenotype of 20 patients with hydralazine-induced systemic lupus erythematosus are described. Four cases of particular interest are discussed in greater detail. Hydralazine sensitivity is more common in women, slow acetylators and the HLA-DR4 phenotype. Symptoms can occur even after many years of treatment and clinical awareness must be maintained for all patients to detect sensitivity at an early stage; there is no timely safe dose even in rapid acetylators. Joint symptoms predominate and full resolution is usual on discontinuing hydralazine. Failure of resolution should raise the suspicion of an underlying cause for the arthritis.
Acetylation↗
Effects of manipulation of sodium balance on erythrocyte sodium transport.
The effects of changing sodium balance on blood pressure (BP) and erythrocyte sodium transport were investigated in normotensive first-degree relatives of hypertensive patients and control subjects randomised to receive low and high salt diets for two weeks, separated by a two week washout period. Changing from high to low salt intake produced a significant fall in standing diastolic pressure (DBP) in control subjects but not in the offspring of hypertensive patients. In both groups erythrocyte sodium efflux was not changed significantly by either manoeuvre, but the relatives had a significantly higher ouabain insensitive sodium efflux rate constant on both the low and the high salt diet compared to the controls (P less than 0.05). These results are not in keeping with the hypothesis which suggests the release of a humoral sodium pump inhibitor in response to sodium loading but lend support to the view that there is a disturbance of membrane permeability to sodium in subjects genetically prone to hypertension.
Adult↗
Selective renal medullary damage and hypertension in the rat: the role of vasopressin.
The induction of selective renal medullary damage by 2-bromoethylamine hydrobromide (BEA) results in polyuria and raised blood pressure. In view of the likely elevation of plasma vasopressin we have investigated the role of vasopressin (AVP) in the elevated blood pressure in this model. Plasma vasopressin levels in BEA pretreated rats were raised significantly (2 +/- 0.6 pg/ml vs 0.8 +/- 0.1 in normal rat, P less than 0.05) but not to pressor levels. In addition, pressor responsiveness was investigated in renal medullary damaged rats. There was a reduced response to vasopressin and noradrenaline but no alteration with angiotensin II. A specific V1, receptor AVP antagonist [d(CH2)5Tyr(Me)AVP] produced no fall in blood pressure but returned the noradrenaline dose-response curve to normal. This suggests an interaction between vasopressin and the sympathetic nervous system in this model. Thus there is no evidence that vasopressin contributes to the rise in blood pressure produced by chemical renal medullectomy and other mechanisms have to be sought.
Angiotensin II↗