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Effects of propranolol and atenolol on blood pressure and plasma renin activity in patients with moderate hypertension.

A double-blind crossover trial was completed in 15 patients with moderate hypertension and the effects of propranolol (Inderal) 80 mg twice a day and atenolol (Tenormin) 100 mg twice a day were assessed on blood pressure, pulse rate and plasma renin activity (PRA), while patients were maintained on 1 cyclopenthiazide tablet (Navidrex K) per day. Both agents caused a significant reduction in blood pressure and pulse rate with patients at rest and during exercise. Plasma renin activity was significantly reduced by both agents in subjects with normal and high renin levels (with PRA 2-8 ng/ml/h and greater than 8 ng/ml/h respectively). Blood pressure responses could not be correlated with renin status or reduction in pulse rate. No adverse effects were attributable to either of the two beta-adrenergic blocking agents and we concluded that a beta1-selective agent, which has the advantage of not aggravating bronchospasm, can replace the non-selective propranolol.

Adult↗

Hypotensive action of verapamil in a group of hydralazine-dependent hypertensive patients.

Sixteen hydralazine-dependent hypertensive patients (7 females) were included in this clinical study. All patients were being treated with hydralazine, cyclopenthiazide and propranolol in the first visit to the laboratory. Two drugs were maintained during the study: the beta blocker and the diuretic. Hydralazine was discontinued and replaced by placebo during 3 weeks and after this period, verapamil was instituted at increasing doses. Replacing hydralazine by verapamil a better control of hypertension was obtained with a daily dose of 400 mg. The calcium entry blocker causes shortening of PEPc interval probably by reducing afterload which was only observed with the highest dose of verapamil (400 mg). ECG intervals were not modified by the different treatments with the exception of PR which was significantly increased by the major dose of verapamil. The calcium antagonist produced a stable reduction of blood pressure without affecting left ventricular function.

Adult↗

Polysubstrates: substances that interact with renal contraluminal PAH, sulfate, and NMeN transport: sulfamoyl-, sulfonylurea-, thiazide- and benzeneamino-carboxylate (nicotinate) compounds.

Some N-containing xenobiotics were recently shown to behave as bisubstrates; that is, they interact with and are transported by both the contraluminal transport system for organic anions (PAH) and the contraluminal transport system for organic cations (NMeN). Thus we determined whether other classes of N-containing substrates, such as sulfamoyl-, sulfonylurea-, thiazide- and benzeneamino-carboxylate (nicotinate) compounds, amongst them diuretics and other drugs, also interact with both transporters. To test this, we applied the stop-flow peritubular capillary perfusion method with initial flux measurements and determined app. Ki values for these substrates on PAH, sulfate and NMeN transport. We found that the following compounds interact with 1) the PAH transporter: benzene carboxylates, benzenesulfonylureas and benzenesulfonamides (as long as their acid pKa value is below 9.5). 2) the sulfate transporter: 2-anilinobenzoates, benzenesulfonylureas, polysubstituted sulfamoylbenzoates and some sulfamoylthiazides with electronegative charge accumulation around an anionic site. 3) the NMeN transporter: anilinobenzoates, sulfamoylbenzoates and benzenesulfonamides, if they bear an N-containing pyridine, pyrrolidine, furylmethylamino or thiazide group. There are, however, exceptions when H-bond formation might be responsible for interaction with that transporter. The data confirm the specificity rule for each transporter and the concept that one and the same substrate can match the requirements for several transporters. Thus the loop diuretics furosemide and piretanide, the thiazide diuretics hydrochlorothiazide, cyclopenthiazide and bendroflumethiazide and the sulfonylureas tolbutamide, chlorpropamide and torasemide interact with all three tested transport systems for PAH, sulfate and NMeN. Therefore, they are able to accomplish complex transport interactions with different transporters.

Animals↗

Evaluation of phototoxic properties of oral antidiabetics and diuretics. Photohemolysis model as a screening method for recognizing potential photosensitizing drugs.

The oral hypoglycemic drugs carbutamide, chlorpropamide, glibenclamide, glubornuride, gliclazide, glipizide, gliquidone, glisoxepide, glymidine, tolazamide and tolbutamide, and the diuretics acetazolamide, bemetizide, bendroflumethiazide, benzthiazide, benzylhydrochlorothiazide, bumetanide, butizide, chlorazanile, chlorothiazide, chlortalidone, clopamide, cyclopenthiazide, cyclothiazide, diazoxide, etozoline, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, mefruside, metolazone, piretanide, polythiazide, trichlormethiazide, and xipamide were investigated for photohemolytic properties in vitro. Irradiation with a SOL 3 apparatus (solar simulating irradiation) revealed hemolysis in the presence of five oral hypoglycemic agents and in the presence of 19 out of the 25 tested diuretics. Photohemolysis was induced in the presence of three substances, respectively, after exposure to UVA or visible light. UVB alone did not induce phototoxic hemolysis in the presence of the tested drugs. Compared to clinical reports on photosensitivity reactions, the photohemolysis model seems a good predictive model in recognizing potential photosensitizing sulfonamides.

Dermatitis, Phototoxic↗

Enhancement of p-aminohippurate accumulation in renal cortical slices after repeated administrations of various organic anionic drugs to rats of different ages.

After repeated administrations of various organic anionic drugs to rats of different ages, an enhancement of paminohippurate accumulation was observed in renal cortical slices from adult but not from newborn and infant rats. The effect can be interpreted as specific substrate-induced stimulation of the organic anion transport.

Aging↗

Effect of long-term diuretic treatment on body-potassium in heart-disease.

Plasma and total body potassium have been measured in 151 patients with chronic heart-disease, 83 of whom were taking diuretics and potassium supplements. After allowance for age and body-size, the deficit in total body-potassium was only 3-5% (100-150 mmol) in the diuretic group. 13 of the 83 patients taking diuretic had hypokalaemia (less than 3-5 mmol/1) but the potassium deficit was no greater than in the patients with normal plasma-potassium. There was no relation between the dose of potassium supplements and either the plasma-potassium or the total body-potasium. It is suggested that potassium depletion is not a major problem in patients with heart-failure treated with diuretics. The dose of potassium supplements should therefore be determined entirely by the plasma-potassium.

Adult↗

Inappropriate antihypertensive therapy in the elderly.

Six symptomless patients aged 64-84 (mean 72) years received antihypertensive therapy from their family doctors. Pretreatment systolic pressures ranged from 160 to 220 mm Hg and disastolic pressures from 80 to 120 mm Hg. Within one week of starting therapy all six patients were admitted as emergencies with epidoses of unconsciousness. Admission systolic pressures ranged from 80 to 150 mm Hg and diastolic pressures from 50 to 90 mm Hg. Before admission each patient had experiences symptoms of postural hypotension and had become housebound. After antihypertensive therapy was stopped, one patient had a residual left homonymous hemianopia but the others recovered completely. A raised systolic and distolic pressure is common in the elderly; potent antihypertensive treatment may seriously impair the quality of life and is often unecessary.

Age Factors↗

Relation between renal and hepatic excretion of drugs. XIV. Elimination of ioglycamic acid after nephrectomy, bile duct ligation, and after treatment with hormones or xenobiotics in young and adult rats.

Ioglycamic acid (IGA) is effectively eliminated in young and adult rats via urine and bile. After administration of low doses hepatic excretion dominates whereas following high supply renal elimination surpasses biliary excretion. Hepatic transport of IGA is active, indicated by the occurrence of a transport maximum in vivo and by a distinct accumulation of this drug within liver slices in vitro. Renal removal of IGA is preferentially caused by glomerular filtration. A tubular reabsorption obviously does not occur because forced diuresis (mannitol, furosemide) does not increase renal excretion of this substance. As calculated from our clearance data and as a result of accumulation experiments in vitro on renal cortical slices the active tubular secretion of this organic anion can be excluded. In principle there are no qualitative changes in IGA elimination between the 20th and 55th day of life, but active hepatic transport of the drug is significantly lower in young, immature rats. After bile duct ligation, renal excretion of IGA increases distinctly in both age groups, whereas in adult rats bilateral nephrectomy (NX) is followed by a significant decrease in its hepatic excretion in dependence on time after kidney removal. In young rats NX is without consequences on hepatic excretion of IGA. It is possible to stimulate renal and/or hepatic excretion of IGA by repeated administration of T3, dexamethasone, or phenobarbital. The effect of stimulation is different in kidney and liver and depends on age, too.

Animals↗

Relation between renal and hepatic excretion of drugs: X. Excretion of nalorphine in young and adult rats pretreated with hormones or xenobiotics.

Different processes are involved in renal and hepatic excretion of organic anions and cations. In contrast to our knowledge of anion excretion, information about cation transport in kidney and liver is relatively scarce. In this study, the elimination of nalorphine was investigated to characterize the relation between renal and hepatic excretion of organic cations. Nalorphine is excreted effectively both via kidney and liver. However, its hepatic excretion dominates in adult rats. In young, 20-day-old animals biliary nalorphine elimination is immature and the excreted amounts are significantly lower. Renal excretion of nalorphine is quite similar in rats of both ages. After bile duct ligation renal excretion of nalorphine increases significantly in adult rats whereas it remains unchanged in young ones. Remarkably, after bilateral nephrectomy hepatic elimination of nalorphine is even diminished in both age groups. In further experiments renal excretion of nalorphine could be stimulated in adult rats after repeated administration of trometamol, triiodothyronine, or dexamethasone; these treatments had no consequences on biliary secretion of nalorphine.

Aging↗

Controlled clinical study on antihypertensive treatment with a diuretic and methyldopa compared with a beta-blocking agent and hydralazine.

Twenty-eight previously untreated patients with essential hypertension were included in a randomized double-blind cross-over study comparing the results of treatment with the established combination of a thiazide and methyldopa (regimen A) with the combination of a beta-receptor blocker and hydralazine (regimen B). Three patients each developed intolerable side-effects on each regimen but they were all treated successfully on the alternative regimen. The remaining 22 patients obtained a significant reduction in BP at rest and during exercise on both treatments, with no significant difference between the two schedules. Heart rate was significantly reduced at rest and during exercise with regimen B, while a significant reduction was also obtained following exercise on regimen A. There was no significant difference between the two regimens as to tolerable side-effects during treatment, which were registered in about 60% of the patients on each scheme. However, 64% of the patients were treated satisfactorily without side-effects on either regimen. It is concluded that the combination of a beta-blocking agent and hydralazine is without obvious advantages compared with the combination of thiazide and methyldopa in obtaining initial BP control in patients with essential hypertension.

Blood Pressure↗