Anti-aldosteronergic effect of torasemide.

The diuretic actions of torasemide and furosemide were studied in normotensive rats and in deoxycorticosterone acetate (DOCA)-saline-loaded hypertensive rats. Torasemide (0.3-3 mg/kg) and furosemide (3-30 mg/kg) had a dose-dependent and significant diuretic action in normotensive rats. Potassium retention was only observed in the case of torasemide. Torasemide also had a dose-dependent and significant diuretic action in DOCA-saline-loaded hypertensive rats, whereas furosemide did not. Higher doses of torasemide (10 mg/kg) and furosemide (100 mg/kg) increased both plasma renin activity and aldosterone concentration in normotensive rats in a similar manner. In vivo aldosterone receptor binding was determined to test the possible anti-aldosteronergic effect of torasemide. Torasemide inhibited the binding of aldosterone to its receptor in the cytoplasmic fraction of rat kidney in a dose-dependent manner, while furosemide produced no effect. These results suggest strongly that an anti-aldosteronergic action of torasemide contributes to producing less kaliuresis.     

Torasemide, but not frusemide, increases intracellular cAMP and cGMP content in the aorta of the renal hypertensive rat.

Repeated oral administration of the novel loop diuretic torasemide (3 mg kg-1) and frusemide (30 mg kg-1) for 7 days, elicited a significant fall in the systolic blood pressure in the one-kidney, one-clip Goldblatt renal hypertensive rat (RHR). The hypotensive action was greater in the torasemide group than in the frusemide group. Furthermore torasemide increased intracellular cAMP and cGMP content in aorta of RHR. Frusemide caused no effect. It is hypothesized that the increase in adenosine- or guanosine-nucleotides is involved in the antihypertensive action of torasemide, but not in that of frusemide.     

Pharmacological properties of the new potent diuretic torasemide in rats and dogs

Torasemide, a pyridine-3-sulfonylurea derivative, has potent diuretic activity in rats and dogs. In both species urinary volume and electrolyte excretion increased linearly with the logarithm of the dose, thus resembling the profile of a high ceiling diuretic. The minimum effective dose by oral route was 0.2 mg/kg in the rat and less that 0.1 mg/kg in the dog. Maximal effect was obtained with about 10 mg/kg. Experiments by oral and i.v. routes in the rat indicated that torasemide was equally potent by both oral and parenteral administration. In both rats and dogs, urinary excretions induced by torasemide were similar to those obtained with furosemide. However, for the same natriuretic effect, potassium losses with torasemide were significantly less than with furosemide. On a weight basis, torasemide was 9-40 times more potent than furosemide in the rat and about 10 times in the dog. After oral administration the diuretic effects of torasemide started within 20 min and lasted approximately 2 h in the rat and more than 8 h in the dog. The activity of torasemide was not decreased after a repeated daily oral dose of 10 mg/kg for 15 days in the rat. Torasemide at a daily oral dose of 5 mg/kg for 12 days effectively reduced the arterial blood pressure in desoxycortone induced hypertension in the rat. Besides the diuretic and antihypertensive effects no other significant pharmacological effects were observed with torasemide in the different in vitro and in vivo experiments. Torasemide was practically fully absorbed by the gastrointestinal tract, its bioavailability by oral route ranged from 80 to 100%.(ABSTRACT TRUNCATED AT 250 WORDS)     

EFFECTS OF TORASEMIDE ON RENAL HAEMODYNAMICS AND FUNCTION IN ANAESTHETIZED DOGS

1. We examined the effects of torasemide (0.3 and 1 mg/kg i.v.) on renal haemodynamics and function employing renal clearance and stop-flow techniques in anaesthetized dogs and compared these with furosemide (1 and 3 mg/kg i.v.). 2. Torasemide and furosemide did not influence renal haemodynamics, in the renal clearance study, but caused a dose-related and significant increase in urine flow and urinary excretion of sodium and potassium. Torasemide and furosemide increased fractional excretion of sodium in the distal tubules with a relatively small increase in the fractional excretion of lithium (index of sodium excretion at the proximal tubules, FELi). The diuretic profile of torasemide was of long duration, compared with that of furosemide. 3. Torasemide and furosemide inhibited sodium reabsorption at the distal portion of the tubules in the stop-flow study. 4. It is suggested from these results, that the main diuretic site of action of torasemide is the ascending limb of the loop of Henlé.     

Antihypertensive effect of naftopidil (KT-611), a novel alpha 1-adrenoceptor antagonist, in freely moving experimental hypertensive rats and dogs

The antihypertensive effect of naftopidil (KT-611) following single oral administration was investigated in normotensive Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR), DOCA-Salt hypertensive rats (DHR), 2-kidney 1-clip renal hypertensive rats (RHR) and Grollman type renal hypertensive dogs with 1-kidney (RHD); and it was compared with that of the selective alpha 1-adrenoceptor antagonist prazosin. The blood pressure and heart rate were measured under the unanesthetized, unrestrained state through an arterial catheter that was chronically implanted into the abdominal aorta. In SHR and WKY, both KT-611 (10 and 30 mg/kg, p.o.) and prazosin (1 and 3 mg/kg, p.o.) markedly inhibited the pressor response to the alpha 1-adrenoceptor agonist phenylephrine (3 micrograms/kg, i.v.). KT-611 (10 to 100 mg/kg, p.o.) showed a dose-dependent hypotensive effect in SHR, DHR and RHR but not in WKY. The hypotensive effect of KT-611 reached maximum at 0.5-1 hr, lasted for 4-6 hr and was more potent in DHR and RHR than in SHR. The potency of KT-611 was 1/10-1/30 weaker than that of prazosin. In RHD, single oral administration of KT-611 (1 to 10 mg/kg) caused a dose-dependent and long-lasting hypotensive effect. These results suggest that KT-611 has a long-lasting hypotensive effect in experimental hypertensive animal models.     

Torasemide (LUPRAC): a review of its pharmacological and clinical profile

Loop diuretics potently excrete water and electrolytes and therefore have been widely prescribed for the treatment of various kinds of edema for a long time. The potent diuretic action of loop diuretics, however, often causes hypokalemia, and therefore potassium sparing diuretics have also been supplied as a concomitant drug. Torasemide (LUPRAC), a novel diuretics, shows not only an effective loop diuretic action but also a potassium sparing action due to its anti-aldosteronergic effect. Torasemide also has a high bioavailability and is only slightly influenced by meals in humans. In addition, its pharmacodynamic features contribute to its stable diuretic action without any individual differences. In animal experiments, torasemide showed about a tenfold more potent diuretic action in comparison with furosemide, an authentic loop diuretic. On the one hand, the increase in the urinary potassium excretion by torasemide was relatively slight compared to the increase in urinary sodium excretion and, as a result, the urinary sodium to potassium (Na+/K+) ratio increased. The diuretic profile of torasemide was equal to that of the concomitant use of furosemide and an anti-aldosteronergic drug, spironolactone. Torasemide showed a significant efficacy and safety in comparison with furosemide in the patients with edema in both domestic and foreign clinical studies. Moreover, torasemide also showed a decreased rate of cardiac death in comparison to furosemide in patients with chronic heart failure in a large-scale clinical study (TORIC Study). The difference in cardiac death between these two diuretics has been suggested to depend on the anti-aldosteronergic effect of torasemide. In Japan, no new loop diuretics have been developed in over 10 years. Torasemide is therefore expected to be useful as an effective diuretic for diseases with edema.     

Antihypertensive effects of nisoldipine and reference drugs in certain types of hypertensive rats

The hypotensive effects of nisoldipine (Bay K 5552), compared with those of nifedipine, nicardipine and hydralazine, in normotensive rats (NR), spontaneously hypertensive rats (SHR), DOCA-NaCl hypertensive rats (DNR) and renal hypertensive rats (RHR), were studied. The changes in plasma renin activity (PRA) after treatment with nisoldipine and these reference drugs were also studied. The results of this study revealed that: 1. Nisoldipine caused more potent antihypertensive effects in SHR, DNR and RHR than in NR. 2. The antihypertensive effects of nisoldipine in SHR were almost equipotent to those of nifedipine, nicardipine and hydralazine. However, in NR, DNR and RHR, the effects of nisoldipine were weaker than those of the reference drugs. 3. The positive chronotropic effects of nisoldipine were less remarkable than those elicited by nifedipine, nicardipine and hydralazine in all types of hypertensive rats, except SHR. 4. As did nifedipine and nicardipine, nisoldipine caused an increase of the plasma renin activity in NR and SHR, though its potency was weaker than those of nifedipine and nicardipine.     

Antihypertensive and cardiovascular effects of the new calcium antagonist YH334

Antihypertensive effect of YH334 was examined in various experimental hypertension rat models and the systemic and regional hemodynamic profiles of the compound were investigated in conscious spontaneously hypertensive rats (SHR). The antihypertensive potency of YH334 is found to be more than 10 times stronger than that of nitrendipine in the all hypertensive models. The effective doses to lower the initial blood pressure by 20% (ED₂₀) of YH334 were 1.4 mg/kg in normotensive rats (NR), 0.7 mg/kg in SHR, 0.1 mg/kg in DOCA salt hypertensive rats (DHR) and 0.4 mg/kg in renal hypertensive rats (RHR), and the ED₂₀ values of nitrendipine were 15.8 mg/kg in NR, 7.1 mg/kg in SHR, 1.7 mg/kg in DHR and 4.8 mg/kg in RHR. The primary hemodynamic effect of YH334 was characterized by increasing CI and SVI and reducing TPRI of which hemodynamic profile is similar to that of nitrendipine. Both compounds seem to produce potent antihypertensive effects by lowering peripheral resistance in the skeletal muscles. In the organ bath study using isolated rabbit aorta, YH334 was found to be a potent voltage dependent calcium channels blocker without significant inhibitory effect on the receptor operated calcium channels like the most of other dihydropyridine type calcium antagonists. Furthermore, YH334 showed acute diuretic and natriuretic effects in conscious SHR, which may render the unnecessary restriction of sodium in the diet of those patients on long term hypertension therapy. This effect would provide an additional benefit to its potent antihypertensive activity.     

Torasemide. A review of its pharmacological properties and therapeutic potential.

Torasemide (torsemide) is a high-ceiling loop diuretic which acts on the thick ascending limb of the loop of Henle to promote rapid and marked excretion of water, sodium and chloride. Like furosemide (frusemide), its major site of action is from the luminal side of the cell. Torasemide is at least twice as potent as furosemide on a weight-for-weight basis, produces equivalent diuresis and natriuresis at lower urinary concentrations and has a longer duration of action, allowing once-daily administration without the paradoxical antidiuresis seen with furosemide. Torasemide also appears to promote excretion of potassium and calcium to a lesser extent than furosemide. In trials of up to 48 weeks' duration in patients with mild to moderate essential hypertension, torasemide, administered as a single daily dose, has been shown to achieve adequate blood pressure control reaching steady-state within 8 to 12 weeks. Those patients not responding initially have generally responded to a doubling of the dose. Comparative trials of up to 6 months show torasemide is as effective as indapamide, hydrochlorothiazide or a combination of triamterene/hydrochlorothiazide in maintaining control of blood pressure. Torasemide has also been used successfully to treat oedematous states associated with chronic congestive heart failure, renal disease and hepatic cirrhosis. In short term trials control of blood pressure, bodyweight and residual oedema has been sustained. Torasemide appears to be a useful alternative to furosemide in these patients, providing potent and long-lasting diuresis while being relatively potassium and calcium sparing. In clinical trials to date torasemide has been well tolerated with adverse effects of a mild, transient nature reported by only small numbers of patients. Changes in biochemical parameters have been common, including decreases in plasma sodium and potassium levels and increases in plasma creatinine and uric acid levels. These changes are typical of loop diuretics. No changes were clinically significant nor were clinically relevant changes noted in glucose metabolism, cholesterol or triglyceride levels or in haematological values. Thus, torasemide is an interesting new loop diuretic with potential use in the treatment of mild to moderate essential hypertension and of oedematous states in which diuretic therapy is warranted. Preliminary studies suggest it to be as efficacious as other diuretics in common use and to have some advantage over furosemide in duration of action and in effects on potassium and calcium. However, further long term trials in larger groups of patients are needed to delineate the place of torasemide in therapy fully, both as a single agent and in combination with other currently accepted drug regimens.     

Torasemide for the treatment of heart failure

Diuretics play an essential role in modern cardiovascular therapy, and are currently recommended for the treatment of congestive heart failure. Torasemide has been developed as a newer type of loop diuretic with a longer half-life, longer duration of action, and higher bioavailability compared to the most commonly used loop diuretic, furosemide. Torasemide also appears to have additional actions beyond the pure diuretic effect, such as anti-aldosterone effect and vasorelaxation effect. Studies have also investigated whether the superior pharmacokinetics and pharmacological activity of torasemide result in a favorable clinical outcome. Their results have indicated that, in comparison with furosemide, torasemide improves left ventricular function, reduces mortality as well as the frequency and duration of heart failure-related hospitalization, and improves quality of life, exercise tolerance and NYHA functional class in patients with congestive heart failure. Thus, torasemide appears to be a promising loop diuretic that contributes to a better management of patients with heart failure. Definitive clinical trials in a double-blind fashion are warranted.     

Antihypertensive effect of a novel calcium antagonist, SD-3211, in experimental hypertensive rats.

The antihypertensive effect of SD-3211, a structurally novel type of nondihydropyridine calcium antagonist, was assessed using several types of experimental hypertensive rats. Oral administration of SD-3211 (10, 20, and 30 mg/kg) to conscious spontaneously hypertensive rats (SHR), deoxycorticosterone acetate-salt hypertensive rats (DHR) and 2-kidney, 1-clip renal hypertensive rats (RHR) resulted in a dose-dependent decrease in systolic blood pressure (SBP). The hypotensive effect of SD-3211 in these hypertensive rats was more pronounced than in normotensive rats (NR). The potencies of SD-3211 for the hypotensive effect in the hypertensive rats and NR were 5-7 times greater than that of diltiazem but 2-3 times less than that of nicardipine. Furthermore, SD-3211 showed longer-lasting hypotensive action than diltiazem and nicardipine, at the respective equihypotensive dose. During the course of hypotension, SD-3211 did not exert any influence on heart rate (HR) in any type of hypertensive rats or NR, in contrast to the appearance of tachycardia with nicardipine in SHR, DHR, and NR and of bradycardia with diltiazem in DHR. At doses of 10 and 30 mg/kg, the hypotensive doses, SD-3211 elicited a dose-dependent natriuresis but no kaliuresis in SHR. In the chronic study using SHR, SD-3211 at 10 mg/kg/day showed an antihypertensive effect during an administration period of 12 consecutive weeks. These results allow us to conclude that SD-3211 has a potent and long-lasting hypotensive action with little cardiac effect.     

Effects of an angiotensin-converting enzyme (ACE) inhibitor, SA446, on tissue ACE activity in normotensive, spontaneously hypertensive, and renal hypertensive rats

Effects of an angiotensin-converting enzyme (ACE) inhibitor, SA446, on the renin-angiotensin system, particularly on tissue ACE activity, were studied in Wistar-Kyoto normotensive rats (WKY), spontaneously hypertensive rats (SHR), and two-kidney, one-clip renal hypertensive rats (RHR) by repeated oral administration for 7 days. SA446 (45 mg/kg/day p.o.) inhibited ACE activity in the lung, brain, kidney, heart, and whole blood throughout the administration period in WKY, but showed a slight hypotensive action and no inhibition of aorta ACE activity. On the other hand, SA446 had an apparent hypotensive action at the same dose in SHR and inhibited ACE activity significantly in the aorta as well as the kidney and whole blood during the administration period. Furthermore, enzyme activity in the aorta, kidney, heart, and whole blood was also inhibited at a hypotensive dose of SA446 (10 mg/kg/day p.o.) in RHR. The inhibition in whole blood and kidney was almost complete, and the inhibition in the aorta was greater on day 7 than on day 1. The maximum decrease of blood pressure was correlated with the maximum inhibition in aorta ACE activity, but not in brain, lung, or heart ACE activity. In addition, a good positive correlation was observed between the basal blood pressure and the basal aorta ACE activity in WKY, SHR, and RHR, although there was no correlation in the brain, lung, kidney, heart, or whole blood. These results suggest that the antihypertensive action of SA446 by repeated administration may be due to inhibition of arterial ACE activity in addition to inhibition of plasma and kidney ACE activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Torasemide: a pharmacoeconomic review of its use in chronic heart failure.

Torasemide is a loop diuretic used for the treatment of hypertension and for oedema in chronic heart failure (CHF), renal failure and cirrhosis. The efficacy of torasemide in reducing salt and water retention in CHF has been established in double-blind comparative studies against furosemide. Torasemide has been shown to be at least as effective as furosemide in terms of total volume of urine excreted and also has a longer duration of action. The efficacy of torasemide (in terms of improved CHF symptoms and reduced pulmonary congestion, oedema and bodyweight) has been shown in randomised controlled trials and confirmed in large postmarketing studies. In addition, data from postmarketing studies have shown that patients receiving torasemide had significantly reduced hospital admission rates compared with patients receiving furosemide. Pharmacoeconomic assessments of torasemide have focused on its effect in reducing hospitalisation. Hospitalisation costs due to CHF decreased by 86% during the 11.2-month period of torasemide treatment, compared with the 6-month period prior to treatment, in a US retrospective study assessing medical and pharmacy claims data. Overall, average monthly costs for patients decreased by 56.6% after 5.1 months (from $US1,897.28 to $US823.70 per patient per month; PPPM), and by 76% after 11.2 months (from $US1,944.76 to $US470.76 PPPM) of torasemide treatment. In the furosemide group, average monthly costs for patients increased moderately from $US227.28 to $US261.18 PPPM after 12 months. Direct comparison of the torasemide and furosemide study groups was not possible because the group receiving torasemide had much higher healthcare resource use at baseline. Compared with furosemide, torasemide was associated with reduced rates of hospital admissions for CHF and/or cardiovascular causes in 3 studies, a retrospective analysis conducted in Germany, a prospective US study of patients enrolled from hospital admissions and a decision-analysis model. As a result, the direct costs of treatment for CHF or cardiovascular diseases for patients treated with torasemide were less than those with furosemide. However, in the US study, there was no statistically significant difference in hospital admissions for all causes and/or in overall direct medical costs, although the study was not powered to show this. In another US study of managed care patients with New York Heart Association (NYHA) class II or III CHF, no difference in clinical or economic outcomes was observed between patients taking torasemide or furosemide; despite the higher acquisition costs for torasemide, total costs were similar for both groups. Torasemide was found to be more cost effective than furosemide in terms of cost per patient with improved functional (NYHA) class of CHF severity in a retrospective German analysis, although this measure is not ideal. This study also evaluated indirect costs (for loss of productivity of employed patients) and resultssuggest torasemide has a favourable effect in reducing days off work compared with furosemide, although the population of employed patients in the study was very small. Torasemide has been shown to improve some measures of quality of life in 2 studies. It was associated with higher quality-of-life scores than furosemide in a 6-month study, but the differences were only significant at month 4. In another study, torasemide significantly improved fatigue, but full study details are yet to be published. CONCLUSIONS: Despite the higher acquisition cost of torasemide over furosemide, pharmacoeconomic analyses have shown that torasemide is likely to reduce overall treatment costs of CHF by reducing hospital admissions and readmissions. Torasemide has generally shown clinical and economic advantages over furosemide, although more long term data are needed to confirm these results and to further investigate effects on quality of life. There are limitations to the currently available pharmacoeconomic data, but present data support the use of torasemide as a first-line option for diuretic therapy in patients with CHF presenting with oedema and especially in those patients not achieving relief of symptoms with furosemide.     

Na+,2Cl-,K+ cotransport system as a marker of antihypertensive activity of new torasemide derivatives.

A series of compounds related to torasemide, a loop diuretic, were synthesized and examined for their diuretic potency and inhibitory activity on the erythrocyte and renal medullary thick ascending limb vesicle Na+,2Cl-,K+ cotransport in Milan hypertensive (MHS) and normotensive (MNS) rat strains, where previous studies had demonstrated an alteration of the cotransport system genetically related to hypertension. From the results of the screening, structure-activity relationships were drawn and two compounds, JDL 961 and C 2921 were selected. Their IC50 on renal vesicle cotransport were similar in the two strains (JDL 961: MHS = 1.8 microM; MNS = 1.2 microM; C 2921: MHS = 4 microM; MNS = 3.8 microM), and were 4-8 times lower than those of torasemide (MHS = 13 microM; MNS = 31 microM, P less than 0.01) and 50-60 times lower than those of bumetanide (MHS = 145 microM; MNS = 206 microM, P less than 0.05) taken as reference compounds. Their ability to reduce the development rate of hypertension was tested both in MHS and in Okamoto spontaneously hypertensive rats (SHR) strain, in which cotransport alterations are opposite to those of MHS. Both torasemide derivatives (7.5 mg.kg-1 os per day) prevented development of hypertension in the two strains. The time course of this hypotensive activity was faster and the percentage of blood pressure fall greater in MHS (20-25%) than in SHR rats (12-15%), even though the absolute value of blood pressure fall was similar in MHS (JDL 961 = -17 mm Hg; C 2921 = -30 mm Hg) and SHR (JDL 961 = -25 mm Hg; C 2921 = -20 mm Hg). A superimposable effect of bumetanide was observed in the two strains, but at 8 times higher daily dose (60 mg.kg-1). These results suggest that new loop diuretics can be selected for their antihypertensive activity on the basis of their in vitro potency in inhibiting the Na+,2Cl-,K+.     

Comparative effects of torasemide and furosemide in rats with heart failure

It has been reported that torasemide but not furosemide, may block the renin-angiotensin-aldosterone system and therefore it might attenuate myocardial remodeling accompanied by left ventricular (LV) dysfunction. We therefore compared the therapeutic effects of torasemide, a long-acting loop diuretic, and furosemide, a short-acting one, on the progression of LV remodeling in a rat model of chronic heart failure (CHF) after experimental autoimmune myocarditis (EAM). CHF was elicited in Lewis rats by immunization with porcine cardiac myosin. Twenty-eight days after immunization, rats were treated for 28 days with torasemide, furosemide, or vehicle. We investigated the effects on metabolic and neurohumoral parameters, cardiac fibrosis and remodeling in EAM rats. Diuresis was increased dose dependently by both torasemide and furosemide, showed an equipotent natriuretic effect. The urinary potassium excretion was significantly increased with furosemide in comparison to torasemide. Myocardial functional parameters were significantly improved by torasemide. Conversely, these parameters did not change in rats receiving furosemide. Torasemide suppressed LV fibrosis, myocardial protein levels of transforming growth factor-beta1, collagen III, and aldosterone synthase and improved survival rate to the control level, but furosemide did not. Moreover, both pharmacological interventions significantly elevated plasma angiotensin II and decreased atrial natriuretic peptide in a dose-dependent manner. Our results demonstrate that compared with furosemide, torasemide treatment significantly improved survival rate, LV function and ameliorated the progression of cardiac remodeling in rats with CHF after EAM.     

Vasodilatory action of loop diuretics: a plethysmography study of endothelial function in forearm arteries and dorsal hand veins in hypertensive patients and controls

INTRODUCTION: Intravenous administration of loop diuretics induces venodilation before the diuretic response. We investigated whether furosemide and torasemide exert a dilatory effect on arteries and veins mediated by endothelial release of nitric oxide. METHODS: We performed intermittent venous occlusion plethysmography to study forearm blood flow and dorsal hand-vein distension in response to furosemide and torasemide infusion in hypertensive patients and healthy controls. RESULTS: Furosemide increased venodilation from 0.56 +/- 0.09 to 0.88 +/- 0.06 (P=0.000) in control subjects and from 0.49 +/- 0.10 to 0.75 +/- 0.12 (P=0.000) in hypertensive patients. Torasemide increased venodilation from 0.46 +/- 0.06 to 0.70 +/- 0.11 (P=0.007) in control subjects and from 0.48 +/- 0.09 to 0.67 +/- 0.12 (P = 0.03) in hypertensive patients. Co-infusion of the Nitric Oxide Synthase Inhibitor (L-NMMA)-blocked this venodilation, and the action was reversed with L-arginine. There were no significant changes in the arterial bed. CONCLUSIONS: Furosemide and torasemide induce a similar dose-response curve venodilation, but they have no effect on the arterial bed. Hypertensive patients show a smaller venous endothelium-dependent response than healthy controls. The venodilation induced by both diuretics requires release of nitric oxide.     

Antihypertensive effect of a new dihydropyridine calcium entry blocker in conscious hypertensive and normotensive rats

The antihypertensive effects of orally administered CD-349, (2-nitratopropyl-3-nitratopropyl-2,6-dimethyl-4-(3-nitrophen yl)- 1,4-dihydropyridine-3,5-dicarboxylate), a new dihydropyridine calcium-entry blocker, were evaluated in comparison with nifedipine in spontaneously hypertensive rats (SHR), renal hypertensive rats (RHR) and normotensive rats (NTR) all in a conscious state. CD-349 (0.3, 1.0 and 3.0 mg/kg) and nifedipine (1.0 mg/kg) produced a long-lasting decrease in mean arterial blood pressure (BP) and an increase in heart rate (HR) in all the rat groups; the effects of CD-349 were dose-dependent and greater in hypertensive rats than in NTR. As compared with nifedipine at the same dose of 1 mg/kg, the hypotensive effect of CD-349 was relatively slower in onset and longer-lasting, thereby suggesting that gastrointestinal absorption of CD-349 was slower than that of nifedipine. The increase in HR associated with the hypotension induced by CD-349 at 1 mg/kg was relatively transient in comparison with that induced by nifedipine at the same dose in both types of hypertensive rat. From these results, it is expected that CD-349 could be a useful antihypertensive drug.     

The symptoms of unilateral inflammation in spontaneously hypertensive,renal hypertensive and normotensive wistar kyoto and wistar rats

Widy-Tyszkiewicz E, Kohutnicka M, Mierzejewski P, Czlonkowski A. The symptoms of unilateral inflammation in spontaneously hypertensive, renal hypertensive and normotensive Wistar Kyoto and Wistar rats. Inflammopharmacology. 1994;2:337-343. Spontaneously hypertensive (SHR) and renal hypertensive (RHR), Wistar (NR) and Sham or Wistar Kyoto (WKY) rats were tested for clinical symptoms following inoculation with Freund’s adjuvant in the unilateral hind paw. In the present study, body weight change (during weeks 1–11) was examined once a week and inflammatory score of hindpaw twice a week. The body weight gain was increased in the WKY compared with NR/Sham, SHR and RHR groups. Inflammatory changes were also most profoundly exhibited in the NR/Sham, the SHR and the RHR, compared with the WKY rats. The data may reflect a genetic difference not necessarily related to elevated blood pressure.     

Comparison of the hypotensive and diuretic effects of 1,4-dimorpholino-7-phenylpyrido[3,4]pyridazine (DS-511) and hydrochlorothiazide in Doca, renal and spontaneously hypertensive rats

The hypotensive and diuretic activities of a new diuretic, 1,4-dimorpholino-7-phenylpyrido[3,4-d] pyridazine (DS-511), were compared with those of hydrochlorothiazide (HC) in DOCA, renal and spontaneously hypertensive rats. The results obtained were: 1. During the developing stage of DOCA-hypertension the daily treatment of rats with DS-511 and HC showed significant hypotensive action. During this period the diuretic activity of both agents was clear. 2. During the equilibrium stage of DOCA-hypertension the hypotensive action of DS-511 was indistinct despite its diuretic activity. The hypotensive and diuretic action of HC was not clear. 3. In renal-hypertensive rats the daily treatment of DS-511 and HC caused significant, but weaker hypotension than that in the developing stage of DOCA-hypertension. In these animals the diuretic activity of both agents was clear. 4. In spontaneously hypertensive rats the daily treatment with DS-511 and HC exhibited a similar hypotensive and diuretic action. 5. In all three kinds of hypertensive rats the diuretic activity of DS-511 was similar to that of HC in the excretion of urine and sodium, but the former was less kaliuretic than the latter.     

Cardiovascular effects of NPK-1886, a new dihydropyridine compound with calcium entry blocking activity

The cardiovascular effect of NPK-1886 (NPK), a novel photostable dihydropyridine compound, was studied by comparing it with that of nifedipine (Nif). In normal Wistar rats (NWR), systolic blood pressure was only slightly depressed by NPK or Nif, while in three types of hypertensive rats (i.e., spontaneously hypertensive rats (SHR), renal hypertensive rats (RHR) and DOCA-saline-induced hypertensive rats (DOC-Na-R)), the hypotensive potency of NPK was more than or equal to that of Nif. The effectiveness of NPK on the normal and hypertensive models was in the following order: DOC-Na-R, RHR, SHR, NWR. Coronary perfusion flow in Langendorff's heart was increased almost the same extent by NPK and Nif. On isolated rabbit aortic strips, the antagonistic potencies of NPK, like those of Nif, were greater for calcium than for norepinephrine, serotonin and angiotensin II. The negative ino- and chronotropic potency of NPK in isolated guinea-pig right atria was less than that of Nif. The slow membrane action potentials of guinea-pig papillary muscle were suppressed by NPK, but less than by Nif, with manifestations of a reduction of Vmax and AP-duration. These results indicate that NPK has a potent hypotensive effect on hypertensive models and a weaker cardiac inhibition. The general toxicity of NPK was lower than that of Nif.