Nitrendipine in hypertension that is difficult to control.

Fifty-five patients suffering from essential or renal hypertension who had been insufficiently treated previously with combination therapy using diuretics and beta-blockers as well as reserpine, clonidine, prazosin, captopril, or minoxidil have been included in this open study. In addition to receiving diuretics and beta-blockers alone or in combination with reserpine, clonidine, or methyldopa, the patients were given nitrendipine in a dose of 2 X 20 to 2 X 40 mg/day. A normalisation of blood pressure values was attained in 46 of the 55 patients; 18 of these patients have been treated for more than 1 year. Few side-effects were observed. Dizziness and ankle oedema each occurred once. A rash occurred in one patient, causing the withdrawal of nitrendipine. No complaints of headache and palpitations were made. It may be concluded that nitrendipine is well suited as a partner in the combination treatment of patients with essential or renal hypertension that is difficult to stabilise.

Safety aspects of long-term nitrendipine therapy.

More than 1,700 patients with essential or renal hypertension were treated with nitrendipine; data from 967 of these were included in a data pool, and safety data were evaluated. Treatment duration was between 7 days and 2 years. The most frequent side-effects were headache, flush, oedema, dizziness, and palpitations due to the pharmacodynamic effect of the drug. All other side-effects had an incidence below 2%. Eighty-two of the 967 patients stopped therapy before the end of the trial. In 33 of these patients, this was probably due to the side-effects of nitrendipine. Hematological and clinical chemistry data did not indicate any systemic or organ damage. When nitrendipine was combined with thiazides, a lowering of plasma potassium levels could be found, which, however, did not necessitate any therapy.

[3-Amino-2H-1,2,4-benzothiadiazine-1,1-dioxides with antihypertensive and possibly diabetogenic activity (author's transl)]. / 3-Amino-2H-1,2,4-benzothiadiazin-1,1-dioxide mit antihypertensiver und potentieller diabetogener Wirkung.

By reaction of dialkylaminoalkylamines or omega-amino-alkylethers with 2H-1,2,4-benzothiadiazine-1,1-dioxides bearing a group in the 3-position labile towards nucleophilic substitution (Cl, CH3S, CH3CO2), the corresponding 3-substituted amino-2H-1,2,4-benzothiadiazine-1,1-dioxides are obtained. A series of these compounds exerts an antihypertensive effect in the renally hypertonic rat after oral administration and in the "two-kidney hypertensive dog" after parenteral administration. Two compounds (1 and 4) were studied thoroughly in comparison to diazoxide (16) and the known piperazino compound (17). At 10 mg/kg in the rat, diazoxide causes a marked reduction of water and electrolyte excretion but at this dosage 1 and 4 are neither diuretic nor antidiuretic. In the hyperglycaemia test on normal rats at a dosage 30--100 times that required for an antihypertensive effect, 1 and 4 show after 300 mg/kg no hyperglycaemic effect and after 1000 mg/kg p.o. a very weak one. 17 has a weak hyperglycaemic effect at 300 mg/kg diazoxide a strong one. However, intensive glucose loading studies on diabetic rats (reduced glucose-tolerance) and on metabolically healthy rats with glucose loading showed that compounds 1 and 4 as well as the piperazine derivative 17 inhibit insulin release, albeit in higher doses than does diazoxide. In animals with insulin resistance a diabetic metabolic condition occurs with high blood-sugar levels. Owing to this possible diabetogenic activity, testing and application of 1, 4 and the known 7-chloro-3-(4-methyl-1-piperazinyl)-2H-1,2,4-benzothiadiazine-1,1-dioxide for blood-sugar lowering activity to human volunteers is not considered appropriate.

[Synthesis and comparative pharmacological studies of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylates with non-identical ester functions (author's transl)]. / Synthese und vergleichende pharmakologische Untersuchungen von 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridin-3,5-dicarbonsäureestern mit nicht-identischen Esterfunktionen.

Michael-addition of 3-aminocrotonic acid ester 7 to aralkylidene acetoacetic acid esters 6 is followed by ring closure to give novel 4-aryl-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylates 8 with non-identical ester functions. In the series of 3-nitrophenyl derivatives (8, Ar=3-nitrophenyl) the pharmacological activities (coronary vasodilation, antihypertensive activity) of the asymmetrically substituted derivatives are shown to be superior to those of the corresponding symmetrically substituted derivatives in many cases. One representative of this class 3-ethyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (nitrendipine, Bay e 5009, No. 3) was selected for further development as an antihypertensive drug.

Pharmacological studies of the antihypertensive effect of nitrendipine.

1,4-Dihydro-2,6-dimethyl-4(3-nitrophenyl)-3,5-pyridine carboxylic acid, 3-ethyl-5-methyl ester (nitrendipine, Bay e 5009) is a new vasodilatory calcium antagonist with pronounced hypertensive efficacy. Doses of 0.3-31.5 mg/kg p.o. lower the blood pressure of rats with spontaneous, renal and desoxycorticosterone acetate (DOCA)-hypertension. Doses of 0.03-10.0 mg/kg p.o. lower the blood pressure of dogs with renal hypertension. The hypotensive effect is about 10 times less in normotensive rats. No increase in tolerance occurred during therapeutic studies lasting 5 weeks in hypertensive rats and several days in hypertensive dogs. There were no signs either of acquired tolerance developing during these studies. Dogs in fentanyl analgesia respond to i.v. administration of 0.001-0.03 mg/kg with a reduction in peripheral vascular resistance and an increase in cardiac output and heart rate. The stroke volume remains unchanged. The vasodilatory effect occurs at different degrees in different vascular beds. The most pronounced increases in vascular flow were measured in the muscular vessels of the hind quarters and in the coronary vessels. The mesenterical, skin and brain blood flows were much less affected.

Effect of a new calcium antagonist, nitrendipine, on blood pressure and heart rate of conscious, unrestrained dogs.

The acute effects of a single dose of a new calcium-antagonistic vasodilator, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine carboxylic acid, 3-ethyl-5-methyl ester (nitrendipine, Bay e 50090, on blood pressure and heart rate was examined in conscious dogs by means of a radio-telemetric method. Nitrendipine caused a dose-dependent fall in mean arterial blood pressure of up to 30% in renal hypertensive dogs in a dose range of 0.3-3.15 mg/kg p.o., which was maximal within 2-3 h and was maintained for up to 8 h after a single dose. In normotensive dogs, nitrendipine was somewhat less active. The fall in blood pressure was accompanied by an increase in heart rate, which was less pronounced and less persistent than after administration of hydralazine. Nitrendipine was found about 20 times more potent in its antihypertensive action than hydralazine.

[2-aminodihydropyridines / Structure and antihypertensive activity (author's transl)]. / 2-Aminodihydropyridine. Struktur und antihypertensive Wirksamkeit.

Replacement of the 2-alkyl group by amino in the structure of cardiovascular 4-aryl-2,6-dialkyl-1,4-dihydropyridine-3,5-dicarboxylates 1 is tolerated without loss of antihypertensive activity. The rules found for the substitution of the aromatic ring and the ester functions in 1 still hold for the novel 2-amino-1,4-dihydropyridines 6, 7 and 9 obtained by Michael addition of acetamidines to alpha, beta-unsaturated enones. 2-Dialkylamino-3,4-dihydropyridines 11 surprisingly also show good antihypertensive activity. In this case a displacement of the double bond in the heterocycle must also be taken into account. A 2-trifluoromethyl substitution in the phenyl residue and ester groups with low lipophilicity are optimal in this series.

Pharmacology of Bay g 2821, a long-acting, high-ceiling diuretic.

Bay g 2821 is a diuretic, from a new class of chemical substances, with both the efficacy of diuretics with a high-ceiling activity, such as furosemide, bumetanide and ethacrynic acid, and the prolonged duration of action of thiazides. Pharmacological investigations showed that Bay g 2821 was more potent than furosemide in dogs but less potent in rats. Bay g 2821 did not differ from furosemide in excretion of electrolytes. Further studies showed that Bay g 2821 had an antihypertensive effect in dogs, spontaneously hpertensive rats, and in rats with artificially-induced renal hypertension. Other pharmacological studies did not reveal any other significant effects.

Regional distribution of vascular resistance in two models of experimental renovascular hypertension.

The regional distribution of the peripheral vascular resistance was studied in normotensive and hypertensive Wistar rats. Two models of experimental hypertension were investigated: (I) in 32 animals the right renal artery was constricted by a silver clip (two-kidney Goldblatt hypertension); (II) in 46 animals the left kidney was removed and the right renal artery was clipped as in the first group (one-kidney Goldblatt hypertension). The normotensive control group comprised 61 untreated animals of the same strain and age. The distribution of cardiac output to 14 tissues was determined by means of the particle distribution technique. The resistance was increased in all regions investigated, a decreased or unchanged resistance was not observed. For most of the investigated tissues the regional resistance was increased exactly in proportion to the total peripheral resistance (TPR). Exceptions to this were found in 2 regions where the change of local resistance deviated from that of TPR: the splanchnic area and the skeletal muscle. In both cases the 2 models differed from each other. In the two-kidney model the increase of resistance in the splanchnic circulation was more intense than in other organs. In contrast, in the one-kidney model the local change of resistance was less than that of TPR. The change of skeletal muscle resistance was not significantly different from the change of TPR in the two-kidney model, while in the one-kidney model the increase of local resistance was significantly higher than that of TPR. It is concluded that the etiology of the abnormal resistance is different in the 2 models investigated and that known extrinsinc pressor factors may play a role in the two-kidney, but not in the one-kidney Goldblatt hypertension.