Dihydropyridines with potent hypotensive activity prepared by the Hantzsch reaction

Loev, Bernard; Ehrreich, Stewart J.; Tedeschi, Ralph E.

doi:10.1111/j.2042-7158.1972.tb08919.x

Cited by 41 publications

(9 citation statements)

References 3 publications

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“…For this purpose, SK&F 24260 was chosen because it is a long-acting and potent hypotensive drug 10 having rather little cardiodepressant action. 1112 In the five dogs that received a single injection of SK&F 24260 (30 jug/kg), the systolic and diastolic blood pressures clearly were lower than those of untreated dogs (series 1 experiments), 74 ± 9 and 33 ± 6 mm Hg as against 133 ± 12 and 63 ± 9 mm Hg in the untreated dogs.…”

Section: Series 4: Modification Of the Effects Of Methoxamine By A Vamentioning

confidence: 99%

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Role of the peripheral vasculature in changes in venous return caused by isoproterenol, norepinephrine, and methoxamine in anesthetized dogs.

Imai¹,

Satoh²,

Taira³

1978

Circulation Research

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SUMMARY We studied effects on venous return of a-and /8-adrenergic agonists in anesthetized dogs. Blood from the superior and inferior venae cavae (venous return) was drained at the level of the tricuspid valve into a reservoir, from which blood was pumped into the right atrium at a constant rate. Isoproterenol infused into the ascending aorta or the right atrium increased the venous return and heart rate and decreased systemic blood pressure. The increase in venous return produced by isoproterenol given into the right atrium was not significantly different from that produced by isoproterenol administered into the ascending aorta, although the increase in heart rate was more marked with the latter route of administration. Norepinephrine infused into the ascending aorta increased the systemic blood pressure, venous return, and heart rate. Methoxamine infused into the ascending aorta increased the systemic blood pressure and decreased the venous return but produced no change in heart rate. Isoproterenol increased the venous return even when the sinoaortic baroreceptor reflex was eliminated. Propranolol abolished the increase in venous return caused by isoproterenol and reversed the increase in venous return caused by norepinephrine. The results suggest that a decrease in venous resistance mediated through a j8-adrenergic mechanism is important in increasing venous return, whereas an increase in venous resistance mediated through an a-adrenergic mechanism is responsible for a decrease in venous return.REFLEX augmentation of sympathetic tone by carotid sinus hypotension 1 " 3 or stimulation of the lumbar sympathetic nerves 4 causes an increase in venous return which has been attributed to an increase in venous tone. "3 Intravenous injection of epinephrine or norepinephrine also increases venous return, 5 " 7 and this also has been attributed to an increase in venous tone or to a decrease in venous capacitance.6 ' 7 Kaiser et al. 6 observed, in dogs on cardiopulmonary bypass, that isoproterenol, epinephrine, and phenylephrine all increase venous return. They interpreted the increased venous return induced by epinephrine and phenylephrine as being due to venoconstriction mediated by a-adrenergic stimulation and the increase in venous return caused by isoproterenol as also due to venoconstriction mediated by venous /?-adrenergic receptors. Green 8 also observed that isoproterenol increased venous return in dogs on right heart bypass. However, as opposed to the explanation given by Kaiser et al.,6 Green suggested that the increase in venous return caused by isoproterenol resulted in large part from dilation of venous resistance vessels.In view of the present state of our knowledge of vascular mechanisms and adrenergic receptors in- Received March 9, 1977; accepted for publication June 9, 1978. volved in changes in venous return induced by sympathomimetic amines, we designed the present experiments. For this purpose, we used the openloop method in which the cardiac input was held constant, and examined the effects on ...

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Section: Series 4: Modification Of the Effects Of Methoxamine By A Vamentioning

confidence: 99%

“…9 We also investigated how the actions of these three sympathomimetic amines would be modified by elimination of the baroceptor reflex, by /8-adrenergic receptor blockade by propranolol, or by reduction of vascular tone by a vasodilator drug, SK&F 24260. 10 …”

mentioning

confidence: 99%

Role of the peripheral vasculature in changes in venous return caused by isoproterenol, norepinephrine, and methoxamine in anesthetized dogs.

Imai¹,

Satoh²,

Taira³

1978

Circulation Research

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“…SK&F 24260 (1,4-dihydro-2,6-dimethyl4-(2-trifuorm elt hylphenyl)-3,5-pyridinedicarboxylic acid diethyl ester) is a potent hypotensive drug thought to act by direct vasodilatation (Loev, Ehrreich & Tedeschi, 1972). In anaesthetized dogs hypotension was caused by intravenous doses of 10,ug/kg while hypotension and tachycardia persisted for 4-8 h following the oral administration of doses of 1 mg/kg to hypertensive conscious dogs.…”

Section: Introductionmentioning

confidence: 99%

HYPOTENSIVE AND VASODILATOR ACTIONS OF SK&F 24260, A NEW DIHYDROPYRIDINE DERIVATIVE

Fielden¹,

Owen²,

Taylor³

1974

British J Pharmacology

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1 The blood pressure of conscious normotensive, Goldblatt-hypertensive and genetichypertensive rats and normotensive dogs was lowered by SK&F 24260 (1,4-dihydro-2,6-dimethyl-4-(2-trifluormethylphenyl)-3,5-pyridinedicarboxylic acid diethyl ester). 2 Tachycardia always accompanied the hypotension. In rats propranolol abolished the tachycardia but in dogs there was only a small reduction in the heart rate response. 3 In conscious dogs there was an increase in left ventricular output and a marked fall in total peripheral resistance. 4 SK&F 24260 dilated resistance vessels in rat hindquarters. Dilatation was caused by doses of SK&F 24260 some 50 times smaller than those of hydrallazine. 5 In preparations of cat skeletal muscle and intestinal vascular beds SK&F 24260 selectively dilated resistance vessels in preference to capacitance vessels and resembled hydrallazine rather than papaverine which has no such selectivity. 6 Pre-capillary sphincter vessels were also dilated by SK&F 24260. Changes in fluid equilibrium caused by SK&F 24260 were consistent with selective dilatation of resistance vessels.

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“…In the present study in addition to nitroglycerin, 3 vasodilators, i.e., verapamil, trimetazidine, and 3,5-dicarbethoxy-2,6-dimethyl-4-(2-trifluoromethyl-phenyl)-1,4-dihydro pyridine (SK&F 24260) (13,14) were used, since in the previous studies (7,8) …”

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confidence: 99%

Differential effects of nitroglycerin, trimetazidine, verapamil and SK&F 24260 on venous return as revealed by the open-loop method in the dog.

1980

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Abstract-To obtain detailed information concerning the effects of different vaso dilators on venous return, experiments were carried out on 28 dogs by the use of the open-loop method. Blood from the superior and inferior venae cavae was drained at the level of the tricuspid valve into a reservoir, from which blood was pumped into the right atrium at a constant flow rate. Changes in reservoir volume reflected a total blood shift from the experimental dog and indicated changes in venous return. Drugs were administered into the ascending aorta. Nitroglycerin (1-10 pg/kg) decreased systemic blood pressure, total peripheral resistance and venous return but scarcely altered heart rate. Trimetazidine (0.3-3 mg/kg) decreased systemic blood pressure, total peripheral resistance, venous return and heart rate. Verapamil (10-100 ug/kg) decreased systemic blood pressure, total peripheral resistance and heart rate, and increased venous return. SK&F 24260 (1-10 fig/kg) decreased systemic blood pres sure, total peripheral resistance and increased venous return. Only high doses (10 30 pg/kg) of SK&F 24260 reduced heart rate. Rigorous measurements of systemic output showed that nitroglycerin (10 pg/kg), trimetazidine (3 mg/kg), verapamil (100 pg/kg), SK&F 24260 (10 pg/kg) produced no change in this parameter. SK&F 24260 increased venous return even when sino-aortic baroreceptor reflex was eliminated, ruling out reflex venoconstriction as a possible cause of the increased venous return. The results suggest the following: [1] Vasodilators like SK&F 24260 and verapamil increase venous return by decreasing arterial and/or venous resistance. [2] If the effect which increases venous capacitance prevails over the effect which decreases ar terial and/or venous resistance, venous return is reduced as is the case of nitroglycerin and trimetazidine.Nitroglycerin reduces the left ventricular end-diastolic pressure and volume (1-4), and such is considered to be one of mechanisms responsible for the antianginal action of nitro glycerin (1, 2, 4-6). The reduction in these 2 parameters is thought to be due mainly to a decrease in venous return (3, 4). Thus, it was of interest to investigate the effect on venous return of other vasodilators used for prevention of attacks of angina pectoris. In previous studies (7,8) we demonstrated that some of vasodilators increased venous return whereas others decreased it. However, in those studies we measured venous return by noncannulating type flow probes of electromagnetic flow meters placed at the superior and the inferior vena cava in anesthetized open-chest dogs and did not control cardiac input (the closed-loop method). Thus, it was hardly discernible whether the observed change in venous return by a certain vasodilator would be due to its effect on vasculature or on the heart. Most

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Dihydropyridines with potent hypotensive activity prepared by the Hantzsch reaction

Cited by 41 publications

References 3 publications

Role of the peripheral vasculature in changes in venous return caused by isoproterenol, norepinephrine, and methoxamine in anesthetized dogs.

Role of the peripheral vasculature in changes in venous return caused by isoproterenol, norepinephrine, and methoxamine in anesthetized dogs.

HYPOTENSIVE AND VASODILATOR ACTIONS OF SK&F 24260, A NEW DIHYDROPYRIDINE DERIVATIVE

Differential effects of nitroglycerin, trimetazidine, verapamil and SK&F 24260 on venous return as revealed by the open-loop method in the dog.

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