Studies on the autonomic nervous system with SK&F 92657, a new antihypertensive agent causing direct arterial vasodilatation and beta-adrenoceptor blockade.

The beta-adrenoceptor-blocking properties of SK&F 92657, D,L-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine, were studied in both in vivo and in vitro. The pA2 against isoprenaline tachycardia (beta 1 effect) in isolated guinea pig right atria was 7.16 (6.14-7.87). In contrast, histamine-induced tachycardia was unaffected by SK&F 92657. The pA2 against isoprenaline relaxation of guinea pig tracheal muscle (beta 2 effect) was 7.03 (6.28-7.61). In vivo ED50's against isoprenaline tachycardia (beta 1) and vasodilation (beta 2) in anesthetized cats were 5.7 x 10(-8) and 6.2 x 10(-8) mol/kg, i.v., respectively. Increases in heart rate caused either by activation of autonomic reflexes or by stimulation of efferent cardiac sympathetic nerves were also antagonized by SK&F 92657. The beta-adrenoceptor blockade caused by SK&F 92657 was shown to be competitive both in vivo an vitro and to be equally effective on beta 1- and beta 2-receptor populations. SK&F 92657 was a weak partial agonist in vivo and had only minimal local anesthetic activity. The compound had no direct effect on the functioning of the autonomic nervous system, apart from beta-blockade, but reflexes maintaining homeostasis were reduced because (1) SK&F 92657 is a beta-adrenoceptor antagonist preventing reflex increases in heart rate and cardiac output, and (2) it is a potent vasodilator counteracting reflex vasoconstriction. Postural reflexes were unaffected because SK&F 92657 selectively dilates arterial blood vessels.

Hemodynamic profile of a new antihypertensive agent D,L-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine (SK&F 92657).

The properties of a new antihypertensive agent, SK&F 92657, D,L-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine, have been studied. The compound, given intravenously, subcutaneously, or orally, caused a sustained fall in systemic blood pressure of conscious genetically hypertensive rats, normotensive cats, and renal hypertensive dogs. The fall in blood pressure of genetically hypertensive rats was maintained during 52 days of chronic dosing with no development of tolerance. The hemodynamic effects and mechanism of action of SK&F 92657 were investigated in anesthetized cats and dogs using a variety of techniques. Blood pressure was lowered by a direct vasodilator effect on precapillary blood vessels (arteries, arterioles), particularly in the renal, coronary, and skeletal muscle vasculatures, giving an overall decrease in total peripheral resistance with no significant change in cardiac output. In contrast, SK&F 92657 had no significant effect on capacitance blood vessel (veins, venules) tone or on vascular reactivity to vasoconstrictors and consequently did not cause postural hypotension. The beta-adrenoceptor-blocking actions of the drug prevented reflex increases in heart rate and cardiac output, except in the conscious dog, where vagal control of heart rate was predominant. It was also concluded that SK&F 92657 was not acting by alpha-adrenoceptor blockade, ganglion blockade, or inhibition of angiotensin II responses. A "central" action was unlikely, as SK&F 92657 caused vasodilatation in denervated autoperfused vascular beds.

Effect of tilting on the pressor responses to McN-A-343, a muscarinic sympathetic ganglion stimulant.

1 In anaesthetized cats and dogs treated with mecamylamine, the pressor response to McN-A-343 was increased when the animals were changed from a supine to a head-up, tilted position. This potentiation was not seen in rats. 2 The potentiation of the McN-A-343 pressor response was not affected by propranolol, destruction of the brain, or removal of the intestines, spleen or adrenal glands. It was promptly abolished by applying pressure to the lower half of the tilted animal. No increase in the pressor response to McN-A-343 occurred when cats were tilted head down. The potentiated response in tilted cats was abolished by atropine. 3 The pressor effects of adrenaline, noradrenaline, tyramine and angiotensin in cats treated with mecamylamine were either reduced or unchanged when the animal was changed from the supine to the tilted position. In one cat not treated with mecamylamine in which orthostatic hypotension occurred, tilting potentiated the pressor responses to dimethyl phenylpiperazinium iodide. 4 In cats anaesthetized with chloralose, the reflex pressor response to bilateral carotid occlusion was reduced by tilting. After mecamylamine treatment the residual atropine-sensitive response to carotid occlusion was potentiated when the animal was placed in the tilted position. 5 These results suggest that muscarinic stimulation of sympathetic ganglia by McN-A-343 raises blood pressure by predominantly reducing venous capacity, in contrast to noradrenaline and angiotension which increase blood pressure mainly by arterial vasoconstriction. 6 It is not clear whether this is a general property of sympathetic ganglionic stimulation or is restricted to stimulation of muscarinic sites.

Hospital or home care for the severely disabled: a cost comparison.

A case study of severely disabled patients needing regular mechanical help with breathing following poliomyelitis was set up in 1970 to establish what medical, technical, and social support would be required for home rather than hospital care. In this paper these two care alternatives are considered from an economic point of view and a detailed cost comparison is made between entirely hospital based care and predominantly home care.

Hypotensive and vasodilator actions of SK&F 24260, a new dihydropyridine derivative.

1 The blood pressure of conscious normotensive, Goldblatt-hypertensive and genetic-hypertensive 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.