A study of the selectivity and potency of rauwolscine, RX 781094 and RS 21361 as antagonists of alpha-1 and alpha-2 adrenoceptors.

In a comparative study using various in vivo and in vitro models, the alpha-1/alpha-2 adrenoceptor blocking potencies and selectivities were quantitatively assessed for the purported alpha-2 adrenoceptor selective antagonists rauwolscine, RX 781094 and RS 21361. In pithed normotensive rats, RX 781094 showed direct agonist activity at postjunctional alpha-1 and alpha-2 adrenoceptors and had an indirect tachycardic effect. RS 21361 exhibited but minor actions on diastolic pressure and did not influence heart rate.

Sgd 101/75: cardiovascular effects in various animal preparations; interactions with vascular postjunctional alpha 1- and alpha 2-adrenoceptors.

The effect of the imidazolidine Sgd 101/75 (2-[2-methylindazol-4-imino]-imidazolidine HCl) on blood pressure, as well as its alpha-adrenoceptor agonist activity and affinity for these receptors, were examined in various animal preparations. After both intravenous administration to conscious spontaneously hypertensive rats and intravenous injection or infusion via the vertebral artery in chloralose-anaesthetized cats, Sgd 101/75 (1-10 mg kg-1) elicited pressor responses. Intracisternal application of Sgd 101/75 (1 mg kg-1) to chloralose-anaesthetized cats did not affect blood pressure.

Alpha 1/alpha 2-adrenoceptor agonist selectivity of mono- and dihydroxy-2-N,N-DI-n-propylaminotetralins.

The pressor activities and the identity of the postjunctional alpha-adrenoceptors involved were determined for a series of congeneric mono- and dihydroxy-substituted 2-N,N-di-n-propylaminotetralins and N,N-di-n-propyldopamine (DPDA) following i.v. administration to pithed normotensive rats.

Interaction between dilazep and alpha-adrenoceptors.

Dilazep, 1,4-bis-[3-(3,4,5-trimethoxybenzoyl-oxy)propyl]perhydro-1,4-diazep ine, is a novel antianginal agent with an unusual chemical structure. The drug is a weak calcium antagonist. In pithed rats dilazep (10-100 mg/kg i.

Sgd 101/75 is distinguished from other selective alpha 1-adrenoceptor agonists by the inhibition of its pressor responses by calcium entry blockade and vasodilatation in pithed rats and cats.

The vasopressor effects of the selective alpha 1-adrenoceptor agonist Sgd 101/75 (2-[2-methylindazol-4-imino]-imidazolidine HCl) were analyzed in pithed rats and cats. Vasodilatation by the beta 2-adrenoceptor agonist salbutamol (1 mg/kg i.v.

Calcium-dependency of the pressor responses to selective 5-hydroxytryptamine receptor agonists in pithed rats.

The pressor responses to six selective 5-HT receptor agonists, quipazine, TMFPP, Org 10155, Ru 24969, 5-methoxytryptamine and 5-methoxy-N,N-dimethyltryptamine, were quantified and tested for calcium dependency following i.v. administration to pithed normotensive rats.

Antihypertensive activity and interaction with alpha-adrenoceptors of tibalosine ([1-(2, 3-dihydro-5-benzo-(b)-thienyl)-2-(4-phenyl-butylamino)-1-propanol], CP 804 S) in rat and cat preparations.

The antihypertensive and hypotensive effects and the interaction with postjunctional alpha 1- and alpha 2-adrenoceptors of tibalosine were studied in various animal preparations. Tibalosine (CP 804 S, 1-10 mg/kg) elicited dose-dependent reductions in blood pressure upon i.v.

Differential effect of calcium entry blockers on alpha 1-adrenoceptor-mediated vasoconstriction in vivo.

The effects of the calcium entry blockers nifedipine, (-)-verapamil and the dihydropyridine derivative PY 108-068 were evaluated on the increase in diastolic pressure of pithed normotensive rats caused by the selective alpha 1-adrenoceptor agonists cirazoline, (-)-phenylephrine, (+/-)-erythro-methoxamine, (-)-amidephrine and St 587 [(2-chloro-5-trifluoromethylphenylimino)-2-imidazolidine] as well as by the mixed alpha 1/alpha 2-adrenoceptor agonists clonidine and DPI [(3,4-dihydroxyphenylimino)-2-imidazolidine]. The calcium entry inhibitors (up to 3 mg/kg) caused 3- to 5-fold, parallel rightward shifts of the log dose-pressor effect curves to cirazoline, (-)-phenylephrine, (+/-)-erythro-methoxamine and (-)-amidephrine accompanied by only a slight depression of the maximal pressor response. In contrast, the calcium entry inhibitors produced a dose-dependent profound depression of both maximum and slope of the log dose-pressor response curves to St 587 and clonidine.

Selective stimulation of vascular postjunctional alpha-adrenoreceptors by (-)-amidephrine in rats and cats.

The vasopressor and chronotropic responses of (-)-amidephrine and the receptor types involved were studied in pithed rats of different strains and in pithed cats. The increase in diastolic pressure of pithed rats after i.v.

Role of ganglionic M-1 and M-2 receptors in the neuronal control of the cardiovascular system of the normotensive rat as determined with pilocarpine.

The adrenoceptors involved in the increase in diastolic pressure and heart rate elicited by i.v. administration of pilocarpine to the pithed rat were assessed using as pharmacological tools the alpha 1-adrenoceptor antagonist prazosin, the alpha 2-adrenoceptor antagonist rauwolscine, the beta 1-adrenoceptor blocker atenolol and the beta 2-adrenoceptor blocker ICI 118,551.

Peroxidase secretion from rat lacrimal gland cells in vitro: II. The role of calcium in stimulus-secretion coupling.

The role of calcium in stimulus-secretion coupling in rat lacrimocytes was investigated. Monolayers of lacrimocytes released peroxidase into the incubation medium upon stimulation with calcium ionophore A 23187, L-norepinephrine, L-phenylephrine and tyramine. Our lacrimocyte preparation can be considered free of endogenous catecholamines, because lacrimocytes derived both from normal and from reserpinized rats responded to tyramine with respect to peroxidase secretion.

Peroxidase secretion from rat lacrimal gland cells in vitro. I. Alpha-adrenergic stimulation in the absence of alpha-adrenoceptors.

The identification of alpha-adrenergic receptors and subdivision into alpha 1- or alpha 2-subtypes were studied by measuring the specific binding of the radioligands [3H]-prazosin as well as [3H]-clonidine to membranes prepared from homogenized rat lacrimal glands. The absence of high-affinity binding for [3H]-prazosin as well as for [3H]-clonidine indicates that rat lacrimal glands do not possess a substantial amount of alpha 1- and alpha 2-adrenoceptors. The binding data correspond with the characterization by pharmacological means.

Inhibitors of the angiotensin I converting enzyme as antihypertensive drugs.

Inhibitors of the angiotensin I converting enzyme (captopril, enalapril) offer a new principle in the drug treatment of hypertension and congestive heart failure. The present survey deals with the mode of action of the converting enzyme inhibitors, including possible interference with the renin-angiotensin systems in the kidney, the vascular wall and the brain, with the kallikrein--bradykinin system and with the sympathetic nervous system, at both pre- and postjunctional sites. Furthermore, the haemodynamic pattern as well as the therapeutic applications are discussed, including the most important side-effects, contra-indications, interactions and clinical pharmacokinetic properties.

Interaction between beta 2-adrenoceptor-mediated vasodilation and alpha 1-adrenoceptor-mediated vasoconstriction in the pithed normotensive rat.

With pithed normotensive rats we studied the interaction between beta 2-adrenoceptor-mediated vasodilation and alpha 1-adrenoceptor-mediated vasoconstriction. The selective beta 2-adrenoceptor agonist salbutamol was used to elicit vasodilatation. To induce alpha 1-adrenoceptor-mediated vasoconstriction, the selective alpha 1-adrenoceptor agonists cirazoline, St 587, and methoxamine were used.

Interaction between beta 2-adrenoceptor-mediated vasodilation and alpha 2-adrenoceptor-mediated vasoconstriction in the pithed normotensive rat.

With pithed normotensive rats we studied the interaction between beta 2-adrenoceptor-mediated vasodilation and pressor responses elicited by vasopressin, the selective alpha 2-adrenoceptor agonists B-HT 920 and UK 14,304, and the alpha 2-adrenoceptor-mediated pressor responses of (--)-norepinephrine, tyramine [via neuronally released (--)-norepinephrine], alpha-methylnorepinephrine, and (--)-epinephrine. Salbutamol was used as a selective agonist of beta 2-adrenoceptors. The selective beta 2-adrenoceptor antagonist ICI 118,551 was employed to reveal the intrinsic beta 2-adrenoceptor activation induced by alpha-methylnorepinephrine and (--)-epinephrine, measured as a potentiation of the increase in diastolic pressure.

Differential role of M-1 and M-2 receptors in sympathetic ganglia of the pithed normotensive rat in alpha adrenoceptor-mediated vasoconstriction.

In the pithed normotensive rat the adrenoceptors involved in the hypertensive and tachycardic effects of the muscarinic ganglionic stimulants 1,1-dimethyl-4-carboxypiperidine methylester (DMCPM) and (4-m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium (McN-A-343) were analyzed. The selective alpha-1 adrenoceptor antagonist prazosin, the selective alpha-2 adrenoceptor antagonist rauwolscine, the selective beta-1 adrenoceptor antagonist atenolol and the selective beta-2 adrenoceptor antagonist ICI 118,551 were used as tools for the identification of the adrenoceptors. DMCPM elicited a release of catecholamines which activated vascular alpha-1, alpha-2 and cardiac beta-1 adrenoceptors.

Interaction of clonidine, its methylene-bridged analog, St 1913, and the benzylic hydroxyl-substituted derivative, St 1965, with alpha 1- and alpha 2-adrenoreceptors.

The effects of benzylic hydroxyl substitution on the activity of a close structural analog of clonidine was assessed at alpha 1- and alpha 2-adrenoreceptors both in vitro and in vivo in order to uncover possible differences that this substitution may have on the effects of imidazolines and phenethylamines at adrenoreceptors. In all test systems, the presence of the benzylic hydroxyl group was associated with a consistent and marked decrease in activity. These findings are in agreement with our previous studies with imidazolines having different pharmacological profiles and different physicochemical properties than the clonidine derivatives reported herein.

Hypotensive activity of calcium entry blockers in rats. Relationship with depression of alpha 2-adrenoceptor-mediated vasopressor responses.

The hypotensive activity of a series of calcium entry blockers and various other vasodilators was quantified in pentobarbitone-anesthetized rats. Hypotensive activity was correlated linearly with the potency of these vasoactive agents to depress alpha 2-adrenoceptor-induced pressor responses in pithed rats. However, vasodilatation as such also influenced alpha 2-adrenoceptor-mediated vasoconstrictor processes.

Differential inhibition of alpha 2-adrenoceptor-mediated pressor responses by (+)- and (-)-verapamil in pithed rats.

The inhibitory effects of (+)- and (-)-verapamil on the hypertensive responses brought about by the alpha 2-adrenoceptor agonist B-HT 920 were investigated in pithed normotensive rats. (-)-Verapamil was found to be about 4 times more potent with respect to depressing alpha 2-pressor responses compared with (+)-verapamil. To rule out the effect of 'unspecific' vasodilatation after the administration of the stereoisomers of verapamil, vasopressin was continuously infused into the carotid artery of pithed rats in a separate series of experiments.

Effect of adrenalectomy and demedullation of the adrenals on vasopressor responses to stimulation of postjunctional alpha 2-adrenoceptors.

After adrenalectomy performed 18-12 h previously, the vasopressor responses induced by stimulation of postjunctional alpha 2-adrenoceptors (agonist: B-HT 920) were attenuated in pithed normotensive rats in contrast to pressor responses mediated by postjunctional alpha 1-adrenoceptors (agonist: cirazoline). Aldosterone and desoxycorticosterone both enhanced the vasopressor responses to the alpha 2-adrenoceptor agonist B-HT 920 in adrenalectomized rats, but did not fully restore the effects. Demedullation of the adrenals also attenuated the vasoconstrictor processes evoked by stimulation of postjunctional alpha 2-adrenoceptors 18-22 h later.