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Biomedical subjects

B Wilffert

Publications and source records attributed to B Wilffert.

At least 91 records · Page 5Linked to original sources
PubMed1984

Differential effects of the calcium entry blocker D 600 on contractions of rat and guinea-pig aortas, elicited by various alpha-1 adrenoceptor agonists.

Contractions of rat and guinea-pig aortas to the alpha-adrenoceptor agonists I-norepinephrine, cirazoline , St 587, clonidine and Sgd 101/75 and the effect of calcium entry blockade by D 600 on the responses were evaluated. In rat aorta, D-600 (10(-8) to 10(-5) M) effectively and concentration-dependently reduced the maximal responses to St 587, clonidine and Sgd 101/75 (maximal percentage inhibition 84 +/- 2.1, 86 +/- 4.1 and 65 +/- 2.8, n = 5-6, respectively) in contrast to those of I-norepinephrine and cirazoline (maximal percentage inhibition 23 +/- 2.1 and 21 +/- 4.1, n = 6, respectively). Reducing the receptor number on rat aorta by approximately 85% by means of the irreversible blocker dibenamine did not result in a greater sensitivity of norepinephrine-induced contractions toward D 600. Prazosin was found 800 to 1000 times more potent than yohimbine in antagonizing the contractile effects of St 587, clonidine and cirazoline on rat and guinea-pig aortas. No difference existed between the pA2 values of prazosin and yohimbine against the different agonists; the pA2 values of prazosin and yohimbine were significantly higher in rat aorta than those in guinea-pig aorta. The results can be explained by assuming the existence of two different agonist recognition sites on the alpha-1 adrenoceptor on rat aorta, whereas the alpha-1 adrenoceptor on guinea-pig aorta contains one agonist recognition site only. The architecture of the alpha-1 adrenoceptor on rat aorta must therefore be different from that in guinea-pig aorta.

Adrenergic alpha-Agonists↗
PubMed1984

Effects of urapidil on blood pressure and adrenoceptors in various animal models.

The interaction with alpha- and beta-adrenoceptors, and the antihypertensive and hypotensive effects of urapidil were studied in various animal models. Urapidil reduced the mean arterial pressure (MAP) of conscious normotensive and spontaneously hypertensive rates after oral administration. Urapidil antagonized alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed rats, elicited by cirazoline and B-HT 920, respectively. Urapidil itself caused pressor responses of limited magnitude at high doses in pithed rats, which were not blocked by yohimbine, prazosin or ketanserin. Urapidil displayed partial beta 1-adrenoceptor intrinsic activity in pithed rats. Urapidil was more potent in reducing MAP after infusion via the vertebral artery as compared to infusion via the femoral artery of chloralose-anaesthetized cats. The results suggest that urapidil reduces blood pressure via blockade of peripheral vascular alpha-adrenoceptors, and beta-receptor blockade. A centrally mediated hypotension not involving alpha 2-adrenoceptors may contribute to the antihypertensive effect.

Animals↗
PubMed1983

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.) or by the converting enzyme inhibitor captopril (5 mg/kg i.v.) antagonized the vasoconstriction by Sgd 101/75 in pithed rats. The effect of salbutamol was abolished by restoration of the baseline diastolic pressure by infusion of vasopressin. Calcium entry blockade by nifedipine (0.1-3 mg/kg i.v.) and (-)-verapamil (0.3 and 1 mg/kg i.v.) dose dependently inhibited the rise in the diastolic pressure induced by Sgd 101/75 pithed rats. This inhibition could not be attenuated by an infusion of vasopressin. In pithed cats, nifedipine most effectively antagonized the pressor effects of Sgd 101/75. In this respect, Sgd 101/75 is different from other alpha 1-adrenoceptor agonists, which are known to elicit a vasoconstriction which is virtually insensitive to vasodilatory measures and calcium entry blockade. These findings may be explained on the basis of a further subdivision of vascular postjunctional alpha 1-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1983

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. Pilocarpine indirectly activated vascular alpha 1- and cardiac beta 1-adrenoceptors. By using the M-1 antagonist pirenzepine and the mixed M-1/M-2 antagonist dexetimide, pilocarpine was shown to be a mixed M-1/M-2 agonist. Pilocarpine initiated antagonistic effects on intrasynaptic alpha 2-adrenoceptor-mediated pressor responses and not on those triggered by extrasynaptic alpha 2-adrenoceptors. During vasopressin infusion to counteract a possible vasodilator action of pilocarpine, it was demonstrated that pilocarpine indirectly activated alpha 1- and alpha 2-adrenoceptors. The results support the hypothesis that intra- and extrasynaptic alpha 2-adrenoceptors comprise different populations and that the neuronal control of alpha 2-adrenoceptors is mediated by ganglionic M-2 receptors.

Animals↗
PubMed1983

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. This effect was reversed after an infusion with adrenaline. The combination of aldosterone and adrenaline produced full recovery of the increase in diastolic pressure elicited via alpha 2-adrenoceptors in adrenalectomized (18-22 h) animals. The results suggest that circulating adrenaline and aldosterone (or corticosterone) are required for optimal functioning of vascular postjunctional alpha 2-adrenoceptors.

Adrenal Cortex Hormones↗
PubMed1983

Effect of captopril on sympathetic neurotransmission in pithed normotensive rats.

Captopril significantly diminished the basal diastolic blood pressure and the vasopressor response to electrical stimulation of the thoracic-lumbar spinal cord in pithed normotensive rats. The reduction of the hypertensive response to electrical stimulation was more pronounced after bilateral adrenalectomy. Captopril also diminished the vasopressor response to intravenously administered (-)-noradrenaline. Pretreatment of the animals with indomethacin had no effect on the vasopressor response to electrical stimulation and did not affect the sympathoinhibition of captopril. After bilateral nephrectomy, 18-24 h previously, the basal diastolic blood pressure and the vasopressor response to electrical stimulation were reduced and captopril had no additional inhibitory effect on these parameters. In indomethacin-pretreated animals with intact kidneys, restoration of the basal diastolic blood pressure with angiotensin II (AII) completely abolished the sympathodepressive effect of captopril. When the reduction in basal diastolic blood pressure with captopril was prevented by vasopressin, converting enzyme inhibition had no depressive effect on the hypertensive response to intravenously administered (-)-noradrenaline and did not influence sympathetic neurotransmission in animals with intact adrenals. However, a small, but significant reduction of the hypertensive response to electrical stimulation by captopril was still detectable in bilaterally adrenalectomized rats. The results suggest that endogenous AII facilitates sympathetic neurotransmission in vascular smooth muscle of pithed normotensive rats. However, the modulatory action of endogenous AII largely results from an effect on basal arteriolar smooth muscle tone and should, therefore, be considered as non-specific facilitation. Genuine prejunctional facilitation of the sympathetic neurotransmission in vascular smooth muscle can only be observed after bilateral adrenalectomy but this effect of endogenous AII appears of minor significance, at least in pithed normotensive rats.

Animals↗
PubMed1983

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. For DPI about 10- and 100-fold parallel displacements to the right without reduction of the maximum were found following treatment with 1 and 3 mg/kg of nifedipine, respectively. Infusion of vasopressin to counteract the vasodilatory action produced by the calcium entry inhibitors did not significantly change the pattern of interference observed under the conditions of decreased baseline diastolic pressure. The results indicate that alpha 1-adrenoceptor-mediated vasoconstriction in the pithed normotensive rat, which is characterized by its sensitivity to blockade by prazosin and its relative insensitivity to antagonism by yohimbine or rauwolscine, can be subdivided into two distinct processes which are differentially influenced by blockade of calcium entry.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1983

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. administration of (-)-amidephrine was not influenced by pretreatment with propranolol (1 mg/kg, i.v.), reserpine (2 x 5mg/kg in 48 h i.p.) or yohimbine (1 mg/kg, i.v.), but was strongly antagonized by prazosin (0.1 mg/kg, i.v.). In pithed cats, the pressor responses were antagonized by prazosin (1 mg/kg, i.v.) but much less so by yohimbine (1 mg/kg, i.v.). (-)-Amidephrine elicited minor positive chronotropic responses in pithed rats and pithed cats. This tachycardia was not influenced by propranolol (1 mg/kg, i.v.) but was abolished by prazosin (0.1--1.0 mg/kg). The results show that (-)-amidephrine acts as a selective agonist at vascular postjunctional alpha 1-adrenoreceptors in pithed rats and pithed cats. The positive chronotropic effects are attributable to stimulation of alpha 1-adrenoreceptors in the heart.

Adrenergic alpha-Agonists↗
PubMed1983

Cardiovascular effects of dopamine and some methylated and fluorinated derivatives in pithed normotensive rats.

The cardiovascular effects of dopamine, (R)-alpha-methyldopamine, (S)-alpha-methyldopamine, (R)-alpha-fluoromethyldopamine, (R,S)-alpha-difluoromethyldopamine and (R)-alpha-fluoromethyltyramine were characterized in the pithed normotensive rat. The activity on alpha 1-adrenoceptors in the resistance vessels of the pithed rat was identified by prazosin antagonism, on alpha 2-adrenoceptors by rauwolscine antagonism, on beta 1-adrenoceptors by chronotropic effects sensitive to atenolol antagonism and on vascular beta 2-adrenoceptors by potentiation of pressor responses by ICI 118,551. Indirect sympathomimetic effects were studied by reserpine pretreatment and the influence of neuronal uptake by the effect of cocaine on the chronotropic effects of the agents. The alpha-methyl substitution induces pronounced beta 2-agonistic properties especially for the (S)-enantiomer, which also displays some selectivity for alpha 2-adrenoceptors. This selectivity is diminished by the substitution of one fluorine atom in the methyl group. The introduction of two fluorine atoms leads to a reduction in potency on all adrenoceptors studied.

Adrenergic alpha-Agonists↗
PubMed1983

Hemodynamic characterization of pinacidil in rats. Comparison with hydralazine.

Pinacidil (N"-cyano-N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine monohydrate; P1134) is a new vasodilator drug with a direct relaxant effect on vascular smooth muscle. Its hemodynamic properties, in comparison with those of hydralazine, were studied in conscious normotensive and spontaneously hypertensive rats; anesthetized normotensive rats; pithed normotensive rats; pithed normotensive rats subjected to electrical stimulation of the spinal cord. Radioligand binding studies on rat cerebral membranes were carried out to study a possible affinity for pinacidil towards alpha 1- and alpha 2-adrenoceptors, respectively. The observations made in conscious and anesthetized rats suggest that both pinacidil and hydralazine are predominantly arterial vasodilators. In conscious animals reflex tachycardia was elicited by both drugs. Neither pinacidil nor hydralazine possessed substantial affinity for alpha 1- or alpha 2-adrenoceptors, as concluded from radioligand binding studies. Pinacidil interferes with the pressor response to postsynaptic alpha 2-adrenoceptor stimulation in pithed rats, possibly reflecting weak calcium antagonistic activity of the drug. Pinacidil did not interfere with the electrically induced release of noradrenaline from presynaptic sites. All results suggest that pinacidil is a direct-acting arteriolar dilator, which on a molar base is somewhat more potent than hydralazine.

Animals↗
PubMed1983

Re-evaluation of the selectivity of 2-N,N-dimethylamino-5,6-dihydroxy-1,2,3, 4-tetrahydronaphthalene (M-7) as an agonist of postjunctional alpha-2 adrenoceptors in the pithed normotensive rat.

The quality of the postjunctional alpha adrenoceptors involved in the increase in diastolic pressure caused by 2-N,N-dimethylamino-5, 6-dihydroxy-1,2,3,4-tetrahydronaphthalene (M-7) were re-evaluated in pithed normotensive rats. The antagonism by yohimbine (1 mg/kg) was most pronounced, whereas prazosin (0.1 mg/kg) had no effect on the hypertensive responses to low doses of M-7, but clearly attenuated those to the higher amounts (greater than 10 micrograms/kg i.v.). A pretreatment with the combination of both alpha adrenoceptor antagonists markedly depressed slope and maximum of the log dose-pressor response curve to M-7. The selective beta-2 adrenoceptor antagonist ICI 118, 551 caused an enhancement of the pressor effects of the higher doses of M-7 which was most profound after the combined treatment with prazosin and yohimbine. M-7 showed a dose-dependent depressor effect in phentolamine (30 mg/kg)-treated pithed rats of which diastolic pressure was raised by infusion of vasopressin. It is concluded that M-7, in addition to its reported alpha-2 adrenoceptor agonistic properties, stimulates postsynaptic alpha-1 adrenoceptors in higher doses. In pithed normotensive rats, however, M-7 also interacts with vascular beta-2 adrenoceptors giving rise to vasodilatation. This action can strongly interfere with the vasoconstrictor effect of M-7.

Adrenergic alpha-Antagonists↗
PubMed1983

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. McN-A-343, however, was induced by a release of neurotransmitter stimulation of predominantly vascular alpha-1 and cardiac beta-1 adrenoceptors. Both DMCPM and McN-A-343 were characterized with respect to their ability to stimulate muscarinic-1 (M-1) and/or muscarinic-2 (M-2) receptors. To demonstrate the M-1 component the selective M-1 receptor antagonist pirenzepine was used. M-2 receptor activation was identified by means of the muscarinic receptor-induced bradycardia after pretreatment with a high dose of atenolol. DMCPM proved to be a mixed M-1/M-2 agonist, in contrast to McN-A-343 which behaved as a rather selective M-1 agonist. The data led us to formulate the hypothesis that the activation of ganglionic M-1 receptors elicits the stimulation of predominantly alpha-1 adrenoceptors in the vascular wall. Activation of ganglionic M-2 receptors may induce an additional stimulation of vascular alpha-2 adrenoceptors. The increase in heart rate seems to be mediated by beta-1 adrenoceptors only.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1982

Central and peripheral alpha-adrenoceptors.

The recent interest in the characterization and functional, role of alpha-adrenoceptors has prompted us to study the following different, although interdigitated, lines of research: (a) The functional role of calcium ions in the process of vasoconstriction, induced by alpha 2-adrenoceptor stimulation. We have shown in various animal species that the vasoconstriction induced by alpha 2-adrenoceptor stimulation with specific agonists is impaired by various organic and inorganic calcium antagonists. This finding suggests that the influx of extracellular calcium is required in order to enable the occurrence of vasoconstriction, mediated by the stimulation of vascular alpha 2-adrenoceptors. (b) The functional role of cardiac presynaptic alpha 2-adrenoceptors in the bradycardiac effect of clonidine and related congeners. In the pentobarbitone-anaesthetized rat, the stimulation of cardiac presynaptic alpha 2-adrenoceptors appears to be a highly relevant mechanism, which in combination with the facilitation of the vagal reflex bradycardia explains the bradycardiac action of clonidine and related drugs. (c) The possible extrasynaptic location of postsynaptic alpha 2- and beta 2-adrenoceptors in vascular smooth muscle. A comparison of the influence of the blocking potency of selective alpha 1- and alpha 2-adrenoceptor antagonists on the vasoconstrictor and tachycardia effects of catecholamines, either released endogenously or injected via an exogenous route, has suggested that the alpha 2- and beta 2-adrenoceptors are probably located at extrasynaptic sites, whereas the alpha 1-adrenoceptors are rather situated within the synapse. (d) The characterization of alpha-adrenoceptors involved in the central hypotensive and sedative activities of clonidine. Experiments with selective alpha-adrenoceptors blocking agents have revealed that the central alpha-adrenoceptors involved in the hypotensive and sedative effects of clonidine are most likely to correspond to the alpha 2-subtype.

Adrenergic alpha-Agonists↗
PubMed1982

Indications for vascular alpha- and beta-2 adrenoceptors in synapses of the muscarinic pathway in the pithed normotensive rat.

In the pithed normotensive rat the adrenoceptors involved in the hypertensive and tachycardic effects of the indirectly acting sympathomimetic agent tyramine and of electrical stimulation of the spinal cord (TH5-L4 or C7-Th1) were analyzed. The tools used for the identification of the adrenoceptors were the selective alpha-1 adrenoceptor blocking drug prazosin, the selective alpha-2 adrenoceptor antagonist rauwolscine, the beta-1 blocker atenolol and the selective beta-2 adrenoceptor blocking agent ICI 118,551. The participation of vascular alpha-2 adrenoceptors in the pressor response of tyramine was shown. The increase in blood pressure induced by electrical stimulation of the spinal cord (TH5-L4) was used to demonstrate that alpha-2 adrenoceptors were activated via ganglionic muscarinic receptors. The tachycardia evoked by electrical stimulation of the spinal cord (C7-Th1) was not influenced by beta-2 adrenoceptor blockade. It was enhanced, however, by the alpha-2 adrenoceptor antagonist rauwolscine. It is hypothesized that activation of ganglionic nicotinic receptors leads to stimulation of the nearest varicosities interfering with alpha-1 adrenoceptors. However, activation of ganglionic muscarinic receptors may lead to an additional release of neurotransmitter in the more distant varicosities endowed with alpha-2 or beta-2 adrenoceptors.

Animals↗
PubMed1982

The inhibitory effect of newer calcium antagonists (nimodipine and PY-108-068) on vasoconstriction in vivo mediated by postsynaptic alpha 2-adrenoceptors.

In the pithed rat, stimulation of postsynaptic alpha 1 as well as alpha 2-adrenoceptors is known to cause vasoconstriction. The two newer nifedipine-related calcium antagonistic agents nimodipine and PY-108-068 proved potent inhibitors of pressor responses induced by the selective alpha 2-receptor agonist B-HT 920. The maximal pressor effect of B-HT 920 was significantly reduced, whereas the hypertensive effects brought about by selective postsynaptic alpha 1-adrenoceptor stimulation were, but slightly, impaired by nimodipine and PY-108-068 and the maximal increase in diastolic pressure was not affected by the calcium antagonists. Under beta-blockade and suppression of alpha 1-adrenoceptor-mediated vasoconstrictor effects by prazosin, the resulting alpha 2-adrenoceptor-induced vasopressor response to (-)-norepinephrine proved also very sensitive towards the inhibitory action of nimodipine and PY-108-068. In comparison with nifedipine, PY-108-068 was 3.9 and nimodipine 5.1-times more potent with respect to reducing vasopressor responses of B-HT 920.

Animals↗