Biomedical subjects

A de Jonge

Publications and source records attributed to A de Jonge.

At least 37 records · Page 2Linked to original sources

PubMed1985

Calcium dependency of vasoconstriction mediated by alpha 1- and alpha 2-adrenoceptors.

A survey is given of the calcium dependency of vasoconstriction mediated by alpha 1- and alpha 2-adrenoceptors. In all species studied and with all drugs investigated, it has been confirmed that alpha 2-adrenoceptor-mediated vasoconstriction is sensitive to calcium entry blockade with calcium antagonists, both in vivo and, under suitable experimental circumstances, also in vitro. The calcium entry promotor (calcium agonist) Bay k8644 appears to behave as a mirror image of the calcium-entry blockers. alpha 1-Adrenoceptor-agonist-induced vasoconstriction shows a differential picture with respect to the dependency of extracellular calcium. Accordingly, the vasoconstriction induced by the alpha 1-agonists cirazoline, (-)-phenylephrine, (+/-)-erythro-methoxamine, and (-)-amidephrine is not primarily dependent upon an influx of calcium, whereas other compounds like St 587 and Sgd 101/75 cause vasoconstriction which is very sensitive to drug-induced calcium entry blockade. It may be possible that different recognition sites of the alpha1-adrenoceptors are involved. In this connection, the calcium-entry promotor Bay k8644 does not simply behave as the mirror image of calcium entry blockers.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1985

Calcium utilization in the vasoconstriction to enantiomers of SK&F 89748-A.

The effects of calcium entry blockade on the vasoconstriction to the selective alpha-1 adrenoceptor agonists d- and I-SK&F 89748-A (1,2,3,4-tetrahydro-8-methoxy-[5-methylthiol] -2-naphthalenamine HCl) in pithed rats and in rat and guinea-pig isolated aortas were studied. The log-dose response curves for the increase in diastolic pressure in pithed rats to i.v. injections of both enantiomers of SK&F 89748-A were maximally shifted only 5-fold to the right after pretreatment of the animals with nifedipine (1 or 3 mg/kg i.a.) or l-verapamil (0.3 or 1 mg/kg i.a.), showing the relative insensitivity of the vasopressor responses to SK&F 89748-A to these calcium entry blockers. In the rat isolated aorta, the contractile responses to the l-enantiomer of SK&F 89748-A were significantly more susceptible to calcium entry blockade with l-verapamil, nifedipine and D600 than the d-isomer. The contractions of the guinea-pig isolated aorta to both isomers proved highly insensitive to calcium slow channel blockade by D600. These results indicate that the contractions of vascular smooth muscle in pithed rats in vivo and of guinea-pig isolated aortas in vitro initiated by the d-and l-isomers of SK&F 89748-A are largely dependent upon processes not requiring an influx of extracellular calcium. The differential sensitivity to calcium entry blockade of the contractile responses of rat isolated aortas to the d- and l-isomers of SK&F 89748-A may reflect different ways of interaction of both enantiomers with the alpha-l adrenoceptor on rat aorta.

Adrenergic alpha-Agonists↗

PubMed1985

Interference of enantiomers of lofexidine with alpha-adrenoceptors.

Some alpha-adrenoceptor-mediated cardiovascular activities and alpha-adrenoceptor binding affinities for (+)- and (-)-lofexidine (Dexlofexidine and Levlofexidine) have been studied in comparison with racemic lofexidine. In pithed normotensive rats, i.v. (-)-lofexidine elicited pressor effects at doses (0.1-30 micrograms/kg), which were approximately 20 times lower than those of the (+)-isomer. Both yohimbine and prazosin in selective amounts of 1.0 and 0.1 mg/kg (i.v., -15 min), respectively, attenuated the increase in diastolic pressure induced by (+/-)-, (+)- and (-)-lofexidine, showing the involvement of alpha 1- as well as alpha 2-adrenoceptors in the vasopressor responses. No differences were observed in the sensitivity of the pressor effects of the (+)- and (-)-enantiomers to blockade by either yohimbine or prazosin. Following i.v. administration to pentobarbitone-anaesthetized normotensive rats, (-)-lofexidine (0.5-5.0 micrograms/kg) was found about 20 times more effective than the dextrorotatory isomer in decreasing mean arterial pressure and heart rate. The increase in heart rate evoked by electrical stimulation in pithed rats was dose-dependently reduced by (+/-)-, (-)- and (+)-lofexidine, the (-)-isomer being about 30 times more potent than the (+)-isomer. Similarly, the electrical stimulation-induced increase in diastolic pressure was also most effectively impaired by the laevorotatory enantiomer of lofexidine. (-)-Lofexidine showed an approximately 9-fold higher affinity than (+)-lofexidine for the alpha 2-adrenoceptor-like binding sites in rat brain membranes identified by [3H]-clonidine and was 4 times more potent at displacing [3H]-prazosin from alpha 1-adrenoceptors. It is concluded that the alpha-adrenoceptor activity of lofexidine resides predominantly in the (-)-isomer. The isomeric activity ratio of the enantiomers of lofexidine (about 20-fold) is higher than normally found for other imidazolines.

Animals↗

PubMed1985

Cardiovascular effects and interaction with adrenoceptors of urapidil.

Urapidil is a novel antihypertensive agent, chemically related to uracil. Its cardiovascular profile was evaluated in a variety of pharmacological models. Urapidil caused a significant decrease of blood pressure in intact rats, both hypertensive (SHR) and normotensive (WKY), as well as in alpha-glucochloralose-anaesthetized cats. Reflex tachycardia was not observed. An analysis in pithed rats showed that urapidil is an alpha-adrenoceptor blocking drug with an obvious selectivity for postsynaptic alpha 1- over alpha 2-adrenoceptors. The alpha 1-adrenoceptor blocking potency proved quantitatively less than that of prazosin. Experiments on isolated aorta preparations and radioligand binding studies confirmed the selectivity of urapidil for alpha 1- over alpha 2-adrenoceptors. The involvement of urapidil with presynaptic alpha 2-adrenoceptors proved negligible. Urapidil proved to possess modest but significant beta 1-adrenoceptor blocking activity, accompanied by a certain degree of intrinsic sympathomimetic activity (TSA) at the level of the cardiac beta 1-adrenoceptors. No significant interaction with vascular beta 2-adrenoceptors was observed. High doses of urapidil caused pressor effects of a probably unspecific nature; neither alpha-adrenoceptors nor 5HT-receptors were involved. When injected into the vertebral artery of the cat, urapidil caused a significant central hypotensive effect which was different from that of clonidine and related drugs, since it could not be blocked by yohimbine (alpha 2-receptor antagonist). Similarly, the modest sedation produced by urapidil in mice remained uninfluenced by yohimbine. The urapidil molecule does not contain any stereoisomers. Accordingly, one and the same molecule possesses the following pharmacodynamic properties: postsynaptic alpha 1-adrenoceptor blockade; weak postsynaptic alpha 2-adrenoceptor blockade; modest but selective beta 1-adrenoceptor blockade with ISA; central hypotensive activity not mediated by central alpha 2-adrenoceptors.

Animals↗

PubMed1984

Effect of pithing on the postjunctional sympatho-inhibitory action of captopril in cats.

Pithing of anaesthetized normotensive cats significantly lowered the arterial blood pressure and augmented plasma renin activity (PRA). Captopril dose-dependently diminished mean arterial blood pressure in both pithed and intact anaesthetized normotensive cats. The hypotensive effectiveness of captopril was most pronounced in pithed cats. Captopril inhibited the hypertensive response to intravenously administered noradrenaline in pithed cats, but did not attenuate the hypertensive response to noradrenaline in intact cats. The results do not exclude that the hypotensive activity of captopril in intact cats may be causally independent of the attenuating effect of converting enzyme inhibition on the postjunctional alpha-adrenoceptor mediated vasoconstriction as observed in pithed animals.

Animals↗

PubMed1984

Interactions between the putative calcium entry promotor Bay k 8644 and pressor responses produced by alpha 1- and alpha 2-adrenoceptor agonists in the pithed normotensive rat.

Interactions between the putative calcium entry promotor Bay k 8644 and both alpha 1- and alpha 2-adrenoceptor mediated increases in diastolic pressure were studied in the pithed normotensive rat. The alpha 2-adrenoceptor mediated pressor responses elicited by B-HT920, TL-99, DP-6,7-ADTN and B-HT958 were potentiated by Bay k 8644, reflected by a leftward shift and an increase in the maximum of the log dose-pressor response curves. The alpha 1-adrenoceptor-mediated effects elicited by cirazoline, methoxamine, (-)-amidephrine, St 587, (-)-phenylephrine and Sgd 101/75 were less enhanced by Bay k 8644. Only a leftward shift of the dose-response curves was observed, which was most pronounced for (-)-phenylephrine and Sgd 101/75. The alpha 1- and alpha 2-adrenoceptor-mediated pressor components of (-)-noradrenaline were similarly distinguished by Bay k 8644 as observed for the selective alpha 1- or alpha 2-adrenoceptor agonists. Effects of Bay k 8644 on the increase in diastolic pressure mediated by B-HT 920, St 587 and cirazoline were also studied after pretreatment with the calcium entry blocker nifedipine. After additional pretreatment with nifedipine the potentiation by Bay k 8644 observed for B-HT 920 and St 587 was more pronounced. The presence of nifedipine had no effect on the interaction between Bay k 8644 and cirazoline. It is concluded that Bay k 8644 behaves as a mirror image of nifedipine.+

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1984

Lack of relationship between intrinsic activity and susceptibility of pressor responses to blockade by nifedipine among the alpha 2-adrenoceptor agonists B-HT 920 and B-HT 958.

Following i.v. bolus injections into pithed normotensive rats, the maximal diastolic pressor responses to B-HT 920 and B-HT 958 amounted to 115 and 35 mm Hg, respectively. Prazosin (0.1 mg/kg, i.v., -15 min) was without effect on the log dose-pressor effect curve of B-HT 958, whereas yohimbine (1 mg/kg, i.v., -15 min) shifted this curve about 30-fold to the right, showing the exclusive participation of alpha 2-adrenoceptors in the vasoconstrictor response to B-HT 958. In doses of 10 and 30 mg/kg, B-HT 958 displaced the log dose-vasoconstrictor effect curve of B-HT 920 approximately 6- and 30-fold, respectively, to the right, illustrating the partial agonism of B-HT 958 at postjunctional vascular alpha 2-adrenoceptors. Despite the marked difference in intrinsic activity of B-HT 920 and B-HT 958, the calcium entry blocker nifedipine exhibited a comparable inhibitory action on the vasopressor responses to both agonists. This finding indicates that partial and full agonism at vascular alpha 2-adrenoceptors are not related to the susceptibility of the initiated pressor response to inhibition by calcium entry blockade.

Adrenergic alpha-Agonists↗

PubMed1984

Inhibitory dopamine receptors on sympathetic neurons innervating the cardiovascular system of the pithed rat. Characterization and role in relation to presynaptic alpha 2-adrenoceptors.

Additional experimental evidence was obtained for an inhibitory function of prejunctional alpha 2-adrenoceptors and/or dopamine receptors located on noradrenergic neurons innervating the heart and resistance vessels of the pithed normotensive rat. Mixed alpha 2-adrenoceptor/dopamine receptor agonists, differing in selectivity towards either receptor type, i.e. N,N-di-n-propyldopamine (DPDA), 2-N, N-di-n-propylamino-6, 7-dihydroxy-1,2,3,4-tetrahydro-naphthalene (DP-6,7-ADTN), B-HT 920 and B-HT 933 (azepexole) were used. In pithed normotensive rats, DPDA (30 and 100 micrograms/kg/min) dose-dependently inhibited the electrical stimulation-induced increase in diastolic pressure, but did not significantly affect the stimulation-evoked increase in heart rate. The inhibition exerted by DPDA was blocked by haloperidol and sulpiride (0.3 mg/kg of each), but not by yohimbine (1 mg/kg), indicating the involvement of dopamine receptors. In this respect, sulpiride and haloperidol were found approximately equipotent. DP-6,7-ADTN (10 and 30 micrograms/kg/min) impaired both tachycardic and vasoconstrictor responses in a dose-dependent manner. Sulpiride (0.3 mg/kg) only partially restored the DP-6,7-ADTN-depressed stimulation-evoked increase in diastolic pressure, whereas yohimbine (1 mg/kg) alone was without effect. The combination of both antagonists completely prevented the inhibition caused by DP-6,7-ADTN. On the other hand, yohimbine (1 mg/kg), but not sulpiride (0.3 mg/kg), selectively antagonized the DP-6,7-ADTN-induced inhibition of stimulation-evoked tachycardia. B-HT 920 (1, 3 and 10 micrograms/kg/min) very effectively reduced the increase in diastolic pressure and heart rate caused by electrical stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗

PubMed1984

Effect of chronic elevation of plasma calcium concentration by PTH or vitamin D3 on blood pressure and hypotensive activity of nifedipine in rats.

The influence of a chronically elevated total plasma calcium concentration on blood pressure and heart rate was investigated in conscious normotensive rats. The plasma calcium concentration was elevated by continuous subcutaneous infusion with parathormone (PTH) after parathyreoidectomy, and by oral treatment with vitamin D3. In both groups an elevated blood pressure was observed at the 1st day of treatment only. Blood pressure was returned to pretreatment values from the second day of treatments onwards. No significant changes in heart rate, due to hypercalcaemia, were observed. In hypercalcaemic rats, the calcium entry inhibitor nifedipine proved more potent in reducing blood pressure than in normocalcaemic control animals. Hydralazine was equipotent in reducing blood pressure in both groups. It is suggested, that the vasoconstrictor effects of a chronically elevated total plasma calcium concentration in conscious rats does not obviously result in a chronically elevated blood pressure, but rather in an enhanced sensitivity of the blood pressure towards calcium entry blockade.

Animals↗

PubMed1984

Quantitative relationships between alpha-adrenergic activity and binding affinity of alpha-adrenoceptor agonists and antagonists.

Quantitative relationships between in vitro affinity for alpha 1- and alpha 2-adrenoceptors (specific binding sites in rat brain membranes of [3H]prazosin and [3H]clonidine, respectively) and in vitro and in vivo alpha 1/alpha 2-adrenoceptor agonist/antagonist activities were derived for a series of 11 alpha-adrenergic antagonists and 35 agonists of dissimilar chemical structure. For the antagonists, the alpha 1/alpha 2-binding selectivity ratio most significantly correlated with the functional alpha 1/alpha 2-blocking selectivity ratios assessed in vitro (rabbit isolated pulmonary artery: antagonism of alpha 1-adrenoceptor-induced vasoconstriction and alpha 2-adrenoceptor-evoked facilitation of transmitter release) and in vivo (antagonism of alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats). These results show that the in vitro alpha 1- and alpha 2-adrenoceptor binding affinities of the antagonists provide adequate information concerning their functional alpha 1- and alpha 2-adrenoceptor blocking potencies against agonists. For the agonists, the central, alpha 2-adrenoceptor-elicited, hypotensive activity was not correlated with alpha 1-adrenoceptor binding affinity but was most significantly described in terms of affinity for alpha 2-adrenoceptors and a parabolic dependence on log P' (octanol/buffer; pH 7.4; 37 degrees C). The relevance of log P' in the regression is explained by the difference in accessibility to the membrane-bound alpha 2-adrenoceptors in the radioligand displacement experiments and the central medullary (hypotensive) alpha 2-adrenoceptors in the intact animal. In contrast, the affinity parameters for alpha 1- and alpha 2-adrenoceptors were found to be poor descriptors of the hypertensive potency of the agonists in which alpha 1- and alpha 2-adrenoceptors are known to play a role. The correlations in which the individual binding parameters and the combination of both variables were included reached only a moderate significance level.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1984

Effect of salbutamol and the PDE-inhibitor RA 642 on the clonidine withdrawal syndrome in rats.

The effect of continuous subcutaneous infusion of clonidine and the influence of concomitant treatment with salbutamol as well as the acute effects of the PDE-inhibitor RA 642 on heart rate and blood pressure of conscious normotensive rats were studied. The severity of the cardiovascular clonidine withdrawal symptoms was positively related to the amount of clonidine infused during treatment. Concomitant infusion of salbutamol (12 mg/kg/day) and clonidine (300 microgram/kg/day) attenuated the clonidine withdrawal tachycardia in conscious normotensive rats. No difference existed in the isoprenaline induced tachycardia in pithed normotensive rats, 8-14 h after cessation of infusion with clonidine (300 microgram/kg/day) and saline, clonidine and salbutamol (12 mg/kg/day), or saline alone. The PDE-inhibitor RA 642 (12 mg/kg, i.p.) aggravated the clonidine withdrawal syndrome in conscious normotensive rats. These data may indicate that long-term treatment with clonidine induces a hyperactivation of the adenylate-cyclase/cAMP-system.

Albuterol↗

PubMed1984

Invariable susceptibility to blockade by nifedipine of vasoconstriction to various alpha 2-adrenoceptor agonists in pithed rats.

The sensitivity of the increase in diastolic pressure brought about by the selective agonists of alpha 2-adrenoceptors, B-HT 920, B-HT 933, xylazine, UK-14,304, M-7, TL-99 and DP-6, 7-ADTN in pithed normotensive rats to blockade by the calcium entry inhibitor nifedipine has been investigated. To exclude any participation of vascular alpha 1- and beta 2-adrenoceptors, as well as cardiac beta 1-adrenoceptors, in the pressor responses, the study was made after treatment of the pithed rats with prazosin (0.1 mg kg-1) and (-)-propranol (1 mg kg-1). Without exception, the preferential agonists of alpha 2-adrenoceptors elicited vasoconstrictor responses which were susceptible to inhibition by nifedipine (0.03-1 mg kg-1) in a dose-dependent manner regardless of the differences in intrinsic activity of the compounds. The pressor activity was almost completely abolished after 1 mg kg-1 of nifedipine. The results show that vasoconstriction induced in pithed rats by various selective stimulating agents of postjunctional vascular alpha 2-adrenoceptors is invariably and equally sensitive to attenuation by nifedipine. This susceptibility of alpha 2-adrenoceptor-mediated vasoconstriction to impairment by blockade of calcium entry is not dependent on the nature, the potency or the efficacy of the agonist.

Adrenergic alpha-Agonists↗

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

Effect of age on the prejunctional alpha-adrenoceptor-mediated feedback in the heart of spontaneously hypertensive rats and normotensive Wistar Kyoto rats. Evidence for a physiological role of prejunctional alpha 2-adrenoceptors.

The prejunctional alpha 2-adrenoceptor-mediated feedback in the heart of pithed young and adult spontaneously hypertensive rats (SHR) and corresponding normotensive Wistar Kyoto rats (WKY) was studied. After electrical stimulation of the sympathetic outflow from the spinal cord to the heart, B-HT 920 induced an inhibition of the cardiac response, which was significant at stimulation frequencies up to 1 Hz in young SHR and WKY and up to 2 Hz in the adult animals. Rauwolscine produced a potentiation of the cardiac response to electrical stimulation in SHR, which was significant from 0.2-10 Hz in young SHR and from 0.1-10 Hz in adult SHR. In young WKY, rauwolscine did not potentiate the increase in heart rate to sympathetic nerve stimulation, whereas in adult WKY alpha 2-adrenoceptor blockade by rauwolscine significantly potentiated the cardiac response to electrical stimulation at frequencies in the range of 0.2-10 Hz. In SHR the potentiation of the cardiac response to sympathetic nerve stimulation by rauwolscine was much stronger than in WKY. These results suggest that in adult animals the prejunctional alpha 2-adrenoceptor mediated feedback is more developed than in young rats. In contrast with young WKY, a significant endogenous feedback can be demonstrated in adult WKY. In SHR, however, the physiological role of prejunctional alpha 2-adrenoceptors is much more important.

Aging↗

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

Hypotensive and alpha-adrenergic activities of 2-(2,3,6-trichlorophenylimino) and 2-(2,3-dichloro-6-methylphenylimino) imidazolidine, two potent derivatives of clonidine.

1 alpha-Adrenergic activities (hypotension, bradycardia, sedation) and affinities of clonidine and two newly substituted derivatives, 2-(2,3,6-trichlorophenylimino)imidazolidine (I) and 2-(2,3-dichloro-6-methylphenylimino)imidazolidine (II), were determined in various in vitro and in vitro models.2 In anaesthetized normotensive rats, the intravenous -log doses (mol/kg) of clonidine, compound I and II required to decrease mean arterial pressure by 20% were 7.96, 8.39 and 7.79, respectively, and to reduce heart rate by 20% were 7.85, 8.23 and 7.91, respectively. Comparable potencies were obtained in vagotomized rats. Following vertebral arterial infusion of clonidine, compound I and II into anaesthetized cats, the -log doses for 20% diminution in mean arterial pressure were 8.72, 9.17 and 7.92, respectively.3 In pithed normotensive rats, the intravenous -log doses (mol/kg) of clonidine, compound I and II required to elevate diastolic pressure by 50 mmHg were 7.49, 7.80 and 8.04, respectively, whereas 50% of the maximal inhibition of electrical stimulation-induced tachycardia was obtained at -log doses of 8.20, 8.25 and 8.34, respectively.4 In mice, the intraperitoneal -log doses (mol/kg) needed for a prolongation of the hexobarbitone-induced loss of the righting reflex by 100% were 6.51, 6.55 and 6.60 for clonidine, compound I and II, respectively.5 Compounds I and II displayed a higher affinity for alpha(1)- and alpha(2)-adrenoceptors than clonidine, identified in rat cerebral membranes by [(3)H]-prazosin and [(3)H]-clonidine.6 The results show that 2,3,6-trisubstituted derivatives of clonidine are potent alpha-adrenoceptor stimulants. This new class of congeners may have potential for pronounced hypotensive activity following systemic application. It is not likely that among members of this series, hypotensive potency can be separated from sedative activity.

Adrenergic alpha-Agonists↗