Dopamine receptors in human basilar arteries

After phenoxybenzamine (10(-5) M), pretreatment, and in the presence of propranolol (10(-6) M) and indomethacin (2.8 X 10(-6) M), dopamine caused a marked concentration-dependent relaxation of isolated strips of human basilar artery contracted with PGF2 alpha. This effect was mimicked by apomorphine, 6,7-ADTN and SK&F 38393, but N,N-diethyl dopamine, N,N-di-n-propyl-dopamine and 5,6-ADTN caused only slight relaxation. (+)-Butaclamol, cis-alpha-flupenthixol, fluphenazine and haloperidol competitively antagonised the relaxant effects of dopamine, but sulpiride was ineffective in concentrations as high as 1.3 X 10(-4) M. These findings show that the dopamine receptors in the human basilar artery closely resemble those in the smooth muscle of the rabbit isolated mesenteric and splenic arteries, and the dog renal and mesenteric arteries in vivo, but differ from those located presynaptically on sympathetic nerve terminals.     

Pharmacological characterization of the dopamine receptor coupled to cyclic AMP formation expressed by rat mesenteric artery vascular smooth muscle cells in culture.

1. Mesenteric artery vascular smooth muscle cells derived from male Wistar rats and grown in culture were prelabelled with [3H]-adenine and exposed to a range of dopamine receptor agonists and antagonists. Resultant [3H]-cyclic AMP formation was determined and concentration-effect curves constructed, in the presence of propranolol (10-6) M) and the phosphodiesterase inhibitor IBMX (5 x 10(-4) M). 2. Ka apparent values for D1/DA1 dopamine receptor agonists SKF 38393, fenoldopam, 6,7-ADTN, and dopamine were 0.06, 0.59, 4.06 and 5.77 x 10(-6) M respectively. Although fenoldopam and SKF 38393 were more potent than dopamine, they were partial agonists with efficacies, relative to dopamine of approximately 48% and 24% respectively. 6,7-ADTN, in contrast, behaved as a full agonist. 3. Dopamine-stimulated cyclic AMP formation was inhibited in a concentration-dependent manner by the D1/DA1 dopamine receptor selective antagonists, SCH 23390 and cis-flupenthixol (Ki values 0.53 and 36.1 x 10(-1) M respectively). In contrast, the D2/DA2 dopamine receptor selective antagonists, domperidone and (-)-sulpiride, were less potent (Ki values 2.06 and 5.82 x 10(-6) M respectively). Furthermore, the stereoisomers of SCH 23390 and cis-flupenthixol, SCH 23388 and trans-flupenthixol, were at least two orders of magnitude less potent (Ki values 0.14 and 13.2 x 10(-6) M respectively) indicating the stereoselective nature of this receptor. 4. Our results indicate that rat mesenteric artery vascular smooth muscle cells in culture express a dopamine receptor coupled to cyclic AMP formation, which has the pharmacological profile, characteristic of the D1 dopamine receptor subfamily.     

Vasodilator effects of dopaminomimetics in the perfused rat kidney

The renal vascular effects of dopaminomimetics were studied in the isolated perfused rat kidney after pretreatment with 10(-5) M phenoxybenzamine and 10(-5) M sotalol and after contraction of the vascular bed with prostaglandin F2 alpha (10(-7) to 3 x 10(-6) M). Under these conditions, our criterion for vascular dopaminomimetic activity was renal vasodilation, competitively inhibited by d-butaclamol (10(-8) M) but not by 1-butaclamol (3 x 10(-8) M). Dopamine is active at micromolar concentrations (ED50 = 2.53 +/- 0.34 x 10(-6) M). The N-alkylated analogues of dopamine preserve this activity if the alkyl group is a methyl group (epinine) or two n-propyl groups (di-n-propyl-dopamine). The catechol nucleus appears essential for renal vascular dopaminomimetic activity (SK&F 38393, active; p-tyramine, di-n-propyl-m-tyramine and RU 24926, inactive). Bromocriptine reproduces renal dopaminergic vasodilation with an ED50 of 1.3 +/- 0.14 x 10(-6) M. The study of structure-activity relationships of dopaminomimetics relates the vascular dopamine receptor, associated with renal vasodilation, to the dopamine receptor, associated with stimulation of dopamine-sensitive adenylate cyclase.     

Blockade of dopamine receptors in the renal vasculature by isomers of flupenthixol and sulpiride

We studied the renal vascular effects of flupenthixol and sulpiride isomers in the isolated perfused rat kidney in the presence of phenoxybenzamine (10(-5) M) and sotalol (10(-5) M). The vascular bed was contracted with prostaglandin F2 alpha (10(-7) -3 X 10(-6) M) and dose-dependently relaxed with dopamine. Cis-flupenthixol (10(-9)-10(-7) M) antagonized competitively the response to dopamine (apparent pA2 = 8.34 +/- 0.09; mean +/- SD) without affecting papaverine-induced relaxation. Trans-flupenthixol was without effect at 10(-7) M. The dopamine receptor antagonist activities of the sulpiride isomers are low and d-sulpiride is twice as active as 1-sulpiride. Thus, the renal vascular dopamine receptor can be further characterized by the relative antagonist activities of cis-flupenthixol and sulpiride and by a rather low stereospecificity in favor of d-sulpiride.     

Effects of dopamine receptor agonists and antagonists at peripheral neuronal and vascular dopamine receptors in the anaesthetised cat

The potencies of several putative dopamine receptor agonists and antagonists have been determined and compared at neuronal and vascular dopamine receptors in anaesthetised cats. N,N-diethyldopamine and the N,N-di-n-propyl derivatives of 5,6-ADTN (6-amino-5,6,7,8-tetrahydro-1,2-napthalenediol) and 6,7-ADTN (6-amino-5,6,7,8-tetrahydro-2,3-napthalenediol) were, relatively, much more potent agonists than dopamine at neuronal dopamine receptors on the terminals of sympathetic nerves supplying the heart and nictitating membrane than at the vascular dopamine receptors in the mesenteric vascular bed. SK&F 82526 [6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-di ol] showed the reverse profile. Haloperidol, (+/-) sulpiride, cis alpha-flupenthixol, and fluphenazine were much more potent antagonists at neuronal dopamine receptors than at vascular dopamine receptors. The profiles of activity of the agonists and antagonists show that neuronal and vascular dopamine receptors in the cat are different; in addition, the neuronal dopamine receptors in the cat heart and nictitating membrane closely resemble those in the dog femoral vasculature, whereas the vascular dopamine receptors in the cat mesenteric vascular bed are very similar to those in the dog mesenteric circulation.     

Effect of tertatolol and of its metabolites and structural analogues in isolated perfused rat kidney vasculature.

The renal vascular effect of tertatolol and analogues was investigated in isolated rat kidney perfused at constant flow in an open circuit with Krebs-Henseleit solution after vascular tone had been reestablished by bolus injections of serotonin or other vasoconstrictor drugs. Against serotonin-induced vasoconstriction, (+/-)tertatolol (3 X 10(-7)-3 X 10(-5) M) evoked concentration-dependent relaxation (IC 50 = 4.6 +/- 0.4 X 10(-6) M), (-)tertatolol was more active than the racemic and (+)tertatolol was less active. (+/-)Tertatolol competitively antagonized serotonin-induced renal constriction (pA2 = 5.6 +/- 0.2). Tertatolol metabolites (4-OH tertatolol, 4,5-di-OH tertatolol, and sulfoxy tertatolol) were inactive. (+/-)Sotalol and (+/-)nadolol, were also inactive in this model and (-)bunolol induced renal vasodilatation only at concentrations 40 times higher than (-)tertatolol. The renal response to tertatolol was not linked to release of prostaglandins or dopamine or to interaction with the dopamine receptor, since neither indomethacin nor SCH 23390 affected tertatolol-induced renal vasodilatation. Tertatolol also elicited relaxation of N6-cyclohexyladenosine-induced renal vasoconstriction (34 +/- 7% relaxation at 3 X 10(-5) M) but was inactive when renal vascular tone was raised by prostaglandin F2 alpha, angiotensin II, or neuropeptide Y in the presence of norepinephrine.     

The involvement of smooth muscle P2X receptors in the prolonged vasorelaxation response to purine nucleotides in the rat mesenteric arterial bed

1. ATP and adenine dinucleotides can elicit three different types of vasomotor response in the rat mesenteric arterial bed; vasocontraction, rapid relaxation (which may be masked by contraction) and slow and prolonged vasorelaxation. Contraction is mediated by smooth muscle P2X receptors and rapid relaxation by endothelial P2Y receptors. The mechanism of prolonged relaxation is, however, controversial. 2. In the present study, bolus injection of doses of alpha,beta-methylene ATP (alpha,beta-meATP; 5 pmol - 0.5 micromol; P2X receptor agonist) in methoxamine-preconstricted rat isolated mesenteric arterial beds, mimicked the action of ATP, causing contraction (R(max) 76+/-9 mmHg) followed by prolonged relaxation (78+/-11%; t(1/2) 14.6+/-1.5 min). KCl also elicited a biphasic response (R(max) contraction 73+/-8 mmHg; R(max) prolonged relaxation 70+/-6%; t(1/2) 7.7+/-1.9 min). 3. P2X receptor desensitization caused by perfusion with alpha,beta-meATP (10 microM) abolished contraction and prolonged relaxation to doses of alpha,beta-meATP (50 nmol). Rapid relaxation (32+/-7%; t(1/2) 32+/-2 s) was revealed, which was abolished by removal of the endothelium using distilled water. 4. Sodium deoxycholate treatment blocked contractile and prolonged relaxation responses to alpha,beta-meATP, ATP and KCl, whilst distilled water treatment had no significant effect on either phase of the biphasic responses. 5. These data indicate that smooth muscle P2X receptors are involved in both phases of the biphasic response (contraction followed by prolonged relaxation) to purine nucleotides in the rat isolated mesenteric arterial bed. Caution should be applied when using sodium deoxycholate to remove the endothelium because of possible damage caused by the detergent to receptors and/or the vascular smooth muscle.     

Mechanism of action of dopamine on the guinea-pig gastro-oesophageal junction in vitro.

1 The effect of dopamine on longitudinal muscle strips of the guinea-pig isolated gastro-oesophageal junction was compared with the response obtained to phenylephrine, isoprenaline and clonidine. Phenylephrine (5 x 10(-7) to 5 x 10(-5) M) produced a dose-related contraction, whilst dopamine (10(-6) to 10(-4) M) and isoprenaline (5 x 10(-7) to 2 x 10(-5) M) produced dose-related relaxations. Clonidine was ineffective in doses up to 10(-5) M. 5-Hydroxytryptamine (5-HT) produced a contraction. 2 Phenylephrine was antagonized by alpha 1-adrenoceptor antagonists but unaffected by beta-adrenoceptor antagonists, whilst the opposite was the case for isoprenaline. A mixture of alpha- and beta-adrenoceptor antagonists was required to inhibit completely dopamine-induced relaxations. 5-HT (3 x 10(-7) M) was specifically antagonized by methysergide (3 x 10(-6) M). 3 pA2 values for a range of alpha-adrenoceptor and dopamine receptor antagonists were determined against dopamine and phenylephrine. The relative order of potency of the antagonists was the same for both antagonists and was prazosin greater than spiroperidol greater than phentolamine greater than domperidone greater than haloperidol, with pimozide and metoclopramide being inactive. 4 Tyramine caused dose-related relaxations of the gastro-oesophageal strips which were susceptible to the same range of antagonists as dopamine. 5 Cocaine (6 x 10(-6) M) and desmethylimipramine (3 x 10(-7) M) reduced the relaxations induced by dopamine and tyramine but there were quantitative differences in the antagonism. 6 Tissue from reserpine pretreated guinea-pigs was insensitive to tyramine but the response to dopamine was only partly reduced. 7 Histological examination of the strips revealed the presence of smooth muscle but only a sparse adrenergic innervation. 8 The results suggest that dopamine acts partly indirectly and partly directly on postjunctional alpha- and beta-adrenoceptors. There is no evidence for an action on specific dopamine receptors.     

Dopexamine: a novel agonist at peripheral dopamine receptors and beta 2-adrenoceptors.

Dopexamine is an agonist at peripheral dopamine receptors and at beta 2-adrenoceptors. Dopexamine has approximately one-third the potency of dopamine in stimulating the vascular DA1-receptor in the dog, resulting in a fall in renal vascular resistance of 20% at 2.3 X 10(-8) mol kg-1 (i.a.). Prejunctional DA2-receptors are also stimulated by dopexamine, resulting in a reduction of neurogenic vasoconstriction in the rabbit isolated ear artery (IC50 of 1.15 X 10(-6)M) and of neurogenic tachycardia in the cat (ID50 of 5.4 X 10(-8) mol kg-1, i.v.), with a potency six and four times less respectively than that of dopamine. By contrast, dopexamine is approximately 60 times more potent than dopamine as an agonist at the beta 2-adrenoceptor of the guinea-pig isolated tracheal chain, with an EC50 of 1.5 X 10(-6)M. Both dopexamine and dopamine are weak agonists at the guinea-pig atrial beta 1-adrenoceptor over the concentration range 10(-7) to 10(-4) M, but dopexamine has an intrinsic activity of only 0.16 relative to dopamine. Dopexamine does not stimulate postjunctional alpha 1- or alpha 2-adrenoceptors in the canine isolated saphenous vein, whereas dopamine is an agonist, approximately 120 times less potent than noradrenaline. Unlike dopamine and salbutamol, dopexamine does not cause arrhythmias in the guinea-pig isolated perfused heart at doses of up to 10(-5) mol, which is a thousand times the minimum cardiostimulant dose. The combination of agonist properties at peripheral dopamine receptors and at beta 2-adrenoceptors, with little or no activity at alpha- and beta 1-adrenoceptors gives dopexamine a novel pharmacological profile. This may confer advantages over dopamine in the treatment of acute heart failure.     

Effects of dobutamine on isolated canine cerebral, coronary, mesenteric, and renal arteries

The effects of dobutamine on helical strips of isolated canine cerebral, coronary, mesenteric, and renal arteries was investigated. Dobutamine contracted only renal arterial strips under resting condition. When renal and mesenteric arterial strips were partially contracted with prostaglandin F2 alpha (PGF2 alpha), dobutamine caused further concentration-related contraction, while coronary arterial strips were relaxed. Cerebral arterial strips, on the other hand, did not significantly respond to dobutamine. After treatment with 10(-5) M dl-phenoxybenzamine hydrochloride (POB) for 1 h, dobutamine-induced contractions of partially precontracted mesenteric and renal arterial strips were converted to relaxations. Relaxations of coronary arteries were not potentiated by the alpha-antagonist, but were attenuated by treatment with 10(-6) M propranolol and 10(-6) M metoprolol to a similar extent. On the other hand, relaxations of mesenteric and renal arterial strips were not inhibited by metoprolol but by propranolol. Droperidol (3 X 10(-5) M) failed to significantly alter the concentration-response curve for dobutamine. These results suggest that dobutamine causes vasoconstriction mediated by apha-adrenergic receptor and vasodilatation mediated by beta 1- and beta 2-adrenoceptors. Dobutamine does not appear to act on dopamine receptors.     

Alpha2-adrenoceptor antagonists evoke endothelium-dependent and -independent relaxations in the isolated rat aorta.

This study was designed to determine whether the alpha2-adrenoceptor antagonists idazoxan, yohimbine, and rauwolscine cause endothelium-dependent and -independent responses in the rat aorta. Rings of rat aorta, with and without endothelium, were suspended for the measurement of isometric force in modified Krebs-Ringer bicarbonate solution (37 degrees C; aerated with 95% O2 and 5% CO2). The alpha2-adrenoceptor antagonists, in the concentration range of 10(-8)-10(-6) M, relaxed phenylephrine-contracted rings with, but not those without endothelium. alpha2-Adrenoceptor antagonists (3 x 10(-6) M for 1 min) increased the accumulation of cyclic guanosine monophosphate (cGMP) about twofold in the aortas with endothelium. The relaxation and the increased cGMP induced by alpha2-antagonists were attenuated by methylene blue (10(-6) M) and N(G)-nitro-L-arginine (L-NA, 3 x 10(-5) M), whereas propranolol (10(-6) M) did not affect the relaxation. In concentrations >10(-6) M, alpha2-adrenoceptor antagonists relaxed the rat aorta without endothelium. The endothelium-independent relaxation by alpha2-adrenoceptor antagonists was abolished by increased external K+ and reduced significantly by tetraethylammonium (TEA, 10(-2) M, a Ca2+-dependent K+ channel blocker), but not inhibited by glibenclamide (10(-5) M, an ATP-sensitive K+ channel blocker). In the rabbit aorta, only endothelium-independent relaxations were observed with alpha2-adrenoceptor antagonists in the concentration range of 10(-8)-10(-5) M, and these relaxations were not antagonized by TEA. These results suggest that alpha2-adrenoceptor antagonists relax the rat aorta through endothelium-dependent mechanism at lower concentrations and endothelium-independent mechanisms at higher concentrations. The endothelium-dependent relaxations are likely to be mediated by the endothelium-derived relaxing factor (EDRF)/NO pathway because they are associated with the accumulation of cGMP, whereas the endothelium-independent relaxations may be caused by the opening of potassium channels in the vascular smooth muscle.     

Contractile responses to sumatriptan and ergotamine in the rabbit saphenous vein: effect of selective 5-HT(1F) receptor agonists and PGF(2alpha)

Contractile responses to ergotamine, sumatriptan and the novel 5-HT(1F) receptor agonists, LY334370 and LY344864 were examined using the rabbit saphenous vein. Ergotamine (pEC(50)=8.7+/-0.06) was 30 fold more potent than 5-hydroxytryptamine (5-HT) (pEC(50)=7.2+/-0.13) and 300 fold more potent than sumatriptan (pEC(50)=6.0+/-0.08) in contracting the rabbit saphenous vein in vitro. The selective 5-HT(1F) receptor agonists, LY334370 or LY344864 (up to 10(-4) M), did not contract the rabbit saphenous vein. The contractile response to ergotamine in this tissue resulted from activation of both alpha(1) and 5-HT(1B/1D) receptors based on the observation that prazosin (10(-6) M), an alpha-adrenoceptor antagonist, and GR127935 (10(-8) M) a 5-HT(1B/1D) receptor antagonist, dextrally shifted the contractile response to ergotamine. In contrast, prazosin (10(-6) M) did not alter contraction to sumatriptan whereas GR127935 (10(-8) M) was a potent antagonist (-log K(B)=10.0) suggesting that sumatriptan-induced contraction of the rabbit saphenous vein was mediated only by activation of receptors similar or identical to 5-HT(1B/1D) receptors. PGF(2alpha) (3x10(-7) M) produced a modest increase (approximately 5.0 - 10.0% maximum PGF(2alpha) contraction) in saphenous vein force. Precontraction with PGF(2alpha) (3x10(-7) M) dramatically augmented the potency and maximal contractile response to sumatriptan (pEC(50)=7.1) and modestly enhanced the contractile potency of ergotamine (pEC(50)=9.0) in the rabbit saphenous vein. However, PGF(2alpha) (3x10(-7) M) only unmasked a contraction to the 5-HT(1F) receptor agonists when concentrations exceeded 10(-5) M, concentrations considerably higher than their 5-HT(1F) receptor affinities. LY334370 (10(-6) M) pretreatment did not alter contraction to either sumatriptan or ergotamine and a higher concentration (10(-5) M) of LY334370 or LY344864 inhibited contraction to sumatriptan. Thus, activation of 5-HT(1F) receptors will not induce vascular contraction (either alone or following modest tone with PGF(2alpha)) or augment contraction to other contractile agonists in the rabbit saphenous vein.     

Presynaptic alpha-adrenoceptors: do exogenous and neuronally released noradrenaline act at different sites?

The effects of dopamine receptor and alpha-adrenoceptor agonists and antagonists on the stimulation-evoked overflow of radioactivity from strips of dog saphenous vein previously loaded with [3H]-noradrenaline have been examined alone and in combination. In the presence of neuronal and extraneuronal catecholamine uptake inhibitors, noradrenaline (0.1-1 X 10(-6)M) and dopamine (0.01-1 X 10(-6)M) both inhibited the stimulation-evoked overflow of radioactivity. Sulpiride (1 X 10(-6)M) was without effect and prazosin (1 X 10(-7)M) had little effect on stimulation-evoked overflow but yohimbine enhanced it approximately 2 fold; the effect of yohimbine was similar at concentrations of 1 X 10(-7) and 1 X 10(-6)M. Sulpiride abolished the inhibitory effect of dopamine on stimulation-evoked overflow, but was without effect against noradrenaline. When allowance was made for the effects of yohimbine, alone, on overflow, yohimbine (1 X 10(-7)M) had no effect against dopamine and minimal effects against noradrenaline. A similar result was obtained when the concentration of yohimbine was increased to 1 X 10(-6)M. Prazosin did not antagonize the effect of noradrenaline. In the absence of the uptake inhibitors, clonidine (0.01-1 X 10(-5)M) inhibited stimulation-evoked overflow of radioactivity. Yohimbine (1 X 10(-6)M) was without effect on its own and antagonized the effects of clonidine at a concentration of 0.1 X 10(-5)M, but not at 0.01 or 1.0 X 10(-5)M. These findings suggest that dopamine inhibits overflow by stimulating presynaptic dopamine receptors on the terminals of the noradrenergic nerves supplying the dog saphenous vein.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of 5-hydroxytryptaminergic autoreceptors in the rat hypothalamus

5-hydroxytryptamine (5-HT) (3 X 10(-9) to 10(-6) M) produced a concentration-related inhibition of potassium-evoked tritium release from slices of rat hypothalamus preloaded with [3H]-5-HT. The response to 5-HT was unaffected by the presence of yohimbine (10(-6) M), pimozide (10(-7) M), domperidone (10(-7) M) or tetrodotoxin (10(-7) M), indicating that the response was not mediated via alpha 1- or alpha 2-adrenoceptors or dopamine receptors and that the receptors that were involved were located directly on the 5-HT nerve terminal. The 5-HT antagonist metergoline (10(-8) to 3 X 10(-7) M) produced a parallel rightward shift in the concentration-effect curve to 5-HT with no reduction in the size of the maximum response. The pA10 value for metergoline was 6.82 and the slope of the Arunlakshana-Schild plot was not significantly different from 1.0 indicating that it was a competitive antagonist. Methiothepin produced a similar effect to metergoline whilst cyproheptadine and methysergide were less potent as antagonists of 5-HT and were not competitive. Cinanserin was inactive. Thus we have characterized the 5-HT autoreceptor in the rat hypothalamus using a classical pharmacological approach and found that it has more in common with the autoreceptor which we have previously identified in the raphe nuclei of the rat than it has with the 5-HT receptor located on dopamine neuroterminals in the striatum.     

Studies on the effects of viprostol in isolated small blood vessels and thoracic aorta of the rat.

1. The effects of viprostol, prostaglandin E2 (PGE2) and nitroglycerin were studied in basilar artery, small mesenteric artery and the vein parallel to it as well as thoracic aorta of the rat. 2. In KCl-contracted basilar artery, viprostol produced a concentration-related biphasic response, contraction at concentrations less than 3 X 10(-6) M and relaxation at concentrations greater than 3 X 10(-6) M. PGE2 produced a concentration-related contraction while nitroglycerin produced a concentration-related relaxation. 3. In KCl-contracted small mesenteric artery, viprostol produced a biphasic response which was similar to that in the basilar artery. PGE2 produced a contraction and nitroglycerin produced relaxation in a concentration-dependent manner. 4. In KCl-contracted small mesenteric vein, in contrast to basilar and mesenteric artery, viprostol produced only a concentration-related relaxation in the range of 1 X 10(-6) to 1 X 10(-4) M. PGE2 produced a contraction and nitroglycerin produced a concentration-related relaxation. 5. In KCl-contracted thoracic aorta, PGE2 produced a biphasic response, relaxation at concentrations less than 3 X 10(-7) M and a concentration-related contraction at concentrations greater than 3 X 10(-7) M. Viprostol only produced a concentration-related contraction at concentrations greater than 1 X 10(-6) M, which was significantly less in magnitude than the contraction produced by PGE2. Nitroglycerin produced a concentration-related relaxation as seen in the small vessels. 6. In conclusion, the present data demonstrate that viprostol is a vasorelaxant agent which effectively dilates KCl-contracted basilar, small mesenteric artery and vein, but not the thoracic aorta of rat.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relaxation of rabbit aorta by chlordimeform

Chlordimeform N'-(4-choro-O-tolyl)-N,N-dimethyl-formamidine; CDF), an acaracide-insecticide, relaxed helically cut strips of rabbit thoracic aorta and deadventitiated aorta strips. Relaxations by CDF of aorta strips contracted by 5 x 10(-7) M prostaglandin F2 alpha were not altered by the antimuscarinic agent atropine (10(-5) M), the beta-adrenergic antagonist propranolol (10(-5) M), the histamine H2 antagonist cimetidine (2 x 10(-4) M), the dopamine antagonist haloperidol (10(-5) M) or the Na+-K+-ATPase inhibitor ouabain (5 x 10(-6) M). CDF further relaxed deadventitiated strips contracted by 10(-6) M NE or 40 mM potassium and then partially relaxed by 10(-5) M verapamil. CDF (10(-5) M) potentiated contractions caused by the addition of calcium to potassium depolarized strips in zero calcium media, but higher concentrations reduced calcium-induced contractions. The highest CDF concentration (10(-2) M) not only prevented tension increase on calcium addition, but also progressively decreased tension to below baseline levels. The addition of 10(-2) M CDF to aorta strips not contracted by a vasoactive agent decreased resting tension. This relaxation was usually maximal at 10(-3) M and less at 10(-2) M. Thus, CDF relaxes vascular smooth muscle, not by antagonism at the usual vascular relaxant receptors, but by interference with calcium utilization.     

Pharmacological characterization of renal vascular dopamine receptors

We present an in vitro method for studying the renal effects of dopamine in the isolated rat kidney. The organ is perfused in an open circuit and can be maintained satisfactorily for up to 180 min. The responses to dopamine were studied in the presence of phenoxybenzamine (10(-5) M) and sotalol (10(-5) M) while stable renal vasoconstriction was maintained by perfusion with prostaglandine F2 alpha. Dopamine induced dose-dependent renal vasodilation with an ED50 of 2.53 X 10(-6) moles/liter, which was not modified by reserpine pretreatment. (+) Butaclamol but not (-) butaclamol shifted the dopamine dose-response curve to the right in a parallel fashion, indicating competitive antagonism. Haloperidol and sulpiride at concentrations without intrinsic effect on vascular resistance also acted as competitive inhibitors for dopamine. Calculation of empirical pA2 values yielded the following relative potencies for these antagonists: (+) butaclamol greater than haloperidol greater than sulpiride. The renal vascular dopamine receptors are tentatively classified as being of the D1 type.     

Effects of dopamine receptor agonists and antagonists at peripheral neuronal and vascular dopamine receptors in the anaesthetised dog

The interactions between several putative dopamine receptor agonists and antagonists have been examined at neuronal and vascular dopamine receptors in the femoral and mesenteric vascular beds, respectively, of anaesthetised dogs. N,N-di-n- propyldopamine (DPDA) and apomorphine caused vasodilatation in both vascular beds. Cis alpha-flupenthixol, fluphenazine, and sulpiride were much more potent at antagonising DPDA at neuronal than at vascular dopamine receptors. Fluphenazine and sulpiride were as potent against apomorphine as against DPDA at neuronal receptors, but cis alpha-flupenthixol was much less effective. Fluphenazine antagonised the vasodilator effect of apomorphine in the mesenteric vascular bed, but cis alpha-flupenthixol and sulpiride did not, even when used in doses much larger than were effective against DPDA. Further experiments, in dogs pretreated with phenoxybenzamine and propranolol, revealed that cis alpha-flupenthixol, fluphenazine, and sulpiride also antagonised the mesenteric vasodilator effects of dopamine, 2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene, 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene, and 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine, suggesting a common site of action of these drugs and DPDA. Only fluphenazine antagonised responses to apomorphine. The results support the view that neuronal and vascular dopamine receptors in the dog are different. They also show that apomorphine stimulates different receptors from DPDA in the mesenteric vascular bed and, perhaps, in the femoral vascular bed as well.     

Vascular effects of apomorphine and related compounds in the perfused rat kidney

The renal vascular effects of aporphines and related compounds were studied on the isolated perfused rat kidney in the presence of 10(-5) M phenoxybenzamine and 10(-5) M sotalol and after contraction of the vascular bed with prostaglandin F2 alpha (10(-7) -3 X 10(-6) M). Under these conditions, (R)-(-)-apomorphine showed renal dopaminomimetic activity, i.e. renal vasodilation competitively inhibited by (+)-butaclamol (10(-8) M) but not by (-)-butaclamol (3 X 10(-8) M). It had an apparent affinity 25 times higher but a markedly lower intrinsic activity than dopamine. N-n-Propyl and trihydroxylated aporphines were less potent and the mono-10-hydroxylated aporphine was completely inactive. (S)-(+)-Bulbocapnine also showed weak dopaminomimetic activity but tetrahydropapaveroline was devoid of such an effect. (-)-N-(2-Chloroethyl)-norapomorphine (10(-5) M) irreversibly antagonised dopamine-induced renal vasodilation. At concentrations above 3 X 10(-6) M, most aporphines and tetrahydropapaveroline induced additional non-dopamine receptor related renal vasodilation.     

Prejunctional dopamine receptors modulate twitch responses to parasympathetic nerve stimulation in the rabbit isolated rectococcygeus muscle.

Field stimulation of the parasympathetic nerves supplying the rabbit isolated rectococcygeus muscle produced individual twitch responses that were inhibited by dopamine (1 x 10(-8)-1 x 10(-5)M). The twitch-inhibitory effect of dopamine was reversed by haloperidol or sulpiride (1 x 10(-8)-1 x 10(-5)M for either) but not by phentolamine or yohimbine (up to 1 x 10(-4)M). Haloperidol and sulpiride were potent, specific, competitive antagonists of the twitch-inhibitory effect of dopamine; their pA2 values were 8.39 and 7.75, respectively. In contrast, cis alpha-flupenthixol, fluphenazine, bulbocapnine and thioridazine were weak or inactive against dopamine. Concentrations of dopamine that inhibited the twitch response to parasympathetic nerve stimulation had little or no effect on contractions elicited by carbachol or by direct muscle stimulation after abolition of neuronal conduction by tetrodotoxin. Thus, the effects of dopamine on responses elicited by parasympathetic nerve stimulation seem to be exerted at a prejunctional level rather than directly on the smooth muscle. The twitch-inhibitory effect of dopamine was mimicked by epinine, N,N-diethyldopamine, N,N-di-n-propyldopamine, 5,6-ADTN, N,N-di-n-propyl 5,6-ADTN, 6,7-ADTN, apomorphine and Sandoz 27-403. Sulpiride reversed the effects of all these agonists. N,N-di-n-propyl-6,7-ADTN and SK & F 82526 also inhibited the twitch response but their effects were not reversed by sulpiride. SK & F 38393 and DPI had little effect on the twitch response. The pharmacological characteristics of the presynaptic dopamine receptors in the rabbit rectococcygeus muscle show that they resemble those in the cat heart and rabbit ear artery in some respects but there are differences that suggest that the presynaptic dopamine receptors in the rabbit rectococcygeus muscle constitute a specific subgroup of receptors.