Vasodilatory effects of adenosine A2 receptor agonists CGS 21680 and CGS 22492 in human vasculature.

The vasodilatory effects of the adenosine analogs, 5'-N-ethylcarboxamidoadenosine (NECA), 2-[p-(2-carboxyethyl)phenethyl amino]-5'-N-ethylcarboxamidoadenosine (CGS 21680) and 2-[(2-cyclohexylethyl)amino]adenosine (CGS 22492) in human coronary, internal mammary artery and saphenous vein were examined in vitro. All produced concentration-dependent relaxations in arterial as well as venous rings contracted with 35 mM KCl. The concentration-response curves for NECA and CGS 21680 were parallel in the coronary. The adenosine A2 receptor antagonist, 9-chloro-2-(2-furyl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine (CGS 15943A) significantly attenuated the relaxing response to the adenosine analogs in coronary artery. Although NECA and CGS 22492 were equally as effective at the highest concentration administered (both achieving approximately 70% relaxation at 10(-4) M) NECA (EC50 = 1.25 +/- 0.11 microM) induced greater vasodilation at lower concentrations than CGS 22492 (EC50 = 11.27 +/- 1.53 microM). CGS 21680 was the least potent of the agents tested achieving only 44% relaxation at 10(-4) M (EC50 = 4.71 +/- 0.46 microM). Coronary artery appeared to be more responsive than internal mammary artery or saphenous vein which displayed only marginal relaxation to these agents.

Protein kinase C and phospholipase C in adenosine receptor-mediated relaxation in coronary artery.

The effect of adenosine, 2-chloroadenosine (CAD), and 5'-(N-ethylcarboxamido)-adenosine (NECA) on the contraction produced by phorbol 12,13-dibutyrate (PDB) was investigated in porcine coronary artery in vitro to determine whether adenosine receptor-mediated relaxation was linked to protein kinase C. Also, the coronary relaxation produced by adenosine and NECA in KCl-contracted coronary rings was investigated before and after treatment with the phospholipase C inhibitor neomycin to examine a possible link between phospholipase C and adenosine receptor-mediated relaxation. Ring segments of coronary artery were suspended in organ baths for measurement of isometric force. PDB (10 nM-1 microM) caused concentration-dependent contraction, and this response was significantly attenuated by pretreatment with the protein kinase C inhibitor staurosporine (200 nM) but not 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (10 microM). Treatment of rings with either adenosine, CAD, or NECA (100 microM) significantly attenuated the PDB-induced contraction, whereas treatment with either sodium nitroprusside (SNP; 1 microM) or isoproterenol (Isop; 1 microM) did not affect the contraction produced by PDB. The attenuation of the PDB-induced contraction by adenosine and its analogues was blocked by prior treatment of the coronary rings with 8-phenyltheophylline (10 microM). In a separate series of experiments, pretreatment of rings with the phospholipase C inhibitor neomycin (1 mM) resulted in a significant attenuation of the relaxing response to both adenosine and NECA while having no significant effect on the relaxation-response to SNP or Isop. These results provide indirect evidence that adenosine receptor-mediated relaxation in porcine coronary artery may be linked to modulation of protein kinase C and phospholipase C.

G proteins subserve relaxations mediated by adenosine receptors in human coronary artery.

The coupling of the human coronary adenosine receptor to a G protein was investigated in vitro. Hearts were obtained from accidental death victims and the left anterior descending coronary artery (LAD) was taken for experimentation. Cholera toxin (CT) and pertussis toxin (PT) ADP-ribosylated proteins with Mr of 45, 49 (CT), and 41 (PT) kDa. Both processes were sensitive to GTP gamma S. In LAD rings contracted with KCl, adenosine (ADO) and its analogs 5'-N-ethylcarboxamidoadenosine (NECA) and 2-chloroadenosine (CAD) produced concentration-dependent relaxation. These concentration-response curves were shifted to the right significantly in the presence of the competitive ADO receptor antagonist, 8-phenyltheophylline (8-PT), indicating the involvement of ADO receptors. Treatment with NaF/AlCl3, which uncouples G protein-mediated responses, caused significant attenuation of the relaxation responses to ADO, NECA, and CAD. When the rings were incubated with CT, there was an attenuation of the relaxations produced by ADO, CAD, NECA, and isoproterenol (ISOP). Incubation with PT resulted in significant inhibition of the relaxations induced by ADO, NECA, and CAD. The results provide evidence for the presence of CT- and PT-sensitive G protein(s) subserving the relaxing adenosine receptors in human coronary artery.

Inhibition of adenylate cyclase attenuates adenosine receptor-mediated relaxation in coronary artery.

This study was designed to evaluate whether the adenylate cyclase inhibitor 2',5'-dideoxyadenosine (DDA) would attenuate the relaxation produced by adenosine analogs in order to provide functional evidence in support of the working hypothesis that adenosine receptor-mediated relaxation of coronary artery involves adenylate cyclase. Rings from porcine left anterior descending coronary artery were mounted in organ chambers for measurement of isometric force. Rings contracted with KCl (30 mM) relaxed in a concentration-dependent manner to 2-chloroadenosine (CAD), 5'-N-ethylcarboxamidoadenosine (NECA), isoproterenol, sodium nitroprusside (SNP) and forskolin. Treatment of coronary rings with DDA (50 microM) significantly attenuated the relaxation produced by CAD, NECA, forskolin and isoproterenol, but had no effect on the relaxation response to SNP. The nucleoside transport inhibitor dilazep (10 microM) completely reversed the inhibitory effect of DDA on the relaxation produced by forskolin and CAD, whereas dilazep only partially reversed the DDA inhibition of NECA-induced relaxation. In a membrane preparation from porcine coronary artery CAD, but not NECA, increased cyclic AMP production in a GTP-dependent manner. DDA significantly decreased basal cyclic AMP production and also decreased CAD-, forskolin-, GTP- and NaF-stimulated cyclic AMP production. These results provide functional and biochemical evidence in support of the working hypothesis that adenosine receptor-mediated coronary relaxation involves adenylate cyclase. Furthermore, the results from this study suggest that the signaling mechanisms responsible for adenosine receptor-mediated coronary relaxation are more complicated than a single receptor coupled with adenylate cyclase because 1) dilazep completely reversed the inhibitory effect of DDA on the CAD relaxation but not the NECA relaxation, and 2) NECA did not increase cyclic AMP production.

Adenosine receptor-mediated coronary artery relaxation and cyclic nucleotide production.

We investigated the involvement of adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) in adenosine (ADO) receptor-mediated coronary artery relaxation. Rings from left anterior descending coronary artery, with the endothelium mechanically removed, contracted with prostaglandin F2 alpha and relaxed in a concentration-dependent manner to ADO, 2-chloroadenosine (CAD), l-N6-(2-phenylisopropyl)adenosine (R-PIA), and 5'-(N-ethylcarboxamido)adenosine (NECA). These relaxations were blocked by addition of the ADO receptor antagonist 8-(sulfophenyl)theophylline (8-SPT), indicating ADO receptor involvement. In an endothelium-free membrane preparation, ADO, CAD, and R-PIA all stimulated adenylate cyclase activity in a concentration-dependent manner, and these responses were blocked by 8-SPT. The increase in adenylate cyclase activity produced by ADO, CAD, and R-PIA was completely dependent on the presence of guanosine 5'-triphosphate, suggesting G protein involvement. Surprisingly, NECA and CGS-21680 did not increase adenylate cyclase activity. Unlike atrial natriuretic factor, neither NECA, CAD, R-PIA, nor ADO increased guanylate cyclase activity, suggesting that cGMP is not involved in ADO receptor-mediated relaxation. Data presented in this study support the hypothesis that ADO receptor-mediated coronary artery relaxation may involve cAMP; however, the inability of NECA and CGS-21680 to stimulate adenylate cyclase suggests that the ADO receptor-signaling mechanisms in coronary artery may be more complicated than agonist interaction with a single adenylate cyclase-coupled A2 adenosine receptor.

Effects of CGS-15943A on the relaxations produced by adenosine analogs in human blood vessels.

The antagonistic effects of CGS-15943A on the relaxations produced by adenosine and its analogs in human blood vessels were investigated in vitro. Donor hearts were the source of coronary arteries, whereas the internal mammary arteries and saphenous veins were obtained from patients undergoing coronary bypass surgery. Adenosine and its analogs, 5'-N-ethylcarboxamidoadenosine (NECA) and 2-chloroadenosine (CAD), produced concentration-dependent relaxations in KCl-contracted coronary rings. CGS-15943A antagonized, significantly, the relaxations produced by adenosine, NECA and CAD in coronary arteries. Similarly, the adenosine receptor antagonist, 8-phenyltheophylline (8PT, 10-mumol/l), caused a significant attenuation of the relaxing responses to adenosine, NECA and CAD in coronary arteries. In rings obtained from internal mammary arteries and saphenous veins, adenosine, NECA and CAD all produced concentration-dependent relaxations. These relaxations were smaller in magnitude than those obtained in coronary arteries, and were slightly greater in rings contracted with 10 mumol/l prostaglandin F2 alpha (PGF2 alpha) as compared to 35 mmol/l KCl. However, the mammary arteries and saphenous veins relaxed completely in response to 100 mumol/l papaverine. CGS-15943A (10 mumol/l) did not antagonize the relaxing effects of adenosine and its analogs in these vessels. The results show that coronary arteries are more responsive than mammary arteries or saphenous veins to the relaxing effects of adenosine analogs and that these relaxing responses are dependent on the contracting agent. Furthermore, CGS-15943A demonstrated antagonism of the adenosine response in coronary arteries.

Fluoride produces endothelium-dependent relaxation and endothelium-independent contraction in coronary artery.

NaF produced endothelium-dependent relaxation and endothelium-independent contraction in porcine, bovine, canine and human coronary artery rings precontracted with either KCl or prostaglandin F2 alpha. For practical reasons the porcine coronary artery was selected to investigate the mechanisms responsible for these responses. Methylene blue, indomethacin, N-ethylmaleimide, pertussis toxin and cholera toxin all significantly attenuated the endothelium-dependent relaxation caused by fluoride. Pretreatment with deferoxamine had no effect on relaxation and superoxide dismutase/catalase potentiated the relaxation produced by fluoride. Fluoride also contracted vessels with or without the endothelium to equal tension levels and had no apparent relaxing effect on basal tone. The contraction produced by fluoride was significantly attenuated by pertussis toxin and cholera toxin; however, none of the other agents examined significantly altered contraction. Bradykinin also caused endothelium-dependent relaxation and this response was significantly attenuated by methylene blue but not indomethacin. Therefore, fluoride appears to relax the arteries by releasing an endothelium-derived relaxing factor similar to that released by bradykinin (methylene blue sensitive) and one or more prostanoid type endothelium-derived relaxing factor(s) (indomethacin sensitive). Furthermore, fluoride relaxation and contraction may be guanine nucleotide-binding regulatory protein-mediated based on sensitivity to the guanine nucleotide-binding regulatory protein modulators.

Relaxation by adenosine and its analogs of potassium-contracted human coronary arteries.

The present study was an attempt to characterize the adenosine receptor in human coronary arteries, and to establish the dependence of the relaxations mediated by this receptor on a functional endothelium. Human coronary arteries were obtained from organ donors. Adenosine and its analogs (5'-N-ethyl-carboxamido-adenosine, NECA; N6-L-phenylisopropyladenosine, L-PIA; 2-chloroadenosine, CAD), all inhibited the contraction induced by 25 mmol/l KCl in a concentration-dependent manner and the order of potency was found to be: NECA greater than CAD greater than L-PIA greater than adenosine. These relaxations were antagonized by 8-phenyltheophylline (8PT). At higher concentrations of KCl, the relaxations were attenuated. In rings which relaxed in response to endothelium-dependent relaxing agents (bradykinin and A23187), NECA and CAD produced relaxations similar to those produced in rings which did not show endothelium-dependent responses. The results suggest that the coronary adenosine receptor (probably A2) mediates relaxations which may not be dependent on the relaxing function of the endothelium.

Adenosine receptor-mediated relaxation in coronary artery: evidence for a guanyl nucleotide-binding regulatory protein involvement.

The involvement of a guanine-nucleotide-binding regulatory protein (G protein) in the relaxing responses to adenosine receptor agonists was investigated in bovine coronary vessels. Ring segments of left anterior descending artery branches were suspended in organ baths for measurement of isometric tension. The adenosine analogs, 5'-N-ethylcarboxamidoadenosine (NECA) and 2-chloroadenosine (CAD) caused concentration-dependent relaxations of coronary rings contracted with KCl. The relaxing effects of NECA and CAD were antagonized by the adenosine receptor antagonist 8-phenyltheophylline indicating the involvement of an adenosine receptor. In a separate series of experiments, incubation with cholera toxin inhibited the relaxing responses to NECA, CAD and isoproterenol but not those produced by sodium nitroprusside. Treatment with forskolin did not reduce the relaxing responses to NECA or CAD. N-ethylmaleimide and NaF/AlCl3 caused significant inhibition of the relaxations produced by both NECA and CAD. Incubation with pertussis toxin was without effect on relaxations induced by NECA and CAD. These results provide evidence for the involvement of G protein (possibly stimulatory G proteins) in the relaxing effects mediated by the bovine coronary artery adenosine receptor.

Evidence for adenosine receptor-mediated hyperpolarization in coronary smooth muscle.

The effects of adenosine and its analogues, 5'-N-ethyl-carboxamidoadenosine (NECA) and 2-chloroadenosine (CAD), were studied on resting membrane potential of bovine coronary artery. The resting membrane potential averaged -51 +/- 1 mV. KCl (50 mM) caused a significant decrease of the resting membrane potential (-30 +/- 1 mV). In separate series of experiments suffusion of the arterial strips with adenosine, NECA, or CAD, at concentrations of 10(-5)M, produced significant increases in resting membrane potential (-68 +/- 1, -80 +/- 2, and -88 +/- 4 mV, respectively). The hyperpolarizing responses to adenosine, NECA, and CAD appeared to have been mediated by an adenosine receptor, since they were blocked by the adenosine receptor antagonist, 8-phenyltheophylline (10(-5) M). The data suggest that activation of an adenosine receptor can result in hyperpolarization of coronary smooth muscle cells.

Effects of adenosine analogs and ouabain on rhythmicity in human coronary artery.

The effects of adenosine receptor agonists and ouabain on rhythmicity were studied in coronary arteries obtained from 12 human donors. Ring segments of left anterior descending coronary arteries were suspended in organ baths for measurement of isometric tension. Prostaglandin F2 alpha (PGF2 alpha:10 microM) produced tonic contractions followed by phasic relaxations. The phasic relaxations were completely abolished by either 100 nM ouabain or 50 mM KCl and changed to tonic contraction. The rhythmicity was also inhibited in K+-free medium. The adenosine analogs, 5'-N-ethylcarbo-xamidoadenosine (NECA) and 2-chloroadenosine (CAD) caused a concentration-dependent relaxation of the maximum force, minimum force, and decreased the frequency of rhythmicity. In rings that did not show phasic activity in response to PGF2 alpha, NECA and CAD produced concentration-dependent relaxation of the tonic contraction. Prior treatment with ouabain (100 nM) prevented the relaxing response of these compounds and the development of rhythmicity. Our data show that PGF2 alpha-induced rhythmicity in human coronary arteries could be inhibited by ouabain, alterations in K+ concentrations and by adenosine analogs. The relaxations produced by adenosine analogs could also be inhibited by ouabain.

Roles of calcium and the endothelium in the relaxations produced by 5'-N-ethylcarboxamidoadenosine (NECA).

The aim of the present investigation was to evaluate the endothelium dependency in the relaxations by the adenosine analog, 5'-N-ethylcarboxamidoadenosine (NECA), and the requirement for extracellular calcium in endothelium-dependent and independent relaxations. In prostaglandin F2 alpha (PGF2 alpha)-contracted bovine coronary arteries with intact endothelium, bradykinin produced relaxations in calcium medium but not in calcium-free medium. Removal of the endothelium abolished the relaxing response to bradykinin. In calcium medium, NECA produced similar relaxations in coronary arteries with intact and mechanically disrupted endothelium. The relaxation-response curves for NECA were shifted to the right in parallel in calcium free medium. Sodium nitroprusside produced concentration-dependent relaxations which were endothelium-independent. Removal of calcium from the bathing medium caused partial but significant attenuation of these relaxations. The results indicated that in bovine coronary artery, relaxations induced by NECA were endothelium-independent. Also bradykinin-induced relaxations are totally dependent on calcium whereas the endothelium-independent relaxing agents such as NECA and sodium nitroprusside require calcium only partially for their relaxations.

Effects of felodipine and verapamil on transmission in the isolated superior cervical ganglion of the rat.

The effects of Ca2+ channel blockers verapamil and felodipine on transmission in the isolated superior cervical ganglion and conduction in the cervical sympathetic nerve trunk of the rat were examined by recording compound postganglionic action potentials as indexes of ganglionic transmission. Both verapamil and felodipine blocked ganglionic transmission but only at high concentrations, verapamil being more effective in this regard than felodipine. Increasing (from 2.2 to 4.4 mM) or decreasing (from 2.2 to 0.4 mM) Ca2+ concentration did not significantly affect the inhibitory action of these agents. Neither agent had any significant effect on conduction of compound action potential along the preganglionic cervical sympathetic nerve trunk. The results suggest that the observed ganglionic blocking effects of these drugs are apparently unrelated to Ca2+ channel blockade.

Biochemical and pharmacological characterization of ganglionic dopamine receptors.

The presence and the subtype of dopamine receptors in sympathetic ganglia were investigated. Using dopamine as well as preferential agonists and antagonists for the DA-1 and DA-2 receptor subtypes, we have studied dopamine receptors in both dog and rat sympathetic ganglia. Dopamine, fenoldopam, a DA-1 receptor agonist, and quinpirole, a DA-2 receptor agonist, caused significant inhibition of ganglionic transmission. The inhibitory action of quinpirole was selectively antagonized by the DA-2 receptor antagonist S-sulpiride but not by the DA-1 receptor antagonist R-sulpiride. In contrast, the inhibition of ganglionic transmission produced by fenoldopam was antagonized by R-sulpiride but not S-sulpiride. The selective DA-1 receptor antagonist, SCH 23390 did not alter the inhibitory effect of fenoldopam at the ganglia. Dopamine and fenoldopam increased vascular but not ganglionic cyclic AMP. The increase in vascular cyclic AMP was antagonized by the DA-1 receptor antagonists SCH 23390 and R-sulpiride. Quinpirole caused a modest but significant decrease in ganglionic cyclic AMP, sensitive to blockade by S-sulpiride. These results show that dopamine and selective DA-1 and DA-2 receptor agonists inhibit ganglionic transmission by activating two distinct subtypes of dopamine receptors located on sympathetic ganglia.

Effect of dopamine receptor activation on ganglionic transmission and cyclic AMP levels in the stellate ganglia and renal arteries of the dog.

By using selective dopamine (DA) receptor agonists and antagonists, we have demonstrated previously the presence of DA-2- and DA-1-like DA receptors in the stellate ganglia of the dog. Activation of either DA-2- or DA-1-like receptors by quinpirole or fenoldopam, respectively, leads to inhibition of ganglionic transmission. In the present study we have examined the involvement of DA receptor subtypes in the action of DA on ganglionic transmission. Inasmuch as stimulation of DA receptors is linked to the activation (DA-1) or inhibition (DA-2) of the enzyme adenylate cyclase, we have also measured the accumulation of cyclic AMP (cAMP) for biochemical characterization of ganglionic DA receptors. In isolated stellate ganglia treated with phentolamine and propranolol, DA caused concentration-dependent inhibition of ganglionic transmission as evidenced by reductions in the amplitude of the evoked postganglionic compound action potentials. The inhibitory effect of DA on ganglionic transmission was antagonized by both the DA-1 receptor antagonist, R-sulpiride, and the DA-2 receptor antagonist, S-sulpiride. However, the more potent and selective DA-1 receptor antagonist, SCH-23390, failed to antagonize the DA-induced inhibition of ganglionic transmission. Isolated stellate ganglia were also utilized for the measurement of cAMP. Neither DA nor the selective DA-1 receptor agonist, fenoldopam, caused any significant changes in cAMP, suggesting the lack of an adenylate cyclase-linked DA-1 receptor in the ganglia. On the other hand, beta adrenoceptor activation by isoproterenol produced a 3-fold increase in cAMP content of the stellate ganglia.(ABSTRACT TRUNCATED AT 250 WORDS)

Activation of DA1 receptors by dopamine or fenoldopam increases cyclic AMP levels in the renal artery but not in the superior cervical ganglion of the rat.

In the isolated superior cervical ganglion of the rat, activation of either DA1 or DA2 receptors leads to inhibition of ganglionic transmission. Using dopamine as well as relatively selective dopamine receptor agonists and antagonists we have performed electrophysiological as well as biochemical experiments to study the nature of dopamine receptors in this sympathetic ganglion. Fenoldopam, a selective DA1 receptor agonist caused marked inhibition of the compound postganglionic action potential evoked by stimulation of preganglionic nerve. The inhibitory effect of fenoldopam was antagonized by the DA1 receptor antagonist R-sulpiride but not by the DA2 receptor antagonist S-sulpiride. However, the more potent and selective DA1 receptor antagonist SCH-23390 failed to antagonize ganglion blocking effect of fenoldopam indicating that DA1 receptor in sympathetic ganglia is different from that in blood vessels. The superior cervical ganglion also contains DA2 receptors inasmuch as quinpirole, a DA2 receptor agonist, caused inhibition of ganglionic transmission which was antagonized by S-sulpiride but not by R-sulpiride. The existence of both subtypes of dopamine receptor in the superior cervical ganglion was ascertained further as dopamine itself caused inhibition of ganglionic transmission which was antagonized by either S- or R-sulpiride. Again, however, the DA1 receptor antagonist SCH-23390 failed to antagonize the ganglion blocking effect of dopamine. To characterize further the ganglionic DA1 receptor we sought to demonstrate whether or not ganglionic DA1 receptor is linked to the enzyme adenylate cyclase as is known to be the case for peripheral DA1 or central D1 dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological characterization of dopamine receptors in the stellate ganglia with selective DA1 and DA2 receptor agonists and antagonists.

Experiments were performed with fenoldopam (SKF-82526), a selective DA1 receptor agonist, and quinpirole (LY-171555), a selective DA2 receptor agonist, to determine their actions on ganglionic transmission. Fenoldopam caused significant inhibition of the tachycardia elicited during preganglionic stellate stimulation; however, it did not alter the positive chronotropic responses to postganglionic stellate stimulation, suggesting that the compound exerts its inhibitory action at the ganglia. Electrophysiological experiments in the isolated stellate ganglia showed that fenoldopam produced inhibition of ganglionic transmission as indicated by a significant reduction in the magnitude of the compound postganglionic action potential elicited during preganglionic nerve stimulation. The inhibition of ganglionic transmission produced by fenoldopam both under in vivo and in vitro conditions was antagonized by R-sulpiride and metoclopramide, but not by SCH 23390, S-sulpiride or phentolamine. Quinpirole produced significant inhibition of the tachycardia elicited during both preganglionic as well as postganglionic cardiac sympathetic nerve stimulation. This action of quinpirole was antagonized by RS-sulpiride. In electrophysiological experiments it was discovered that quinpirole caused a significant reduction in the magnitude of the compound action potential elicited during stimulation of preganglionic stellate nerve fibers. This inhibition of ganglionic transmission produced by quinpirole was antagonized by S- but not by R-sulpiride. Although phentolamine antagonized the inhibitory action of quinpirole, it was much less effective than S-sulpiride. Norepinephrine also produced inhibition of ganglionic transmission in the isolated stellate ganglia which was antagonized by phentolamine but not by S-sulpiride. These results demonstrate the presence of two subtypes of specific dopamine receptors in the stellate ganglia.(ABSTRACT TRUNCATED AT 250 WORDS)

Ganglionic dopamine receptors as mediators of the inhibition of neurogenic vasoconstriction produced by fenoldopam.

We have performed experiments to study the action of fenoldopam, a DA1 receptor agonist, on neurogenic vasoconstriction elicited during preganglionic sympathetic nerve stimulation. Infusion of fenoldopam to anaesthetized dogs decreased mean blood pressure and caused significant impairment of hindlimb vasoconstriction produced by preganglionic lumbar sympathetic nerve stimulation. The inhibitory action of fenoldopam on neurogenic vasoconstriction was antagonized by R-sulpiride but not by SCH-23390. However, SCH-23390 was more effective than R-sulpiride in antagonizing the hypotensive action of fenoldopam. These results demonstrate that fenoldopam produces inhibition of vascular sympathetic neurotransmission by activating dopamine receptors located at sympathetic ganglia, and this receptor may not be similar to the vascular DA1 receptor.

Pharmacological analysis of the actions of SKF 82526 on cardiovascular dopamine receptors.

We have performed experiments with SKF 82526, a selective dopamine (DA1) receptor agonist to determine whether this compound would activate either ganglionic and/or central DA receptors. Bilateral hindlimb perfusion was carried out at controlled flow rates and changes in hindlimb perfusion pressure were recorded to evaluate the action of SKF 82526 on vascular resistance in anesthetized dogs. Intracisternal administration of SKF 82526 (10 and 40 micrograms/kg) did not produce any changes in blood pressure, heart rate or hindlimb vascular resistance. When the same doses were administered i.v., SKF 82526 produced hypotension and a decrease in perfusion pressure in the innervated limb, whereas perfusion pressure in the denervated limb was not altered. Intravenous SKF 82526 did not produce any changes in heart rate. When given into the lower abdominal aorta, SKF 82526 caused a dose-dependent decrease in perfusion pressure only in the innervated hindlimb, no significant changes in perfusion pressure occurred in the denervated limb. The hypotensive and the hindlimb vasodilatory actions of SKF 82526 could be antagonized by RS-sulpiride. It was discovered that SCH 23390, a selective DA1 receptor antagonist was most potent in blocking the hypotensive action of i.v. SKF 82526; however, it did not influence the neurogenic hindlimb vasodilation produced by intra-aortic SKF 82526. On the other hand, R-sulpiride, another selective DA1 receptor antagonist significantly antagonized the hypotensive as well as hindlimb vasodilatory actions of SKF 82526. S-sulpiride, a selective DA2 receptor antagonist, was least effective in blocking hypotension and did not influence the hindlimb vasodilatory action.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibitory effect of adenosine on transmission in sympathetic ganglia.

The effect of bath-applied adenosine on transmission in the isolated superior cervical ganglion of the rat was investigated. The compound post ganglionic action potential was recorded as an index of ganglionic transmission. Adenosine and 2-chloroadenosine were equipotent in producing a dose-dependent inhibition of the amplitude of the compound action potential. At the highest concentration tested (1 mM) adenosine and 2-chloroadenosine produced about 30% decrease in the amplitude of the compound action potential. This inhibitory effect was antagonized by theophylline (1 and 100 microM) which by itself had no significant effect on ganglionic transmission. The adenosine uptake blocker dipyridamole (1 and 100 microM) failed to potentiate the inhibitory action of adenosine. Both 4-aminopyridine (20 microM) and high frequencies of stimulation (3, 10 and 20 Hz) were effective in nearly completely abolishing the inhibitory effect of adenosine on ganglionic transmission. The results suggest that the inhibitory effect of adenosine on ganglionic transmission may be the result of activation of presynaptic adenosine receptors in the ganglion.