Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dopexamine hydrochloride (DPX) is a dopamine analog and it possesses agonistic action at DA-1 receptors and beta 2-adrenoceptors. It also is a weak agonist at DA-2 receptors. In the present study, we have examined the anatomical localization of DPX binding sites in rat kidney and their functional significance in terms of the renal effects of this compound. In receptor-ligand binding studies, [3H]-DPX was found to bind specifically to sections of rat kidney in a time (maximum binding at 60 min), temperature (optimal temperature 25 degrees C) and concentration (highest specific/non-specific ratio at 2 nmol/l) dependent manner. Autoradiographic studies revealed the presence of [3H]-DPX binding sites in renal tubules, glomerulus and various layers of small and large blood vessels. Inhibition studies with SCH 23390, ICI 118.551 and 1-sulpiride showed that DPX binds primarily to DA-1 receptors in tubules, only to beta 2-adrenoceptors in glomerulus and to beta 2-adrenoceptors, DA-1 and DA-2 receptors in blood vessels. Also, DPX caused concentration related increases in cyclic AMP levels in rat kidney membrane particles, which could be completely abolished by a combined presence of SCH 23390 and propranolol suggesting that both binding sites of DPX are linked to adenylate cyclase. In functional studies DPX (1 microgram/kg.min for 30 min) produced a modest fall in blood pressure, pronounced tachycardia and slight but significant increase in renal blood flow (11%). These responses were accompanied by increases in urine output (97%), urinary sodium excretion (89%), and fractional excretion of sodium (132%). There was no change in glomerular filtration rate. Propranolol pretreatment abolished DPX-induced hypotension and tachycardia but seemed to potentiate the natriuretic responses to DPX. On the other hand, SCH 23390, a DA-1 receptor antagonist completely abolished DPX-induced hypotension, natriuresis and diuresis without affecting tachycardia. These results indicate that (1) DPX binds predominantly to DA-1 receptors in renal tubules, to beta 2-adrenoceptors in glomerulus and to beta 2-adrenoceptors, as well as DA-1 and DA-2 receptors in renal blood vessels (2) DPX stimulates cAMP formation in the kidney by activating both DA-1 and beta 2-adrenoceptors and (3) DPX produces natriuresis and diuresis by selectively activating DA-1 receptors located on renal tubules.
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PMID:Biochemical, autoradiographic and pharmacological evidence for the involvement of tubular DA-1 receptors in the natriuretic response to dopexamine hydrochloride. 167 60

Radioligand binding studies have demonstrated convincingly the coexistence of beta 1 and beta 2 adrenoceptors in the human heart. Both subtypes are involved in the increase in tissue levels of cyclic adenosine monophosphate in isolated, electrically driven, human right atria and in the activation of adenylate cyclase in human cardiac membrane preparations. In isolated, electrically driven strips of human right atria, isoproterenol increased contractile force through stimulation of both beta 1 and beta 2 adrenoceptors, while the selective beta 2-adrenoceptor agonist, procaterol, caused its positive inotropic effect predominantly through beta 2-adrenoceptor stimulation. Norepinephrine, however, increased contractile force solely via beta 1-adrenoceptor stimulation. In this preparation, dobutamine also acted as a full agonist, producing a positive inotropic effect through stimulation of both beta-adrenoceptor subtypes. Dopexamine hydrochloride, on the other hand, having an approximately 10-fold greater affinity for right atrial beta 2 than for beta 1 adrenoceptors, acted as a partial agonist (maximal positive inotropic effect: about 30% that of isoproterenol). Similar effects have been obtained in human right and left ventricular strips; thus, there can be no doubt that cardiac beta 2 adrenoceptors can contribute to the positive inotropic effects of beta-adrenoceptor agonists in the human heart. Besides mediating positive inotropic effects, right atrial beta 2 adrenoceptors may be involved in the regulation of heart rate since, in healthy volunteers, the selective beta 2-adrenoceptor antagonist, ICI 118,551, was more potent than the selective beta 1-adrenoceptor antagonist, bisoprolol, in antagonizing isoproterenol-induced tachycardia, when both antagonists were administered in doses that selectively occupied more than 90% of beta 2 and beta 1 adrenoceptors, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The functional importance of beta 1 and beta 2 adrenoceptors in the human heart. 290 Jun 1