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)

SK&F 85174 (3-allyl-6-chloro-2,3,4,5-tetra-hydro-1-(4-hydroxy-phenyl)-1-H-3-benzaze pine-7, 8-diol methanesulfonate) the N-allyl derivative of SK&F 82526, a selective postjunctional dopaminergic agonist, retains the potent agonist activity of the parent molecule at the postjunctional dopamine receptor, as evidenced by activation of the dopamine-sensitive adenylate cyclase in rat caudate homogenates (EC50 = 11 nM). However, unlike SK&F 82526, SK&F 85174 is a potent inhibitor of adrenergic neurotransmission. This neuroinhibitory effect can be demonstrated both in isolated vascular preparations, and in in situ preparations in the anesthetized dog measuring both cardiac and vascular neurotransmission. In each of these preparations, the effect of SK&F 85174 can be blocked by the dopamine receptor antagonists, metoclopramide, or 1-sulpiride, showing that its action occurs via activation of prejunctional dopamine receptors. Inhibition of the responses to sympathetic nervous system activation, when combined with the ability to increase renal blood flow by stimulation of postjunctional dopamine receptors, could make SK&F 85174 an effective therapeutic agent for a variety of cardiovascular disorders, including angina pectoris, hypertension, and congestive heart failure.
J Cardiovasc Pharmacol
PMID:Neuroinhibitory effects of SK&F 85174, a novel dopamine receptor agonist. 241 Jul 14

The validity of the hypothesis that cyclic AMP (cAMP) is the 2nd messenger for cell activation was reexamined. Some enzymological aspects of adenyl cyclase (AC) should cause concern: the lack of data on the stoichiometry of cAMP formation in mammalian systems and the unusual enzymatic properties, as well as lack of end-product inhibition and linearity. Furthermore, adenyl cyclase assays may lack precision and accuracy; this may depend on the organ studied. There are also problems of artefactual formation of cAMP during the work-up of cAMP extracts. Thus CrP, Pi, or ATP might influence this process and the actual measurement of cAMP, but solid data are apparently not available. Although a hormone-sensitive AC system has now been reconstituted from pure beta-adrenergic receptor, guanine nucleotide regulatory protein (Ns), and from bovine brain, the sensitivity to isoprenaline was very low and many questions remain--questions about the role of ions and Ns, in particular. The assumption that cAMP is the sole 2nd messenger is questioned since other nucleotides (AMP, ADP) and adenosine may change even more during hormone stimulation, and these compounds can also modulate protein kinase at concentrations often observed in vivo. Doubt over cAMP's role also stems from the observation that basal cAMP levels are sufficiently high to stimulate maximally protein kinase. Discrepancies between cAMP formation and lipolysis during isoprenaline or forskolin stimulation have been observed, and could indicate either compartmentalization of cAMP or alternatively disprove the cAMP hypothesis.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1985
PMID:Is there a role for cAMP and adenyl cyclase? 241 Jul 32

Various physiological changes of platelets and the vascular smooth muscle cell are intimately related. For this reason, in addition to the number of features in common between platelets and vascular smooth muscle and the increased risk for thromboembolic complication in essential hypertension, the platelet was used as an experimental model for the investigation of calcium-dependent functional anomalies associated with hypertension. It is demonstrated, by a sequential analysis of receptor and postreceptor events, that platelets in hypertension exhibit (a) a greater adenylate cyclase-activation and c-AMP-accumulation response to PGE1, (b) an enhanced epinephrine-induced phosphorylation response, and (c) an increased shape change sensitivity to serotonin and epinephrine. The anomalies in these calcium-dependent processes are linked to elevated free calcium concentrations in platelets from hypertensive subjects.
J Cardiovasc Pharmacol 1985
PMID:Platelets and hypertension. 241 69

Activation of adrenoceptors of the alpha 2-subtype can cause an inhibitory or an excitatory response, depending on the cellular system affected. At the plasma membrane, where the extracellular signal is transduced via the alpha 2-adrenoceptor into an intracellular signal, only one transduction process has clearly been established until now by studies in various cellular systems, namely the inhibition of adenylate cyclase. The enzyme inhibition, which is caused by activation of alpha 2-adrenoceptors, is mediated by the inhibitory guanine nucleotide-binding regulatory component (Ni). This component serves as coupler between the activated alpha 2-adrenoceptor and the adenylate cyclase. Selective inactivation of Ni by pertussis toxin not only impairs the alpha 2-adrenoceptor-mediated adenylate cyclase inhibition but also the overall cellular response caused by activation of the receptors. It is suggested that Ni and the adenylate cyclase inhibition mediated by this regulatory protein is the major cellular transduction process following interaction of agonists with alpha 2-adrenoceptors.
J Cardiovasc Pharmacol 1985
PMID:Coupling mechanisms of alpha 2-adrenoceptors. 241 70

In hypertensive cardiac hypertrophy, inotropic responsiveness of alpha and beta adrenergic stimuli is reduced. We have previously shown that hearts from two-kidney, one-clip renal hypertensive rats (RHR) have increased beta-adrenergic receptor density and a defect in the guanine nucleotide regulatory protein, leading to decreased adenylate cyclase activity. In spontaneously hypertensive rats (SHR), beta-receptor density was decreased with no change in adenylate cyclase. In these present experiments, we have shown that the alpha 1-adrenergic receptor changes are in the opposite direction, decreasing in RHR and increasing in SHR. All these changes are reversible within 4 weeks following removal of the clipped kidney in RHR, at which time blood pressure and heart weight have also returned towards normal. Further studies on the excitation-contraction pathway have indicated that c-AMP-stimulated protein kinase is decreased in SHR with no changes seen in RHR. Subcutaneous infusion of epinephrine leads to some increase of cardiac mass associated with decreased beta-adrenergic receptors element and decreased adenylate cyclase activity. However, following angiotensin II infusion, even though hypertrophy is more pronounced, no changes in receptors or cyclase are detected. We conclude that different models of hypertensive cardiac hypertrophy associated with different biochemical defects in the adrenergic excitation response pathway, and that if some of these changes become irreversible, further cardiac deterioration and even heart failure may ensue.
J Cardiovasc Pharmacol 1985
PMID:Excitation-contraction coupling in hypertrophied myocardium. 241 74

The sympathetic nervous activity contributes to the pathophysiology of essential hypertension in an early phase and in younger patients mainly through increased beta-adrenoceptor-mediated functions and in a later phase and in older patients in whom beta-adrenoceptor-mediated functions are blunted, through increased alpha-adrenoceptor-mediated and calcium-influx-dependent vasoconstriction. Intracellular free calcium concentration is elevated in platelets of hypertensive patients and relates directly to the degree of their blood pressure, likely reflecting increased intracellular calcium concentration in vascular smooth muscle cells. A sympathetic factor is suggested further by the enhanced alpha 1-and alpha 2-adrenoceptor-mediated and calcium influx-dependent, vasoconstriction both of which are normalized by antihypertensive treatment in parallel with a normalization of intracellular free calcium and of the increased adrenaline sensitivity of platelets. The higher sensitivity to adrenaline for thrombin-induced calcium increases in platelets of hypertensive patients indicates potentiation of calcium influx (and mobilization from intracellular stores) by adrenaline, a mechanism that is mediated by alpha 2-adrenoceptors. As this effect is more pronounced in younger patients, increased adenylate cyclase sensitivity may prevail in the early and alterations in calcium influx-dependent mechanisms in the later phase of essential hypertension. The transition into a hypertensive state with reduced-reflex cardiovascular counterregulation codetermines the antihypertensive effectiveness of calcium antagonists in these patients.
J Cardiovasc Pharmacol 1985
PMID:Adrenoceptors, calcium, and vasoconstriction in normal and hypertensive humans. 241 75

Adrenoceptors of various subtypes mediate the renal functional responses to alterations in efferent renal sympathetic nerve activity, the neural component, and renal arterial plasma catecholamine concentrations, the humoral component, of the sympathoadrenergic nervous system. Under normal physiologic as well as hypertensive conditions, the influence of the renal sympathetic nerves predominates over that of circulating plasma catecholamines. In most mammalian species, increases in efferent renal sympathetic nerve activity elicit renal vasoconstrictor responses mediated predominantly by renal vascular alpha-1 adrenoceptors, increases in renin release mediated largely by renal juxtaglomerular granular cell beta-1 adrenoceptors with involvement of renal vascular alpha-1 adrenoceptors only when renal vasoconstriction occurs, and direct increases in renal tubular sodium and water reabsorption mediated predominantly by renal tubular alpha-1 adrenoceptors. In most mammalian species, alpha-2 adrenoceptors do not play a significant role in the renal vascular or renin release responses to renal sympathoadrenergic stimulation. Although renal tubular alpha-2 adrenoceptors do not mediate the increases in renal tubular sodium and water reabsorption produced by increases in efferent renal sympathetic nerve activity, they may be involved through their inhibitory effect on adenylate cyclase in modulating the response to other hormonal agents that influence renal tubular sodium and water reabsorption via stimulation of adenylate cyclase.
J Cardiovasc Pharmacol 1985
PMID:Neural control of renal function: role of renal alpha adrenoceptors. 241 43

The present study was undertaken to investigate beta-adrenoceptor-adenylate cyclase coupling in a myocardial ventricular membrane preparation and in isolated renal glomeruli of cellophane perinephritis hypertensive rats. Adenylate cyclase activity and [125I]iodocyanopindolol binding were differentially affected in these preparations. In isolated glomeruli of hypertensive rats a reduced intrinsic activity of isoproterenol was associated with an apparent loss of the guanine nucleotide-sensitive high-affinity state of the beta-adrenoceptors, whereas their absolute number was unchanged when compared with the normotensive control rats. On the other hand, in the sarcolemmal preparation of hypertensive rats adenylate cyclase activity, the relative amount of high-affinity states, and the density of beta-adrenoceptors were not different from the respective values in normotensive controls. Experiments performed on isolated glomeruli of rats with unilateral cellophane perinephritis that developed only moderate hypertension provide evidence that the apparent loss of the high-affinity state is a consequence of hypertension, since no difference was observed in glomeruli from the wrapped, as compared with the intact kidney.
J Cardiovasc Pharmacol
PMID:Alterations of the glomerular beta-adrenoceptor-linked adenylate cyclase system in perinephritis hypertension. 241 95

Previous studies have shown that left ventricular (LV) hypertrophy in renal hypertensive rats (RHR) is associated with reduced responsiveness to beta-adrenergic stimulation (isoproterenol) but not to calcium or cardiac glycosides. To determine whether this impairment is restricted to beta-receptor agonists or extended to include other stimulants of the adenylate cyclase system, inotropic responses to glucagon and to vasoactive intestinal peptide (VIP) were determined in isolated paced hearts (Langendorff preparation) from RHR and strictly matched sham-operated controls. The response (delta peak LV +dP/dt) to both agonists was significantly reduced in RHR, whether expressed in absolute value or in percent of baseline. It averaged 59.3 +/- 19.3 (SE) mm Hg X s-1 in RHR at the highest dose of VIP (15 micrograms) and a perfusion pressure (PP) of 50 mm Hg as compared with 255 +/- 68.4 in controls (p less than 0.01). The responses to glucagon were determined at two levels of perfusion pressure--50 and 80 mm Hg--to determine the influence, if any, of possible alterations in myocardial perfusion on differences between the normal and hypertrophied hearts. At both PP levels the LV +dP/dt response was significantly lower in RHR--+ 374 +/- 103 vs. + 1,026 +/- 166 mm Hg X s-1 (p less than 0.005) or + 120 +/- 5 vs. + 143 +/- 7% of baseline value (p less than 0.02) for PP of 50 mm Hg; and 392 +/- 154 vs. + 1,732 +/- 251 mm Hg X s-1 (p less than 0.01) or + 112 +/- 4 vs. + 160 +/- 2% (p less than 0.001) for PP of 80 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol
PMID:Inotropic responsiveness in hypertensive left ventricular hypertrophy: impaired inotropic response to glucagon and vasoactive intestinal peptide in renal hypertensive rats. 242 81

The most important central autonomic pathways in the control of arterial blood pressure are the baroreceptor reflex pathway and descending pathways from the hypothalamus. Central neurotransmitters in these pathways are L-glutamate, substance P, norepinephrine (NE), gamma-aminobutyric acid, epinephrine, neuropeptide Y, and acetylcholine. At peripheral autonomic neurovascular junctions, there are prejunctional alpha 2- and dopamine-2 receptors, which inhibit NE release, and beta- and serotonin receptors, which stimulate NE release. Postjunctional alpha 1-receptors open sodium channels, open calcium channels via phosphoinositol release, and release intracytoplasmic calcium. Postjunctional alpha 2-receptors, which are extrasynaptic, inhibit adenylate cyclase and also open calcium channels. In animal models of hypertension, changes in alpha-receptor density have been reported. In spontaneously hypertensive rats, increased renal beta- and alpha 2-receptors, respectively, may enhance renin release and cause sodium and water retention. In experimental (renovascular) hypertension, vascular postsynaptic (vasoconstrictor) alpha 1- and alpha 2-receptors are increased. In both models of hypertension, beta-receptors are down-regulated. Selective alpha 1-antagonists, such as indoramin and prazosin, decrease arterial blood pressure by postsynaptic alpha 1-blockade; alpha 2-receptor inhibition of NE release is unaffected so that there is no beta-receptor-mediated tachycardia.
J Cardiovasc Pharmacol 1986
PMID:Alpha-adrenoreceptors in hypertension. 242 93


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