Elevation Of Cyclic Adenosine Monophosphate Research Articles

Coffee Intake and Serum Lipids in Men

To the Editor.— Williams et al 1 report a significant elevation in plasma apolipoprotein B associated with coffee intake in excess of two cups per day. The authors also reported that low-density lipoprotein (LDL) cholesterol levels were somewhat elevated while total plasma cholesterol levels correlated poorly with coffee intake. It is unfortunate that other caffeinecontaining substances could not be fully evaluated, for caffeine would appear to be the causative agent involved. Methylxanthines, such as caffeine, are inhibitors of 3′,5′-phosphodiesterase. Caffeine administration, therefore, may result in elevated cyclic adenosine monophosphate levels within adipocytes, thereby prolonging lipolysis initiated under normal metabolic demands. Upon liberation from the adipocyte, fatty acids are transported to the liver, where they are reesterified and the resultant triglycerides packaged for release in very-low-density lipoprotein (VLDL), which also contains apolipoprotein B. Catabolism of VLDL triglycerides results in the production of an intermediate, which accepts cholesterol esters, ultimately becoming LDL.

The genesis of arrhythmias during myocardial ischemia. Dissociation between changes in cyclic adenosine monophosphate and electrical instability in the rat.

It has been proposed that increases in tissue cyclic adenosine monophosphate during ischemia may be responsible for the induction of arrhythmias that occur during the early minutes of ischemia. We have tested this hypothesis using the isolated perfused rat heart with coronary artery occlusion for 30 minutes. In control hearts, after a transient small rise, cyclic adenosine monophosphate content remained close to its preischemic value (3.0 +/- 0.1 nM/g dry weight) throughout the period of occlusion. Eight percent (1/12) of the hearts fibrillated. Ninety-two percent (11/12) of the hearts exhibited ventricular tachycardia, and the mean total number of premature ventricular complexes was 528 +/- 121. Inclusion of epinephrine (1.0 microM) in the perfusion fluid elevated cyclic adenosine monophosphate prior to coronary occlusion (to 10.7 +/- 0.6 nM/g dry weight) and also throughout the ischemic period. It also increased arrhythmias such that 83% (20/24) of hearts fibrillated, 100% exhibited ventricular tachycardia, and the mean number of premature ventricular complexes increased to 747 +/- 86. Inclusion of forskolin (0.2 microM), which stimulates adenyl cyclase independently of the beta-receptor, increased cyclic adenosine monophosphate content to a greater extent than epinephrine, to 14.1 +/- 0.9 nM/g dry weight before the onset of ischemia and to 8.2 +/- 0.4 nM/g dry weight after 30 minutes of ischemia. Despite the large increase in cyclic adenosine monophosphate, there was no increase in rhythm disturbances which were less than those seen in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial membrane function and drug action in heart failure

Calcium lons play a major role in controlling both the electrical and mechanical activity of the heart. These important regulatory functions are affected when calcium moves across cellular membranes, including the sarcolemma and sarcoplasmic reticulum. These membranes are composed of a hydrophobic lipid bilayer, which constitutes a barrier to the flux of ions in which are embedded a number of intrinsic membrane proteins. Some of the latter are involved in the movement of calcium between different regions of the myocardial cell. The “downhill” movement of calcium from regions of high Ca ++ activity in the extracellular space and sarcoplasmic reticulum into the cytosol, where Ca ++ concentration is much lower, is mediated by “channels” that are probably lined by hydrophilic regions of the intrinsic membrane proteins. The sarcolemmal calcium channels, which carry the slow inward current that is responsible for the plateau phase of the cardiac action potential, is regulated by a voltage-sensitive gating mechanism that controls the access of ions to the channel. The calcium permeability of the sarcoplasmic reticulum, which regulates the calcium release into the cytosol that initiates cardiac systole, may be regulated by the calcium pump adenosine triphosphatase (ATPase) protein, also responsible for the active transport of calcium back into the sarcoplasmic reticulum during diastole. Drugs that affect the flux of ions through membrane “channels” can act by inducing the phosphorylation of membrane proteins, for example, phospholamban in the cardiac sarcoplasmic reticulum, which is phosphorylated in response to elevated cyclic adenosine monophosphate (cAMP) induced by β-receptor agonists. Other agents may bind directly to channel proteins, for example, tetrodotoxin, which binds specifically to the fast channel. It appears likely that many drugs, including antiarrhythmic agents and possibly calcium channel blockers, may modify ion fluxes through membrane channels by an interaction with functionally important membrane lipids surrounding the hydrophobic regions of the “channel” proteins. Abnormal calcium movements may contribute to the depression of myocardial contractility seen in the failing heart. These alterations may be produced by abnormalities in both the “channel” proteins and the membrane lipids in which the channels are embedded. It is not clear whether these abnormalities, and the resulting depression of contractility in the failing heart, represent a “defect” that shortens survival in these patients or whether the accompanying reduction in energy demand may be at least in part compensatory.

Endogenous cyclic AMP does not modulate transport of hexoses, nucleosides, or nucleobases in chinese hamster ovary cells

In a previous study we have demonstrated that neither extracellular nor intracellular cyclic adenosine monophosphate (AMP) levels directly affect the uptake of nucleosides, nucleobases, or hexoses by various types of cultured mammalian cells. Uptake of these nutrients into cells, however, involves two processes operating in tandem: facilitated transport across the membrane and intracellular phosphorylation; and uptake rates generally reflect the rates of substrate phosphorylation rather than of transport. In the present study we have examined the question of whether substrate transport per se is regulated by intracellular cyclic AMP. Initially various cell lines, grown both in suspension and monolayer culture, were screened for their cyclic AMP response to prostaglandin E1, isoproterenol, and inhibitors of cyclic AMP phosphodiesterase. Prostaglandin E1 treatment of Chinese hamster ovary cells was selected as the system giving the largest and most consistent (50-fold to 100-fold) elevation of cyclic AMP. Rapid kinetic techniques were used to measure the transport of 3-O-methylglucose, thymidine, adenosine, hypoxanthine, and adenine in wild-type cells and in mutant sublines incapable of phosphorylating these substrates. In no case was an increase in intracellular cyclic AMP accompanied by a significant change in the rate of transport of these substrates, although prostaglandin E1 slightly inhibited the transport of various substrates.

Prostaglandin E 2, cyclic adenosine monophosphate and morphine analgesia

Intravenous administration of prostaglandin E 2 (PGE 2) to mice results in a significant distribution of PGE 2 into the brain and an elevation of cyclic adenosine monophosphate (cAMP) in the midhindbrain and corpus striatum. Neither acute morphine administration nor morphine tolerance alters this response. Morphine alone also elevates cAMP levels. Although these elevations are blocked by the narcotic antagonist, naloxone, they only occur at supra-analgesic doses. Therefore morphine analgesia does not correlate with either elevation of cAMP levels or antagonism of PGE 2-induced elevations of cAMP.

Effects of vasopressin and prostaglandin E 1 on the adenyl cyclase-cyclic 3',5'-adenosine monophosphate system of the renal medulla of the rat.

Vasopressin increased adenyl cyclase activity in homogenates of both inner and outer renal medulla of the rat. It also increased the concentration of cyclic 3',5'-adenosine monophosphate (AMP) in slices of both inner and outer medulla but not in renal cortex. In the inner medulla, a concentration of prostaglandin E(1) (PGE(1)), which was ineffective by itself significantly reduced the stimulation of adenyl cyclase activity and cyclic AMP concentration induced by vasopressin. These results are consistent with the hypothesis that PGE(1) can compete with vasopressin for adenyl cyclase-binding sites. However, the findings in the outer medulla suggest the situation is more complex. Although 10(-8) M PGE(1) had no effect by itself and inhibited the vasopressin-induced elevation of cyclic AMP, larger amounts of PGE(1) increased both adenyl cyclase activity and cyclic AMP levels. The maximum effect on the latter parameter was at least 6 times as great as that of maximum amounts of vasopressin.