Biomedical subjects
Publications and source records attributed to J G Gerber.
There are currently six beta-adrenoceptor blocking drugs on the market. Although all the drugs competitively interact with the beta-adrenergic receptors, their pharmacokinetics and ancillary properties distinguish them from one another. By understanding these differences, the various beta-adrenoceptor drugs can be rationally used to a therapeutic advantage.
The relationship of the renal excretion of prostaglandin E2 (PGE2) to urine flow during a water diuresis was examined using radioimmunoassay (RIA) and gas chromatography-mass spectrometry (GC-MS). Seven normal women fasted overnight were water loaded with 20 ml/kg orally, and each hour for 3 h they drank water to replace the urine volume plus 20 ml. The osmolality of the collected urines ranged from 49 to 1,073 mosmol/kg. Assay of urinary PGE2 concentrations by both RIA and GC-MS gave a correlation coefficient of 0.94. Eight normal women were then studied with a water diuresis sustained for 6 h. The excretion of PGE2 (measured with the validated RIA) increased for the 1st 2-3 h (from 1.8 +/- 0.5 to 25.8 +/- 16.6 pg X kg-1 X min-1), but then fell to base-line level by the 5th h (to 2.9 +/- 0.8 pg X kg-1 X min-1) even though the water diuresis was sustained. The urinary concentration vs. time curves for PGE2 and for the freely diffusible solute urea were compared. PGE2 concentration remained elevated for 3 h before falling (from the 100 pg/ml range to 15 pg/ml) while urea concentration decreased steadily from the 1st h. This finding suggests that the early urinary PGE2 excretion was not a washout phenomenon and is consistent with a transient increase in PGE2 synthesis. We conclude that urinary excretion of PGE2 is not a simple function of urine flow after a water load. There is a transient initial increase in urinary PGE2 excretion at the start of a water load that probably reflects an increase in renal PGE2 synthesis. However, with a sustained water diuresis, PGE2 excretion falls, indicating that an enhanced PGE2 synthesis rate is not required to sustain a water diuresis.
Administration of theophylline has been shown to enhance gastric acid secretion in humans. Because theophylline has been reported to be a poor inhibitor of phosphodiesterase but a better adenosine receptor antagonist, we tested the hypothesis that there are inhibitory "R site" adenosine receptors on parietal cells. Utilizing isolated dispersed canine parietal cells, we measured acid secretion by the [14C]aminopyrine accumulation technique. We tested the effect of increasing concentrations of 2-chloroadenosine (10(-7), 10(-6), 10(-5) M) and L-N6-phenylisopropyl adenosine (L-PIA) (10(-7), 10(-6), and 10(-5) M), stable analogs of adenosine with specificity for the R sites, on aminopyrine uptake produced by submaximal stimulating concentrations of histamine (1 microM) plus isobutyl methylxanthine (3 microM) or carbachol (1 microM). Histamine-stimulated parietal cell aminopyrine uptake was 4.3- +/- 0.4-fold above basal; 2-chloroadenosine inhibited this response in a dose-dependent fashion with a 57 +/- 6% inhibition at 10(-5) M.L-PIA also inhibited histamine-stimulated aminopyrine uptake with a 67 +/- 11% inhibition at 10(-5) M. Carbachol-stimulated aminopyrine uptake was 5.8- +/- 1.6-fold above basal, but 2-chloroadenosine had no significant effect on this response. Theophylline, 300 microM, and 8-phenyltheophylline, 10 microM, reduced the inhibitory effect of 2-chloroadenosine. 8-Phenyltheophylline was inactive in inhibiting the parietal cell phosphodiesterase activity and the IC50 of theophylline for phosphodiesterase was 1 mM. Because prostaglandins inhibit parietal cell uptake of aminopyrine in a pattern similar to 2-chloroadenosine, we also tested the possibility that prostaglandins are involved in the 2-chloroadenosine response.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of cholinergic stimulation on gastric acid secretion was examined in mongrel dogs using an in vivo and an in vitro preparation for comparison. The gastric fistula dog was used for the in vivo studies, and methacholine was infused directly into the artery supplying the fundus of the stomach to avoid systemic hemodynamic changes. Isolated parietal cells were used for the in vitro studies. In vivo, methacholine infused at 1 microgram/min was found to stimulate gastric acid secretion that was inhibited 98.5 +/- 1.4% by intravenously administered metiamide (H2 blocker) and 72 +/- 11% by intra-arterially administered glucagon. Glucagon had no effect on histamine stimulated acid secretion. In vitro, increasing concentrations of methacholine from 10(-7), 10(-6) to 10(-5) M stimulated [14C]aminopyrine uptake into parietal cells in a concentration dependent manner. This effect of methacholine was unaltered by 10(-4) M metiamide or 10(-6) M glucagon. However, atropine 10(-5) M totally blocked the stimulatory effect of methacholine. Our data suggest that the cholinergic mechanism of acid secretion is different when examined in vivo vs. in vitro even in the same species. In vivo histamine dependency has a major contribution to the cholinergic mechanism of acid secretion, whereas in vitro the interaction of the cholinergic agonist at the muscarinic receptor results in acid stimulation that does not require the presence of histamine.
Because PGE2 and F2 alpha are derivatives of arachidonic acid, the effect of pH on dissociation of the carboxyl group would be expected to alter the lipid solubility of these substances and consequently their efflux from the distal nephron. To assess this possibility on the single nephron level, 20-nl samples of chromatographically pure [3H]prostaglandins were microinjected into early distal tubules and their recovery was compared with that of [14C]insulin in rats undergoing osmotic diuresis with NaHCO3 or Na2SO4 containing HCl. Although urine flow rates were similar, there was a striking elevation of urine pH in bicarbonate-loaded rats (7.87 +/- 0.017 vs. 5.66 +/- 0.067). To examine luminal factors acting on prostaglandin movement, collections of early distal fluid were made and total [CO2] was measured by microcalorimetry. There was no difference in distal flow rate, whereas total [CO2] and calculated pH were significantly elevated in the bicarbonate-loaded rats (7.66 +/- 0.029 vs. 6.07 +/- 0.093). We found that tubular efflux of both prostaglandins from the distal nephron is very small as the maximum efflux measured in acid-loaded rats was only 4% of the injected quantity. However, there was no efflux of PGE2 when microinjection was made into distal tubules of bicarbonate-loaded animals. All isotope excreted in the urine was the unchanged parent prostaglandin and both prostaglandins were coexcreted with inulin for all injections in bicarbonate- and acid-loaded animals. These results suggest that permeability of the distal nephron to PGE2 and F2 alpha is normally very low. Nevertheless, permeability of PGE2 can be further reduced when urine pH is elevated.
We tested the hypothesis that there are adenosine receptors in the gastric fundus responsible for the modulation of acid secretion to secretagogues. We utilized anesthetized gastric fistula dogs and infused both the secretagogues (histamine, 0.5 microgram/min and methacholine, 1 microgram/min) and adenosine through the gastric artery supplying the fundus of the stomach to avoid systemic effects of the drug. Adenosine infused to a concentration of 30 microM inhibited histamine-stimulated acid secretion from 197 +/- 25 to 68 +/- 19 microEq/15 min and inhibited methacholine-stimulated acid secretion from 280 +/- 48 to 81 +/- 24 microEq/15 min. Intravenously infused theophylline to a plasma concentration of 17 micrograms/ml (94 microM) blocked the inhibitory effect of adenosine on gastric acid secretion but did not affect the inhibitory effect of prostaglandin E2 on gastric acid secretion. In contrast, the specific phosphodiesterase inhibitor RO 20 1724 did not alter the inhibitory effect of adenosine on gastric acid secretion. In addition to its effect on gastric acid secretion, adenosine was found to be a potent vasodilator of gastric blood vessels. Our data suggest that there are inhibitory adenosine "R" receptors in the gastric fundus that modulate acid secretion to both histamine and methacholine.
Somatostatin, secretin, and glucagon have been shown to inhibit gastric acid secretion in vivo and thus have been postulated to act directly on the parietal cell. To test the hypothesis that these peptides directly influence the acid secretory cells, we studied the effect of the three gastrointestinal hormones using aminopyrine uptake as an index of acid production. The parietal cells were stimulated to increase aminopyrine uptake by submaximal concentrations of histamine (10(-6) mol/l), methacholine (10(-6) mol/l), and pentagastrin (10(-6) mol/l), but in no concentrations did these gastrointestinal hormones affect any of the secretagogues' response. Our data suggest that gastrointestinal peptides do not modulate acid secretion at the parietal cell level.
1 The effect of intrarenal histamine, dimaprit (H2-agonist) and 2-(2-pyridyl) ethylamine (H1-agonist) on renin release was examined in anaesthetized dogs. 2 In dogs with intact kidneys, histamine and dimaprit administration resulted in renal vasodilatation, a two fold increase in urinary sodium excretion, and no change in renal renin release. 2(2-Pyridyl) ethylamine administration resulted in renal vasodilatation, a 25% decrease in urinary sodium excretion and a significant increase in renin release. 3 In dogs with non-filtering kidneys, dimaprit administration resulted in renal vasodilatation and a significant increase in renin release, while 2(2-pyridyl) ethylamine administration resulted in renal vasodilatation but no change in renin release. 4 Our data suggest that histamine is a potential participant in the release of renin through stimulation of H2-receptors, but it is a weak agonist. 5 In addition, the direct effect of histamine analogues on renin release is modulated by their effects on electrolyte excretion probably by influencing the renal chemoreceptor release of renin mediated by the macula densa.
Animal experiments have suggested that salt-balance, prostaglandin synthesis, and renal function are important determinants of the nondiuretic vascular effects of furosemide. To investigate the influence of these factors in humans, we studied 10 normal volunteers and five anephric patients. The volunteers were studied on three occasions: when on a 10 mEq/day sodium diet, on a 250 mEq/day sodium diet, and on a 10 mEq/day sodium diet with indomethacin, 200 mg/day. The anephric patients were studied immediately after dialysis. Plethysmographic methods were used to measure venous capacitance and blood flow in the calf before, and at 5, 10, and 15 minutes after furosemide, 80 mg, iv. Blood was obtained before and 15 minutes after furosemide for determination of plasma renin activity by radioimmunoassay and of plasma 6-keto-prostaglandin F1 alpha by chromatography-mass spectrometry. We found that furosemide significantly increased venous capacitance in the calf of the normal volunteers on a low salt diet. Indomethacin, high salt intake, or lack of renal function was sufficient to inhibit this effect. Plasma renin activity increased only in the group that had the increase in venous capacitance. Limb blood flow decreased gradually in the 15 minutes following administration of furosemide in the normal volunteers, regardless of salt balance or indomethacin, but remained unchanged in the anephric patients. Plasma 6-keto-prostaglandin F1 alpha was less than 30 pg/ml in all samples. Indomethacin concentration averaged 1.3 micrograms/ml in volunteers on the drug. To determine whether indomethacin, salt intake or renal function affected another venodilator, we studied an additional group of normal and uremic volunteers who received 0.6 mg nitroglycerin sublingually.(ABSTRACT TRUNCATED AT 250 WORDS)
The role of prostaglandins in the control of blood pressure is not well understood. Prostaglandins of the 2 series are ubiquitous local hormones derived from the unsaturated fatty acid, arachidonic acid. Prostaglandins are produced by most mammalian cells. Locally produced prostaglandins may modulate blood pressure by opposing the vasoconstrictor effect of norepinephrine and angiotensin II, as well as by limiting the extent of sympathetic neurotransmission. In addition, renally generated prostaglandins are involved in the release of renin, inhibition of antidiuretic hormone action, and excretion of sodium chloride. Because prostaglandins have multiple effects in the kidney, vasculature, and sympathetic neurotransmission, the use of nonsteroidal antiinflammatory drugs (which inhibit prostaglandin synthesis) has not resulted in a consistent effect on blood pressure in humans. Clinical studies using indomethacin have reported an increase, no change, or a decrease in blood pressure after drug administration. Because of this unpredictability in response, the addition of a nonsteroidal antiinflammatory drug to an already hypertensive patient should be followed by more frequent blood pressure measurements.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
The role of renal alpha and beta adrenoceptor activation and prostaglandin synthesis in mediating renin release to intrarenal infusions of the natural neurotransmitters, norepinephrine and epinephrine, was assessed in anesthetized mongrel dogs. Intrarenal infusions of norepinephrine and epinephrine at doses adjusted to reduce renal blood flow by 20 and 50% of baseline values elicited renin release that was not completely blocked by either alpha adrenoceptor blockade with phentolamine or beta adrenoceptor blockade with propranolol. The renin release that persisted during propranolol administration was abolished by the alpha adrenoceptor antagonist, phentolamine, and by the prostaglandin synthetase inhibitor, indomethacin. The beta adrenergic component of renin release, elicited in the presence of phentolamine, was not blocked by indomethacin but abolished by propranolol. These data are consistent with the hypothesis that norepinephrine and epinephrine stimulate renin release by activation of both the renal beta and renal alpha adrenoceptors. The beta adrenoceptor-stimulated renin release appears to be direct and independent of the prostaglandin system, whereas the alpha adrenoceptor-stimulated renin release appears to be indirect and dependent on the generation of endogenous prostaglandins.
Loop diuretics, of which furosemide is a prototype, have physiological actions over and above their natriuretic effects to increase renal blood flow, cause renin release, and increase peripheral venous capacitance. The three criteria necessary to show that prostaglandins (PGs) are involved in the action of furosemide include: 1) drug administration should stimulate PG production; 2) infusion of PGs or their precursors should mimic the effect of the drug; and 3) inhibition of PG synthesis must alter the physiological response of the drug. Furosemide administration is associated with an increase in the urinary excretion of all the renal PGs, which suggests that the drug stimulates the deesterification of arachidonic acid from cellular phospholipids. In addition, intrarenal administration of arachidonic acid, PGI2, or PGE2 to experimental animals causes renal vasodilation and renin release, which suggests that PGs can mediate the renovascular and renin-releasing effects of furosemide. Finally, cyclooxygenase inhibitors like indomethacin can block the renal vasodilation, the renin release, and the increase in venous capacitance caused by furosemide administration. The above findings provide a firm basis for the hypothesis that the extradiuretic effects of furosemide to increase renal blood flow, cause renin release, and increase peripheral venous capacitance are mediated by the PG system. Less conclusive are data linking PGs to the renal tubular effects of furosemide and other loop diuretics.
Explore the source record for details and available documents.
The effect of direct intragastric artery infusion of prostaglandins E2 and I2, arachidonic acid, dimaprit (histamine H2 agonist), and 2',2'-pyridylethylamine (histamine H1 agonist) on gastric mucosal blood flow was examined in dogs to elucidate the relationship between gastric secretory state and mucosal blood flow in dogs. These compounds were chosen because of their diverse effect on gastric acid secretion. Gastric fundus blood flow was measured both electromagnetically with a flow probe around the left gastric artery which supplies the fundus almost exclusively, and by the radioactive microsphere technique. Intraarterial infusion of all the compounds resulted in gastric mucosal vasodilation even though PGE2, PGI2, and arachidonic acid inhibit gastric acid secretion, dimaprit stimulated gastric acid secretion, and 2',2'-pyridylethylamine does not affect gastric acid secretion. There was total agreement in the blood flow measurements by the two different techniques. Our data suggest that gastric acid secretion and gastric vasodilation are independently regulated. In addition, the validity of the studies in which the aminopyrine clearance indicates that prostaglandins are mucosal vasoconstrictors needs to be questioned because of the reliance of those measurements on the secretory state of the stomach.
The role of histamine-1 receptors in modulating gastric acid secretion was evaluated in anesthetized dogs with gastric fistulas. Histamine receptor agonists were infused directly into the gastric artery supplying the fundus to avoid any systemic hemodynamic effects. Two experimental approaches were taken to try to determine whether histamine-1 receptors participate in the control of acid secretion. Firstly, we measured the effect of the H1-receptor antagonist, hydroxyzine dihydrochloride, on histamine and dimaprit stimulated acid secretion. Secondly, we measured the effect of H1-receptor agonist on dimaprit stimulated gastric secretion. Although H1-receptor antagonist enhanced stimulated gastric acid secretion to histamine, the antagonist also enhanced stimulated gastric acid secretion to dimaprit (H2-agonist), suggesting that the enhanced gastric acid secretion after administration of H1-receptor antagonist is not because of the inhibition of histamine receptor at the gastric fundus. In addition, 2 doses of H1-receptor agonist infused into the gastric fundus had no effect on dimaprit stimulated gastric acid secretion. These data suggest that H1-receptors do not modulate gastric acid secretion at the level of the gastric fundus in the dog.
The pharmacologic interaction between tricyclic antidepressants and clonidine at the alpha 2-adrenoceptor was examined in human platelets by quantifying the ability of tricyclic antidepressant drugs to inhibit clonidine-stimulated platelet aggregation in vitro. Platelet aggregation induced by increasing concentrations of clonidine (0.3 to 3 microM) was not altered by pretreatment of the platelets with 10 microM imipramine. Imipramine at concentrations above 100 microM attenuated clonidine-induced platelet aggregation, but this was a nonspecific drug effect because the high concentrations of imipramine inhibited adenosine diphosphate-induced platelet aggregation as well. Desmethyldoxepin and nortriptyline also inhibited platelet aggregation nonspecifically at higher concentrations (greater than 10 microM). We were also not able to establish a specific interaction between alpha-methlnorepinephrine (the active metabolite of methyldopa) and the tricyclic antidepressants at the platelet alpha 2-adrenoceptor. Our data suggest that if there is an adverse dynamic interaction between tricyclic antidepressants and clonidine, the interaction occurs at a site other than the alpha 2-adrenoceptor.