Effects of prostaglandin E2, analogs, fatty acids, and indomethacin on fibrinogen level.

Dose-response relations in rabbits for 3-h intravenous infusion of prostaglandin E2 (PGE2) and (15S)-15-methyl-1-prostaglandin E2 methyl ester (MePGE2) on plasma fibrinogen and systolic blood pressure were determined and described by regression equations. MePGE2 was 20 times more active than PGE2. Fibrinogen synthetic rate responses to PGE2 and MePGE2 were estimated. Infusion of the PGE2 precursor, arachidonic acid, elevated plasma fibrinogen, but fibrinogen response to 0.5-9 mg/kg arachidonic acid was unrelated to dose and half that given by 3 mg/kg PGE2. Slow infusion of several other fatty acids raised plasma fibrinogen as effectively as arachidonic acid, but prostaglandins D2 and F2alpha had only a slight effect. Infusion of 30 times the indomethacin dose that blocks platelet prostaglandin synthetase did not alter the plasma fibrinogen response to arachidonic acid. Indomethacin did not inhibit plasma fibrinogen elevations following ACTH or endotoxin infusion, or subcutaneous turpentine injection. Intravenous infusion of two cyclic ether prostaglandin endoperoxide analogs, (15S)-hydroxy-9alpha, 11alpha-(epoxymethano) prosta-5Z, 13E-dienoic acid, and (15S)-hydroxy-11alpha, 9alpha(epoxymethano) prosta-5Z, 13E-dienoic acid, failed to increase plasma fibrinogen.     

Insulin infusion normalizes cardiovascular responses and plasma noradrenaline after oral glucose in type 1 (insulin-dependent) diabetes

We examined whether the abnormal regulation of the cardiovascular system and plasma noradrenaline observed after oral glucose in insulin-dependent diabetic patients could be normalized by intravenous infusion of insulin. Eight patients with type 1 (insulin-dependent) diabetes were examined after an oral glucose load with and without simultaneous infusion of insulin. Insulin infusion increased plasma insulin from 0.07 to 0.31 nmol/l. In the control experiment (glucose only), mean heart rate and mean arterial systolic blood pressure remained unchanged and plasma noradrenaline (NA) decreased (p less than 0.05). After oral glucose plus intravenous insulin, mean heart rate increased by 11% and mean systolic blood pressure by 5% (p less than 0.05, p less than 0.01), whereas plasma NA did not change significantly. The present study indicates that physiologic increments in plasma insulin concentration are of importance in the regulation of the cardiovascular system and plasma NA following an oral glucose load.     

Influence of elevated renin substrate on angiotensin II and arterial blood pressure in conscious mice

The present experiments were performed to determine the influence of intravenous administration of renin substrate on plasma angiotensin II levels and mean arterial blood pressure in conscious C57BL/6J mice. Mice with chronic indwelling femoral arterial and venous catheters were acutely or chronically administered intravenous doses of a synthetic peptide corresponding to the 14 amino acids on the N-terminal of angiotensinogen. A dose-dependent increase in arterial blood pressure was observed as the intravenous bolus dose of the renin substrate was increased from 0.18 to 180 nmol kg(-1) with a maximal increase in pressure of 40 +/- 3 mmHg achieved following administration of the 18 nmol kg(-1) bolus (n = 11). Additional experiments demonstrated that a sustained intravenous infusion of the renin substrate led to a long-term increase in arterial blood pressure. The continuous infusion of renin substrate at 0.05 nmol kg(-1) min(-1) for 3 days did not alter arterial blood pressure from the control level of 119 +/- 5 mmHg (n = 5); however, arterial blood pressure significantly increased to 129 +/- 6 mmHg with an infusion rate of 0.5 nmol kg(-1) min(-1) and further increased to 141 +/- 3 mmHg when the renin substrate infusion was increased to 5.0 nmol kg(-1) min(-1). Finally, the infusion of renin substrate at 5.0 nmol kg(-1) min(-1) resulted in a significant increase in plasma angiotensin II concentration from 34 +/- 6 pg ml(-1) in vehicle-infused mice to 288 +/- 109 pg ml(-1). These results demonstrate that modulation of the circulating level of angiotensinogen can alter the plasma angiotensin II level and arterial blood pressure in normal animals.     

Implication of the systolic hump in systemic arterial pressure waves

The systolic hump in the aortic blood pressure wave is defined as the aorticresistance component proportional to the aortic blood flow superimposed on the windkessel component. An electrical analogue comprising a series resistance (aortic resistance) plus a resistance (peripheral resistance) and capacitance (aortic compliance) in parallel (i.e. windkessel component) is used for analysis. Curve fitting using the leastsquares method is performed on calculated and measured blood pressure waves from dogs under haemodynamical conditions induced by infusion of three drugs (noradrenaline, isoproterenol and acetylcholine). The curve fitting RMS (root mean square) errors are <3% for blood pressure waves and <30% for blood flow waves, with good agreement between measured and calculated blood flow waveforms. Infusion of noradrenaline and acetylcholine is found to induce a significant decrease and increase in the aortic resistance, respectively. Although only a small fraction of the blood pressure wave, the systolic hump has a marked effect on the systolic pressure waveform.     

Application of a new technique--blood pressure clamping--for analysis of prostaglandin interference with sympathetic neurotransmission in man

To circumvent baroreceptor reflexes following drug-induced interference sympathetic neurotransmission, a new technique - blood pressure clamping--has developed. This implies that the sympathetic activity in an awake human is 'clamped' at a supranormal level by infusion of a vasodilator. In 11 healthy volunteers nitroprusside or saline was randomly infused in two consecutive 2-h periods. Plasma and urinary catecholamine levels were analysed by liquid chromatography. The experiments were repeated after random administration of the prostaglandin synthesis inhibitor, ibuprofen, or placebo. In the basal state (no ibuprofen, saline infusion) the mean arterial blood pressure was 81.4 +/- 2.3 mmHg, the heart rate was 60.9 +/- 0.3 beats min-1 and the plasma level of noradrenaline was 1.12 +/- 0.15 nM. Infusion of nitroprusside at a dose lowering the mean blood pressure by 11.6 +/- 1.6 mmHg and increasing the heart rate to 74.6 +/- 2.9 beats min-1 elevated plasma noradrenaline to 2.86 +/- 0.39 nM. After pretreatment with ibuprofen (saline infusion), the systemic blood pressure, the heart rate, and the plasma and urinary levels of noradrenaline were unaffected in comparison to before drug (80.1 +/- 2.3 mmHg, 58.4 +/- 0.3 beats min-1 and 1.13 +/- 0.12 nM respectively). Infusion of nitroprusside at a rate lowering the blood pressure by 11.2 +/- 2.4 mmHg and increasing the heart rate to 74.4 +/- 0.5 beats min-1, elevated the plasma level of noradrenaline to 2.46 +/- 0.38 ng ml-1, which is not different from before ibuprofen. The amount of nitroprusside required to lower the blood pressure was not different in the presence and absence of ibuprofen.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Effect of Progesterone on Coronary Blood Flow in Anaesthetized Pigs

The present study was designed to investigate the effect of progesterone on the coronary circulation and to determine the mechanisms involved. In pigs anaesthetized with sodium pentobarbitone, changes in left circumflex or anterior descending coronary blood flow caused by intravenous infusion of progesterone at constant heart rate and arterial blood pressure were assessed using an electromagnetic flowmeter. In 14 pigs, infusion of 1 mg h(-1) of progesterone caused an increase in coronary blood flow without affecting left ventricular dP/dtmax (rate of change of left ventricular systolic pressure) and filling pressures of the heart. In a further four pigs, this vasodilatory coronary effect was enhanced by graded increases in the dose of the hormone of between 1, 2 and 3 mg h(-1). The mechanisms of the above response were studied in the 14 pigs by repeating the experiment after haemodynamic variables had returned to the control values observed before infusion. In six pigs, blockade of muscarinic cholinoceptors and adrenoceptors with atropine, propranolol and phentolamine did not affect the coronary vasodilatation caused by progesterone. In the remaining eight pigs, this response was abolished by intracoronary injection of N(omega)-nitro-L-arginine methyl ester (L-NAME) even when performed after reversing the increase in arterial blood pressure and coronary vascular resistance caused by L-NAME with continuous intravenous infusion of papaverine. The present study showed that intravenous infusion of progesterone primarily caused coronary vasodilatation. The mechanism of this response was shown to involve the endothelial release of nitric oxide.     

Failure of naloxone to reduce the clonidine induced reduction of blood pressure and plasma noradrenaline in patients with essential hypertension

Studies in animals and man indicate a functional interaction between the adrenergic and the opiate systems. In the present study the effect of the opiate receptor blocker naloxone on the reduction of blood pressure and plasma noradrenaline induced by the alpha 2-agonist clonidine was investigated in nine patients with essential hypertension. In a randomised manner the patients received a bolus dose of naloxone (10 micrograms/kg) or physiological saline followed by a slow infusion of naloxone (5 micrograms/kg/h) or saline, respectively. Fifteen minutes after the respective bolus dose, clonidine (3 micrograms/kg) was infused over 10 minutes. Naloxone had no effect on the clonidine induced hypotension and reduction of plasma noradrenaline. Accordingly, there is no evidence that the clonidine induced reduction of blood pressure and plasma noradrenaline involves opiate receptors that can be blocked by naloxone. Plasma adrenaline increased significantly during the early phase of naloxone infusion.     

The effect of angiotensin AT1 receptor blockade in the brain on the maintenance of blood pressure during haemorrhage in sheep

The effect of systemic or intracerebroventricular (ICV) infusion of the angiotensin AT₁ receptor antagonist losartan on blood pressure during hypotensive haemorrhage was investigated in five conscious sheep. Mean arterial pressure (MAP) was measured during haemorrhage (15 mL kg^?1 body wt). Losartan (1 or 0.33 mg h^?1) was given to sheep by ICV, intravenous or intracarotid administration, beginning 60 min before and continuing during the haemorrhage. During control infusion of ICV artificial cerebrospinal fluid, MAP was maintained until 13.16 ± 0.84 mL kg^?1 blood loss, when a rapid reduction of at least 15 mmHg in arterial pressure occurred (the decompensation phase). ICV infusion of losartan at 1 mg h^?1 caused an early onset of the decompensation phase after only 9.8 ± 0.8 mL kg^{? 1} of blood loss compared with control. Intravenous infusion of losartan (1 mg h^?1) also caused an early onset (P < 0.05) of the decompensation phase at 10.2 ± 1.0 mL kg^?1 blood loss. This dose of losartan inhibited the pressor response to ICV angiotensin II, but not to intravenously administered angiotensin II, indicating that only central AT₁ receptors were blocked. Bilateral carotid arterial administration of losartan at 0.33 mg h^?1 caused an early onset of the decompensation phase during haemorrhage at 11.06 ± 0.91 mL kg^?1 blood loss (P < 0.05), which did not occur when infused by intravenous or ICV routes. The results indicate that an angiotensin AT₁-receptor-mediated mechanism is involved in the maintenance of MAP during haemorrhage in sheep. The locus of this mechanism appears to be the brain.     

Effect of intravenous infusion of verapamil in patients of severe hypertension

Thirty patients with diastolic blood pressure of 120 mm Hg or more were administered a bolus dose of verapamil (0.15 mg/kg) followed immediately by an intravenous infusion at a rate of 0.005 mg/kg/min for one hour. The patients were monitored during this period and three hours following the discontinuation of the infusion. The systolic, diastolic and mean blood pressures before verapamil administration were 221.4 +/- 7.5, 134.3 +/- 2.7 and 163.4 +/- 4.1 mm Hg respectively, which decreased to 170.1 +/- 5.2, 99.1 +/- 3.7 and 122.8 +/- 3.6 mm Hg after intravenous bolus of verapamil. The fall in all the levels of blood pressure was significant (p less than 0.001) and was maintained at the lower levels throughout the infusion period and even three hours after discontinuation of the therapy. No untowards effects were observed and there was no significant change in heart rate and electrocardiogram. It, thus, proves to be an useful addition to the therapeutic armamentarium in the acute management of severe hypertension.     

Inhibition by prostaglandin E1 of gastric secretion in the dog

1. The effect of prostaglandin E(1) (PGE(1)) on gastric secretion was studied in dogs equipped with gastric fundic pouches, either innervated (Pavlov) or denervated (Heidenhain).2. PGE(1) inhibited gastric secretion (volume, acid concentration, acid output, pepsin output) when given either by constant intravenous infusion or by single intravenous injection. The degree of inhibition was dose dependent.3. The antisecretory effect of PGE(1) was demonstrated against gastric stimulants which operate through different mechanisms. Thus, PGE(1) counteracted the secretogogue effect of:(a) histamine dihydrochloride; the ED(50) was 0.5-1.0 mug/kg. min for a submaximal dose, and 1.0-1.5 mug/kg. min for a maximal dose;(b) pentagastrin; the ED(50) was around 0.25 mug/kg. min;(c) food; the ED(50) was 0.5 to 0.75 mug/kg. min;(d) 2-deoxyglucose; the ED(50) was less than 0.1 mug/kg. min.4. Although in some experiments, nausea and vomiting were observed during administration of PGE(1), the antisecretory property of the substance is not related to a vomiting reflex, since(a) an antiemetic, such as atropine, prevented vomiting without interfering with the effect of PGE(1), and(b) profuse vomiting elicited by apomorphine did not reduce gastric secretion stimulated by either histamine or pentagastrin.5. The mechanism by which PGE(1) inhibits gastric secretion is unknown. Studies by others have shown that the compound reduces gastric mucosal blood flow, inhibits acid formation from gastric mucosa when applied in vitro and may change the rate of formation of gastric cyclic AMP. It is likely that PGE(1) interferes with biochemical processes, within parietal and chief cells, which lead to elaboration of gastric juice.6. Unlike most gastric inhibitors, PGE(1) appears to act as a protective shield against most, if not all, gastric stimulants. Since prostaglandins of the E series are naturally occurring substances and are normally present in the stomach, they may play a role in the regulation of gastric secretion.     

In vivo effect of noradrenaline on the cyclic AMP level in rat corpora lutea

Under in vitro conditions adrenaline and noradrenaline can stimulate the production of cyclic AMP in rat corpora lutea to a similar extent as a maximal dose of LH. The present study was undertaken to compare the effects of noradrenaline and LH under in vivo conditions. Anaesthetized rats bearing 2 days old corpora lutea were either infused intraarterially with noradrenaline (0.4 microgram/min) or given a single intraarterial injection of 5 micrograms LH. The cAMP levels in whole ovaries had increased already after 30 sec of noradrenaline infusion. These levels remained high for a few minutes and, thereafter the effect decreased with time. No effect was seen after 20 min of infusion. Infusion of noradrenaline for 20 min increased cAMP in corpora lutea, but not in non-luteal tissue. LH was effective both in luteal and non-luteal tissue. The results show that noradrenaline in vivo can increase the cAMP content only in corpus luteum and within a rather short time period (5 min). This effect is different from that seen with LH which, instead, acts on both corpus luteum and stromal tissue.     

Cyclic adenosine 3', 5'-monophosphate in cerebrospinal fluid during thermoregulation and fever.

1. Samples of cerebrospinal fluid (c.s.f.) have been taken from the cisterna magna of unanaesthetized cats, whilst rectal temperature was recorded, during exposure of the animals to various ambient temperatures and during fever induced by pyrogen. The concentration of adenosine 3', 5'-monophosphate (cyclic AMP) in samples of c.s.f. has been assayed. 2. Cats exposed to low ambient temperatures (-2 to +2 degrees C) for 3 h maintained body temperature by both behavioural and autonomic heat gain activity. Exposure of cats to high ambient temperatures (44 - 45 degrees C) for 3.5 h caused a rise in body temperatures of about 2.5 degrees C, despite behavioural and autonomic heat loss activity. Neither cold nor heat stress had a significant effect on c.s.f. cyclic AMP. 3. Fever induced by intravenous Shigella dysenteriae (2 and 20 mug/kg) was associated with a dose-related increase in the concentration of cyclic AMP in c.s.f. Paracetamol (75 mg/kg) injected I.P. before the onset of fever, suppressed the increase in both temperature and c.s.f. cyclic AMP in response to pyrogen. Paracetamol (50 and 100 mg/kg), injected after the onset of fever, caused a fall in temperature, which was not associated with a decrease in the concentration of cyclic AMP in c.s.f. 4. Fever induced in cats by intravenous Shigella dysenteriae (20 mug/kg) was associated with an increase in the concentration of cyclic AMP in plasma as well as in c.s.f. 5. The sodium salt of cyclic AMP (0.1-10 mg/kg) injected I.V. into unanaesthetized cats caused a dose-related hypothermia, which was associated with autonomic heat loss activity and a dose-related increase in the concentration of cyclic AMP in cisternal c.s.f., which was not mimicked by adenosine. 6. It is concluded that the raised concentrations of cyclic AMP in c.s.f., in response to pyrogen I.V., do not mediate fever in the cat and that the concentration of cyclic AMP in cisternal c.s.f. may be affected by changes in the plasma concentration of the nucleotide.     

Effect of various antihypertensive drugs on plasma fibrinogen levels in patients with essential hypertension

In recent years, substantial evidence has accumulated to unambiguously implicate high plasma fibrinogen levels as a major cardiovascular risk factor. An open prospective and randomised pilot study was therefore undertaken in mild to moderate hypertensives to evaluate the effect of various antihypertensive drugs viz enalapril, felodipine and prazosin on the blood pressure and plasma fibrinogen levels. The systolic and diastolic blood pressures were determined at 0, 4 and 8 weeks whereas plasma fibrinogen assays were done at baseline and at the end of the 8th week of treatment in all the drug-treated groups. It was observed that although all the three drugs effectively controlled blood pressure, only enalapril significantly reduced plasma fibrinogen levels. Due to this additional effect, enalapril has potential to control two major cardiovascular risk factors--hypertension and high plasma fibrinogen levels--simultaneously.     

Application of a new technique-blood pressure clamping-for analysis of prostaglandin interference with sympathetic neurotransmission in man

To circumvent baroreceptor reflexes following drug-induced interference with sympathetic neurotransmission, a new technique - blood pressure clamping - has been developed. This implies that the sympathetic activity in an awake human is ‘clamped’ at a supranormal level by infusion of a vasodilator. In 11 healthy volunteers nitroprusside or saline was randomly infused in two consecutive 2-h periods. Plasma and urinary catecholamine levels were analysed by liquid chromatography. The experiments were repeated after random administration of the prostaglandin synthesis inhibitor, ibuprofen, or placebo. In the basal state (no ibuprofen, saline infusion) the mean arterial blood pressure was 81.4 ± 2.3 mmHg, the heart rate was 60.9 ± 0.3 beats min^-1 and the plasma level of noradrenaline was 1.12 ± 0.15nM. Infusion of nitroprusside at a dose lowering the mean blood pressure by 11.6 ± 1.6 mmHg and increasing the heart rate to 74.6 + 2.9 beats min^-1 elevated plasma noradrenaline to 2.86 ± 0.39 nM. After pre-treatment with ibuprofen (saline infusion), the systemic blood pressure, the heart rate, and the plasma and urinary levels of noradrenaline were unaffected in comparison to before drug (80.1±2.3 mmHg, 58.4 ± 0.3 beats min^-1 and 1.13±0.12nM respectively). Infusion of nitroprusside at a rate lowering the blood pressure by 11.2 ± 2.4 mmHg and increasing the heart rate to 74.4 ± 0.5 beats min^-1, elevated the plasma level of noradrenaline to 2.46 ± 0.38 ng ml^-1, which is not different from before ibuprofen. The amount of nitroprusside required to lower the blood pressure was not different in the presence and absence of ibuprofen. These data indicate that ibuprofen does not affect sympathetic neurotransmission during a moderate increase in adrenergic activity and, hence, that locally formed prostaglandins do not modulate such transmission under these conditions.     

Effects of the calcium antagonist felodipine on the sympathetic and renin-angiotensin-aldosterone systems in essential hypertension

Studies were performed in 10 male patients with untreated essential hypertension, WHO grade I-II, aged 25-62 years, to explore the acute (single dose) and long-term (8 weeks) effects of felodipine on sympathetic activity--evaluated by plasma and urinary catecholamines--as related to blood pressure, heart rate and the activity in the renin-angiotensin-aldosterone system. The patients were hospitalized for 8 (acute) and 6 (long-term) days and were maintained on a standardized daily intake of sodium (150 mmol), potassium (75 mmol) and water (2,500 ml). Acute felodipine administration (10 mg) significantly reduced blood pressure and increased heart rate. Plasma and urinary noradrenaline, plasma renin activity and angiotensin II increased, whereas plasma and urinary adrenaline, dopamine, aldosterone and plasma vasopressin were unaltered. Long-term felodipine treatment, 10 mg twice daily, reduced blood pressure to a similar extent as acute felodipine administration, but heart rate was not significantly changed. Plasma noradrenaline 3 and 12 hours after the last dose and urinary noradrenaline were increased, whereas plasma and urinary adrenaline and dopamine were unchanged. Plasma renin activity and angiotensin II were increased 3 hours, but unchanged 12 hours after the last dose. Plasma aldosterone was unchanged but urinary aldosterone increased. Plasma vasopressin was unchanged. The changes in plasma noradrenaline as related to blood pressure, heart rate, plasma renin activity and angiotensin II during long-term felodipine treatment may reflect decreased cardiac and renal beta-adrenoceptor-mediated responses. Increased renal clearance of aldosterone could partly explain the unaltered plasma aldosterone level in spite of increased plasma angiotensin II following long-term felodipine treatment.     

Increased resistance to haemorrhage induced by intracerebroventricular infusion of hypertonic NaCl in conscious sheep.

The effect of elevated cerebrospinal fluid Na+ concentration (CSF [Na+]) on the tolerance of blood loss, and concomitant cardiovascular and humoral responses were studied in conscious sheep. A slow (0.7 ml kg-1 min-1) venous haemorrhage was continued until the mean systemic arterial pressure suddenly decreased to less than 50 mmHg, or in the absence of hypotension, until a total blood loss of 25 ml kg-1. Significantly more blood had to be removed to induce hypotension in animals receiving an intracerebroventricular (i.c.v.) infusion (0.02 ml min-1) of 0.5 M NaCl (starting 30 min before haemorrhage and continued throughout the experiment) compared to control haemorrhages without concomitant i.c.v. infusion (22.7 +/- 1.2 ml vs 16.9 +/- 0.9 ml kg-1). In one animal, subjected to 0.5 M NaCl infusion, the blood pressure was still maintained at 25 ml kg-1 of haemorrhage. In spite of a larger blood loss, animals receiving i.c.v. infusion of hypertonic NaCl had an improved recovery of the blood pressure after haemorrhage, due to a better maintained cardiac output rather than to a reinforced increase of the vascular resistance. The improved cardiovascular responses to haemorrhage during elevated CSF [Na+] are not readily explained by the effects on the plasma concentrations of vasopressin, angiotensin II or noradrenaline, although the latter was augmented. The plasma protein concentration decreased already during the 30 min of hypertonic NaCl infusion preceding haemorrhage, and the haemodilution caused by the subsequent blood removal was aggravated, which indicates that this treatment also causes transfer of fluid to the plasma compartment. We conclude that elevated CSF [Na+] increases tolerance to haemorrhage and improves cardiovascular function after blood loss in sheep. Since the haemodynamic responses in many respects were similar to those reported in response to the systemic administration of a small volume of hypertonic NaCl solution in haemorrhagic shock, part of the effect of that treatment may be mediated via cerebral effects of increased Na+ concentration.     

Vasoactive intestinal peptide suppresses migrating myoelectric complex of rat small intestine independent of nitric oxide

The involvement of nitric oxide (NO) in the biological response to vasoactive intestinal peptide (VIP) on the migrating myoelectric complex (MMC) of small bowel and systemic arterial blood pressure was investigated in the rat. Animals were supplied with bipolar electrodes for electromyography of the small intestine and blood pressure was assessed by a pressure transducer connected to a carotid artery. In the first session, Nomega-nitro-L-arginine (L-NNA) was administered intravenously at 1, 2, 4 and 20 mg kg(-1). Effects of L-NNA at 1 and 20 mg kg(-1) were also studied after L-arginine 300 mg kg(-1). In the second session, intravenous infusion of VIP 500 pmol kg(-1) min(-1) was administered before and after L-NNA at 1 and 20 mg kg(-1). L-NNA at increasing doses stimulated myoelectric spiking of the small bowel until at 4 mg kg(-1) the MMC was disrupted and irregular spiking induced. Neither at 1 nor 20 mg kg(-1) did L-NNA affect the inhibitory motility response or decrease of blood pressure induced by VIP at a dose of 500 pmol kg(-1) min(-1). Our results show that effects of VIP on motility of the small intestine and systemic arterial blood pressure are direct and not dependent on NO as a common final link.     

Actions of histamine, secretin, and PGE2 on cyclic AMP production by isolated canine fundic mucosal cells.

Cyclic AMP production was studied in isolated canine fundic gastric mucosal cells. Histamine, prostaglandin E2 (PGE2), and secretin increased cyclic AMP production by unenriched mucosal cells. In separated cell fractions, histamine stimulation of cyclic AMP production correlated with the parietal cell content of the fractions. Secretin in concentrations above 1 nM stimulated cyclic AMP production, and this effect correlated with the pepsinogen content of the separated cell fractions. At concentrations above 1 microM, PGE2 stimulated cyclic AMP production; this effect was found in all separated cell fractions and was not associated with any of the available cell markers. PGE2 stimulation of cyclic AMP production was, however, negatively correlated with the parietal cell content. Thus, histamine stimulated cyclic AMP production by parietal cells and secretin stimulated production of cyclic AMP by chief cells. PGE2 stimulation of cyclic AMP production could not be localized to a single cell type but occurred primarily in nonparietal cells.     

Cardiovascular effects of preparation CIBA 34,276-Ba and imipramine

The cardiovascular effects of compound CIBA 34,276-Ba and imipramine were compared.In the conscious dog, intravenous infusion or oral administration of compond CIBA 34,276-Ba had only a slight effect on blood pressure and heart rate, whereas the intravenous administration of imipramine gave rise to clearcut tachycardia and did not influence blood pressure.In dogs anaesthetized with chloralose, compound CIBA 34,276-Ba reduced blood pressure and heart rate slightly, diminished cardiac output when given in high doses and increased total peripheral resistance. Imipramine administered in the same doses had no effect on blood pressure, increased heart rate and led to qualitatively similar but quantitatively more pronounced changes in cardiac output and peripheral resistance than compound CIBA 34,276-Ba.In cats anaesthetized with allobarbitone, compound CIBA 34,276-Ba and imipramine in doses up to 3 mg/kg i.v. had only a slight effect on blood pressure, contractile force and heart rate. A negative inotropic effect was evident after intravenous administration of 3 mg/kg imipramine.In the isolated guinea-pig atrium imipramine increased cardiac contractile force in a concentration of 1 mcg/ml, while both compounds displayed a cardiodepressant effect with 10 mcg/ml.In conscious renal hypertensive rats, both compounds had no effect on blood pressure, but reduced blood pressure in the same animals anaesthetized with ether.     

Negligible role of catecholaminergic receptors in the anteroventral third ventricular region in mediating vasopressin-releasing and cardiovascular actions of prostaglandin E2

The aim of this study was to pursue the roles of the catecholamine receptors in the anteroventral third ventricular region (AV3V), a cerebral site engaged in various stress responses, in prostaglandin (PG) E₂-evoked vasopressin (AVP) release and cardiovascular action. Experiments were conducted in conscious rats in which cerebral and vascular cannulae had been implanted chronically. Local infusion (0.5 μl, 1 min) of dopamine (150 nmol), a D₁-dopaminergic agonist SKF 38393 (17 nmol) and an α-adrenergic agonist phenylephrine (150 nmol), as well as PGE₂ (7 nmol), into the AV3V enhanced plasma AVP 5 min later, without affecting plasma osmolality and electrolytes. In contrast to the increases in both arterial pressure and heart rate observed when PGE₂ was applied, dopamine and SKF 38393 did not affect these variables, and phenylephrine elevated only arterial pressure. The AV3V infusion of a β-agonist isoproterenol (100 nmol) did not change plasma AVP, although it decreased arterial pressure and increased heart rate. The increase in plasma AVP by dopamine was not blocked by the preinfusion of the D₂-antagonist sulpiride (13 nmol) into the AV3V 10 min before, but was abolished by that of the D₁-antagonist SCH-23390 (8 nmol). The effects of phenylephrine on both plasma AVP and the blood pressure were prevented by the preadministration of the α-antagonist phenoxybenzamine (13 nmol). However, the pretreatments with phenoxybenzamine, sulpiride or SCH 23390 did not inhibit the responses of AVP, arterial pressure and heart rate caused by PGE₂. These antagonists were without significant effect on AVP and other variables when given alone. The infusion sites of PGE₂ and the other drugs identified histologically included the AV3V structures such as the organum vasculosum laminae terminalis or its vicinity, median preoptic nucleus, medial preoptic nucleus and periventricular hypothalamic nucleus. Dopamine or phenylephrine administered into the cerebral ventricle at the same dose as used in the AV3V application did not exert a significant effect on plasma AVP, arterial pressure and heart rate. These results suggest that catecholamine receptors in the AV3V may not be involved in the AVP-secreting, tachycardiac and pressor responses evoked by topical action of PGE₂ on this area, despite their ability to influence hormone release and cardiovascular function. Received: 3 November 1998 / Accepted: 7 July 1999