Effects of indomethacin on regional blood flow in conscious rabbits--a microsphere study.

In an attempt to reveal the importance of prostaglandins in the control of regional blood flow 20 mg/kg b.wt. indomethacin was given i.v. in conscious resting rabbits. Regional blood flow determinations were made before and 20 min after the injection using the labelled microsphere technique. The blood flow in the stomach wall was reduced by 0.75 +/- 0.17 g . min-1 . g-1 from a level of 1.64 +/- 0.24 g . min-1g-1. In jejunum the corresponding figures were 0.44 +/- 0.12 and 1.26 +/- 0.17 and in the brain 0.29 +/- 0.10 and 1.24 +/- 0.10. The blood flow in the liver via the hepatic artery increased by 0.20 +/- 0.02 g . min-1 . g-1 from a level of 0.13 +/- 0.02 g . min-1 . g-1. In the retina there was a reduction in blood flow by 2.75 +/- 1.03 mg . min-1 from a starting level of 15.1 +/- 2.3 mg . min-1. In a number of other tissues investigated there were no significant effects of the drug. The results suggest that under resting conditions prostaglandins play a role in the control of blood flow in the gastrointestinal tract, the brain and the retina--tissues which are likely to be rather active under such conditions.     

Development of enhanced blood flow responses to prostaglandin E1 in carrageenan-induced granulation tissue

The distribution of cardiac output (c.o.) was measured by the radioactive microsphere method in rats at different time intervals after the implantation of carrageenanimpregnated sponges. The amount of blood distributed to the developing granulomata increased from day 5 after sponge implantation to day 7, but showed no further increase at day 10. A similar pattern in blood flow was observed in the skin covering the granulomata. Injection of PGE₁ (100 ng) into the sponges led to an increase in blood flow, the magnitude of which became gradually larger between days 5 and 10. A similar, though less marked increase in sensitivity to PGE₁ was observed in the skin covering the granulomata, PGE₁ causing a significant increase in blood flow to the skin on day 10. These changes in sensitivity to exogenous PGE₁ may be due to decreasing levels of endogenous PGE and/or maturation of the newly formed blood vessels in the granulation tissue.     

Effects of indomethacin on regional blood flow in conscious rabbits—a microsphere study

In an attempt to reveal the importance of prostaglandins in the control of regional blood flow 20 mg/kg b.wt. indomethacin was given i.v. in conscious resting rabbits. Regional blood flow determinations were made before and 20 min after the injection using the labelled microsphere technique. The blood flow in the stomach wall was reduced by 0.75 ± 0.17 g·min^-1·g^-1 from a level of 1.64 ± 0.24 g·min^-1·g^-1. In jejunum the corresponding figures were 0.44 ± 0.12 and 1.26 ± 0.17 and in the brain 0.29 ± 0.10 and 1.24 ± 0.10. The blood flow in the liver via the hepatic artery increased by 0.20 ± 0.02 g·min^-1·g^-1 from a level of 0.13 ± 0.02 g·min^-1·g^-1. In the retina there was a reduction in blood flow by 2.75 ± 1.03 mg·min^-1 from a starting level of 15.1 ± 2.3 mg·min^-1. In a number of other tissues investigated there were no significant effects of the drug. The results suggest that under resting conditions prostaglandins play a role in the control of blood flow in the gastrointestinal tract, the brain and the retina—tissues which are likely to be rather active under such conditions.     

Influence of prostaglandin E2 and indomethacin on interferon-γ production by cultured peripheral blood leukocytes of multiple sclerosis patients and healthy donors

The addition of indomethacin to concanavalin A (Con A)-induced cultures of human peripheral blood leukocytes (PBL) caused an increase in interferon response, regardless of whether the PBLs were derived from multiple sclerosis (MS) patients or from control donors. Specifically the response rates increased from 71 to 100% in controls and from 24 to 53% in MS patient-derived cultures. The amounts of interferon produced also increased in both groups by 0.8 log U/ml. However, interferon yields of nonresponsive cultures becoming interferon-producing only after indomethacin treatment remained relatively low. In control cultures, maximal increases of interferon production were obtained with doses of 0.05 to 0.1 µg/ml indomethacin; for MS patients higher doses were needed—0.1 to 0.5 µg/ml. Conversely, a relatively low dose (0.05 µg/ml) of exogenous prostaglandin E₂ (PGE₂) was able to inhibit interferon production completely in MS patient-derived cultures, whereas in control cultures higher doses were needed (0.1 to 1.0 µg/ml). Analysis of endogenous PGE₂ levels in the PBL cultures revealed that PGE₂ production was similar in nonresponder MS cultures and responder control cultures but that MS leukocytes were more sensitive to the inhibitory effect of PGE₂ on interferon production. We conclude that in a minor percentage of MS patient-derived PBL cultures, the deficiency in interferon- (IFN-) production can be (partially) overcome by treatment of the cells with indomethacin. However, in the major part of nonresponder MS cultures, indomethacin has no effect, indicating that the PG system is not the major cause for the defective interferon response in MS.     

Influence of prostaglandin E1 on the terminal vascular bed

Experiments were performed to explore the influence of (PGE1) prostagandin E1 on the local regulation of blood flow in the terminal vascular bed of the rat mesoappendix. The vasomotor activity of PGE1 on specific vascular components of the microcirculation as well as its effects on vascular responsiveness to locally applied vasoconstrictor and vasodilator agents were documented by direct in vivo microscopic observation. Locally administered PGE1 transiently dilated all muscular microvessels. Unlike the other naturally occurring vasodilator agents such as bradykinin and histamine, PGE1 antagonized the constrictor action of angiotensin, epinephrine, norepinephrine, and vasopressin long after its vasodilator activity had vanished. However, PGE1 did not interfere with the constrictor activity of serotonin, nor did it alter vascular responsiveness to the dilators, bradykinin, and histamine. Findings suggest that PGE1 may serve as a local hormonal regulator of blood flow in the microcirculation by virtue of its vasodilator properties and its ability to suppress vascular responsiveness to endogenous constrictor amines and polypeptides.     

Acute hyperoxaemia-induced effects on regional blood flow, oxygen consumption and central circulation in man

AIM: Despite numerous in vitro and animal studies, circulatory effects and mechanisms responsible for the vasoconstriction seen during hyperoxaemia are yet to be ascertained. The present study set out to: (i) set up a non-invasive human model for the study of hyperoxia-induced cardiovascular effects, (ii) describe the dynamics of this effect and (iii) determine whether hyperoxaemia also, by vasoconstriction alters oxygen consumption (O(2)). METHODS: The study comprised four experiments (A, B, C and D) on healthy volunteers examined before, during and after 100% oxygen breathing. A: Blood flow (mL min(-1).100 mL(-1) tissue), venous occlusion plethysmography was assessed (n = 12). B: Blood flow was recorded with increasing transcutaneous oxygen tension (P(tc)O(2)) levels (dose-response) (n = 8). C: Heart rate (HR), stroke volume, cardiac output (CO) and systemic vascular resistance (SVR) was assessed using echocardiography (n = 8). D: O(2) was measured using an open circuit technique when breathing an air-O(2) mix (fraction of inhaled oxygen: F(i)O(2) = 0.58) (n = 8). RESULTS: Calf blood flow decreased 30% during O(2) breathing. The decrease in calf blood flow was found to be oxygen dose dependent. A similar magnitude, as for the peripheral circulation, of the effect on central parameters (HR/CO and SVR) and in the time relationship was noted. Hyperoxia did not change O(2). An average of 207 (93) mL O(2) per subject was washed in during the experiments. CONCLUSION: This model appears suitable for the investigation of O(2)-related effects on the central and peripheral circulation in man. Our findings, based on a more comprehensive (central/peripheral circulation examination) evaluation than earlier made, suggest significant circulatory effects of hyperoxia. Further studies are warranted to elucidate the underlying mechanisms.     

Responses of the cerebral blood flow to hypo-and hypercapnia after inhibition of prostaglandin biosynthesis by indomethacin

Quantitative investigation of the local cerebral blood flow by the hydrogen clearance method and of the blood flow into the brain by means of an electromagnetic flowmeter showed that inhibition of prostaglandin biosynthesis by indomethacin inhibits the response of the cerebral vessels to hypercapnia, whereas the effects of hypocapnia are not only preserved but are actually enhanced. This difference in the response of the brain vessels to hypo- and hypercapnia during inhibition of prostaglandin biosynthesis suggests that effects of hyper- and hypocapnia are produced by different mechanisms. It is postulated that a decrease in the prostaglandin concentration reduces the sensitivity of the brain vessels to hypercapnia and increases their sensitivity to hypocapnia.Problem Laboratory for Pharmacology of the Cardiovascular System, Department of Pharmacology, Erevan Medical Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR V. V. Zakusov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 87, No. 3, pp. 240–243, March, 1979.     

Endogenous prostaglandins as local regulators of blood flow in man: effect of indomethacin on reactive and functional hyperaemia.

1. The contribution of endogenously formed prostaglandins of the E series (PGE) to the development of reactive and functional hyperaemia was studied in the human forearm. 2. Forearm blood flow was recorded using venous occlusion plethysmography. The concentration of prostaglandin E-like substances (PLS) in the venous effluent from the muscle was analysed using bio-assay. For inhibition of PG biosynthesis, indomethacin (1-25 mg/kg body weight) was administered. 3. Following 5 min of arterial occlusion, a marked hyperaemia developed during the next 150 sec. Indomethacin, while not affecting the resting arterial blood flow, significantly decreased the peak level as well as the duration of the hyperaemia. The total reactive hyperaemia was 25 ml./100 ml. tissue before, and 13 ml./100 ml. tissue after administration of indomethacin. 4. During sustained isometric forearm contraction, and following isometric and dynamic forearm muscle activity, a moderate hyperaemia was observed. This was significantly diminished when indomethacin had been administered, although not to the same extent as the reactive hyperaemia. The total hyperaemia in the absence and presence of indomethacin was 113 and 77 ml./100 ml. tissue, respectively, in connexion with isometric contraction and 206 and 120 ml./100 ml. tissue, respectively, following dynamic work. 5. The venous concentration of PLS was very low at rest. A significantly increased concentration was observed after ischaemia. This increased release of PLS was entirely suppressed by indomethacin. With the present assay method, muscular activity elicited no detectable change in the venous concentration of PLS. 6. It is concluded that reactive hyperaemia depends to a considerable extent on an intact PGE synthesis. It is furthermore suggested that endogenous PGE may contribute to the functional hyperaemia that appears during and after muscle activity.     

Role of prostaglandin E2 and indomethacin in the febrile response of pigeons

Intravenous (i.v.) injection of 10 microg/kg Escherichia coli lipopolysaccharide (LPS), applied at 13:00, evoked in pigeons a biphasic rise of core temperature (T(core)), so that LPS induced with a latency of 30 min first a decrease of T(core), and 90 min after LPS, T(core) increased, obtaining maximum values from 18:00 to 20:00. Prostaglandins have been considered to be importantly involved in fevers in mammals. To investigate an involvement of prostaglandins in the cyclic variations of T(core) in birds, pigeons were injected i.v. with either 10 mg/kg indomethacin (INDO) or 100 mg/kg aspirin, or they were treated with intracerebroventricular (i.c.v.) injections of 100 microg/kg INDO at various times before or after LPS. When INDO or aspirin was i.v. injected 30 or 15 min before LPS, it diminished the initial decrease of T(core) by more than 50%, whereas the i.v. injection of these drugs 2 and 4 h after LPS did not affect the febrile rise of T(core). i.c.v. injections of INDO given either before or after LPS neither influenced the initial drop of T(core) nor the following febrile hyperthermia. Both the i.v. injection of 1 mg/kg prostaglandin E(2) (PGE(2)) and the i.c.v. injection of 1 microg/kg PGE(2) lowered T(core). Our observations suggest that prostaglandins are not involved in the febrile elevation of T(core) in pigeons, but appear to participate in the decrease of T(core), which shortly follows the i.v. injection of LPS. This initial drop of T(core) following LPS may be caused by a peripheral action of prostaglandins because it was not influenced by the i.c.v. injection of indomethacin.     

Effect of prostaglandin E1 and noradrenalin on cerebrovascular tone and arterial blood pressure

Prostaglandin E₁ (PGE₁), in solution with ethanol, when injected into the carotid artery, increases the tone of the cerebral blood vessels and the arterial blood pressure, whereas PGE₁ without ethanol gives the opposite effect. When PG biosynthesis is blocked by indomethacin, the pressor effect of noradrenalin on the cerebral vessels was considerably increased. It is postulated that PGE₁ is an important component of the system participating in the genesis of cerebral hypertension and determining the character of its course.     

Effects of indomethacin on cerebral blood flow during hypercapnia in cats

To study the contribution of prostaglandins to cerebral vasodilatation during hypercapnia, we inhibited prostaglandin synthesis with indomethacin. We measured cerebral blood flow (CBF) in anesthetized cats with 15-micrometers microspheres during normocapnia (PCO2 approximately 33 Torr), moderate hypercapnia (PCO2 approximately 49 Torr), and severe hypercapnia (PCO2 approximately 65 Torr) before and after intravenous administration of vehicle or indomethacin (3 and 10 mg/kg). Hypercapnia produced graded increments in blood flow to all areas of the brain. Administration of indomethacin did not change control CBF or significantly attenuate increases in CBF during hypercapnia. We examined efficacy and specificity of inhibition of prostaglandin synthesis by indomethacin using the cranial window method. Arachidonic acid (100 and 200 micrograms/ml) and acetylcholine (10(-7) and 10(-6)M or 10(-6) and 10(-5) M), dissolved in artificial cerebrospinal fluid, dilated pial arteries in a dose-dependent fashion. Intravenous administration of indomethacin blocked vasodilatation produced by arachidonic acid but did not affect the response to acetylcholine. Thus indomethacin, at a dose that effectively blocks prostaglandin synthesis, did not alter resting CBF or attenuate the increase in CBF during hypercapnia. This study suggests that steady-state cerebral vasodilatation during hypercapnia is largely preserved after inhibition of prostaglandin synthesis.