Bradykinin in reflex cardiovascular responses to static muscular contraction

We examined the contribution of bradykinin to the reflex hemodynamic response evoked by static contraction of the hindlimb of anesthetized cats. During electrical stimulation of ventral roots L7 and S1, we compared the cardiovascular responses to hindlimb contraction before and after the following interventions: inhibition of converting enzyme (kininase II) with captopril (3-4 mg/kg, n = 6); inhibition of kallikrein activity with aprotinin (Trasylol, 20,000-30,000 KIU/kg, n = 8); and injection of carboxypeptidase B (500-750 U/kg, n = 7). Treatment with captopril augmented the rise in mean arterial blood pressure and maximal time derivative of pressure (dP/dt) caused by static contraction from 21 +/- 3 to 39 +/- 7 mmHg and 1,405 +/- 362 to 2,285 +/- 564 mmHg/s, respectively. Aprotinin attenuated the contraction-induced rise in mean arterial blood pressure (28 +/- 4 to 9 +/- 2 mmHg) and maximal dP/dt (1,284 +/- 261 to 469 +/- 158 mmHg/s). Carboxypeptidase B reduced the cardiovascular response to static contraction. Thus the mean arterial blood pressure response was decreased from 36 +/- 12 to 24 +/- 11 mmHg, maximal dP/dt from 1,618 +/- 652 to 957 +/- 392 mmHg/s, and heart rate from 12 +/- 2 to 7 +/- 1 beats/min. These data suggest that stimulation of muscle afferents by bradykinin contributes to a portion of the reflex cardiovascular response to static contraction.     

Prostaglandins modulate baroreflex-induced changes in blood pressure and myocardial function in anesthetized dogs

The purpose of our study was to investigate the role of prostaglandins in the changes in myocardial function and peripheral and coronary vascular resistance which accompany a generalized increase in sympathetic tone caused by carotid baroreflex unloading in the anesthetized dog. Bilateral carotid artery occlusion (BCO) with heart rate held constant by electrical pacing (150 beats/min) resulted in increases in systolic, (33%) diastolic (40%), and mean (35%) arterial pressures, LV systolic pressure (33%) and left ventricular (LV) dP/dt (37%). After blockade of prostaglandin synthesis with indomethacin (N = 11) or meclofenamate (N = 6) the increases in systolic (41%), diastolic (45%), and mean (41%) arterial pressures, LV systolic pressure (39%), LV dP/dt (52%), and cardiac work caused by BCO were significantly greater, in spite of the initially higher baseline values (11-18%) following the administration of the drugs. In contrast, the changes in circumflex coronary blood flow and coronary vascular resistance to BCO were essentially the same before and after inhibition of prostaglandin synthesis. Systemic prostaglandin synthesis may, therefore, play a significant role in the control of systemic arterial pressure and myocardial function, most probably by modulating the release of norepinephrine from adrenergic nerve terminals, without adversely affecting coronary blood flow regulation.     

Reflex effect of skeletal muscle mechanoreceptor stimulation on the cardiovascular system

To determine the potential for mechanical stimulation of skeletal muscle to contribute to the reflex cardiovascular response to static contraction (exercise reflex), we examined the cardiovascular effects caused by either passive stretch or external pressure applied to the triceps surae muscles. First, the triceps surae were stretched to an average developed tension of 4.8 +/- 0.3 kg. This resulted in increases in mean arterial pressure (MAP) of 28 +/- 7 mmHg, dP/dt of 1,060 +/- 676 mmHg/s, and heart rate (HR) of 6 +/- 2 beats/min (P less than 0.05). Additionally, increments of 0.3, 0.5, 1.0, 2.0, 4.0, and 8.0 kg of tension produced by passive stretch elicited pressor responses of -6 +/- 1, 7 +/- 1, 16 +/- 3, 21 +/- 8, 28 +/- 6, and 54 +/- 9 mmHg, respectively. External pressure, applied with a cuff to the triceps surae to produce intramuscular pressures (125-300 mmHg) that were similar to those seen during static contraction, also elicited small increases in MAP (4 +/- 1 to 10 +/- 1 mmHg) but did not alter HR. Transection of dorsal roots L5-L7 and S1 abolished the responses to passive stretch and external pressure. Moreover, when the triceps surae were stretched passively to produce a pattern and amount of tension similar to that seen during static hindlimb contraction, a significant reflex cardiovascular response occurred. During this maneuver, the pressor response averaged 51% of that seen during contraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

H2O2 increases production of constrictor prostaglandins in smooth muscle leading to enhanced arteriolar tone in Type 2 diabetic mice

Our previous study showed that arteriolar tone is enhanced in Type 2 diabetes mellitus (T2-DM) due to an increased level of constrictor prostaglandins. We hypothesized that, in mice with T2-DM, hydrogen peroxide (H(2)O(2)) is involved in the increased synthesis of constrictor prostaglandins, hence enhanced basal tone in skeletal muscle arterioles. Isolated, pressurized gracilis muscle arterioles ( approximately 100 microm in diameter) of mice with T2-DM (C57BL/KsJ-db(-)/db(-)) exhibited greater basal tone to increases in intraluminal pressure (20-120 mmHg) than that of control vessels (at 80 mmHg, control: 25 +/- 5%; db/db: 34 +/- 4%, P < 0.05), which was reduced back to control level by catalase (db/db: 24 +/- 4%). Correspondingly, in carotid arteries of db/db mice, the level of dichlorofluorescein-detectable and catalase-sensitive H(2)O(2) was significantly greater. In control arterioles, exogenous H(2)O(2) (0.1-100 micromol/l) elicited dilations (maximum, 58 +/- 10%), whereas in arterioles of db/db mice H(2)O(2) caused constrictions (-28 +/- 8%), which were converted to dilations (maximum, 16 +/- 5%) by the thromboxane A(2)/prostaglandin H(2) (TP) receptor antagonist SQ-29548. In addition, arteriolar constrictions in response to the TP receptor agonist U-46619 were not different between the two groups of vessels. Endothelium denudation did not significantly affect basal tone and H(2)O(2)-induced arteriolar responses in either control or db/db mice. Also, in arterioles of db/db mice, but not in controls, 3-nitrotyrosine staining was detected in the endothelial layer of vessels. Thus we propose that, in mice with T2-DM, arteriolar production of H(2)O(2) is enhanced, which leads to increased synthesis of the constrictor prostaglandins thromboxane A(2)/prostaglandin H(2) in the smooth muscle cells, which enhance basal arteriolar tone. These alterations may contribute to disturbed regulation of skeletal muscle blood flow in Type 2 diabetes mellitus.     

ATP stimulates chemically sensitive and sensitizes mechanically sensitive afferents

We examined whether ATP stimulation of P2X purinoceptors would raise blood pressure in decerebrate cats. Femoral arterial injection of the P2X receptor agonist alpha,beta-methylene ATP into the blood supply of the triceps surae muscle induced a dose-dependent increase in arterial blood pressure. The maximal increase in mean arterial pressure (MAP) evoked by 0.1, 0.2, and 0.5 mM alpha,beta-methylene ATP (0.5 ml/min injection rate) was 6.2 +/- 2.5, 22.5 +/- 4.4, and 35.2 +/- 3.9 mmHg, respectively. The P2X receptor antagonist pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (2 mM ia) attenuated the increase in MAP elicited by intra-arterial alpha,beta-methylene ATP (0.5 mM), whereas the P2Y receptor antagonist reactive blue 2 (2 mM ia) did not affect the MAP response to alpha,beta-methylene ATP. In a second group of experiments, we tested the hypothesis that ATP acting through P2X receptors would sensitize muscle afferents and, thereby, augment the blood pressure response to muscle stretch. Two kilograms of muscle stretch evoked a 26.5 +/- 4.3 mmHg increase in MAP. This MAP response was enhanced when 2 mM ATP or 0.1 mM alpha,beta-methylene ATP (0.5 ml/min) was arterially infused 10 min before muscle stretch. Furthermore, this effect of ATP on the pressor response to stretch was attenuated by 2 mM pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (P < 0.05) but not by the P1 purinoceptor antagonist 8-(p-sulfophenyl)-theophylline (2 mM). These data indicate that activation of ATP-sensitive P2X receptors evokes a skeletal muscle afferent-mediated pressor response and that ATP at relatively low doses enhances the muscle pressor response to stretch via engagement of P2X receptors.     

Effects of prostaglandins on the cerebral circulation in the goat

The role of prostaglandins in producing cerebrovasodilation during hypercapnia was tested in goats. Cerebral blood flow (CBF) changes with increasing arterial PCO2 were measured before and after prostaglandin synthesis inhibition with indomethacin or ibuprofen. Both drugs produced significant decreases in CBF under control anesthetized conditions but had no significant effect on the cerebrovascular response to increased arterial PCO2. The effects of direct intracerebrovascular infusion of prostaglandin E₂ (PGE2), prostaglandin F2α (PGF2α) and prostacyclin were also measured. In the dose range tested (0.1–1 ug/min) PGF2α had no significant effect on cerebral blood flow (CBF). Both PGE2 and PGI2 produced an increase in CBF and the increase produced by PGI2 was significantly greater than that produced by PGE2. The effectiveness of each compound in producing cerebrovascular changes is consistent with the endogenous distribution of prostaglandins within the brain. These results suggest that prostaglandins, particularly PGI1, may be important in modulating cerebrovascular tone but have no role in increasing CBF during hypercapnia.     

Prostaglandin E2 and gestational hypotension in rabbits

Arterial levels of 13,14-dihydro-15-keto-PGE2 (PGE2-M), a stable metabolite of prostaglandin E2 (PGE2) were compared between unanesthetized pregnant (n = 12) and nonpregnant (n = 8) rabbits with the aim of elucidating the role PGE2 in the development of physiological hypotension associated with pregnancy. On the 20th and 22nd days of the 30 day gestation period the mean arterial concentrations of PGE2-M were about 10-times higher (p less than 0.05) and largely variable as compared to that of nonpregnant rabbits. Mean arterial pressure was not lower on either the 20th (69 +/- 4 mmHg, mean +/- SD) or the 22nd (70 +/- 3 mmHg) days of gestation (dg) than in nonpregnant rabbits (69 +/- 4 and 73 +/- 6 mmHg, respectively). On the 23rd dg hypotension was invariably present (61 +/- 5 mmHg vs 72 +/- 4 in nonpregnants, p less than 0.001), but arterial levels of PGE2-M (31.0 +/- 31.6 ng/ml) did not overcome those measured on earlier, normotensive days of gestation. Hypotension was also evident in a subgroup of pregnant rabbits (n = 4) with low PGE2-M concentrations in the nonpregnant range (3.2 +/- 1.5 ng/ml vs 1.9 +/- 1.2 in nonpregnant rabbits, ns). Since the arterial level of PGE2-M proved to correlate (p less than 0.001) with both the uteroplacental venous and renal venous PGE2 concentrations, we suggest that a key role of uteroplacental and renal PGE2 played in the development of gestational hypotension is not probable in rabbits.     

The unfolding and attempted refolding of mitochondrial aspartate aminotransferase from pig heart.

The role of prostaglandins in the regulation of muscle protein breakdown is controversial. We examined the influence of arachidonic acid (5 microM), prostaglandin E2 (PGE2) (2.8 microM) and the prostaglandin-synthesis inhibitor indomethacin (3 microM) on total and myofibrillar protein breakdown in rat extensor digitorum longus and soleus muscles incubated under different conditions in vitro. In other experiments, the effects of indomethacin, administered in vivo to septic rats (3 mg/kg, injected subcutaneously twice after induction of sepsis by caecal ligation and puncture) on plasma levels and muscle release of PGE2 and on total and myofibrillar protein breakdown rates were determined. Total and myofibrillar proteolysis was assessed by measuring production by incubated muscles of tyrosine and 3-methylhistidine respectively. Arachidonic acid or PGE2 added during incubation of muscles from normal rats did not affect total or myofibrillar protein degradation under a variety of different conditions in vitro. Indomethacin inhibited muscle PGE2 production by incubated muscles from septic rats, but did not lower proteolytic rates. Administration in vivo of indomethacin did not affect total or myofibrillar muscle protein breakdown, despite effective plasma levels of indomethacin with decreased plasma PGE2 levels and inhibition of muscle PGE2 release. The present results suggest that protein breakdown in skeletal muscle of normal or septic rats is not regulated by PGE2 or other prostaglandins.     

Haemodynamic effects of respiratory alkalosis independent of changes in airway pressure in anaesthetized newborn dogs

We have recently reported a decrease in cardiac output in newborn dogs during respiratory alkalosis which is independent of changes in airway pressure. The present study was designed to characterize the mechanism responsible for this reduction in cardiac output. Twelve newborn coonhounds were anaesthetized with pentobarbital, paralyzed with pancuronium and hyperventilated to an arterial carbon dioxide tension (PaCO2) of 20 torr. Subsequent changes in PaCO2 were achieved by altering the FiCO2. Measurements were made after 30 min at either 40 or 20 torr PaCO2. The sequence of PaCO2 levels was randomized. Compared to normocarbia, respiratory alkalosis resulted in significantly decreased cardiac output (279 +/- 16 to 222 +/- 10 ml/min per kg, mean +/- SEM, P less than 0.001), stroke volume (1.60 +/- 0.10 to 1.24 +/- 0.06 ml/kg; P less than 0.001), maximum left ventricular dP/dt (1629 +/- 108 to 1406 +/- 79 mmHg/s, P less than 0.01) and left ventricular end diastolic pressure (3.9 +/- 0.4 to 2.9 +/- 0.3 mmHg; P less than 0.001). The decrease in cardiac output during respiratory alkalosis is manifest through a decrease in stroke volume, which is due, at least in part, to the decrease in left ventricular end diastolic pressure. The decrease in maximum left ventricular dP/dt is likely a reflection of the decrease in preload, however, a change in myocardial contractility cannot be excluded. We speculate the decrease in filling pressure may be due to an increase in venous capacitance.     

Stimulation of splanchnic afferents reflexly relaxes tracheal smooth muscle in dogs

Although chemical stimulation of abdominal visceral afferents has been shown to reflexly increase cardiovascular and ventilatory function, the effect of stimulating these afferents on airway smooth muscle is unknown. Therefore, we recorded transverse smooth muscle tension from an innervated segment of trachea in chloralose-anesthetized dogs while we topically applied capsaicin (200 micrograms/ml) and bradykinin (0.01-10 micrograms/ml) to the serosal surfaces of the stomach, small intestine, and gallbladder. Application of these irritant substances to the stomach and small intestine decreased tracheal tension and increased mean arterial pressure. However, application of capsaicin and bradykinin to the gallbladder had only small effects on both of these variables. Cutting the splanchnic nerves abolished or greatly attenuated the decreases in tension and increases in mean arterial pressure, whereas cutting the vagi had no effect on them. We conclude that stimulation of splanchnic afferent endings in the stomach and small intestine reflexly relaxes tracheal smooth muscle in dogs. This effect may be one component of the constellation of autonomic responses reflexly evoked by abdominal visceral pain and inflammation.     

Gender differences on the effects of aging on cardiac and peripheral adrenergic stimulation in old conscious monkeys

We examined the effects of gender and aging on cardiac and peripheral hemodynamic responses to beta-adrenergic receptor (beta-AR) stimulation in young (male = 5.9 +/- 0.4 yr old and female = 6.5 +/- 0.7 yr old) and old (male = 19.8 +/- 0.7 yr old and female = 21.2 +/- 0.2 yr old) conscious monkeys (Macaca fascicularis), chronically instrumented for measurements of left ventricular (LV) and arterial pressures as well as cardiac output. Baseline LV pressure, the first derivative of LV pressure (LV dP/dt), cardiac index, mean arterial pressure, total peripheral resistance (TPR), and heart rate in conscious monkeys were not different among the four groups. Increases in LV dP/dt in response to 0.1 microg/kg isoproterenol (Iso) were diminished (P < 0.05) in old males (+99 +/- 11%) compared with young males (+194 +/- 18%). In addition, the inotropic responses to norepinephrine (NE) and forskolin (FSK) were significantly depressed (P < 0.05) in old males. Iso-induced reductions of TPR were less (P < 0.05) in old males (-28 +/- 2%) than in young males (-49 +/- 2%). The changes of TPR in response to NE and FSK were also significantly attenuated (P < 0.05) in old males. However, the LV dP/dt responses to BAY y 5959 (15 microg. kg-1. min-1), a Ca2+ channel promotor independent of beta-AR signaling, were not significantly different between old and young males. In contrast to results in male monkeys, LV dP/dt and TPR responses to Iso, NE, and FSK in old females were similar to those observed in young females. Thus both cardiac contractile and peripheral vascular dynamic responses to beta-AR stimulation are preserved in old female but not old male monkeys. This may explain, in part, the reduced cardiovascular risk in the older female population.     

Effects of bradykinin on DNA synthesis in resting NIL8 hamster cells and human fibroblasts

Bradykinin stimulates [3H]thymidine incorporation and DNA synthesis in resting, serum-deprived NIL8 hamster cells. The ED50 for this stimulation is 4.52 +/- 2.91 nM. Other kinin peptides including lys-bradykinin (kallidin) and met-lys-bradykinin also stimulate [3H]thymidine incorporation in the NIL8 cells, whereas desarg9-bradykinin is without effect, suggesting action of the kinin peptides through type B2 receptors. Bradykinin also stimulates DNA synthesis in IMR-90 human fibroblasts; however, this effect is observed only in the presence of indomethacin, which blocks prostaglandin synthesis. These results suggest that prostaglandins act as negative modulators of the growth-stimulatory effects of bradykinin in the fibroblasts. This conclusion is supported by the observation that exogenously added PGE1, PGE2, PGA1, PGA2, PGB1, and PGB2 strongly inhibit [3H]thymidine incorporation in the human fibroblasts. The direct effect of bradykinin observed in the NIL8 cells may be attributable to the relative resistance of these cells to growth inhibition by prostaglandins.     

Reflex cardiovascular and ventilatory responses to increasing H+ activity in cat hindlimb muscle

Static exercise increases arterial pressure, heart rate, and ventilation, effects which are believed in part to arise reflexly from a metabolic stimulus in the working muscle. In anesthetized cats, we tested the hypothesis that intra-arterial injections of lactic and hydrochloric acid, which created levels of these substances in muscle similar to those seen during contraction, reflexly increased cardiovascular and ventilatory function. Hydrochloric acid (32 and 57 mM; 1 ml) injected into the arterial supply of the triceps surae decreased intramuscular pH from 7.26 +/- 0.05 to 7.17 +/- 0.05 (P less than 0.01) and reflexly increased arterial pressure (23 +/- 7 mmHg; P less than 0.01), heart rate (11 +/- 2 beats/min; P less than 0.001), and ventilation (187 +/- 72 ml/min; P less than 0.05). Static contraction of the triceps surae decreased intramuscular pH from 7.28 +/- 0.06 to 7.13 +/- 0.06 (P less than 0.01). Lactic acid was more potent in causing reflexes than was equimolar HCl. For example, lactic acid containing 4 mM lactate and 0.87 mM H+ reflexly increased arterial pressure, heart rate, and ventilation, whereas 0.87 mM HCl did not. Intra-arterial sodium lactate (13 and 33 mM) at a neutral pH had no effect on these variables. We conclude that contraction-induced accumulation of H+, especially that arising from lactic acid, might provide a metabolic stimulus to evoke reflex autonomic effects.     

Altered muscle metaboreflex control of coronary blood flow and ventricular function in heart failure

We investigated the effect of muscle metaboreflex activation on left circumflex coronary blood flow (CBF), coronary vascular conductance (CVC), and regional left ventricular performance in conscious, chronically instrumented dogs during treadmill exercise before and after the induction of heart failure (HF). In control experiments, muscle metaboreflex activation during mild exercise elicited significant reflex increases in mean arterial pressure, heart rate, and cardiac output. CBF increased significantly, whereas no significant change in CVC occurred. There was no significant change in the minimal rate of myocardial shortening (-dl/dt(min)) with muscle metaboreflex activation during mild exercise (15.5 +/- 1.3 to 16.8 +/- 2.4 mm/s, P > 0.05); however, the maximal rate of myocardial relaxation (+dl/dt(max)) increased (from 26.3 +/- 4.0 to 33.7 +/- 5.7 mm/s, P < 0.05). Similar hemodynamic responses were observed with metaboreflex activation during moderate exercise, except there were significant changes in both -dl/dt(min) and dl/dt(max). In contrast, during mild exercise with metaboreflex activation during HF, no significant increase in cardiac output occurred, despite a significant increase in heart rate, inasmuch as a significant decrease in stroke volume occurred as well. The increases in mean arterial pressure and CBF were attenuated, and a significant reduction in CVC was observed (0.74 +/- 0.14 vs. 0.62 +/- 0.12 ml x min(-1) x mmHg(-1); P < 0.05). Similar results were observed during moderate exercise in HF. Muscle metaboreflex activation did not elicit significant changes in either -dl/dt(min) or +dl/dt(max) during mild exercise in HF. We conclude that during HF the elevated muscle metaboreflex-induced increases in sympathetic tone to the heart functionally vasoconstrict the coronary vasculature, which may limit increases in myocardial performance.     

Acute haemodynamic effects of IL-6 treatment in vivo: involvement of vagus nerve in NO-mediated negative inotropism

Interleukin-6 (IL-6) reduces myocardial haemodynamics. However, the intrinsic mechanisms of IL-6 effects are not known. We hypothesized that nitric oxide (NO) synthesised by neuronal synthase (nNOS) can be the molecular mediator of IL-6-mediated cardiac effects. Thus, we investigated in vivo after IL-6 acute administration: (1) the role of NO pathway; (2) the importance of NO derived from nNOS located in intracardiac vagal ganglion in the anterior surface of the left ventricle. Sprague-Dawley (SD) rats (225-250 g) were anaesthetized (sodium pentobarbital 30 mg/kg intraperitoneally administered) and ventilated. The effects of a single IL-6 bolus (100 microg/kg intravenously administered) were studied in four experimental groups: (a) IL-6 (n=6), (b) IL-6 plus 30 mg/kg of L-NAME (an eNOS and nNOS inhibitor; n=6), (c) IL-6 plus 25mg/kg of 7-NI (a specific nNOS inhibitor; n=6), (d) IL-6 plus vagal resection (n=6). We evaluated the following parameters: mean aortic pressure (MAP), left ventricular end systolic pressure (LVESP), left ventricular positive peak dP/dt (PP dP/dt). Data are expressed as mean+/-sem. IL-6 caused a transient but significant reduction of MAP (-21.8% of basal: p<0.05), LVESP (from 130+/-4.2 to 1056.5 mmHg: p<0.05) and PP dP/dt (from 5390+/-158 to 4400+/-223 mmHg/s, p<0.02). Concomitant treatment with L-NAME or 7-NI totally abolished IL-6 effects. Vagal resection significantly reduced the haemodynamic effects (MAP: -10% of basal: p=ns; LVEDS: from 125+/-7.3 to 117+/-6.8 mmHg, p<0.05; PP dP/dt from 5500+/-150 to 5000+/-143 mmHg/s, p<0.05). We conclude that acute administration of IL-6 caused transient but significant cardiac negative inotropism. IL-6 haemodynamic effects are partly due to NO synthesised by nNOS located in vagal left ventricular ganglia.     

Potentiation of bradykinin-induced vascular permeability increase by prostaglandin E2 and arachidonic acid in rabbit skin.

The activity of prostaglandins (PG) in producing vascular permeability was quantitated by dye extraction method in skin of anaesthetized rabbits. PGE1 and PGE2 (0.01-10 mug) produced increase in vascular permeability. Activity was approximately equal to that of histamine (Hist) and 1/20 of that of bradykinin (BK) on a weight basis. The activity of PGF1alpha and PGF2alpha was only 1/20 of that of PGE1 or PGE2. In spite of the relatively low potency of PGE1 and PGE2 in the rabbit, near threshold doses (0.1 or 1 mug) of PGE2 could potentiate permeability responses to bradykinin (0.1 mug) by 10 or 100-fold, respectively. Equivalent doses (0.1 or 1 mug) of histamine could not potentiate the bradykinin responses. Arachidonic acid (AA) at 1 mug, produced a 10-fold potentiation in the permeability response to bradykinin (0.1 mug). Pretreatment of the rabbits with indomethacin (20 mg/kg, i.p.) reduced the responses of BK (0.1 mug) + AA (1 mug) down to a similar magnitude of those seen with bradykinin alone. However, indomethacin did not block responses to either, BK alone, BK + PGE2, or BK + Hist. Various doses (1, 10, 100 and 300 mug) of arachidonic acid alone also produced increase in cutaneous vascular permeability, although its potency was only 1/3-1/8 of that of PGE2. This activity of arachidonic acid was attributed in part to its bioconversion to PGE2, since its activity was significantly reduced by the prostaglandin antagonist, diphloretin phosphate (DPP) (60 mg/kg, i.v.) and by indomethacin (20 mg/kg, i.p.), which blocks conversion of arachidonic acid to prostaglandins. Arachidonic acid may owe some of its permeability increasing effects to histamine release, since its effects were also reduced by the anti-histamine, pyrilamine (2.5 mg/kg, i.v.).     

Effects of prostaglandins on the cerebral circulation in the coat

The role of prostaglandins in producing cerebrovasodilation during hypercapnia was tested in goats. Cerebral blood flow (CBF) changes with increasing arterial PCO2 were measured before and after prostaglandin synthesis inhibition with indomethacin or ibuprofen. Both drugs produced significant decreases in CBF under control anesthetized conditions but had no significant effect on the cerebrovascular response to increased arterial PCO2. The effects of direct intracerebrovascular infusion of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha) and prostacyclin were also measured. In the dose range tested (0.1-1) microgram/min) PGF2 alpha had no significantly greater than that produced by PGE2. The effectiveness of each compound in producing cerebrovascular changes is consistent with the endogenous distribution of prostaglandins within the brain. These results suggest that prostaglandins, particularly PGI2, may be important in modulating cerebrovascular tone but have no role in increasing CBF during hypercapnia.     

Vasoactive properties of dihomo-gamma-linolenic acid and series one prostaglandins in a freshwater teleost, Channa maculata

1. Prostaglandins A1, B1, E1 and F1 alpha (2-120 micrograms/kg), arachidonic acid and dihomo-gamma-linolenic acid (0.1-2 mg/kg) were injected intravenously into Channa maculata and changes in arterial blood pressure were recorded. 2. Injection of PGF1 alpha had no significant effect on arterial blood pressure. Injection of PGA1 and PGE1 was followed by dose-dependent hypotension whereas injection of PGB1 elicited significant dose-dependent increase in arterial blood pressure. 3. Both dihomo-gamma-linolenic acid and arachidonic acid were also depressor agents but dihomo-gamma-linolenic acid was more potent. 4. A single bolus intravenous injection of indomethacin (5 mg/kg) or 4 daily intraperitoneal injections (4 x 10 mg/kg) significantly lowered arterial blood pressure. One hour after pre-treatment of indomethacin, the vascular effects of both prostaglandin precursors were abolished. 5. It appears that the vascular effects of prostaglandins in Channa maculata are qualitatively different from those reported for mammals.     

Stimulatory effects of bradykinin on the ovulatory process in the in vitro-perfused rat ovary

The role of bradykinin in the ovulatory process was investigated using an in vitro-perfused rat ovary model. Stimulation with LH (0.1 micrograms/ml) resulted in 2.6 +/- 0.5 (mean +/- SEM) ovulations per ovary, whereas no ovulations occurred in the nonstimulated control group. Bradykinin (5 microM) added to the perfusion system hourly for 10 h induced 2 of 5 ovaries to ovulate, with 2 and 3 ovulations, respectively. When bradykinin (5 microM) was given as a single dose at 5 or 10 h after LH, the ovulation rate was significantly increased to 11.0 +/- 2.8 and 8.6 +/- 2.0 ovulations per ovary, respectively. A competitive bradykinin antagonist, phenylalanine bradykinin, inhibited the bradykinin-induced increase in LH-stimulated ovulations. The addition of LH, but not of bradykinin, increased the levels of prostaglandin endoperoxide synthase in granulosa cells, but the levels of the enzyme in the residual ovarian tissue were negligible. In contrast, prostacyclin synthase was predominantly located in the residual ovarian tissue. This enzyme was not affected by LH or bradykinin. LH increased the tissue levels of prostaglandins, predominantly prostaglandin E2 (PGE2), at 7 h, whereas the stimulatory effect of bradykinin was smaller, with a preferential increase in prostacyclin (prostaglandin I2) levels. This study indicates a modulatory role of bradykinin, possibly involving prostacyclin late in the ovulatory process, in the rat.     

Interactions between angiotensin II and nitric oxide during exercise in normal and heart failure rats.

We hypothesized that nitric oxide (NO) opposes ANG II-induced increases in arterial pressure and reductions in renal, splanchnic, and skeletal muscle vascular conductance during dynamic exercise in normal and heart failure rats. Regional blood flow and vascular conductance were measured during treadmill running before (unblocked exercise) and after 1) ANG II AT(1)-receptor blockade (losartan, 20 mg/kg ia), 2) NO synthase (NOS) inhibition [N(G)-nitro-L-arginine methyl ester (L-NAME); 10 mg/kg ia], or 3) ANG II AT(1)-receptor blockade + NOS inhibition (combined blockade). Renal conductance during unblocked exercise (4.79 +/- 0.31 ml x 100 g(-1) x min(-1) x mmHg(-1)) was increased after ANG II AT(1)-receptor blockade (6.53 +/- 0.51 ml x 100 g(-1) x min(-1) x mmHg(-1)) and decreased by NOS inhibition (2.12 +/- 0.20 ml x 100 g(-1) x min(-1) x mmHg(-1)) and combined inhibition (3.96 +/- 0.57 ml x 100 g(-1) x min(-1) x mmHg(-1); all P < 0.05 vs. unblocked). In heart failure rats, renal conductance during unblocked exercise (5.50 +/- 0.66 ml x 100 g(-1) x min(-1) x mmHg(-1)) was increased by ANG II AT(1)-receptor blockade (8.48 +/- 0.83 ml x 100 g(-1) x min(-1) x mmHg(-1)) and decreased by NOS inhibition (2.68 +/- 0.22 ml x 100 g(-1) x min(-1) x mmHg(-1); both P < 0.05 vs. unblocked), but it was unaltered during combined inhibition (4.65 +/- 0.51 ml x 100 g(-1) x min(-1) x mmHg(-1)). Because our findings during combined blockade could be predicted from the independent actions of NO and ANG II, no interaction was apparent between these two substances in control or heart failure animals. In skeletal muscle, L-NAME-induced reductions in conductance, compared with unblocked exercise (P < 0.05), were abolished during combined inhibition in heart failure but not in control rats. These observations suggest that ANG II causes vasoconstriction in skeletal muscle that is masked by NO-evoked dilation in animals with heart failure. Because reductions in vascular conductance between unblocked exercise and combined inhibition were less than would be predicted from the independent actions of NO and ANG II, an interaction exists between these two substances in heart failure rats. L-NAME-induced increases in arterial pressure during treadmill running were attenuated (P < 0.05) similarly in both groups by combined inhibition. These findings indicate that NO opposes ANG II-induced increases in arterial pressure and in renal and skeletal muscle resistance during dynamic exercise.