Influence of cyclooxygenase blockade on responses to isoproterenol, bradykinin and nitroglycerin in the feline pulmonary vascular bed

We investigated the effect of indomethacin on responses to isoproterenol, bradykinin and nitroglycerin in the feline pulmonary vascular bed when pulmonary vascular resistance was actively increased by infusion of U46619 in order to determine if vasodilator responses to these agents were dependent on the integrity of the cyclooxygenase pathway. Since pulmonary blood flow and left atrial pressure were held constant, changes in lobar arterial pressure directly reflect changes in lobar vascular resistance. Intralobar injections of isoproterenol, bradykinin, and nitroglycerin decreased lobar arterial pressure in a dose-related manner. Pulmonary vasodilator responses to the lower and midrange doses of bradykinin and nitroglycerin were unchanged in the presence of indomethacin whereas pulmonary responses to the highest doses of nitroglycerin and bradykinin were increased by cyclooxygenase blockade. In contrast, pulmonary vasodilator responses to isoproterenol were significantly attenuated in the presence of propranolol, whereas pulmonary vasodilator responses to bradykinin and nitroglycerin were unchanged after beta blockade. The present data indicate that isoproterenol, bradykinin, and nitroglycerin have significant vasodilator activity in the cat when pulmonary vascular tone is actively increased. These data suggest that the formation of vasodilator cyclooxygenase products such as PGI2 do not mediate vasodilator responses to isoproterenol, bradykinin, and nitroglycerin in the feline pulmonary vascular bed.     

Influence of cyclooxygenase blockade on responses to isoproterenol, bradykinin and nitroglycerin in the feline pulmonary vascular bed

We investigated the effect of indomethacin on responses to isoproterenol, bradykinin and nitroglycerin in the feline pulmonary vascular bed when pulmonary vascular resistance was actively increased by infusion of U46619 in order to determine if vasodilator responses to these agents were dependent on the integrity of the cyclooxygenase pathway. Since pulmonary blood flow left atrial pressure were held constant, changes in lobar arterial pressure directly reflect changes in lobar vascular resistance. Intralobar injections of isoproterenol, bradykinin, and nitroglycerin decreased lobar arterial pressure in a dose-related manner. Pulmonary vasodilator responses to the lower and midrange doses of bradykinin and nitrogylcerin were unchanged in the presence of indomethacin whereas pulmonary responses to the highest doses of nitroglycerin and bradykinin were increased by cyclooxygenase blockade. In contrast, pulmonary vasodilator responses to isoproterenol were significantly attenuated in the presence of propranolol, whereas pulmonary vasodilator responses to bradykinin and nitroglycerin were unchanged after beta blockade. The present data indicate that isoproterenol, bladykinin, and nitroglycerin have significant vasodilator activity in the cat when pulmonary vascular tone is actively increased. These data suggest that the formation of vasodilator cyclooxygenase products such as PGI₂ do not mediate vasodilator responses to isoproterenol, bradykinin, and nitroglycerin in the feline pulmonary vascular bed.     

Role of paraventricular nucleus in the cardiogenic sympathetic reflex in rats

Myocardial ischemia stimulates cardiac spinal afferents to initiate a sympathoexcitatory reflex. However, the pathways responsible for generation of increased sympathetic outflow in this reflex are not fully known. In this study, we determined the role of the paraventricular nucleus (PVN) in the cardiogenic sympathetic reflex. Renal sympathetic nerve activity (RSNA) and blood pressure were recorded in anesthetized rats during epicardial application of 10 microg/ml bradykinin. Bilateral microinjection of muscimol (0.5 nmol), a GABA(A) receptor agonist, was performed to inhibit the PVN. In 10 vehicle-injected rats, epicardial bradykinin significantly increased RSNA 178.4 +/- 48.5% from baseline, and mean arterial pressure from 76.9 +/- 2.0 to 102.3 +/- 3.3 mmHg. Microinjection of muscimol into the PVN significantly reduced the basal blood pressure and RSNA (n = 12). After muscimol injection, the bradykinin-induced increases in RSNA (111.6 +/- 35.9% from baseline) and mean arterial pressure (61.2 +/- 1.3 to 74.5 +/- 2.7 mmHg) were significantly reduced compared with control responses. The response remained attenuated even when the basal blood pressure was restored to the control. In a separate group of rats (n = 9), bilateral microinjection of the ionotropic glutamate antagonist kynurenic acid (4.82 or 48.2 nmol in 50 nl) had no significant effect on the RSNA and blood pressure responses to bradykinin compared with controls. These results suggest that the tonic PVN activity is important for the full manifestation of the cardiogenic sympathoexcitatory response. However, ionotropic glutamate receptors in the PVN are not directly involved in this reflex response.     

Effect of aminazine on cerebral circulation]

In acute experiments on anesthetized cats intravenous injection of chloromazine (2--3 mg/kg) caused a reduction in the tone of the cerebral vessels and decreased the general arterial pressure. The cerebral blood circulation increased with the stable arterial pressure or its moderate decrease. With a significant fall of arterial pressure the cerebral blood flow proved to decrease.     

Differential effects of prostaglandins A1 and A2 on pulmonary vascular resistance in the dog.

The effects of PGA1 and PGA2 were studied in the canine pulmonary vascular bed. Infusion of PGA1 into the lobar artery decreased lobar arterial and venous pressure but did not change left atrial pressure. In contrast, PGA2 infusion increased lobar arterial and venous pressure and the effects of this substance were similar in experiments in which the lung was perfused with dextran or with blood. These data indicate that under conditions of controlled blood flow PGA1 decreases pulmonary vascular resistance by dilating intrapulmonary veins and to a lesser extent vessels upstream to the small veins, presumably small arteries. The present data show that PGA2 increases pulmonary vascular resistance by constricting intrapulmonary veins and upstream vessels. The predominant effect of PGA2 was on upstream vessels and the pressor effect was not due to interaction with formed elements in the blood or platelet aggregation.     

N omega-nitro-L-arginine methyl ester selectively inhibits pulmonary vasodilator responses to acetylcholine and bradykinin.

The effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelium-derived relaxing factor (EDRF) production, on vascular tone and responses were investigated in the pulmonary vascular bed of the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. When pulmonary vascular tone was elevated with U-46619, intralobar injections of acetylcholine, bradykinin, sodium nitroprusside, isoproterenol, prostaglandin E1 (PGE1), lemakalim, and 8-bromo-guanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intravenous administration of L-NAME elevated lobar arterial and systemic arterial pressures without altering left atrial pressure. When U-46619 was infused after L-NAME to raise lobar arterial pressure to levels similar to those attained during the control period, vasodilator responses to acetylcholine and bradykinin were reduced significantly, whereas responses to PGE1, lemakalim, and 8-bromo-cGMP were not altered, and responses to nitroprusside were increased. There was a small effect on the response to the highest dose of isoproterenol, and pressor responses to BAY K 8644 and angiotensin II were not altered. These results are consistent with the hypothesis that EDRF production may involve the formation of nitric oxide or a nitroso compound from L-arginine and that EDRF production may have a role in the regulation of tone and in the mediation of responses to acetylcholine and bradykinin in the pulmonary vascular bed of the cat.     

Bradykinin actively modulates pulmonary vascular pressure-cardiac index relationships

Our objectives were to investigate the pulmonary vascular effects of exogenously administered bradykinin at normal and reduced levels of cardiac index in intact conscious dogs and to assess the extent to which the pulmonary vascular response to bradykinin is the result of either cyclooxygenase pathway activation or reflex activation of sympathetic beta-adrenergic and -cholinergic receptors. Multipoint pulmonary vascular pressure-cardiac index (P/Q) plots were constructed during normoxia in conscious dogs by step-wise constriction of the thoracic inferior vena cava to reduce Q. In intact dogs, bradykinin (2 micrograms X kg-1 X min-1 iv) caused systemic vasodilation, i.e., systemic arterial pressure was slightly decreased (P less than 0.05), Q was markedly increased (P less than 0.01), and mixed venous PO2 and oxygen saturation (SO2) were increased (P less than 0.01). Bradykinin decreased (P less than 0.01) the pulmonary vascular pressure gradient (pulmonary arterial pressure-pulmonary capillary wedge pressure) over the entire range of Q studied (140-60 ml X min-1 X kg-1) in intact dogs. During cyclooxygenase pathway inhibition with indomethacin, bradykinin again decreased (P less than 0.05) pulmonary arterial pressure-pulmonary capillary wedge pressure at every level of Q, although the magnitude of the vasodilator response was diminished at lower levels of Q (60 ml X min-1 X kg-1). Following combined administration of sympathetic beta-adrenergic and -cholinergic receptor antagonists, bradykinin still decreased (P less than 0.01) pulmonary arterial pressure-pulmonary capillary wedge pressure over the range of Q from 160 to 60 ml X min-1 X kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increase in kinins on post-exercise hypotension in normotensive and hypertensive volunteers

Post-exercise hypotension is an important event for blood pressure regulation, especially in hypertensive individuals. Although post-exercise hypotension is a well-known phenomenon, the mechanism responsible is still unclear. The kallikrein-kinin system is involved in blood pressure control, but its role in post-exercise hypotension has not yet been investigated. Thus, the purpose of this study was to investigate the involvement of the vasodilators bradykinin and des-Arg(9)-BK and kallikrein activity in post-exercise hypotension promoted by 35 min of cycle ergometer (CE) or circuit weight-training (CWT) bouts in normotensive and hypertensive individuals. A significant decrease in mean arterial pressure at 45 and 60 min after CE and 45 min after CWT was observed in normotensive individuals. Hypertensive values of mean arterial pressure were significantly reduced at 45 and 60 min after CE and at 60 min after CWT. Before exercise, plasma bradykinin concentrations and kallikrein activity were higher in hypertensive compared to normotensive volunteers. Kinin levels increased in the groups evaluated at the end of the training period and 60 min post-exercise. These data suggest that the kallikrein-kinin system may be involved in post-exercise hypotension in normotensive and hypertensive individuals subjected to CE and CWT bouts.     

Diuretic response to acute hypertension is blunted during angiotensin II clamp

Acute hypertension inhibits proximal tubule (PT) fluid reabsorption. The resultant increase in end proximal flow rate provides the error signal to mediate tubuloglomerular feedback autoregulation of renal blood flow and glomerular filtration rate and suppresses renal renin secretion. To test whether the suppression of the renin-angiotensin system during acute hypertension affects the magnitude of the inhibition of PT fluid and sodium reabsorption, plasma ANG II levels were clamped by infusion of the angiotensin-converting enzyme (ACE) inhibitor captopril (12 microg/min) and ANG II after pretreatment with the bradykinin B(2) receptor blocker HOE-140 (100 microg/kg bolus). Because ACE also degrades bradykinin, HOE-140 was included to block effect of accumulating vasodilatory bradykinins during captopril infusion. HOE-140 increased the sensitivity of arterial blood pressure to ANG II: after captopril infusion without HOE-140, 20 ng x kg(-1) x min(-1) ANG II had no pressor effect, whereas with HOE-140, 20 ng x kg(-1) x min(-1) ANG II increased blood pressure from 104 +/- 4 to 140 +/- 6 mmHg. ANG II infused at 2 ng x kg(-1) x min(-1) had no pressor effect after captopril and HOE-140 infusion ("ANG II clamp"). When blood pressure was acutely increased 50-60 mmHg by arterial constriction without ANG II clamp, urine output and endogenous lithium clearance increased 4.0- and 6.7-fold, respectively. With ANG II clamp, the effects of acute hypertension were reduced 50%: urine output and endogenous lithium clearance increased two- and threefold, respectively. We conclude that HOE-140, an inhibitor of the B(2) receptor, potentiates the sensitivity of arterial pressure to ANG II and that clamping systemic ANG II levels during acute hypertension blunts the magnitude of the pressure diuretic response.     

The blood-brain barrier: an alternative hypothesis

Brain blood vessels, unlike most vessels elsewhere in the body, exhibit a blood-brain barrier (BBB) to certain substances, e.g. trypan blue. Under some circumstances this barrier is no longer effective and the permeability of the vessels increases. Although capillarization is much less in the brain than in many other organs, e.g. heart muscle, total cerebral blood flow per minute is enormous. Consequently, to accommodate a large blood volume with a limited capillary bed, the velocity of blood through brain vessels must be extremely fast. The hypothesis presented in this paper is that this rapid flow results in a low or negative pressure on the endothelium, and plasma and trypan blue are prevented from passing through the wall. The tight junctions of cerebral endothelial cells may be able to withstand only a limited amount of pressure on their luminal surface. If the velocity of blood in brain capillaries decreases, pressure on the endothelium should increase, and brain vessels, like blood vessels elsewhere in the body, become permeable to vital dyes. Other conditions also increase capillary permeability, e.g. acute arterial hypertension or venous congestion. Although brain vessels can adapt to a moderate, gradual change in systemic pressure, when a significant rise in cerebral arterial pressure is abrupt, the compensatory changes in the postcapillary venous bed may be inadequate and consequently intracapillary pressure and vascular permeability are increased. Venous congestion increases intracapillary pressure by restricting capillary outflow as well as by reducing velocity through capillary beds. Under such conditions increased capillary permeability may be indicated by cerebral edema, and even, on occasion, by petechial hemorrhages. In short, if the flow is fast and unimpeded the BBB will be effective; if the velocity decreases, or intracapillary pressure increases for whatever reason, the permeability of the brain endothelium will be abnormally increased.     

Methylene blue selectively inhibits pulmonary vasodilator responses in cats

The effects of methylene blue on vascular tone and the responses to pressor and depressor substances were investigated in the constricted feline pulmonary vascular bed under conditions of controlled blood flow and constant left atrial pressure. When tone was elevated with U46619, intralobar injections of acetylcholine, bradykinin, nitroglycerin, isoproterenol, epinephrine, and 8-bromoguanosine-3',5'-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intralobar infusions of methylene blue elevated lobar arterial pressure without altering base-line left atrial or aortic pressure, heart rate, or cardiac output. When methylene blue was infused in concentrations that raised lobar arterial pressure to values similar to those attained during U46619 infusion, the pulmonary vasodilator responses to acetylcholine, bradykinin, and nitroglycerin were reduced significantly, whereas vasodilator responses to isoproterenol, epinephrine, and 8-bromo-cGMP were not altered. Moreover, the pressor responses to angiotensin II and BAY K 8644 during U46619 infusion and during methylene blue infusion were similar. The enhancing effects of methylene blue on vascular tone and inhibiting effects of this agent on responses to acetylcholine, bradykinin, and nitroglycerin were reversible. These responses returned to control value when tone was again increased with U46619, 30-45 min after the methylene blue infusion was terminated. The present data are consistent with the hypothesis that cGMP may play a role in the regulation of tone in the feline pulmonary vascular bed and in the mediation of vasodilator responses to the endothelium-dependent vasodilators, acetylcholine and bradykinin, and to nitrogen oxide-containing vasodilators such as nitroglycerin.     

Decreased arterial responses in WHHL rabbits, an animal model of spontaneous hypercholesterolemia and atherosclerosis.

We examined changes in blood pressure and blood flow of the arteries of WHHL and Japanese white rabbits after intravenous bolus injections of acetylcholine (3.0 micrograms/kg), bradykinin (0.5 microgram/kg), and sodium nitroprusside (3.0 micrograms/kg) under a condition of anesthesia. These vasodilators lowered the blood pressure and increased the blood flow in WHHL and Japanese white rabbits. The changes in the hemodynamic parameters of WHHL rabbits after injection of sodium nitroprusside were similar to those of Japanese white rabbits. This suggests that the relaxation response of the tunica media was not diminished in WHHL rabbits. In contrast, the changes in the hemodynamic parameters of WHHL rabbits after injection of acetylcholine or bradykinin were significantly lower than those in Japanese white rabbits. In the histopathological and immunohistological examination, atherosclerotic lesions were observed in the ascending aortas of WHHL rabbits. In the surface of the atheromatous plaques, CD31-positive endothelial cells disappeared partly and the accumulation of RAM-11-positive macrophages was observed in these regions. In addition, plasma NO2- and NO3- levels of WHHL rabbits were significantly lower than those of Japanese white rabbits. These findings suggest that relaxation responses derived from arterial endothelial cells were probably depressed in WHHL rabbits due to dysfunction or denudation of the arterial endothelial cells.     

Effect of taurine on the microvessel exchange function and adrenergic response of veins and arteries in the cat skeletal muscle

In cats anesthetized with Uretan and perfused with a constant blood volume, Taurine induced responses of neither arterial nor venous vessels of the skeletal muscle but increased the capillary filtration coefficient without any significant change of the capillary pressure in the skeletal muscle's microvessels. Taurine also increased both the constrictor and the dilatory responses of the arterial and venous vessels. The mechanism of the Taurine effects upon the smooth muscle elements of arteries and veins as well as upon proper mechanisms of capillary pressure control and capillary filtration coefficient, seems to be calcium-dependent.     

Kinins in humans

The kinin peptide system in humans is complex. Whereas plasma kallikrein generates bradykinin peptides, glandular kallikrein generates kallidin peptides. Moreover, a proportion of kinin peptides is hydroxylated on proline(3) of the bradykinin sequence. We established HPLC-based radioimmunoassays for nonhydroxylated and hydroxylated bradykinin and kallidin peptides and their metabolites in blood and urine. Both nonhydroxylated and hydroxylated bradykinin and kallidin peptides were identified in human blood and urine, although the levels in blood were often below the assay detection limit. Whereas kallidin peptides were more abundant than bradykinin peptides in urine, bradykinin peptides were more abundant in blood. Bradykinin and kallidin peptide levels were higher in venous than arterial blood. Angiotensin-converting enzyme inhibition increased blood levels of bradykinin, but not kallidin, peptides. Reactive hyperemia had no effect on antecubital venous levels of bradykinin or kallidin peptide levels. These studies demonstrate differential regulation of the bradykinin and kallidin peptide systems, and indicate that blood levels of bradykinin peptides are more responsive to angiotensin-converting enzyme inhibition than blood levels of kallidin peptides.     

Bradykinin-induced chemoreflexes from skeletal muscle: implications for the exercise reflex

We examined the cardiovascular response to bradykinin stimulation of skeletal muscle afferents and the effect of prostaglandins on this response. Intra-arterial injection of 1 microgram bradykinin into the gracilis muscle of cats reflexly increased mean arterial pressure by 16 +/- 2 mmHg, left ventricular end-diastolic pressure by 1.6 +/- 0.6 mmHg, maximal dP/dt by 785 +/- 136 mmHg/s, heart rate by 11 +/- 2 beats/min, and mean aortic flow by 22 +/- 3 ml/min. The hemodynamic responses were abolished following denervation of the gracilis muscle. The increases in mean arterial pressure and maximal dP/dt were reduced by 68 and 45%, respectively, following inhibition of prostaglandin synthesis with indomethacin (2-8 mg/kg iv). Treatment with prostaglandin E2 (PGE2, 15-25 micrograms ia) restored the initial increase in mean arterial pressure, but not dP/dt, caused by bradykinin stimulation. Injection of PGE2 (15-30 micrograms ia) into the gracilis, without prior treatment with indomethacin, augmented the bradykinin-induced increases in mean arterial pressure and dP/dt. We conclude that small doses of bradykinin injected into skeletal muscle are capable of reflexly activating the cardiovascular system and that prostaglandins are necessary for the full manifestation of the corresponding hemodynamic response. The pattern of hemodynamic adjustment following bradykinin injection into skeletal muscle is very similar to that induced by static exercise. Therefore, it is possible that intense exercise provides a stimulus for this bradykinin-induced reflex in vivo.     

Chronic angiotensin II AT1 receptor blockade increases cerebral cortical microvessel density

Angiotensin II is known to stimulate angiogenesis in the peripheral circulation through activation of the angiotensin II type 1 (AT1) receptor. This study investigated the effect of angiotensin receptor blockade on cerebral cortical microvessel density. Rats (6-7 wk old, n = 5-17) were instrumented with femoral arterial and venous indwelling catheters for arterial blood pressure measurement and drug administration. Rats were treated for 3 or 14 days with the AT1 receptor blocker losartan (50 mg/day in drinking water) or vehicle. Brains were sectioned and immunostained for CD31, and microvessel density was measured. Treatment with losartan for 3 or 14 days resulted in a slight decrease in mean arterial blood pressure (3 days, 92 +/- 1 mmHg; and 14 days, 99 +/- 2 mmHg) compared with vehicle (109 +/- 3 and 125 +/- 4 mmHg, respectively). A furosemide + captopril 14-day treatment group was added to control for the blood pressure change (96 +/- 3 mmHg). Microvessel density increased in groups treated with losartan for 14 days (429 +/- 13 vessels/mm2) compared with vehicle (383 +/- 11 vessels/mm2) but did not change with furosemide + captopril (364 +/- 7 vessels/mm2). Thus AT1 receptor blockade for 14 days resulted in increased cerebral microvessel density in a blood pressure-independent manner.     

Cardiopulmonary reflexes and blood pressure in exercising sinoaortic-denervated dogs

To examine the role of cardiopulmonary receptors in arterial blood pressure regulation during and after exercise, conscious dogs with chronic sinoaortic denervation were subjected to 12 min of light exercise and 12 min of exercise that increased in severity every 3 min. Hemodynamic measurements were made before and after interruption of cardiopulmonary afferents by bilateral cervical vagotomy. During both exercise protocols, after an initial transient decrease, the arterial blood pressure remained close to resting values before and after vagotomy. On cessation of the graded exercise, the arterial blood pressure did not change before, but a rapid and sustained increase in pressure occurred after vagotomy. At the time of this increase the cardiac output and heart rate were returning rapidly to the resting level. The study demonstrates that in the chronic absence of arterial baroreflexes, vagal afferents prevent a rise in arterial blood pressure after vigorous exercise presumably by the action of cardiopulmonary receptors causing a rapid dilatation of systemic resistance vessels.     

Embolization of the hepatic artery in cases of atypical anatomical structural variants in patients with malignant liver tumors

Therapeutic embolization of the hepatic artery was performed in 60 patients with nonresectable malignant liver tumors. Atypical topographical anatomical variants of the arterial system of the liver were revealed in 10 of them (16.7%). In 8 patients two hepatic vessels, one coming out of the celiac artery, the other--out of the upper mesenterial or left gastric artery supplied a tumor with blood. In three of them one vessel was embolized, in five patients both arteries were embolized. The blocking of the entire blood flow of a tumor brought about a positive clinical effect in all the patients. Embolization of one blood-supplying artery alone led to no improvement. A conclusion was made of a necessity to achieve arterial devascularization of the entire tumor tissue area during intravascular therapy.     

Cochlear blood flow during stepwise bleeding and CO2 inhalation in the anaesthetized dog and cat

Normal blood flow values, autoregulatory tendency and CO2 sensitivity of the cochlear blood vessels were studied in acute experiments in anesthetized, artificially ventilated dogs and cats. Cochlear blood flow was measured with the hydrogen-gas clearance technique using 100 mu platinum electrodes implanted into the perilymphatic space. Normal mean cochlear blood flow at normal systemic blood pressure and arterial pH values was found to be 30 +/- 7 ml . 100 g-1 . min-1 in the dog, and 16 +/- 5 ml . 100 g-1 . min-1 in the cat. There was no evidence of the existence of an autoregulatory mechanism of cochlear blood flow during stepwise bleeding in the dog. Blood flow seemed to follow passively the changes of arterial pressure. Cochlear blood flow increased by 79% on 5% CO2 inhalation in the cat, as a result of decreased vascular resistance. The relationship between arterial pCO2 values and cochlear blood flow proved to be exponential.     

Resistance and capacitance functions of gastric vessels under the action of noradrenaline

In acute experiments on cats, the gastric vascular bed being perfused under constant blood flow, the actions of gastric vessels was investigated using newly elaborated approach to their humoral isolation. Increased doses of noradrenaline elicited the dose-dependent constrictive response of gastric arterial vessels. Perfusion pressure increase in the gastric vascular bed under action of the minimal dose of noradrenaline was more pronounced, than in the intestinal vessels. The capacity of the gastric vascular bed under action of the drug changed in different manner, mostly increased, but could be decreased as well. In contrast to the small intestine the gastric vessels are characterized by more pronounced action of noradrenaline on blood depoting processes.