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PubMed2006

Haemoglobin and flow-mediated vasodilation.

A low [Hb] (Hb concentration) is out-balanced by peripheral vasodilation via mechanisms that are incompletely understood. Peripheral vasodilation is influenced by NO (nitric oxide) released from vascular endothelium in response to increased vessel wall shear stress, and absorption by Hb is the main mechanism by which the bioactivity of NO is disarmed. Thus we propose that graded NO absorption is the mechanism through which a low [Hb] is related to peripheral vasodilation. In the present study, we examined the relationship between [Hb] and FMD (flow-mediated vasodilation; 5 min of cuff ischaemia) of the radial and brachial arteries in 33 normal subjects and in 13 patients with Type II diabetes, known to have impaired NO-mediated vasodilation. The smaller radial artery provided the more sensitive test, as it had a 2-fold larger FMD than the brachial artery (22+/-18% compared with 9+/-18% respectively, in normal subjects; means+/-S.D., P<0.05). FMD of the radial artery had a negative correlation with [Hb] (r(2)=-0.66, P<0.05; n=27). In subjects with [Hb] below and above the median of 14.1 g/dl, the radial artery FMD was 30+/-22% compared with 13+/-12% respectively (P<0.05). In diabetic patients, FMD was lower and a co-variation with [Hb] could not be established. Thus, in normal subjects, NO-mediated endothelium-related vasodilation at least partly out-balanced the 'added burden' of a low [Hb] during post-ischaemic reperfusion.

Adult↗
PubMed1996

Effects of hCGRP 8-37 and the NK1-receptor antagonist SR 140.333 on capsaicin-evoked vasodilation in the pig nasal mucosa in vivo.

A novel pig in vivo model was used to study vascular effects of capsaicin, substance P and calcitonin gene-related peptide (CGRP) in the nasal mucosa and skin. An acoustic rhinometer was used to measure changes in nasal cavity volume, mainly representing changes in capacitance vessels in the vascular beds. The non-peptide NK1-receptor antagonist SR 140.333 and the CGRP-receptor antagonist hCGRP 8-37 were used to investigate the role of substance P and CGRP, respectively, in capsaicin-evoked vasodilation mediated through activation of sensory C-fibre afferents. In this study we show that SR 140.333 is a potent inhibitor of substance P-induced vasodilation in the nasal mucosa whereas it has no effect on the capsaicin-evoked responses. Substance P only elicited a minor and shortlasting increase in superficial skin blood flow; this response, however, was completely blocked after administration of SR 140.333. Capsaicin-evoked vasodilation in the skin was slightly reduced by SR 140.333. CGRP-induced vasodilation in the nasal mucosa and skin was of much longer duration than the substance P-induced response, and was thus similar to the vascular effects mediated by capsaicin. hCGRP 8-37 significantly reduced both the CGRP- and capsaicin-mediated vasodilation in the nasal mucosa and the decrease of nasal cavity volume. Although the peak vasodilation in the skin in response to capsaicin, was unaltered by blockade of CGRP-receptors, the integrated response was significantly reduced by hCGRP 8-37. The present results show that vasodilatory responses to activation of afferent nerves in the pig nasal mucosa and superficial skin are mainly dependent on CGRP, while NK1-receptor mechanisms seem to be of no or minor importance.

Animals↗
PubMed2002

Influence of the nature of pre-contraction on the responses to commonly employed vasodilator agents in rat-isolated aortic rings.

The relaxing properties of vasodilator drugs in vitro may depend on the characteristics of the contractile state of the vessel investigated. Rat-isolated thoracic aortas were exposed to different types of pre-contraction. The following vasoconstrictor agents were used: phenylephrine (PhE), a selective alpha1-adrenoceptor agonist; St 587, a partial alpha1-adrenoceptor stimulant; U46619 (U-46). a thromboxane A2 agonist: and potassium ions causing receptor-independent depolarization of the membrane. After pre-contraction, various differential vasodilator drugs were investigated: methacholine (MCh, endothelium dependent), sodium nitroprusside (SNP, NO donor), forskolin (FSK, adenylyl cyclase stimulant) and nifedipine, a Ca2+-antagonist (selective L-type calcium antagonist). The vasodilator activity of these compounds was quantified by their vasodilator potency value (pD2) and efficacy (Emax) obtained from their concentration-response curves. PhE (0.1, 0.3, 3 microM) caused isometric responses of 4.8 +/- 0.3, 6.5 +/- 0.3 and 7.8 +/- 0.5 mN, respectively. An increase of the PhE concentration from 0.1 to 3 microM did not influence the response to FSK while it reduced the pD2 of SNP (8.6 +/- 0.1 to 7.35 +/- 0.1). Under these conditions, only the Emax of MCh was reduced (96.3 +/- 4.3% to 43.3 +/- 6.9%). U46 (0.18, 0.3, 1 microM) increased the contractile force by 7.4 +/- 0.4, 8.8 +/- 0.3 and 10.4 +/- 0.3 mN, respectively. Increasing the concentration of U-46 from 0.18 to 1 microM affected only the efficacy of SNP (84 +/- 4.4% to 17 +/- 8.8%) and MCh (64.5 +/- 12.3% to 0.0 +/- 9.2%) and reduced the potency of FSK (7.91 +/- 0.26 to 7.15 +/- 0.10). The concentration of K+-ions from 25 to 30 and 40 mM increased the contractile force by 4.0 +/- 0.4, 7.0 +/- 0.5 and 10.8 +/- 0.4 mN, respectively. The increase in [K+] caused a potency decrease of FSK (7.1 +/- 0.0 to 5.8 +/- 0.0) whereas both efficacy and potency were reduced for SNP (95.6 +/- 1.8% to 65.8 +/- 1.9% and 8.7 +/- 0.1 to 7.2 +/- 0.1) and MCh (55.4 +/- 3.5% to 24.5 +/- 0.8% and 7.4 +/- 0.3 to 6.1 +/- 0.4). Inhibiting of the endothelial NO production by L-NAME 100 microM resulted after pre-contraction with PhE and potassium in comparable differences in properties for SNP. Pre-contraction with St 587 1, 3, 10 and 30 microM shows comparable results after nifedepine relaxation. The present experiments clearly demonstrate that the characteristics of the applied pre-contraction strongly, but differentially influence both the potency and efficacy of various vasodilator drugs in vitro. Accordingly, in vitro characterization of vasodilator drugs should be performed under a carefully standardized protocol of pre-contraction.

Animals↗
PubMed1987

Impaired forearm vasodilator reserve in patients with microvascular angina. Evidence of a generalized disorder of vascular function?

In previous work, we described a group of patients with angina-like chest pain and normal coronary arteries. These patients had impaired coronary vasodilator responses to the stress of rapid atrial pacing and to the administration of dipyridamole, a potent vasodilator of coronary arterioles. This abnormality appears to be localized to the prearteriolar microvascular bed. To determine whether these patients have a more generalized abnormality of vasodilator reserve, we used mercury-in-Silastic strain-gauge plethysmography to compare their hyperemic responses to forearm ischemia with those of normal controls. After 10 minutes of ischemia, peak forearm flow was 39.9 +/- 5.0 ml per minute per deciliter in the controls [corrected] and 31.7 +/- 10.5 in the patients [corrected] (21 percent reduction; 95 percent confidence interval, 4 percent to 37 percent). Flow responses were also significantly reduced after three and five minutes of ischemia. Correspondingly, the vascular resistance after ischemia was also consistently higher in the patients with microvascular angina. The degree of vasodilator impairment in the peripheral circulation correlated well with the degree of vasodilator impairment in the coronary circulation (r = 0.74; P less than 0.004). Thus, patients with microvascular angina appear to have an impairment of vasodilator reserve that affects not only their coronary circulation but also their peripheral arterial bed.

Adult↗
PubMed2002

Prostaglandins contribute to impaired angiotensin II-induced cerebral vasodilation after brain injury.

This study characterized the effects of fluid percussion brain injury (FPI) on angiotensin II (AII)-induced cerebral vasodilation, determined the role of prostaglandins in such changes and evaluated the contribution of two subtypes of AII receptors (AT(1) and AT(2)) to the effects of AII on cerebrovascular regulation. Topical AII (10(-8), 10(-6), 10(-4) M) elicited vasodilation, which was attenuated by FPI (10 +/- 1; 18 +/- 2; 27 +/- 1% vs. 2 +/- 1; 4 +/- 1; 7 +/- 1%). Such changes in diameter were associated with increases in CSF 6-keto-PGF(1alpha), the stable breakdown product of PGI(2) (1.5 +/- 0.1; 2.1 +/- 0.1; 4.0 +/- 0.3 fold) and TXB(2), the stable breakdown product of TXA(2) (1.2 +/- 0.1; 1.4 +/- 0.1; 1.6 +/- 0.1 fold). However, after FPI, increases in 6-keto PGF(1alpha) were blocked (1.0 +/- 0.1; 1.0 +/- 0.1; 1.1 +/- 0.1 fold) whereas TXB(2) release was enhanced (1.5 +/- 0.1; 1.8 +/- 0.1; 1.9 +/- 0.1 fold). Pretreatment with the cyclooxygenase inhibitor indomethacin (5 mg/kg i.v.) in FPI animals partially protected AII vasodilation (8 +/- 1; 14 +/- 2; 19 +/- 3%). CGP 42112A, a putative AT(2) agonist, elicited vasodilation, which was also blunted by FPI. Such dilation was not associated with CSF prostaglandin changes, and indomethacin did not protect responses altered by FPI. Vasodilatation caused by low concentrations of AII was blunted by an AT(1) antagonist ZD 7155 but unchanged by an AT(2) antagonist PD 123,319. The high AII concentration produced dilation that was blunted by both antagonists. These data show that FPI impairs AII-mediated vasodilation. These data suggest that FPI causes these changes via alteration in an AT(1)-mediated production of prostaglandins. These data additionally suggest that FPI induced impairment of AT(2) mediated vasodilation is independent of an altered production of prostaglandins.

Angiotensin II↗
PubMed1988

Intracellular mechanism of action of vasodilators.

Vasodilators that act directly at the level of the vasculature may be classified as either endothelium-dependent or endothelium-independent agents. Endothelium-dependent agents stimulate the endothelium to produce endothelium-derived relaxing factor (recently identified as NO) which relaxes vascular smooth muscle and increases cGMP. Endothelium-independent vasodilators may be divided into calcium antagonists, alpha 1-adrenergic antagonists, cAMP-elevating agents and cGMP-elevating agents. It is generally accepted that calcium-dependent phosphorylation of myosin light chains initiates smooth muscle contraction. A variety of evidence suggests that certain vasodilators inhibit calcium-dependent phosphorylation of myosin light chains and smooth muscle contraction via activation of cAMP- and cGMP-dependent protein phosphorylation. Since vascular smooth muscle cells and platelets have many properties in common, and since cAMP- and cGMP-elevating vasodilators inhibit both smooth muscle contraction and platelet aggregation, human platelets were used to study the effects of vasodilators on protein phosphorylation. It could be demonstrated that cAMP- and cGMP-regulated protein kinases are the intracellular mediators for prostaglandin-E1- and nitroprusside-induced protein phosphorylation, respectively. Furthermore, prostaglandin-E1- and nitroprusside-stimulated protein phosphorylation was found to be associated with an inhibition of the phosphatidylinositol cycle. Cyclic nucleotide-elevating vasodilators may inhibit smooth muscle contraction and platelet aggregation by regulating the flux through the phosphatidylinositol cycle, and the activity of myosin light-chain kinase and of calcium ATPases.

Animals↗
PubMed2004

Histamine inhibits conducted vasodilation through endothelium-derived NO production in arterioles of mouse skeletal muscle.

Conducted vasodilation along arterioles manifests the spread of hyperpolarization through gap junction channels along endothelium. Whereas histamine increases the permeability of capillary and venular endothelium, its effect on the integrity of arteriolar endothelium is unknown. We tested whether histamine could inhibit conducted vasodilation. In second-order arterioles (2A) supplying the cremaster muscle of C57BL6, PECAM-1-/-, and eNOS-/- mice (8-12 wk), neither resting (16+/-2 microm) nor maximal (38+/-2 microm) diameters were different. Acetylcholine (ACh) microiontophoresis (1 microA, 500 ms pulse) triggered vasodilation that was conducted >1400 microm along arterioles. Neither local (14+/-2 microm) nor conducted vasodilation (10+/-2 microm) was different among mice. Histamine (5 microM) had no effect on resting diameter or local vasodilation to ACh yet inhibited conduction by >50% in C57BL6 and PECAM-1-/- mice (P<0.05); this effect was abolished after blockade of NO synthase or of soluble guanylate cyclase. Washout of histamine restored conduction, though recovery was longer (P<0.05) in PECAM-1-/- mice vs. C57BL6 mice. Remarkably, conducted vasodilation in eNOS-/- mice was insensitive to histamine. These findings indicate that histamine inhibits cell-to-cell coupling through an NO-dependent mechanism and suggests a dynamic interaction among intercellular adhesion molecules and gap junction channels along arteriolar endothelium.

Acetylcholine↗
PubMed1996

Porcine gastroepiploic artery as an in vitro experimental model to study vasodilators in microsurgery.

Arterial vasospasm is a common problem in microsurgery. This pharmacological study compares seven vasodilators-lidocaine, papaverine, nicardipine, verapamil, diltiazem, sodium nitroprusside, and hydralazine-for their efficacy and potency in an experimental model of vasospasm. Porcine gastroepiploic arteries were cut into rings to measure isometric tension development in vitro. The arteries were preconstricted with endothelin-1, a stable thromboxane A2 analogue, norepinephrine, or potassium, and then exposed to increasing concentrations of each vasodilator. Every vasodilator except hydralazine and sodium nitroprusside was efficacious in producing near-maximal relaxation of arteries preconstricted with any vasospastic substance. The five efficacious vasodilators differed markedly in potency, as reflected in the concentrations producing half-maximal relaxation. The order of potency was nicardipine < or = verapamil or diltiazem < papaverine < lidocaine. This study suggests that nicardipine would be the most potent vasodilator for systemic or direct intra-arterial administration. Papaverine and lidocaine, in concentrations employed clinically, were both efficacious as topical vasodilators.

Animals↗
PubMed2002

Mild hypothermia can enhance pial arteriolar vasodilation induced by isoflurane and sevoflurane in cats.

OBJECTIVE: Volatile anesthetics have been shown to dilate cerebral vessels. Recent evidence suggests that mild hypothermia can alter vascular reactivity of the cerebral vessels. However, the effect of mild hypothermia on volatile anesthetic-induced vasodilation of cerebral vessels is unknown. In the present study, we investigated the effect of mild hypothermia on pial arteriolar vasodilation induced by isoflurane and sevoflurane in cats. DESIGN: Prospective, randomized, experimental study with repeated measures. SETTING: Investigational animal laboratory. SUBJECTS: Forty cats were used for the study of systemic administration of volatile anesthetics, and 22 cats were used for the study of topical administration of volatile anesthetics. INTERVENTIONS: This study was approved by the Animal Experiment Committee of Nara Medical University. Animals were anesthetized with pentobarbital to maintain suppressive electroencephalographic patterns, which were introduced to measure direct effects of anesthetic agents after removing metabolic effects. The cranial window technique, combined with microscopic video recording, was used for the measurement of small (50-100 microm) and large (100-200 microm) pial arteriolar diameter in an experiment. Animals were randomly assigned to either a normothermic (37 degrees C) or a hypothermic group (33 degrees C). Desired temperatures were maintained by using a water blanket. In the first phase of the study, the effect of hypothermia on pial arteriolar vasodilation induced by systemic administration of isoflurane or sevoflurane was assessed. Each cat received isoflurane or sevoflurane at 0.5, 1.0, 1.5, and 2.0 minimum alveolar anesthetic concentrations, and the diameter of pial arterioles was measured. In the second group of animals, the direct effect of isoflurane and sevoflurane on pial vessels was evaluated. The artificial cerebrospinal fluid bubbled with isoflurane or sevoflurane (minimum alveolar anesthetic concentrations of 1 or 3) was topically administered in the cranial window. MEASUREMENTS AND MAIN RESULTS: Systemic and topical administration of isoflurane and sevoflurane produced significant dilation of both small and large pial arterioles in a dose-dependent manner during normothermia. In the hypothermic group, vasodilation of small pial arterioles by systemic administration of isoflurane and sevoflurane at a high concentration was significantly larger than in the normothermic group (p <.05). Vasodilation of both small and large pial arterioles by topical administration of isoflurane and sevoflurane was significantly greater in the hypothermic group than in the normothermic group (p <.05). CONCLUSIONS: These results suggest that pial arteriolar vasodilation induced by isoflurane and sevoflurane can be enhanced by mild hypothermia in cats anesthetized with pentobarbital.

Anesthetics, Inhalation↗
PubMed1995

Cardiovascular interactions characterizing the vasodilator components of nicorandil in conscious dogs.

We conducted cardiovascular interaction studies in conscious dogs to characterize the cyclic GMP and KATP channel opener (PCO)-dependent peripheral vasodilator components of nicorandil (NIC). Intravenously (i.v.) administered NIC (6-24 microg/kg/min for 6 h) reduced arterial blood pressure (BP) and increased heart rate (HR), and 15 mug/kg/min NIC was simulated by combining the cyclic GMP vasodilator nitroglycerin (NTG 1-5 microg/kg/min i.v.) with the PCO minoxidil (MNX 0.23 microg/kg i.v.). Tolerance to NTG-induced vasodilation was accelerated by oral isosorbide dinitrate (ISD 400 mg/2.5 days), and MNX was antagonized by the KATP blocker U-37883A (6 microg/kg/min i.v.). U-37883A attenuated NIC-induced hypotension with a mild tachycardia, whereas chronic ISD attenuated and delayed NIC-induced hypotension, with a pronounced tachycardia. Chronic ISD plus U-37883A completely blocked NIC-induced hypotension, although NIC-induced tachycardia persisted. These studies demonstrate that the cyclic GMP component of NIC induces a minimally tachycardiac acute vasodilation at lower drug concentrations resistant to K ATP blockade but cross-tolerant to ISD. Conversely, the PCO component of NIC induces a more tachycardiac vasodilation at higher concentrations free of ISD cross-tolerance but sensitive to KATP blockade. Therefore, low-dose NIC free of adjunctive nitrates should optimize its cyclic GMP vasodilator component for clinical indications.

Animals↗
PubMed1997

Cutaneous vasodilation to acetylcholine in patients with essential hypertension.

Endothelium-dependent vasodilation is reduced in the forearm of patients with essential hypertension. To evaluate whether endothelium-dependent vasodilation is also reduced in the skin microcirculation of patients with essential hypertension, we evaluated the effect of acetylcholine, an endothelium-dependent vasodilator, and sodium nitroprusside, an endothelium-independent vasodilator, on cutaneous and total forearm blood flow in normotensive subjects (n = 8) and matched patients with essential hypertension (n = 9). We infused acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 microg/100 ml forearm tissue/min) and sodium nitroprusside (1, 2, and 4 microg/100 ml forearm tissue/min) into the brachial artery, and we measured cutaneous blood flow (laser Doppler flowmeter) and muscle blood flow (strain-gauge venous plethysmography) modifications. Both the cutaneous and muscle blood flow increases induced by acetylcholine were reduced in patients with essential hypertension as compared with normotensive controls, whereas the skin and muscle vasodilation induced by sodium nitroprusside was similar in the two groups of patients. These data confirm the impairment of endothelium-dependent vasodilation in the muscle vascular bed of patients with essential hypertension and demonstrate the presence of endothelial dysfunction in skin microcirculation.

Acetylcholine↗
PubMed2003

Effects of ketamine on isoflurane- and sevoflurane-induced cerebral vasodilation in rabbits.

Although ketamine has been reported to have little effect on the cerebral circulation when used with other anesthetics, its effect on the cerebral vascular response to volatile anesthetics, which increase cerebral blood flow in a concentration-dependent manner, remains obscure. A closed cranial window was prepared in 15 pentobarbital-anesthetized adult rabbits. The cerebral pial arteriolar alteration induced by either isoflurane (n = 8) or sevoflurane (n = 7) at 0 (before volatile anesthetic), 0.33, 0.67, and 1.0 minimum alveolar concentration (MAC) was measured under three consecutive conditions: intravenous infusion with saline, with ketamine, and with ketamine plus l-arginine. Ketamine reduced the vasodilation induced by 0.67 (120 +/- 9% versus 113 +/- 9%; P <.05) and 1.0 MAC isoflurane (136 +/- 11% versus 118 +/- 10%; P <.05), but l-arginine did not restore the isoflurane-induced cerebral vasodilation. In rabbits inhaling sevoflurane, the degree of cerebral vasodilator response was smaller than that by isoflurane, and the cerebral vasodilation was comparable whether in the presence or absence of ketamine (with or without l-arginine). In conclusion, ketamine reduces isoflurane-induced cerebral vasodilation, apparently independently of nitric oxide formation, while sevoflurane-induced cerebral vasodilation is not significantly affected by ketamine.

Anesthetics, Dissociative↗
PubMed1976

The release of a coronary vasodilator metabolite from the guinea-pig isolated perfused heart stimulated by catecholamines, histamine and electrical pacing and by exposure to anoxia.

1 A procedure involving two guinea-pig isolated hearts perfused in series is described for detecting in the recipient heart the release of a possible coronary vasodilator metabolite from the donor heart. 2 Adrenaline and isoprenaline stimulated the rate and force of contraction and produced a multiphasic coronary vascular response, the predominant phase of which was vasodilatation. When the beta-adrenoceptors of the recipient heart were blocked, stimulation of the donor heart by the catecholamines was associated with a coronary vasodilatation of the recipient heart. 3 Histamine stimulated rate and force of contraction and was predominantly coronary vasodilator. After blockade of histamine H1- and H2-receptors in the recipient heart, coronary vasodilatation followed increases in activity of the donor heart in response to histamine. 4 These vasodilator responses of the recipient heart were attributed to the release from the donor heart of a vasodilator metabolite by the increased activity. This is the proposed mechanism for the predominant coronary vasodilator response to catecholamines and histamine. 5 Periods of electrically-paced tachycardia and anoxia of the donor heart also led to the release of vasodilator activity. 6 The possible identity of the metabolite is discussed.

Animals↗
PubMed1994

Effects of NK1 receptor antagonists on vasodilation induced by chemical and electrical activation of sensory C-fibre afferents in different organs.

The effects of the non-peptide NK1 receptor antagonists, CP 96,345 and RP-67,580, were investigated in a model using anaesthetized pigs. Both the blood flow in the internal maxillary and the bronchial artery (ultrasonic flowmetry) and the superficial blood flow in nasal mucosa and the skin (laser-Doppler flowmetry) were monitored simultaneously. Vasodilation induced by substance P administered i.v. systemically was blocked by pretreatment with CP-96,345, 3 mg kg-1 but not by RP-67,580. CP-96,345 had no effects on the vasodilation induced by calcitonin gene-related peptide or vasoactive intestinal polypeptide. The capsaicin-induced vasodilation in the superficial blood flow of the nasal mucosa and the skin, was reduced after the CP-96,345 pretreatment. The vasodilation induced by capsaicin infusion in the internal maxillary or the bronchial artery was not affected by the CP-96,345 pretreatment. Electrical stimulation of the vagal nerve induced a vasodilation in the bronchial circulation which was not attenuated by pretreatment with CP-96,345. In the nasal mucosa and the skin NK1 receptors seem to be involved in the vasodilation in the superficial small vessels, due to chemical activation of sensory C-fibre afferents. Furthermore, CP-96,345 is a useful tool in the evaluation of NK1 receptor-mediated responses. RP-67,580 which has been shown to have NK1 antagonistic properties in the rat has no such effects in the domestic pig.

Afferent Pathways↗
PubMed1994

A renal vasodilator effect of angiotensin II revealed by dual thromboxane inhibition.

Angiotensin II (AII) stimulates arachidonate release from renal endothelial and other cells. Arachidonate is then metabolized by cyclooxygenase to prostaglandin (PG) H2, then PGI2 and thromboxane A2 (TXA2). PGH2 and TXA2 activate the same receptor and should augment AII-mediated vasoconstriction, whereas PGI2 is a vasodilator. We had previously shown that inhibiting TXA2 synthesis with furegrelate (FRG) redirects PGH2 metabolism toward PGI2, causing renal vasodilation. Because TXA2 synthesis inhibition may be incomplete and unmetabolized PGH2 may cause vasoconstriction, we reasoned that adding a PGH2/TXA2 receptor antagonist (BMS 180,290, formerly SQ 29548 (SQ)) to furegrelate should cause further renal vasodilation in the presence of AII. Eight groups of 10 Sprague-Dawley rats received 120-min intravenous infusions of vehicle, FRG (2 mg.kg-1 plus 2 mg.kg-1.h-1), SQ (2 mg.kg-1 plus 2 mg.kg-1.h-1), FRG plus SQ, AII (10 ng.kg-1.min-1), AII plus FRG, AII plus SQ, or AII plus FRG plus SQ. Mean arterial pressure (MAP), p-[14C]aminohippurate clearance (CPAH), and [3H]insulin clearance were averaged for each rat for the final 90 min in three clearance periods. MAP did not change with any treatment. Estimating renal vascular resistance as MAP/CPAH confirmed a renal vasoconstrictor effect of this dose of AII: 58.1 +/- 6.3 vs. 47.3 +/- 6.8 (arbitrary units) with the vehicle (p < 0.05). FRG, SQ, or their combination did not affect renal vascular resistance, but adding FRG or SQ to AII prevented AII-mediated renal vasoconstriction. Adding both to AII caused net renal vasodilation to 24.8 +/- 2.6 (p < 0.05 vs. vehicle). Inulin clearance changed in the same direction in all groups, but the changes were less marked. We conclude that stimulation of renal arachidonate release by AII combined with TXA2 synthesis inhibition and receptor antagonism results in vasodilation. This renal effect could be due to increased and unopposed renal vasodilator PG (principally PGI2) action.

Angiotensin II↗
PubMed1993

Adenosine is a mediator of ethanol-induced gastric vasodilation in dogs.

The purpose of this study was to assess the role of histamine, adenosine, and prostaglandins as mediators of ethanol-induced gastric vasodilation. In an ex vivo segment of canine stomach, vasodilation occurred within the first minute of replacing luminal saline with ethanol (40% vol/vol). Ethanol caused vascular resistance to progressively decrease by approximately 53% compared with control values. In other experiments, intra-arterial infusion of histamine (300 ng/ml) or adenosine (30 micrograms/ml) to the gastric segment produced similar degrees of vasodilation as observed with ethanol. The response to these vasodilators could be markedly attenuated with specific antagonists of these substances (histamine: pyrilamine plus cimetidine; adenosine: 8-phenyltheophylline). In our final experiments, indomethacin or histamine- or adenosine-receptor antagonists were given before application of topical ethanol. Indomethacin or histamine antagonists had no significant effect on the time course or magnitude of ethanol-induced vasodilation. In contrast, pretreatment with 8-phenyltheophylline significantly reduced changes in vascular resistance during exposure to luminal ethanol. These results suggest that locally released adenosine is an important mediator of ethanol-induced vasodilation in the canine stomach under these conditions.

Adenosine↗
PubMed2004

In vivo role of heme oxygenase in ischemic coronary vasodilation.

The heart constitutively expresses heme oxygenase (HO)-2, which catabolizes heme-containing proteins to produce biliverdin and carbon monoxide (CO). The heart also contains many possible substrates for HO-2 such as heme groups of myoglobin and cytochrome P-450s, which potentially could be metabolized into CO. As a result of observations that CO activates guanylyl cyclase and induces vascular relaxation and that HO appears to confer protection from ischemic injury, we hypothesized that the HO-CO pathway is involved in ischemic vasodilation in the coronary microcirculation. Responses of epicardial coronary arterioles to ischemia (perfusion pressure approximately 40 mmHg; flow velocity decreased by approximately 50%; dL/dt reduced by approximately 60%) were measured using stroboscopic fluorescence microangiography in 34 open-chest anesthetized dogs. Ischemia caused vasodilation of coronary arterioles by 36 +/- 6%. Administration of N(G)-monomethyl-L-arginine (L-NMMA, 3 micromol.kg(-1).min(-1) intracoronary), indomethacin (10 mg/kg iv), and K(+) (60 mM, epicardial suffusion) to prevent the actions of nitric oxide, prostaglandins, and hyperpolarizing factors, respectively, partially inhibited dilation during ischemia (36 +/- 6 vs. 15 +/- 4%; P < 0.05). The residual vasodilation during ischemia after antagonist administration was inhibited by tin mesoporphyrin IX (SnMP, 10 mg/kg iv), which is an inhibitor of HO (15 +/- 4 vs. 7 +/- 2%; P < 0.05 vs. before SnMP). The guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (10(-5) M, epicardial suffusion) also inhibited vasodilation during ischemia in the presence of L-NMMA with indomethacin and KCl. Moreover, administration of heme-L-arginate, which is a substrate for HO, produced dilation after ischemia but not after control conditions. We conclude that during myocardial ischemia, HO-2 activation can produce cGMP-mediated vasodilation presumably via the production of CO. This vasodilatory pathway appears to play a backup role and is activated only when other mechanisms of vasodilation during ischemia are exhausted.

Animals↗
PubMed2003

Coronary blood flow regulation in exercising swine involves parallel rather than redundant vasodilator pathways.

In dogs, only combined blockade of vasodilator pathways [via adenosine receptors, nitric oxide synthase (NOS) and ATP-sensitive K+ (KATP) channels] results in impairment of metabolic vasodilation, which suggests a redundancy design of coronary flow regulation. Conversely, in swine and humans, blocking KATP channels, adenosine receptors, or NOS each impairs coronary blood flow (CBF) at rest and during exercise. Consequently, we hypothesized that these vasodilators act in parallel rather than in redundancy to regulate CBF in swine. Swine exercised on a treadmill (0-5 km/h), during control and after blockade of KATP channels (with glibenclamide), adenosine receptors [with 8-phenyltheophylline (8-PT)], and/or NOS [with Nomega-nitro-l-arginine (l-NNA)]. l-NNA, 8-PT, and glibenclamide each reduced myocardial O2 delivery and coronary venous O2 tension. These effects of l-NNA, 8-PT, and glibenclamide were not modified by simultaneous blockade of the other vasodilators. Combined blockade of KATP channels and adenosine receptors with or without NOS inhibition was associated with increased H+ production and impaired myocardial function. However, despite an increase in O2 extraction to >90% during administration of l-NNA + 8-PT + glibenclamide, vasodilator reserve could still be recruited during exercise. Thus in awake swine, loss of KATP channels, adenosine, or NO is not compensated for by increased participation of the other two vasodilator mechanisms. These findings suggest a parallel rather than a redundancy design of CBF regulation in the porcine circulation.

ATP-Binding Cassette Transporters↗