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At least 703 records · Page 39Linked to original sources
PubMed2005

Orexin 1 receptor activation attenuates neurogenic dural vasodilation in an animal model of trigeminovascular nociception.

The pathophysiology underlying the pulsating quality of the pain of a migraine attack is not fully understood, although trigeminal vascular afferents containing the sensory neuropeptide calcitonin gene-related peptide (CGRP) must have a role. Antimigraine drugs, such as triptans, serotonin 5-hydroxytryptamine(1B/1D) receptor agonists, reproducibly block neurogenic vasodilation associated with CGRP release. We examined the effects of the hypothalamic neuropeptides orexin A and orexin B on neurogenic dural vasodilation, dissecting out the receptor pharmacology with the novel orexin 1 (OX1) receptor antagonist N-(2-methyl-6-benzoxazolyl)-N''-1,5-naphthyridin-4-yl urea (SB-334867). Electrical stimulation of dural afferents (50-300 microA) resulted in reproducible dural vasodilation of 136 +/- 9%. Orexin A 30 microg kg(-1), but not 3 and 10 microg kg(-1), inhibited the dilation brought about by electrical stimulation over 60 min and maximally after 15 min by 60% (t7= 7.138; P < 0.001; n = 8). This response was reversed by pretreatment with the OX1 receptor antagonist SB-334867. Addition of CGRP(8-37) at the point of maximal effect of orexin A produced a further significant decrease in neurogenic dural vasodilation compared with orexin A only. CGRP administration (1 microg kg(-1)) produced a reproducible dural blood vessel dilation of 145 +/- 7% that was not inhibited by intravenous administration of orexin A (30 microg kg(-1)). Orexin B had no significant effect even at the highest dose. The current study demonstrates that orexin A is able to inhibit neurogenic dural vasodilation via activation of the OX1 receptor, resulting in inhibition of prejunctional release of CGRP from trigeminal neurons.

Animals↗
PubMed2001

Effects of coronary revascularisation on myocardial blood flow and coronary vasodilator reserve in hibernating myocardium.

OBJECTIVE: Previous studies have suggested that resting myocardial blood flow is within normal limits in most chronically dysfunctional left ventricular segments which improve function after coronary artery revascularisation (hibernating myocardium). The aim of this study was to assess myocardial blood flow and coronary vasodilator reserve in hibernating myocardium before and after coronary revascularisation. PATIENTS AND METHODS: 30 patients with multivessel coronary disease undergoing coronary revascularisation (21 patients with bypass grafting and nine with coronary angioplasty), and 21 age and sex matched healthy volunteers (controls). Myocardial blood flow (MBF, ml/min/g) was measured by positron emission tomography using oxygen-15 water at rest and after dipyridamole (MBFdip, 0.56 mg/kg in four minutes). Coronary vasodilator reserve was calculated as MBFdip/MBF. Regional wall motion was assessed with echocardiography. RESULTS: Before revascularisation there were 48 remote and 275 dysfunctional myocardial segments, of which 163 (59%) improved function after revascularisation (hibernating). In hibernating segments coronary vasodilator reserve before revascularisation was significantly lower than in remote segments (1.97 (0.7), p < 0.0001) and controls (3.2 (1.5), p < 0.0001). In hibernating segments, myocardial blood flow remained unchanged after revascularisation (0.94 (0.3) v 0.95 (0.3) ml/min/g, p = 0.3) while coronary vasodilator reserve increased (1. 47 (0.7) v 1.98 (1.0), p < 0.0001). Myocardial blood flow was similar in remote, hibernating segments before and after revascularisation and in controls. CONCLUSIONS: This study confirms that myocardial blood flow at rest in hibernating myocardium is within normal limits in most segments, and that hibernating myocardium is characterised by an impaired coronary vasodilator reserve which improves significantly after coronary revascularisation.

Adult↗
PubMed1977

Vasodilator treatment for acute and chronic heart failure.

The current status of the use of vasodilator drugs in the treatment of acute and chronic heart failure has been reviewed. It is apparent that vasodilator treatment can be used effectively in some patients with heart failure with a beneficial haemodynamics response, and that vasodilator agents are likely to find an important place in the management of such patients. Vasodilator treatment may be associated with complications and must be used with care. Though several nonparenteral vasodilator agents have been investigated, no ideal drug is yet available for the treatment of chronic heart failure. Nevertheless, it is probable that suitable drugs will emerge and find an important place in the management of such patients.

Aortic Valve Insufficiency↗
PubMed1999

Coronary endothelium-derived vasodilation during cooling and rewarming of the in situ heart.

The integrity of coronary vascular endothelial vasodilator function during core cooling and rewarming was investigated in a pentobarbital-anesthetized open-chest dog model. Vasodilator response was assessed as the change from baseline blood flow by injecting the endothelial-dependent vasodilator acetylcholine (ACh) (1.0 microg) or the endothelial-independent vasodilator nitroglycerin (NTG) (50 microg) into the left anterior descending (LAD) coronary artery. Change in blood flow was measured using a transit time ultrasonic volume flowmeter technique. During cooling and rewarming LAD blood flow was significantly decreased. After rewarming, aortic pressure was artificially elevated to reach control. This procedure restored heart work (LV-RPP, left ventricular rate pressure product) and coronary perfusion pressure, but LAD blood flow remained lowered. Ability to dilate the vascular bed supplied by LAD, after injections of ACh or NTG, was present both during cooling and rewarming. At 25 degrees C coronary blood flow (LAD) increased from 3 +/- 1 to 9 +/- 1 mL x min(-1) in response to both ACh and NTG. Posthypothermic blood flow increased from 7 +/- 1 to 19 +/- 2 and 20 +/- 3 mL x min(-1) in response to ACh and NTG, respectively. Measured as the percent change from baseline LAD blood flow, the response was not significantly different from the one obtained in prehypothermic hearts. In conclusion, coronary vasodilator function, both endothelium dependent and endothelium independent, is present but not maintained at the same level during cooling to 25 degrees C and rewarming. In spite of the deterioration of cardiac function, no selective defect in the endothelium-dependent response was detected, either during hypothermia or after rewarming.

Acetylcholine↗
PubMed1988

Nitric oxide-induced vasodilation of organic nitrate-tolerant rabbit aorta.

It is postulated that the organic nitrate vasodilator agents, including glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN), are prodrugs, such that biotransformation to the active inorganic metabolite, nitric oxide (NO), occurs prior to the onset of vasodilation. Furthermore, it is proposed that organic nitrate tolerance in vascular tissue involves decreased formation of NO. To test this latter hypothesis, we examined vasodilation induced by NO, GTN, and ISDN in non-tolerant, GTN-tolerant, and ISDN-tolerant rabbit aortic rings (RARs). Isolated RARs were contracted submaximally with phenylephrine; the time of onset of relaxation and percent relaxation of tissue were determined in response to NO (0.3 microM), GTN (0.03 microM), and ISDN (0.12 microM) before and after a 1-h treatment with 500 microM GTN, 500 microM ISDN, or buffer only. The data demonstrated that the response to NO was not changed in GTN-tolerant and ISDN-tolerant tissues, in which there was virtually no GTN-induced or ISDN-induced relaxation. These results are consistent with the postulate that organic nitrate vasodilator drugs must undergo biotransformation to NO before vasodilation can occur and that the mechanism of organic nitrate tolerance involves decreased formation of NO.

Animals↗
PubMed2005

Upregulation of endothelial cell Ca2+ signaling contributes to pregnancy-enhanced vasodilation of rat uteroplacental arteries.

Normal pregnancy is characterized by an increased uterine blood flow due to growth and remodeling of the maternal uterine vasculature and enhanced vasodilation of the uterine arteries. The objective of the present study was to examine the role of endothelial cell Ca2+ signaling in augmented endothelium-mediated vasodilation of uteroplacental arteries in late pregnancy. We performed fura-2-based measurements of the intracellular Ca2+ concentration ([Ca2+]i) in the cytoplasm of endothelial cells simultaneously with diameter in pressurized uterine arteries from nonpregnant (NP) and late-pregnant (LP) rats. Basal levels of endothelial cell [Ca2+]i were higher in arteries from LP rats compared with NP controls. Withdrawal of extracellular Ca2+ resulted in a decrease in the level of basal [Ca2+]i that was significantly larger in arteries of LP than NP rats. The rate of Mn2+ -induced quenching of fura-2 fluorescence was significantly elevated in late pregnancy, implicating augmented Ca2+ influx as a cause of increased basal levels of [Ca2+]i in endothelial cells. Elevation of intraluminal pressure resulted in a transient increase in endothelial [Ca2+]i that was markedly potentiated in late gestation. ACh-induced [Ca2+]i and vasodilator responses were significantly augmented in arteries of LP compared with NP rats and were abolished by BAPTA treatment, demonstrating a critical role of [Ca2+]i elevation in the production of endothelium-derived vasodilators. Together, these results indicate that late pregnancy is a state of enhanced basal and stimulated Ca2+ signaling in endothelial cells of uterine vessels, which may represent an important underlying mechanism for augmented vasodilation in the maternal uterine circulation.

Animals↗
PubMed1984

Adenosine and hypoxic pulmonary vasodilation.

We have previously shown that after exposure to an inspired O2 tension less than 25 Torr, isolated lungs perfused with autologous blood exhibit vasoconstriction followed by dilation. Because adenosine has been implicated as a mediator of hypoxic vasodilation in the systemic circulation and because the concentration of adenosine in the lung has been shown to increase with hypoxia, we tested the hypothesis that adenosine is the mediator of hypoxic pulmonary vasodilation. We first confirmed that adenosine was a vasodilator in isolated lungs of adult male ferrets. Next we added the enzyme adenosine deaminase (ADase), which inactivates adenosine by converting it to inosine, to the perfusate before exposure to one of two levels of hypoxia [inspiratory PO2 (PIO2) 18 or 0 Torr]. In comparison with untreated lungs, the time course of pulmonary arterial pressure at constant flow in lungs treated with ADase (24 mg protein or 6,000 U) was not different; however, when the vessels were constricted at PIO2 25 Torr, ADase prevented vasodilator responses to adenosine administered into either the perfusate or the airways, indicating penetration of active ADase into the interstitium. Unless adenosine released endogenously into the interstitium during hypoxia was somehow protected from the ADase which reached the interstitium, these results indicate that hypoxic pulmonary vasodilation was not mediated by adenosine.

Adenosine↗
PubMed1984

Persistent coronary vasodilation during long-term, supramaximal doses of adenosine.

Active and reactive hyperemias have been observed in the skeletal muscle circulation tachyphylactic to exogenous adenosine following 3-h supramaximal doses of the vasodilator. These findings failed to support a need for adenosine in metabolic control of skeletal muscle blood flow. The present study was conducted to determine if the coronary circulation also develops tachyphylaxis to adenosine while remaining sensitive to other metabolically linked vasodilator mechanisms. Experiments were conducted in eight pentobarbital-anesthetized, open-chest dogs whose blood flow in the left anterior descending coronary artery (LAD) was measured electromagnetically during 3-h infusion of adenosine into the LAD. Measurements of regional myocardial blood flow (radioactive microspheres), myocardial O2 consumption (Fick principle), and percent segment shortening (ultrasonic crystals) were also obtained. Adenosine was infused into the LAD at a rate of 27.0-72.0 mumol/min, depending on blood flow rate. Calculated concentration of adenosine in LAD blood averaged 0.484 +/- 0.111 mumol/ml, which was well in excess of that required for maximal coronary vasodilation. LAD blood flow averaged 21.5 +/- 2.2 ml/min during the preadenosine control condition. LAD blood flow after 3 h adenosine (123.3 +/- 23.0 ml/min) was not significantly different from that after 1-3 min adenosine (105.8 +/- 17.9 ml/min). There was no significant transmural variation in LAD blood flow during adenosine infusion. Adenosine had no significant effect on myocardial O2 consumption or percent segment shortening. Our results demonstrate persistent transmural vasodilation in the canine coronary circulation during long-term, supramaximal doses of adenosine and are consistent with a role for endogenous adenosine in maintenance of coronary vasodilation during sustained elevations in myocardial energy demands.

Adenosine↗
PubMed1985

Role of alpha-receptors in estrogen-induced vasodilation in nonpregnant sheep.

Estradiol-17 beta (E2) produces vasodilation in several systemic vascular beds, but most extensively in the nonpregnant uterus. It has been postulated that E2 induces this vasodilation via blockade of vascular alpha-adrenergic receptors. This hypothesis was tested in six chronically instrumented, nonpregnant sheep by comparing the systemic and uterine hemodynamic responses to intravenous E2, to an alpha-adrenergic receptor blocker, phentolamine, and to both agents given together. Uterine blood flow (UBF) increased significantly after E2 administration, from 20 +/- 7 to 233 +/- 37 (SE) ml/min. In contrast, phentolamine had no detectable effect on UBF or on the UBF response to E2 when both were given together. Similar contrasting responses were observed in the effects of E2 and/or phentolamine on the systemic vasculature. When responses to alpha-agonists were evaluated, there was no evidence of alpha-blockade following E2 despite the substantial vasodilation; in contrast, alpha-blockade was present during phentolamine administration when no vasodilation was noted. Therefore, we conclude that E2-induced vasodilation in chronically instrumented sheep is not mediated through blockade of vascular alpha-adrenergic receptors.

Animals↗
PubMed1985

Unique coronary vasodilator induction by leukotriene D4.

Coronary blood flow (CBF) and myocardial contractility decrease markedly in response to intracoronary administration of leukotriene D4 (LTD4). With steady infusion, however, both CBF and contractility escape, approaching preinfusion values despite ongoing LTD4 administration. To clarify the mechanism of this escape, we reinfused plasma from the coronary vein draining the myocardial area receiving LTD4. Introducing this plasma into a coronary artery caused a marked rise in coronary flow for the duration of the plasma infusion. Coronary flow reduction with vasopressin or mechanical occlusion matching that caused by LTD4 failed to elicit vasodilator production. Thus a unique coronary vasodilator factor is induced by LTD4. Whole blood or platelet-rich plasma incubated with LTD4 in vitro produced the same pattern of coronary dilation on intracoronary infusion; LTD4 incubation with platelet-poor plasma failed to elicit a vasodilation. The vasodilator factor is stable and is not potassium, a prostaglandin, catecholamine, histamine, serotonin, adenosine, adenosine diphosphate, or platelet-activating factor. Production of this leukotriene-induced vasodilator factor may account for the escape from LTD4-induced coronary constriction.

Adenosine↗
PubMed1990

Inosine transiently decreases coronary flow but potentiates vasodilation by adenosine.

To test whether inosine interferes with the action of adenosine, we investigated the effects of intracoronary administration of inosine, adenosine, 8-phenyltheophylline, and adenosine deaminase on isolated rat heart. Inosine did not change heart rate or developed tension but increased the effluent adenosine concentration. Inosine also decreased exogenous adenosine uptake and breakdown. After the start of the inosine infusion (20 microM), a transient 30% decrease of coronary flow took place within 0.5 min. The nucleoside caused sustained vasodilation, dependent on the concentration (30-400 microM). After the infusion we observed a transient vasodilation. A nonvasoactive inosine concentration (10 microM) combined with an adenosine concentration that increased flow by 60% (0.1 microM) raised vasodilation by another 60%. Infusion of adenosine, adenosine deaminase, or 8-phenyltheopylline did not influence the inosine-induced transient decrease of flow, suggesting that this decrease is independent of adenosine and its receptor. We conclude that inosine 1) potentiates the vasodilation induced by adenosine and 2) is a coronary vasodilator but probably also a vasoconstrictor.

Adenosine↗
PubMed1990

Nicotine-induced skeletal muscle vasodilation is mediated by release of epinephrine from nerve terminals.

To determine the role of sympathetic innervation on nicotine-induced alterations in peripheral (hindlimb) blood flow in the pentobarbital-anesthetized dog, one hindlimb was acutely denervated and remained attached to the body by only the femoral artery and vein, whereas the contralateral limb remained innervated and intact. Measurements were made of aortic pressure, femoral artery and venous pressures, femoral artery flow, and plasma catecholamine levels during intravenous systemic infusion of nicotine. The response to nicotine (9-36 micrograms.kg-1.min-1) on the denervated side was a transient increase followed by a persistent decrease in flow and increase in vascular resistance. The response in the innervated limb was a large increase in blood flow and decrease in vascular resistance. The vasoconstrictor and vasodilator responses could be abolished by pretreatment with both propranolol and phentolamine. The vasodilator response could not be abolished by cholinergic or histaminergic receptor antagonism. Hexamethonium abolished all systemic and peripheral responses to nicotine. Desipramine selectively abolished the vasodilator response in the innervated hindlimb. The vasodilator and vasoconstrictor responses could be mimicked with systemic or local administration of epinephrine. We conclude that, in the hindlimbs of dogs, nicotine stimulates the release of epinephrine from nerve terminals and/or tissue stores to activate beta 2-adrenoceptors and promote vasodilation in skeletal muscle of innervated preparations.

Adrenalectomy↗
PubMed1991

N omega-nitro-L-arginine attenuates endothelium-dependent pulmonary vasodilation in lambs.

To investigate the role of endothelium-derived relaxing factor (EDRF) in the regulation of resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation, we studied the hemodynamic effects of N omega-nitro-L-arginine (a new stereospecific EDRF inhibitor) in 10 spontaneously breathing lambs and then compared the hemodynamic responses to five vasodilators during pulmonary hypertension induced by the infusion of U-46619 (a thromboxane A2 mimetic) or N omega-nitro-L-arginine. N omega-nitro-L-arginine caused a significant dose-dependent increase in pulmonary arterial pressure. Pretreatment with L-arginine blocked this increase, but pretreatment with D-arginine did not, suggesting that N omega-nitro-L-arginine is a competitive inhibitor of L-arginine for EDRF production. During U-46619 infusions, acetylcholine, ATP-MgCl2, isoproterenol, sodium nitroprusside, and 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) decreased pulmonary arterial pressure. During N omega-nitro-L-arginine infusions, the decrease in pulmonary arterial pressure caused by acetylcholine and ATP-MgCl2 (endothelium-dependent vasodilators) was significantly attenuated, but the decrease caused by isoproterenol, sodium nitroprusside, and 8-bromo-cGMP (endothelium-independent vasodilators) was unchanged. This study supports the hypothesis that EDRF in part mediates resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation. N omega-nitro-L-arginine is useful for studying EDRF inhibition in intact animals.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Activated oxygen species do not mediate hypercapnia-induced cerebral vasodilation in newborn pigs.

In newborn pigs, vasodilation in response to hypercapnia is dependent on prostaglandin (PG) H synthase. We investigated the contribution of activated oxygen by-products to hypercapnia-induced PGH synthase-dependent dilation of pial arteries and arterioles in anesthetized newborn pigs. Activated oxygen species were generated on the cerebral surface using xanthine oxidase and hypoxanthine. Catalase, H2O2, and iron or N-(2-mercaptopropionyl)-glycine (MPG) were used to separate effects of superoxide anion and hydroxyl radical. All the activated oxygen species tested caused vasodilation of both arteries and arterioles. Vasodilation to all activated oxygen species was largely reversible with only the hydroxyl radical encouraging combination of xanthine oxidase, hypoxanthine, H2O2, and FeCl3, causing significant dilation 20 min after removal of treatment. Cotreatment with MPG blocked this residual dilation. Neither pretreatment with the extracellular superoxide anion radical scavenger, superoxide dismutase (SOD), the intracellular superoxide anion radical scavenger, Tiron, the H2O2 scavenger, catalase, nor hydroxyl radical scavengers, dimethyl sulfoxide (DMSO) and MPG, altered vasodilation of pial arteries or arterioles in response to hypercapnia. Furthermore, the increase in cerebral prostanoid synthesis in response to hypercapnia was not affected by pretreatment with SOD, Tiron, catalase, DMSO, or MPG. We conclude that the progressively reduced forms of oxygen that would be produced during PGH synthase metabolism of arachidonic acid can dilate pial arteries and arterioles of newborn pigs. However, these activated oxygen species are not responsible for the vasodilation to hypercapnia in the newborn pig, suggesting that eicosanoids cause the dilation.

Animals↗
PubMed1994

Indomethacin-sensitive CO2 reactivity of cerebral arterioles is restored by vasodilator prostaglandin.

To investigate the role of vasodilator prostanoids in the CO2-induced relaxation of cerebral arterioles, the present study examined the effect of exogenous prostaglandin (PG) E2 and nonprostanoid vasodilators, adenosine and sodium nitroprusside, on the indomethacin-impaired pial arteriolar response to CO2 in newborn piglets. Reactivity of pial arterioles (52-131 microns diam) was determined using a closed cranial window with intravital microscopy. Cortical prostanoid synthesis was assessed by analyzing for select prostanoids in cerebrospinal fluid sampled from under the cranial window. Inhalation of 7% CO2 caused an elevation of cortical 6-keto-PGF1 alpha and thromboxane (Tx) B2 and increased pial arteriolar diameter by 34 +/- 5%. Two cyclooxygenase inhibitors, indomethacin (5 mg/kg i.v.) and ibuprofen (30 mg/kg i.v.), abolished the CO2-induced elevation of cortical prostanoids. Indomethacin, but not ibuprofen, blocked the CO2-induced increase in pial arteriolar diameter. The indomethacin-impaired vasodilator response to CO2 was restored when PGE2 (0.1-1 microM) was applied topically to the cortical surface. Adenosine (1-100 microM) and sodium nitroprusside (0.5 microM) only partially restored the vasodilator response to CO2. The data suggest that vasodilator prostanoids facilitate cerebrovascular relaxation to CO2 and may play a permissive role in the relaxation response of vascular smooth muscle. The fact that adenosine (adenosine 3',5'-cyclic monophosphate-mediated dilator) and sodium nitroprusside (guanosine 3',5'-cyclic monophosphate-mediated dilator), were partially effective suggests a role for those intracellular signaling pathways. We speculate that receptor activation of intracellular pathways may alter Ca2+ sensitivity of the contractile apparatus in such a way that the relaxation response to CO2 can occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Opioids and nitric oxide contribute to hypoxia-induced pial arterial vasodilation in newborn pigs.

The present study was designed to investigate the contribution of opioids and nitric oxide (NO) to hypoxia-induced pial vasodilation. Newborn pigs equipped with a closed cranial window were used to measure pial arteriolar diameter and to collect cortical periarachnoid cerebrospinal fluid (CSF) for assay of opioids and guanosine 3',5'-cyclic monophosphate (cGMP). Hypoxia-induced pial dilation was potentiated by norbinaltorphimine, 10(-6) M, a kappa-opioid antagonist (25 +/- 2 vs. 33 +/- 3%, n = 5), but was blunted by beta-funaltrexamine, 10(-8) M, a mu-opioid antagonist (28 +/- 2 vs. 19 +/- 1%, n = 5). Hypoxia-induced vasodilation was associated with increased CSF methionine enkephalin, a mu-opioid agonist (884 +/- 29 vs. 2,638 +/- 387 pg/ml, n = 5). N omega-nitro-L-arginine (L-NNA), an NO synthase inhibitor (10(-6) M), also blunted hypoxia-induced vasodilation that was further diminished by coadministration of L-NNA and beta-funaltrexamine (26 +/- 2, 14 +/- 1, and 9 +/- 1%, respectively, n = 5). Reversal of the above order of antagonist administration resulted in similar inhibition of hypoxia-induced pial dilation. Hypoxia-induced vasodilation was also associated with an increase in CSF cGMP that was attenuated by L-NNA (2.1 +/- 0.1- vs. 1.1 +/- 0.2-fold change in CSF cGMP, n = 5). Sodium nitroprusside (10(-6) M) increased CSF cGMP and methionine enkephalin concentration similar to hypoxia. These data suggest that hypoxia-induced pial arterial vasodilation, in part, is due to NO and/or cGMP-induced methionine enkephalin release as well as the direct action of NO.

Amino Acid Oxidoreductases↗
PubMed1995

Dipyridamole, a cGMP phosphodiesterase inhibitor, causes pulmonary vasodilation in the ovine fetus.

Endogenous nitric oxide (NO) modulates fetal pulmonary vascular tone by stimulating guanosine 3',5'-cyclic monophosphate (cGMP) production in vascular smooth muscle. Because cGMP is hydrolyzed and inactivated by phosphodiesterase enzymes, we evaluated the hemodynamic effects of two cGMP-specific phosphodiesterase (PDE5) inhibitors, dipyridamole and zaprinast, in the near-term chronically prepared ovine fetus. Brief (10 min) intrapulmonary infusions of dipyridamole caused dose-dependent increases in left pulmonary artery flow and decreases in left pulmonary arterial resistance that persisted for > 40 min after termination of the infusion. Prolonged (2 h) infusions of dipyridamole caused sustained pulmonary vasodilation throughout the infusion period. To compare the hemodynamic effects of dipyridamole with the PDE5 antagonist zaprinast, we studied the responses to equimolar doses of both agents in four fetuses. Zaprinast caused dose-dependent pulmonary vasodilation that was equivalent to that noted with equimolar doses of dipyridamole. To determine whether adenosine is involved with dipyridamole-induced pulmonary vasodilation, we compared the hemodynamic response to dipyridamole before and after administration of the potent adenosine receptor (P1) antagonist 8-phenyltheophylline (8-PT). Pretreatment with 8-PT markedly attenuated adenosine-induced pulmonary vasodilation but had no effect on the hemodynamic response to dipyridamole. We conclude that cGMP-specific phosphodiesterase activity is important in regulating fetal pulmonary vascular tone. In addition, dipyridamole administration causes dose-dependent pulmonary vasodilation that is equivalent to zaprinast and not primarily due to its effects on adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1996

Pharmacological coupling and functional role for CGRP receptors in the vasodilation of rat pial arterioles.

In this study, we investigated the signal transduction underlying the vasodilator action of calcitonin gene-related peptide (CGRP) in the rat pial arterioles. In an in vivo experiment, changes in pial arterial diameters (20.2 +/- 1.9 microns) were observed under suffusion with mock cerebrospinal fluid containing CGRP (10(-9)-10(-7) M) directly through a closed cranial window. Changes in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in response to CGRP and levcromakalim were measured in the pial arterioles in an in vitro experiment. CGRP-induced vasodilation and cAMP production were significantly inhibited by specific CGRP antibody serum and CGRP-(8-37) fragment, suggesting involvement of the CGRP1 receptor subtype. Vasodilation and increase in cAMP production evoked by CGRP were inhibited not only by glibenclamide (ATP-sensitive K+ channel blocker) but also by charybdotoxin (large-conductance Ca(2+)-activated K+ channel blocker), but this was not the case for the isoproterenol-induced vasodilation and cAMP production. These findings implicate the ATP-sensitive K+ channels and the large-conductance Ca(2+)-activated K+ channels in the CGRP receptor-coupled cAMP production for vasodilation. Further study is required to identify whether the cAMP-dependent K+ channel activation is related to CGRP-induced vasorelaxation of the rat pial arterioles.

Animals↗