Perfusion of Intrapulmonary Arteriovenous Anastomoses Is Not Related to VO2max in Hypoxia and Is Unchanged by Oral Sildenafil.

Background: Perfusion of intrapulmonary arteriovenous anastomoses (IPAVA) is increased during exercise and in hypoxia and is associated with variations in oxygen saturation (SPO2), resulting in blood bypassing the pulmonary microcirculation. Sildenafil is a pulmonary vasodilator that improves SPO2 and endurance performance in hypoxia. The purpose of this study was to determine if 50 mg sildenafil would reduce IPAVA perfusion (QIPAVA) and if the decrement in maximal exercise capacity (VO2max) in hypoxia is related to QIPAVA. We hypothesized that during progressive levels of hypoxia at rest (FIO2 = 0.21, 0.14, 0.12), sildenafil would increase SPO2 and reduce bubble score (estimate of QIPAVA) compared to placebo, and that the decrement in VO2max in hypoxia would be positively correlated with bubble score at rest in hypoxia. Materials and Methods: Fourteen endurance-trained men performed a graded maximal exercise test at sea level and at a simulated altitude of 3000 m, followed by two experimental visits where, after randomly ingesting sildenafil or placebo, they underwent agitated saline contrast echocardiography during progressive levels of hypoxia at rest. Results: All participants experienced a decrement in power output in hypoxia that ranged from 9% to 19% lower than sea level values. Compared to normoxia, bubble score increased significantly in hypoxia (p < 0.001) with no effect of sildenafil (p = 0.580). There was a negative correlation between SPO2 and bubble score (p < 0.001). The decrement in peak power output at VO2max in hypoxia was unrelated to IPAVA perfusion in resting hypoxia (p = 0.32). Several participants demonstrated QIPAVA greater than zero in room air, indicating that arterial hypoxemia may not be the sole mechanism for QIPAVA. Conclusion: These results indicate that the VO2max decrement caused by hypoxia is not related to QIPAVA and that sildenafil does not improve VO2max in hypoxia through modulation of QIPAVA.

Arterio-venous anastomoses in isolated, perfused rat lungs.

Several studies have suggested that large-diameter (>25 µm) arterio-venous shunt pathways exist in the lungs of rats, dogs, and humans. We investigated the nature of these pathways by infusing specific-diameter fluorescent latex particles (4, 7, 15, 30, or 50 µm) into isolated, ventilated rat lungs perfused at constant pressure. All lungs received the same mass of latex (5 mg), which resulted in infused particle numbers that ranged from 1.7 × 107 4 µm particles to 7.5 × 104 50 µm particles. Particles were infused over 2 min. We used a flow cytometer to count particle appearances in venous effluent samples collected every 0.5 min for 12 min from the start of particle infusion. Cumulative percentages of infused particles that appeared in the samples averaged 3.17 ± 2.46% for 4 µm diameter particles, but ranged from 0.01% to 0.17% for larger particles. Appearances of 4 µm particles followed a rapid upslope beginning at 30 sec followed by a more gradual downslope that lasted for up to 12 min. All other particle diameters also began to appear at 30 sec, but followed highly irregular time courses. Infusion of 7 and 15 µm particles caused transient but significant perfusate flow reductions, while infusion of all other diameters caused insignificant reductions in flow. We conclude that small numbers of bypass vessels exist that can accommodate particle diameters of 7-to-50 µm. We further conclude that our 4 µm particle data are consistent with a well-developed network of serial and parallel perfusion pathways at the acinar level.

Dopamine receptor blockade improves pulmonary gas exchange but decreases exercise performance in healthy humans.

Pulmonary gas exchange, as evaluated by the alveolar-arterial oxygen difference (A-aDO2), is impaired during intense exercise, and has been correlated with recruitment of intrapulmonary arteriovenous anastomoses (IPAVA) as measured by agitated saline contrast echocardiography. Previous work has shown that dopamine (DA) recruits IPAVA and increases venous admixture (Q̇s/Q̇t) at rest. As circulating DA increases during exercise, we hypothesized that A-aDO2 and IPAVA recruitment would be decreased with DA receptor blockade. Twelve healthy males (age: 25 ± 6 years, V̇O2 max : 58.6 ± 6.5 ml kg(-1) min(-1) ) performed two incremental staged cycling exercise sessions after ingestion of either placebo or a DA receptor blocker (metoclopramide 20 mg). Arterial blood gas, cardiorespiratory and IPAVA recruitment (evaluated by agitated saline contrast echocardiography) data were obtained at rest and during exercise up to 85% of V̇O2 max . On different days, participants also completed incremental exercise tests and exercise tolerance (time-to-exhaustion (TTE) at 85% of V̇O2 max ) with or without dopamine blockade. Compared to placebo, DA blockade did not change O2 consumption, CO2 production, or respiratory exchange ratio at any intensity. At 85% V̇O2 max , DA blockade decreased A-aDO2, increased arterial O2 saturation and minute ventilation, but did not reduce IPAVA recruitment, suggesting that positive saline contrast is unrelated to A-aDO2. Compared to placebo, DA blockade decreased maximal cardiac output, V̇O2 max and TTE. Despite improving pulmonary gas exchange, blocking dopamine receptors appears to be detrimental to exercise performance. These findings suggest that endogenous dopamine is important to the normal cardiopulmonary response to exercise and is necessary for optimal high-intensity exercise performance.

Hypoxia, not pulmonary vascular pressure, induces blood flow through intrapulmonary arteriovenous anastomoses.

KEY POINTS: Blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) is increased by acute hypoxia during rest by unknown mechanisms. Oral administration of acetazolamide blunts the pulmonary vascular pressure response to acute hypoxia, thus permitting the observation of IPAVA blood flow with minimal pulmonary pressure change. Hypoxic pulmonary vasoconstriction was attenuated in humans following acetazolamide administration and partially restored with bicarbonate infusion, indicating that the effects of acetazolamide on hypoxic pulmonary vasoconstriction may involve an interaction between arterial pH and PCO2. We observed that IPAVA blood flow during hypoxia was similar before and after acetazolamide administration, even after acid-base status correction, indicating that pulmonary pressure, pH and PCO2 are unlikely regulators of IPAVA blood flow. ABSTRACT: Blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) is increased with exposure to acute hypoxia and has been associated with pulmonary artery systolic pressure (PASP). We aimed to determine the direct relationship between blood flow through IPAVA and PASP in 10 participants with no detectable intracardiac shunt by comparing: (1) isocapnic hypoxia (control); (2) isocapnic hypoxia with oral administration of acetazolamide (AZ; 250 mg, three times a day for 48 h) to prevent increases in PASP; and (3) isocapnic hypoxia with AZ and 8.4% NaHCO3 infusion (AZ + HCO3 (-) ) to control for AZ-induced acidosis. Isocapnic hypoxia (20 min) was maintained by end-tidal forcing, blood flow through IPAVA was determined by agitated saline contrast echocardiography and PASP was estimated by Doppler ultrasound. Arterial blood samples were collected at rest before each isocapnic-hypoxia condition to determine pH, [HCO3(-)] and Pa,CO2. AZ decreased pH (-0.08 ± 0.01), [HCO3(-)] (-7.1 ± 0.7 mmol l(-1)) and Pa,CO2 (-4.5 ± 1.4 mmHg; P < 0.01), while intravenous NaHCO3 restored arterial blood gas parameters to control levels. Although PASP increased from baseline in all three hypoxic conditions (P < 0.05), a main effect of condition expressed an 11 ± 2% reduction in PASP from control (P < 0.001) following AZ administration while intravenous NaHCO3 partially restored the PASP response to isocapnic hypoxia. Blood flow through IPAVA increased during exposure to isocapnic hypoxia (P < 0.01) and was unrelated to PASP, cardiac output and pulmonary vascular resistance for all conditions. In conclusion, isocapnic hypoxia induces blood flow through IPAVA independent of changes in PASP and the influence of AZ on the PASP response to isocapnic hypoxia is dependent upon the H(+) concentration or Pa,CO2.

Sildenafil, nifedipine and acetazolamide do not allow for blood flow through intrapulmonary arteriovenous anastomoses during exercise while breathing 100% oxygen.

Blood flow through intrapulmonary arteriovenous anastomoses (IPAVAs) is known to increase in healthy humans during exercise while breathing room air, but is prevented or significantly reduced during exercise while breathing 100% O2, potentially due to vasoconstriction of IPAVAs. Thus, pharmacological interventions that target known pathways regulating the cardiopulmonary circulation may be able to prevent the hyperoxia-induced reduction in IPAVA blood flow (Q̇ IPAVA ) during exercise. In nine healthy human subjects, we investigated the effects of sildenafil (100 mg p.o.), nifedipine (20 mg p.o.) and acetazolamide (250 mg p.o. three times a day for 3 days) on Q̇ IPAVA at rest and during cycle ergometer exercise at 50, 100, 150, 200 and 250 W, while breathing room air (normoxia) and 100% O2 (hyperoxia). Transthoracic saline contrast echocardiography and a 0-5 bubble scoring system were used to detect and assess Q̇ IPAVA qualitatively; ultrasound was used to assess the blood flow velocity oftricuspid regurgitation and the left ventricular outflow tract blood flow to calculate pulmonary artery systolic pressure (PASP) and cardiac output, respectively. Without drugs, bubble scores increased significantly to ≥2 at 150 W in normoxia and to ≤2 at 200 W in hyperoxia. Only nifedipine consistently increased cardiac output at rest and during low-intensity exercise in normoxia and hyperoxia. However, there was no detectable effect of any drug on Q̇ IPAVA ; specifically, bubble scores were the same during exercise in either normoxia or hyperoxia. Accordingly, the reduction in Q̇ IPAVA during exercise while breathing 100% O2 is likely not to be due to the independent pharmacological mechanisms of action associated with sildenafil, nifedipine or acetazolamide.

Increased cardiac output, not pulmonary artery systolic pressure, increases intrapulmonary shunt in healthy humans breathing room air and 40% O2.

Blood flow through intrapulmonary arteriovenous anastomoses (IPAVAs) has been demonstrated to increase in healthy humans during a variety of conditions; however, whether or not this blood flow represents a source of venous admixture (Q̇ VA /Q̇T) that impairs pulmonary gas exchange efficiency (i.e. increases the alveolar-to-arterial PO2 difference (A-aDO2)) remains controversial and unknown. We hypothesized that blood flow through IPAVAs does provide a source of Q̇ VA /Q̇T. To test this, blood flow through IPAVAs was increased in healthy humans at rest breathing room air and 40% O2: (1) during intravenous adrenaline (epinephrine) infusion at 320 ng kg(-1) min(-1) (320 ADR), and (2) with vagal blockade (2 mg atropine), before and during intravenous adrenaline infusion at 80 ng kg(-1) min(-1) (ATR + 80 ADR). When breathing room air the A-aDO2 increased by 6 ± 2 mmHg during 320 ADR and by 5 ± 2 mmHg during ATR + 80 ADR, and the change in calculated Q̇ VA /Q̇T was +2% in both conditions. When breathing 40% O2, which minimizes contributions from diffusion limitation and alveolar ventilation-to-perfusion inequality, the A-aDO2 increased by 12 ± 7 mmHg during 320 ADR, and by 9 ± 6 mmHg during ATR + 80 ADR, and the change in calculated Q̇ VA /Q̇T was +2% in both conditions. During 320 ADR cardiac output (Q̇T) and pulmonary artery systolic pressure (PASP) were significantly increased; however, during ATR + 80 ADR only Q̇T was significantly increased, yet blood flow through IPAVAs as detected with saline contrast echocardiography was not different between conditions. Accordingly, we suggest that blood flow through IPAVAs provides a source of intrapulmonary shunt, and is mediated primarily by increases in Q̇T rather than PASP.

The effects of nitroglycerin, norepinephrine and aminophylline on intrapulmonary arteriovenous anastomoses in healthy humans at rest.

We have investigated the effects of the intravenous infusion of nitroglycerin (NTG), norepinephrine (NE) and aminophylline (AMP) on the opening and recruitment of intrapulmonary arteriovenous anastomoses (IPAVA) in healthy humans at rest. In ten volunteers saline contrast echocardiography was performed during administration of two doses of the NTG (3µgkg(-1)min(-1) and 6µgkg(-1)min(-1)) and NE (0.1µgkg(-1)min(-1) and 0.25µgkg(-1)min(-1)) as well as 30min following the administration of AMP at rate of 6mgkg(-1). Echocardiography was used to assign bubble scores (0-5) based on the number and spatial distribution of bubbles in the left ventricle. Doppler ultrasound was used to estimate pulmonary artery systolic pressure. Using a Finometer the following hemodynamic parameters were assessed: heart rate, stroke volume, cardiac output, total peripheral resistance as well as systolic, diastolic and mean arterial pressure. The most important finding from the current study was that nitroglycerin, norepinephrine and aminophylline in the applied doses were not found to promote IPAVA opening in healthy humans at rest.

Granulocyte colony-stimulating factor fails to enhance leptomeningeal collateral growth in spontaneously hypertensive rats.

The promotion of collateral artery growth is an attractive approach for the treatment of chronic brain hypoperfusion due to occlusive artery disease. We previously reported that hypertension impaired the collateral artery growth of leptomeningeal anastomoses after brain hypoperfusion. Granulocyte colony-stimulating factor (G-CSF) enhances arteriogenesis in a mouse model via a mechanism involving monocyte/macrophage mobilization. However, the arteriogenic effect of G-CSF in hypertension remains unknown. In the present study, we tested whether G-CSF affected collateral artery growth in both normotensive and hypertensive model rat. Left common carotid artery (CCA) occlusion was performed to induce hypoperfusion in the brains of Wistar rats and spontaneously hypertensive rats (SHR). G-CSF was administered subcutaneously for 5 consecutive days. The superficial angioarchitecture of the leptomeningeal anastomoses and the circle of Willis after CCA occlusion and G-CSF treatment were visualized by latex perfusion. Circulating blood monocytes and CD68-positive cells, which represented the macrophages on the dorsal surface of the brain, were counted. G-CSF enhanced leptomeningeal collateral growth in Wistar rats, but not in SHR. G-CSF increased circulating blood monocytes in both Wistar rats and SHR. The number of CD68-positive cells on the dorsal surface of the brain was increased by G-CSF in Wistar rats, but not in SHR. The increase in macrophage accumulation correlated with the observed arteriogenic effects. In conclusion, G-CSF promotes collateral artery growth in the normotensive model rat, but not in the hypertensive model rat.

Catecholamine-induced opening of intrapulmonary arteriovenous anastomoses in healthy humans at rest.

The mechanism or mechanisms that cause intrapulmonary arteriovenous anastomoses (IPAVA) to either open during exercise in subjects breathing room air and at rest when breathing hypoxic gas mixtures, or to close during exercise while breathing 100% oxygen, remain unknown. During conditions when IPAVA are open, plasma epinephrine (EPI) and dopamine (DA) concentrations both increase, potentially representing a common mechanism. The purpose of this study was to determine whether EPI or DA infusions open IPAVA in resting subjects breathing room air and, subsequently, 100% oxygen. We hypothesized that these catecholamine infusions would open IPAVA. We performed saline-contrast echocardiography in nine subjects without a patent foramen ovale before and during serial EPI and DA infusions while breathing room air and then while breathing 100% oxygen. Bubble scores (0-5) were assigned based on the number and spatial distribution of bubbles in the left ventricle. Pulmonary artery systolic pressure (PASP) was estimated using Doppler ultrasound, while cardiac output (Q(C)) was measured using echocardiography. Bubble scores were significantly greater during EPI infusions of 80-320 ng·kg(-1)·min(-1) compared with baseline when subjects breathed room air; however, bubble scores did not increase when they breathed 100% oxygen. At comparable Q(C) and PASP, intravenous DA (16 µg·kg(-1)·min(-1)) and EPI (40 ng·kg(-1)·min(-1)) resulted in identical bubble scores. Subsequent studies revealed that ß-blockade did not prevent hypoxia-induced opening of IPAVA. We suggest that increases in Q(C) or PASP (or both) secondary to EPI or DA infusions open IPAVA in normoxia. The closing mechanism associated with breathing 100% oxygen is independent from the opening mechanisms.

Longitudinal anatomical response of retinal-choroidal anastomosis to anti-vascular endothelial growth factor therapy.

PURPOSE: To evaluate the longitudinal anatomical response of retinal-choroidal anastomosis (RCA) to intravitreal ranibizumab injection using spectral-domain optical coherence tomography (SD-OCT). METHODS: We reviewed the medical records of 21 consecutive patients with RCA who underwent intravitreal ranibizumab injections at the University Eye Clinic of Creteil between January 2009 and June 2010. The SD-OCT features at baseline, at 3 months, and at 12 months were retrospectively analyzed. Based on SD-OCT, RCAs were classified as showing a focal retinal pigment epithelium (RPE) erosion ("erosion sign") over a small, localized RPE elevation; a focal RPE break leaving two free RPE flaps ("flap sign") at the level of a small, localized RPE elevation; or a large convex RPE prominence and a focal funnel-shaped RPE kissing an inverted focal funnel-shaped inner neuroepithelium ("kissing sign"). RESULTS: Twenty-one eyes of 21 patients (3 men and 18 women, aged 81.6 ± 6.8 years) diagnosed with RCA naive to any treatment were included for analysis. Spearman ρ correlation between best-corrected visual acuity and lesion classification was 0.54 (P = 0.01) at Month 3 and 0.85 (P < 0.001) at Month 12. Eyes showing the flap sign at baseline underwent significantly less ranibizumab injections after the loading phase (2.14 ± 0.89 vs. 3.40 ± 0.96, P = 0.007) and showed a greater improvement in best-corrected visual acuity at Month 12 (from 0.52 ± 0.14 to 0.38 ± 0.15, P = 0.03) compared with eyes showing the kissing sign. At 12 months, 3 of 10 eyes with flap sign at baseline showed RCA activity, whereas 7 of 10 regressed to erosion sign phase. Of the 10 eyes with kissing sign at baseline, 6 progressed to a fibroglial scar. CONCLUSION: A flap sign of RCA at baseline seems a favorable prognostic factor as concerns best-corrected visual acuity improvement and the need for retreatment.

Sumatriptan does not affect arteriovenous oxygen differences in jugular and cubital veins in normal human subjects.

Arteriovenous anastomoses (AVAs) may open up during migraine attacks. In studies with anaesthetized and bilaterally vagosympatectomized pigs, triptans reduce AVA blood flow and increase the arteriovenous O2 difference (AVDO2). To investigate whether subcutaneous sumatriptan 6 mg could induce changes in the AVDO2, we measured the AVDO2 in the external jugular vein in healthy subjects. We also measured the AVDO2 in the internal jugular and cubital veins. There were no changes in AVDO2 after subcutaneous sumatriptan, probably because AVA blood flow is limited in humans with an intact sympathetic nervous system.

Neurovascular pharmacology of migraine.

Migraine is a paroxysmal neurovascular disorder, which affects a significant proportion of the population. Since dilation of cranial blood vessels is likely to be responsible for the headache experienced in migraine, many experimental models for the study of migraine have focussed on this feature. The current review discusses a model that is based on the constriction of carotid arteriovenous anastomoses in anaesthetized pigs, which has during the last decades proven of great value in identifying potential antimigraine drugs acting via a vascular mechanism. Further, the use of human isolated blood vessels in migraine research is discussed. Thirdly, we describe an integrated neurovascular model, where dural vasodilatation in response to trigeminal perivascular nerve stimulation can be studied. Such a model not only allows an in-depth characterization of directly vascularly acting drugs, but also of drugs that are supposed to act via inhibition of vasodilator responses to endogenous neuropeptides, or of drugs that inhibit the release of these neuropeptides. We discuss the use of this model in a study on the influence of female sex hormones on migraine. Finally, the implementation of this model in mice is considered. Such a murine model allows the use of genetically modified animals, which will lead to a better understanding of the ion channel mutations that are found in migraine patients.

Use of ACE inhibitors is associated with prolonged survival of arteriovenous grafts.

Vascular access complications are common in hemodialysis patients. To investigate whether the use of angiotensin-converting enzyme (ACE) inhibitors influences the rate of polytetrafluoroethylene (PTFE) graft complications, we compared the rate of intervention-free graft survival among patients treated versus not treated with ACE inhibitors. We retrospectively analyzed the survival of grafts placed at our institution between January 1, 1995, and October 31, 1999. Among 121 grafts, 25 grafts were placed in 19 patients treated with ACE inhibitors and 96 grafts were placed in 68 patients not treated with ACE inhibitors. Follow-up ranged from 1 month to 5 years. Ten of 25 grafts failed in the ACE-inhibitor group and 62 of 95 grafts failed in the non-ACE-inhibitor group. Actuarial intervention-free access survival rates (Kaplan-Meier) were significantly greater in the ACE-inhibitor than non-ACE-inhibitor group (71% versus 53% at 6 months, 58% versus 35% at 12 months, and 44% versus 22% at 24 months; P = 0.04). Using a Cox model adjusting for age, race, sex, and diabetes, the relative risk (RR) for access failure in the ACE-inhibitor group was 53% less than in the non-ACE-inhibitor group (RR, 0.47; p < 0.03). In a more complex Cox model with additional adjustment for comorbid conditions, the RR was even lower (RR, 0.32; P = 0.003) for the ACE-inhibitor compared with non-ACE-inhibitor group (reference = 1.00). The lower RR was observed for patients with and without congestive heart failure. These results suggest that ACE inhibitors offer clinical promise in the prevention of PTFE graft failure. A prospective randomized trial is warranted to confirm the benefit of ACE inhibitors.

Role of alpha-1 adrenoceptor subtypes mediating constriction of the rabbit ear thermoregulatory microvasculature.

An acute in vivo preparation of the microvasculature of the rabbit ear was used to evaluate the functional role of alpha1 (alpha1)-adrenoceptor subtypes in thermoregulatory microcirculation. The effect of alpha1-adrenoceptor subtype blockade on phenylephrine-induced vasoconstriction was assessed with the alpha1A, alpha1B, and alpha1D-adrenoceptor-selective antagonists 5-methyl-urapidil (10(-8) M), chloroethylclonidine (10(-5) M), and 8-[2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol[4.5]deca ne-7,9-dione dihydrochloride (BMY7378) (10(-6) M), respectively. The results demonstrated that pretreatment of the ear microvasculature with 5-methyl-urapidil or BMY7378 shifted the phenylephrine concentration-response curve rightward and significantly changed the log of the phenylephrine concentration, causing half-maximum stimulation (EC50) in arterioles (p < 0.05). BMY7378 shifted the phenylephrine concentration-response curve of the arteriovenous anastomoses about 100-fold rightward (p < 0.05). All three alpha1-adrenoceptor antagonists eliminated the vasoconstrictive effects of phenylephrine on venules. The results indicate that the ear microvasculature has a heterogenous distribution of alpha1-adrenoceptor subtypes. The alpha1A and alpha1D-adrenoceptor subtypes appear to have a greater influence on constrictive function in arterioles, whereas the alpha1D-adrenoceptor is the dominant constrictor of arteriovenous anastomoses. In general, the alpha1-adrenoceptor does not play a major vasoconstrictor role in venules. Chloroethylclonidine, an irreversible alpha1B-adrenoceptor antagonist, induced contractile responses in the ear microvasculature, probably due to its alpha2-adrenoceptor agonist effects. This study extended our understanding of the adrenergic receptor control mechanisms of a cutaneous thermoregulatory end organ characterized by two parallel perfusion circuits providing nutritional and thermoregulatory functions.

Functional profile of almotriptan in animal models predictive of antimigraine activity.

Almotriptan is a new 5-HT(1B/1D) receptor agonist whose clinical efficacy for the treatment of migraine attacks has been demonstrated in Phase III clinical trials. We now compare the functional profile of almotriptan (assessed using animal models) with that of sumatriptan. Almotriptan selectively increased carotid vascular resistance in anaesthetised cats after intravenous or intraduodenal administration (ED(100)=11 microg/kg, i.v.; ED(50)=339 microg/kg, i. d.) and in anaesthetised beagle dogs following intravenous administration (ED(50)=116 microg/kg). A study in anaesthetised cats also demonstrated that almotriptan acts by selectively increasing the resistance of the carotid arteriovenous anastomoses without adversely affecting brain irrigation. In addition, almotriptan inhibited meningeal extravasation produced by electrical stimulation of the trigeminal ganglion in anaesthetised guinea pigs in the dose range of 0.3-3 mg/kg, i.v. In conclusion, almotriptan is both a selective constrictor affecting intracranial blood vessels and an inhibitor of neurogenically evoked plasma protein extravasation of the dura mater.

Pharmacological evidence that alpha1-and alpha2-adrenoceptors mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs.

Vasoconstriction of carotid arteriovenous anastomoses may be involved in the therapeutic action of acutely acting anti-migraine agents, including the triptans and ergot alkaloids. While 5-HT1B/1D receptors mediate the effect of triptans, ergotamine and dihydroergotamine also interact with alpha-adrenoceptors. In the present study, we investigated the potential role of alpha1- and alpha2-adrenoceptors in mediating vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. Ten minute intracarotid infusions of phenylephrine (1, 3 and 10 microg kg(-1) min(-1)) or BHT 933 (3, 10 and 30 microg kg(-1) min(-1)) produced dose-dependent decreases in total carotid and arteriovenous anastomotic conductances; no changes were observed in the capillary fraction. The carotid vascular effects of phenylephrine and BHT 933 were selectively abolished by prazosin (100 microg kg(-1), i.v.) and rauwolscine (300 microg kg(-1), i.v.), respectively. The responses to phenylephrine and BHT 933 were not affected by the selective 5-HT1B/1D receptor antagonist GR127935 (500 microg kg(-1), i.v.). These results show that both alpha1- and alpha2-adrenoceptors can mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. Since vasoconstrictor activity in this in vivo model is predictive of anti-migraine activity, an agonist activity at particularly the alpha2-adrenoceptor subtypes, in view of their less ubiquitous nature, could provide migraine abortive potential. Thus, the present results may aid further understanding of the mode of action of some current anti-migraine agents and may eventually be helpful in the development of future treatment in migraine.

Investigation of the role of 5-HT1B and 5-HT1D receptors in the sumatriptan-induced constriction of porcine carotid arteriovenous anastomoses.

1. It has previously been shown that the antimigraine drug sumatriptan constricts porcine carotid arteriovenous anastomoses via 5-HT1-like receptors, identical to 5-H1B/1D receptors. The recent availability of silent antagonists selective for the 5-HT1B (SB224289) and 5-HT1D (BRL15572) receptor led us to further analyse the nature of receptors involved. 2. In pentobarbitone-anaesthetized, bilaterally vagosympathectomized pigs, sumatriptan (30, 100 and 300 microg kg(-1), i.v.) dose-dependently decreased carotid arteriovenous anastomotic conductance by up to 70+/-5%. 3. The dose-related decreases in carotid arteriovenous anastomotic conductance by sumatriptan (30, 100 and 300 microg kg(-1), i.v.) remained unchanged in animals treated (i.v.) with 1 mg kg(-1) of BRL15572 (maximum decrease: 72+/-3%), but were significantly attenuated by 1 mg kg(-1) (maximum decrease: 30+/-11%) and abolished by 3 mg kg(-1) (maximum decrease: 3+/-7%) of SB224289. The highest dose of SB224289 did not attenuate the hypertension, tachycardia or increases in carotid blood flow induced by bolus injections of noradrenaline (0.1-3 microg kg(-1), i.v.). 4. The results indicate that sumatriptan constricts porcine carotid arteriovenous anastomoses primarily via 5-HT1B, but not via 5-HT1D receptors.

Cranial vascular effects of zolmitriptan, a centrally active 5-HT1B/1D receptor partial agonist for the acute treatment of migraine.

The anti-migraine drug zolmitriptan is a novel 5-HT1B/1D receptor partial agonist which, unlike sumatriptan, has been shown to cross the intact blood-brain barrier. In this study we examined whether or not the ability to access the cerebro-vascular intima affects the way in which a centrally-active 5-HT1B/1D receptor agonist influences cranial haemodynamics. The effects of zolmitriptan on carotid arterial blood flow distribution were studied in anaesthetised cats using radiolabelled microspheres. Zolmitriptan (10-1000 microg kg(-1) i.v.) selectively reduced arteriovenous-anastomotic (AVA) conductance producing a maximum decrease of 92.5+/-2.3%. The drug also produced a modest reduction in extra-cerebral conductance (23.9+/-6.5% maximum reduction at 30 microg kg(-1), i.v.), but was without effect on cerebral conductance. Using laser doppler flowmetry in anaesthetised cats, zolmitriptan (1-30 microg kg(-1), i.v.) produced dose-dependent decreases in ear microvascular conductance (15+/-5 to 60+/-6%) which mirrored decreases in carotid arterial conductance (12+/-11 to 61+/-5%). By contrast, zolmitriptan at doses up to 1000 microg kg(-1) was without effect on cerebral microvascular conductance. Although zolmitriptan crosses the blood-brain barrier and can therefore access the cerebro-vascular intima, this study suggests that this property does not adversely affect cerebrovascular function.

Porcine carotid vascular effects of eletriptan (UK-116,044): a new 5-HT1B/1D receptor agonist with anti-migraine activity.

It has been suggested that opening of cephalic arteriovenous anastomoses may be involved in the headache phase of migraine. Indeed, a number of acutely acting anti-migraine drugs, including the ergot alkaloids and sumatriptan, constrict porcine carotid arteriovenous anastomoses. In this study, using pentobarbital anaesthetised pigs, we investigated the effects of eletriptan, a close structural analogue of sumatriptan, on the distribution of common carotid artery blood flow into arteriovenous anastomotic and nutrient (capillary) fractions. Eletriptan (10, 30, 100, 300 and 1000 microg kg(-1), i.v.) decreased the total carotid blood flow, exclusively by decreasing cephalic arteriovenous anastomotic blood flow; nutrient blood flow, particularly to the ear, skin and fat, was significantly increased. The doses of eletriptan needed to reduce arteriovenous anastomotic blood flow and conductance by 50% (ED50) were, respectively, 117+/-21 microg kg(-1) (251+/-45 nmol kg(-1)) and 184+/-42 microg kg(-1) (396+/-91 nmol kg(-1)); the highest dose caused reductions of 84+/-3% and 77+/-4%, respectively. The eletriptan-induced changes in carotid haemodynamics were clearly attenuated by pretreating the pigs with the selective 5-HT1B/1D receptor antagonist GR127935 (0.5 mg kg(-1)). On the basis of these results, we conclude that (1) the eletriptan-induced constriction of cephalic arteriovenous anastomoses as well as the arteriolar dilatation in head tissues is predominantly mediated by 5-HT1B/1D receptors, and (2) eletriptan should be effective in aborting migraine headache. Clinical studies have already demonstrated its therapeutic action in migraine patients.

The antimigraine agent alniditan selectively constricts porcine carotid arteriovenous anastomoses via 5-HT1B/1D receptors.

In previous studies, we have shown that several 5-HT1B/1D receptor agonists, including sumatriptan, potently constrict porcine carotid arteriovenous anastomoses. This effect seems to be of high predictive value for antimigraine activity. In the present experiments, we studied the effects of a new non-indole 5-HT1B/1D receptor agonist, alniditan, on systemic and carotid haemodynamics in anaesthetised pigs. In control animals, no significant changes in either systemic or carotid haemodynamics were observed after four consecutive i.v. injections of physiological saline (0.5 ml each, every 20 min; n = 4). On the other hand, i.v. doses of alniditan (3, 10, 30 and 100 microg kg(-1) in 0.5 ml saline, every 20 min; n = 6) dose-dependently decreased total carotid conductance (maximum change: -31 +/- 6%) by a selective vasoconstrictor action on arteriovenous anastomoses (maximum change: -72 +/- 5%); the nutrient vascular bed dilated in response to alniditan (maximum change: +103 +/- 39%). The dose of alniditan that decreased arteriovenous anastomotic conductance by 50% was 24 +/- 8 microg kg(-1) (64 +/- 20 nmol kg(-1)). Alniditan produced a slight bradycardia (maximum change: -4 +/- 1%) and a more pronounced hypotensive effect (maximum change: -23 +/- 5%). In six animals pre-treated with the potent and selective 5-HT1B/1D receptor antagonist, GR127935, the alniditan-induced changes in carotid haemodynamics were clearly antagonised, whereas the bradycardia and hypotension remained unaffected. These results suggest that alniditan selectively constricts porcine carotid arteriovenous anastomoses mainly via 5-HT1B/1D receptors and should be able to abort migraine headaches. The latter has indeed been confirmed in initial clinical studies in man.