Carotid Vascular Resistance Research Articles

Melatonin treatment during chronic hypoxic gestation improves neonatal cerebrovascular function

BackgroundFetal chronic hypoxia is associated with blood flow redistribution and oxidative damage in the brain, leading to increased perinatal morbimortality. Melatonin reduces oxidative stress, improves vascular function, and has neuroprotective effects. ObjectivesThis study aimed to determine the effects of an oral melatonin treatment to pregnant ewes at high-altitude, on the cerebrovascular function of their neonates. Study designTen high-altitude pregnant sheep received either vehicle or melatonin (10 mg/d) during the last third of gestation until delivery. Postnatal daily hemodynamic measurements were recorded from lambs until 12 days old. In addition, lambs were submitted to a graded oxygenation protocol to assess cerebrovascular responses. Subsequently, lambs were euthanized, and middle cerebral arteries (MCA) were collected for vascular function, protein levels, and morphostructural analyses. ResultsAntenatal treatment doubled plasma levels of melatonin in pregnant ewes. Melatonin increased carotid flow and decreased carotid vascular resistance in the lambs by the end of the first week. Furthermore, melatonin increased MCA's maximal vasoconstrictor and vasodilator responses, associated with nitric oxide-dependent and independent mechanisms. ConclusionsAn oral treatment with melatonin during pregnancy promotes postnatal cerebral perfusion in chronically hypoxic neonates. Melatonin is a potential treatment for cerebrovascular dysfunction due to perinatal chronic hypoxia.

A method to evaluate dynamic cerebral pressure-flow relationships in the conscious rat.

The classic dogma of cerebral autoregulation is that cerebral blood flow is steadily maintained across a wide range of perfusion pressures. This has been challenged by recent studies suggesting little to no "autoregulatory plateau" in the relationship between cerebral blood flow and blood pressure (BP). Therefore, the mechanisms underlying the cerebral pressure-flow relationship still require further understanding. Here, we present a novel approach to examine dynamic cerebral autoregulation in conscious Wistar rats (n = 16) instrumented to measure BP and internal carotid blood flow (iCBF), as an indicator of cerebral blood flow. Transient reductions in BP were induced by occluding the vena cava via inflation of a chronically implanted intravascular silicone balloon. Falls in BP were paralleled by progressive decreases in iCBF, with no evidence of a steady-state plateau. No significant changes in internal carotid vascular resistance (iCVR) were observed. In contrast, intravenous infusions of the vasoactive drug sodium nitroprusside (SNP) produced a similar fall in BP but increases in iCBF and decreases in iCVR were observed. These data suggest a considerable confounding influence of vasodilatory drugs such as SNP on cerebrovascular tone in the rat, making them unsuitable to investigate cerebral autoregulation. We demonstrate that our technique of transient vena cava occlusion produced reliable and repeatable depressor responses, highlighting the potential for our approach to permit assessment of the dynamic cerebral pressure-flow relationship over time in conscious rats.NEW & NOTEWORTHY We present a novel technique to overcome the use of vasoactive agents when studying cerebrovascular dynamics in the conscious rat. Our method of vena cava occlusion to reduce BP was associated with decreased iCBF and no change in iCVR. In contrast, comparable BP falls with intravenous SNP increased iCBF and reduced iCVR. Thus, the dynamic cerebral pressure-flow relationship shows a narrower, less level autoregulatory plateau than conventionally thought. We confirm our method allows repeatable assessment of cerebrovascular dynamics in conscious rats.

Real-Time Evaluation of Regional Arterial Stiffening, Resistance, and Ocular Circulation During Systemic Administration of Adrenaline in White Rabbits.

PurposeTo evaluate continuous variations of ocular microcirculation by laser speckle flowgraphy and those of regional stiffening by pulse wave velocity (PWV) and vascular resistance under systemic adrenaline administration in rabbits.MethodsSix 16-week-old male rabbits were evaluated. The mean blur rates in the retinal vessel (MBR-RV) and choroid (MBR-CH) were measured. We assessed blood pressure (BP), femoral and carotid vascular resistance, and the heart–ankle (ha)-PWV, heart–femoral (hf)-PWV, and femoral–ankle (fa)-PWV. Adrenaline (100, 300, and 1000 ng/kg) was intravenously administered over a 10-minute period during which the parameters were measured simultaneously every 2 minutes.ResultsThe MBR-RV and MBR-CH values were dose-dependently increased by the adrenaline in parallel with increased BP. At the load of 100 ng/kg adrenaline, the ΔMBR-RV and ΔMBR-CH showed positive correlations with the variation rate in mean arterial blood pressure. Also, the variation rate in carotid vascular resistance and the Δfa-PWV and Δhf-PWV were significantly positively correlated with both the ΔMBR-RV and ΔMBR-CH. At the 300-ng/kg phase, the correlations between the Δha-PWV and both ΔMBR-RV and ΔMBR-CH were canceled; instead, the Δhf-PWV showed a significant negative correlation with the ΔMBR-RV and ΔMBR-CH. At the 1000-ng/kg phase, Δha-PWV again showed significant positive correlations with the ΔMBR-RV and ΔMBR-CH.ConclusionsThese results indicate the possibility that under a systemic administration of adrenaline in rabbits, not only the BP value but also the vascular resistance and arterial function are related to the variation in ocular microcirculation.Translational RelevanceA real-time evaluation system of systemic regional arterial function and ocular microcirculation in rabbits was developed.

CAROTID VASCULAR RESISTANCE ASSOCIATED WITH COGNITIVE FUNCTION AMONG MIDDLE-AGE ADULTS

Objective: Carotid flow velocity and peripheral blood pressure were independently associated with cognitive function among the elderly population, but unknown among middle-aged adults. We aimed to investigate the association between carotid hemodynamics and cognitive performance among the middle-age population. Design and method: A total of 490 middle-age adults (between 30 and 60 years) participated in the ongoing survey (2017–2020) of the Cardiovascular Disease Risk Factors two-Township study and received the Montreal Cognitive Assessment (MOCA) to evaluate the global cognitive function. Carotid-formal pulse wave velocity (cf-PWV) was measured using carotid and femoral arterial tonometry. Carotid vascular resistance was calculated by mean carotid pressure divided into mean carotid volume flow. Results: MOCA levels were similar between men and women (27.1 vs. 27.2, p = 0.6036). Age(r = -0.22, P < 0.001), and education(r = 0.39, p < 0.001) were associated with MOCA. Controlled for age, gender and education, peak systolic velocity (r = 0.077 @left; r = 0.012@Right, all p > 0.05), end diastolic velocity (r = 0.029, r = -0.062, all p > 0.05), mean flow (r = 0.060; r = -0.038, all p > 0.05), carotid resistive index (r = 0.020, r = 0.05, all p > 0.05), carotid pulsatility(r = 0.015; r = 0.058; p > 0.05), diameter(r = 0.060; r = -0.008, all p > 0.05) at both sides were not associated with MOCA. Only carotid vascular resistance (CVR) at left side was associated with MOCA (r = -0.158, p = 0.0010), but not at right carotid artery (r = -0.030, p = 0.5369). CVR@Left (standard beta = -0.144; p = 0.0022) remains associated with MOCA in the multivariable with further controlling glucose, low density lipoprotein and carotid-formal pulse wave velocity. Those with top, 2nd and 3th quartile of CVR@left had 2.4-fold [Odds Ratio = 2.40; 95% confidence intervals = 1.14–5.04], 1.95-fold(1.95;0.93–4.07) and 0.99-fold (0.99;0.45–2.17) risk for poor cognitive performance (MOCA < 26), compared to those with lowest quartile of CVR@left in the multivariable model. Conclusions: Carotid vascular resistance is a marker of cerebrovascular resistance and associated with cognitive performance in middle-aged adults.

Telemetric Recording of Renal and Carotid Blood Flow Velocity and Arterial Blood Pressure Simultaneously in Rats

Hypertension‐induced barotrauma without or with concomitant vasoconstriction, tissue ischemia and hypoxia has been postulated to initiate and drive the pathogenic cascades that lead to hypertension induced tissue injury. Yet the precise temporal relationship between arterial pressure and tissue blood flow over time as causative mechanisms for barotrauma remain unresolved and controversial. A major technical limitation has been the absence of methods allowing simultaneous high fidelity long‐term measurement of blood flow and arterial pressure in conscious animals. Transonic has developed a cutting edge technology to continuously evaluate arterial blood pressure and two blood flow velocity's simultaneously in conscious rats. Here, we report the first demonstration of recording renal and carotid blood flow and arterial pressure using this new multi‐variable telemetric system. A solid state pressure sensor was placed in the abdominal aorta and 0.8mm and 0.5mm in diameter flow probes were sutured on the renal and carotid artery, respectively, in Wistar rats. Both flow velocity signals correlated with the arterial pressure signal and exhibited constant lag times. After 5 min of carbogen breathing carotid vascular resistance decreased by 31±4% while renal vascular resistance decreased by 7±1%. These experiments demonstrate the feasibility of the technique for high fidelity temporal profiling of both blood pressure and blood flows to renal and carotid vascular beds simultaneously in conscious rats. British Heart Foundation funded research.

The effects of acute administration of losartan, angiotensin II type-1 receptor antagonist, on hemodynamics and oxidative stress parameters in malignant hypertensive rats

Malignant hypertension is a severe form of hypertension which pathogenesis is not fully elucidated. The aim of our study was to investigate the role of Angiotensin II on hemodynamic and oxidative stress parameters in model of malignant hypertension by using losartan. Adult males were divided into three groups: normotensive Wister rats, control SHR and losartan treated SHR. Control and SHR group received a single bolus dosage of saline, while the SHR + LOS group received a losartan. Blood pressure, cardiac output, both total peripheral and carotid vascular resistance and carotid blood flow were measured. CAT, SOD and TBARS were determined in the blood samples. The treatment significantly decreased the blood pressure. There was no significant change in cardiac output or carotid blood flow, but treatment resulted in diminishment of vascular resistances, both total peripheral and carotid. There was a tendency to restore the values of SOD activity towards those of the normotensive group, but there were no change in CAT and TBARS levels. Taken together, our results show that a single application of losartan has a strong hypotensive effect. Angiotensin II seems to have a significant role in the malignant hypertension syndrome and it partially affects oxidative stress parameters.

The effects of dexamethasone on post-asphyxial cerebral oxygenation in the preterm fetal sheep.

Exposure to clinical doses of the glucocorticoid dexamethasone increases brain activity and causes seizures in normoxic preterm fetal sheep without causing brain injury. In contrast, the same treatment after asphyxia increased brain injury. We hypothesised that increased injury was in part mediated by a mismatch between oxygen demand and oxygen supply. In preterm fetal sheep at 0.7 gestation we measured cerebral oxygenation using near-infrared spectroscopy, electroencephalographic (EEG) activity, and carotid blood flow (CaBF) from 24 h before until 72 h after asphyxia induced by 25 min of umbilical cord occlusion. Ewes received dexamethasone intramuscularly (12 mg 3 ml(-1)) or saline 15 min after the end of asphyxia. Fetuses were studied for 3 days after occlusion. During the first 6 h of recovery after asphyxia, dexamethasone treatment was associated with a significantly greater fall in CaBF (P < 0.05), increased carotid vascular resistance (P < 0.001) and a greater fall in cerebral oxygenation as measured by the difference between oxygenated and deoxygenated haemoglobin (delta haemoglobin; P < 0.05). EEG activity was similarly suppressed in both groups. From 6 to 10 h onward, dexamethasone treatment was associated with a return of CaBF to saline control levels, increased EEG power (P < 0.005), greater epileptiform transient activity (P < 0.001), increased oxidised cytochrome oxidase (P < 0.05) and an attenuated increase in [delta haemoglobin] (P < 0.05). In conclusion, dexamethasone treatment after asphyxia is associated with greater hypoperfusion in the critical latent phase, leading to impaired intracerebral oxygenation that may exacerbate neural injury after asphyxia.

Role of nitrite in regulation of fetal cephalic circulation in sheep

Nitrite has been postulated to provide a reservoir for conversion to nitric oxide (NO), especially in tissues with reduced oxygen levels as in the fetus. Nitrite would thus provide local vasodilatation and restore a balance between oxygen supply and need, a putative mechanism of importance especially in the brain. The current experiments test the hypothesis that exogenous nitrite acts as a vasodilator in the cephalic vasculature of the intact, near term fetal sheep. Fetuses were first instrumented to measure arterial blood pressure and carotid artery blood flow and then studied 4-5 days later while in utero without anaesthesia. Initially l-nitro-arginine (LNNA) was given to block endogenous NO production. Carotid resistance to flow increased 2-fold from 0.54 ± 0.01 (SEM) to 1.20 ± 0.08 mmHg min ml(-1) (in 13 fetuses, P < 0.001), indicating NO tonically reduces cerebral vascular tone. Sodium nitrite (or saline as control) was then infused in increasing step-doses from 0.01 to 33 μm in half-log increments over a period of 2 h. Carotid artery pressure, blood flow and vascular resistance did not change compared to fetuses receiving saline, even at plasma nitrite concentrations two orders of magnitude above the physiological range. The results indicate that while cephalic vascular tone is controlled by endogenous nitric oxide synthase activity, exogenously administered nitrite is not a vasodilator at physiological concentrations in the vasculature served by the carotid artery of fetal sheep.

Reduced ocular blood flow in asymmetric glaucoma: cause or effect?

Carotid Doppler measures blood flow velocity and vascular resistance index in the central retinal arteries and short posterior ciliary arteries. The blood flow profile of the optic nerve in chronic angle-closure glaucoma (CACG), however, has not been well documented. We report a 48-year-old female patient who presented with grossly asymmetric CACG and was evaluated by carotid Doppler. The patient had coexistent reduced blood flow in the ophthalmic artery of the more afflicted eye. Color Doppler imaging clarifies hemodynamic alterations in the glaucomatous optic nerve and helps to identify vascular aspects of the disease and its treatment.

Milrinone is preferred to levosimendan for mesenteric perfusion in hypoxia-reoxygenated newborn piglets treated with dopamine

INTRODUCTIONThere is little information regarding the comparative hemodynamic effects of adding milrinone or levosimendan to dopamine infusion in hypoxia-reoxygenated (H-R) newborns.RESULTSSeverely hypoxic piglets had cardiogenic shock with depressed cardiac index (CI) and mean arterial pressure (MAP). The hemodynamics deteriorated gradually after initial recovery upon reoxygenation. Heart rate and CI improved with milrinone (D+M) and levosimendan (D+L) administration (P < 0.05 vs. control). Both regimens improved carotid arterial flow and carotid vascular resistance; D+M additionally improved superior mesentric arterial flow (all P < 0.05 vs. control). No effect was found on renal arterial flow or elevated lactate state with either regimen. D+M piglets also had a lower myocardial oxidized/reduced glutathione ratio (P < 0.05 vs. control).DISCUSSIONIn conclusion, adding milrinone or levosimendan to dopamine similarly improved systemic hemodynamics in H-R newborn piglets. Milrinone also improved mesenteric perfusion and attenuated myocardial oxidative stress.METHODSTwenty-eight piglets (1–4 d, 1.5–2.5 kg) were instrumented for continuous monitoring of systemic MAP and pulmonary arterial pressure (PAP), CI, and carotid, superior mesenteric, and renal arterial flows. Piglets were randomized with blinding to sham-operated, H-R control (saline), and H-R dopamine (10 μg/kg/min) with D+M or D+L groups. H-R piglets underwent H-R followed by 2 h of drug infusion after reoxygenation. Tissue was collected for biochemical/oxidative stress testing and histological analysis.

TEMPOL IMPROVES REGIONAL HEMODYNAMICS IN SPONTANEOUSLY HYPERTENSIVE RATS WITH ACUTE RENAL FAILURE: 3C.06

Objective: Acute renal failure (ARF) and hypertension as a comorbid disorders can be found frequently in intensive care unit patients. The aim of our study was to investigate the antihypertensive effects of 4-Hydroxy-2, 2, 6, 6-tetramethylpiperidine-N-oxyl (tempol), synthetic SOD mimetic, on regional haemodynamics in the course of ARF in hypertension. Design and Method: Experiment was performed in anesthetized, six-month-old male spontaneously hypertensive rats (SHR). The right kidney was removed and ARF was induced by clamping the left renal artery for 40 minutes. SHR were divided in 3 experimental groups: sham operated group (SHAM; n = 7); ARF group (ARF; n = 9); and ARF group with tempol treatment (40 mg/kg/h) (ARF+TEM; n = 8). Tempol was given by infusion during the period of three hours after reperfusion. Mean arterial pressure (MAP), carotid blood flow (CBF) and renal blood flow (RBF) were measured and carotid vascular resistance (CVR) and renal vascular resistance (RVR) was calculated 24 h after reperfusion.Conclusion: Our results indicate that in hypertension free oxygen species contribute to renal vasoconstiction, one of the major pathophysiological mechanism of postischemic ARF.

Nitrite Infusion at Physiologic Concentrations Reduces Carotid Vascular Resistance in Fetal Sheep

Nitrite Infusion at Physiologic Concentrations Reduces Carotid Vascular Resistance in Fetal Sheep

Renal and carotid vascular resistance assessed with Doppler sonography

Resistance index (RI) is widely used for the evaluation of circulatory resistance and atherosclerosis with Doppler sonography, but differences in RI among vascular beds have not been fully elucidated. The present study was designed to evaluate the relationship between renal and carotid artery RI and to compare their relative risk factors for an increase in RI. One hundred eighty-five inpatients who underwent sonographic assessment of the renal and carotid arteries were enrolled in the study. Multivariate analyses revealed that age, pulse pressure (PP), and serum glucose level were positively correlated, whereas diastolic blood pressure (DBP) and creatinine clearance were negatively correlated with the RI of the interlobar arteries. Sex (male) and PP correlated positively, whereas DBP correlated negatively with the RI of the common carotid artery (CCA). The RI of the interlobar arteries was positively associated with that of the CCA, even after adjustment for major cardiovascular risk factors. These findings suggest that RI of the renal and carotid arteries increase in parallel to a certain extent. On the other hand, risk factors for the increase of RI of the carotid and renal arteries differed in part, suggesting that specific control of respective risk factors may also be needed to prevent vascular damage in each vascular bed.

Systemic Activation of the Calcium Sensing Receptor Produces Acute Effects on Vascular Tone and Circulatory Function in Uremic and Normal Rats: Focus on Central versus Peripheral Control of Vascular Tone and Blood Pressure by Cinacalcet

Calcium-sensing receptor (CaR) activation decreases serum parathyroid hormone (PTH) and Ca2+ and, despite long-term reductions in mean arterial blood pressure (MAP), may produce acute hypertension in rats, an effect we hypothesized was mediated by constriction of multiple vascular beds. Rats were subjected to 5/6 nephrectomy (NX) or no surgery (Normal); at 7 to 8 weeks, uremia animals were anesthetized and instrumented to record MAP and regional blood flow (carotid, mesenteric, and hindlimb). Cinacalcet [N-(1-naphthalen-1-ylethyl)-3-[3-(trifluoromethyl)phenyl]-propan-1-amine; 1, 3, and 10 mg/kg; 30 min/dose] was infused over 90 min. In NX rats, cinacalcet dose-dependently decreased ionized calcium (iCa2+), elicited a 90% reduction in PTH, and produced dose-dependent self-limiting increases in MAP (from 119 +/- 6 to 129 +/- 5, 142 +/- 4, and 145 +/- 3 mm Hg at the end of each infusion). At 1 mg/kg, carotid vascular resistance (CVR) and mesenteric vascular resistance (MVR) increased to 16 +/- 6 and 18 +/- 6% above baseline, respectively. Hindlimb vascular resistance (HVR) also trended upward (13 +/- 8%). At 3 mg/kg, increases in CVR (38 +/- 10%), MVR (40 +/- 8%), and HVR (39 +/- 14%) were exacerbated; at 10 mg/kg, values remained at or near these levels. The effects of cinacalcet in Normal rats were similar to NX and were attenuated by ganglionic blockade with hexamethonium at low doses but remained significantly elevated at higher doses. Thus, CaR activation acutely increases MAP in uremic and nonuremic rats, responses that occur in parallel to vasoconstriction in multiple vascular beds through both a central and peripheral mechanism of action. Moreover, subsequent mechanistic studies suggest that increases in MAP produced by cinacalcet may be mediated by reduced tonic NO synthase-dependent NO production subsequent to reductions in blood iCa2+.

Effects of estrogen and estrogen–progestogen therapy on homocysteine levels and their correlation with carotid vascular resistance

Objective. To evaluate the correlation between homocysteine levels and carotid vascular resistance in menopausal women submitted to estrogen and estrogen–progestogen therapy.Methods. Eighty-six women with a mean age of 52 years were enrolled in a prospective, randomized, double-blind, 6-month study. Patients were allocated to use one of three oral therapies: placebo (n = 26), micronized estradiol 2 mg/day (n = 30) or micronized estradiol 2 mg/day plus norethisterone acetate 1 mg/day (n = 30). Evaluation of homocysteine levels and Doppler sonography of the common carotid artery, used to calculate pulsatility index (PI), were carried out prior to initiating therapy and at the end of the study. The correlation between these two parameters was evaluated using Pearson's coefficient of correlation.Results. There was a significant reduction in homocysteine levels in the groups treated with estrogen alone or estrogen combined with norethisterone. PI was significantly lower only in users of estrogen alone; however, no significant correlation was found between homocysteine measurements and PI.Conclusion. No significant correlation was found between homocysteine levels and carotid vascular resistance following hormone therapy.

Effects of Enhanced External Counterpulsation on Carotid Circulation in Patients with Coronary Artery Disease

Background: Enhanced external counterpulsation (EECP) is a noninvasive method previously shown to improve measures of myocardial ischemia in patients with coronary artery disease. However, the concomitant effects of EECP on large and small arterial properties have been poorly examined. In a randomized controlled study, we investigated whether arterial stiffness and resistance of the carotid circulation are altered by EECP. Methods: Thirty patients with angiographically demonstrated coronary artery disease were randomized into two groups to receive either ‘sham’ or active EECP therapy for 35 1-hour sessions. The β stiffness index was calculated by the ln(Ps/Pd)/DD equation where Ps and Pd = systolic and diastolic blood pressure, and DD = the ratio between carotid pulse and diastolic diameter, measured by ultrasound sequential frames during the cardiac cycle. Carotid vascular resistance was calculated as the ratio between mean arterial pressure and mean common carotid blood flow. Results: No significant between-group differences were seen in clinical characteristics or carotid hemodynamics at baseline. The β stiffness index and carotid vascular resistance were significantly reduced after 35 h of active EECP (p < 0.01), and the decrease was significantly different when compared with controls (p < 0.05 for β stiffness index and p < 0.001 for carotid vascular resistance). These reductions persisted after multiple covariate adjustment. Conclusions: This study suggests that EECP exerts clear arterial effects on large and small vessels of the carotid circulation. The combined effects on arterial stiffness and vascular resistance are of particular interest in cardiovascular disease involving reduction in blood flow, in which techniques that increase regional blood flow may be beneficial.

A dose-response study of graded reoxygenation on the carotid haemodynamics, matrix metalloproteinase-2 activities and amino acid concentrations in the brain of asphyxiated newborn piglets

It is controversial to choose an appropriate oxygen concentration to resuscitate asphyxiated newborns regarding the clinical and biochemical oxidative effects. We examined the vasomotor response to reoxygenation with graded reoxygenation and the effects on matrix metalloproteinases and amino acids of the immature brain. Thirty-two piglets (1-3 days, 1.5-2.1 kg) were instrumented for continuous monitoring of left common carotid and pulmonary arterial flows (Transonic). Piglets were randomized to a sham-operated control group (without hypoxia/reoxygenation) or 2 h hypoxia induced by decreasing the inspired oxygen concentration to 10-15%, followed by reoxygenation with 21, 50 or 100% oxygen for 1 h and then 21% oxygen for 3 h (n=8 each). The brains were then flash frozen and analyzed for matrix metalloproteinases and amino acid levels by zymography and HPLC, respectively. After 2 h oxygen deprivation, the absolute carotid flow remained similar but accounted for 38% of cardiac output (increased from 17% at baseline, p=0.001). During early reoxygenation, the flow rose in the piglets resuscitated with air (p<0.05), but not in those with supplemental oxygen. Carotid vascular resistance correlated significantly with the arterial partial pressure of oxygen (r=0.7). There was an oxygen-dependent increase in global cerebral activity of matrix metalloproteinase-2 with specific increases in the basal ganglia of all hypoxic-reoxygenated brains. There were no significant differences in glutamate and other amino acids in any brain regions. Although using high oxygen concentration to resuscitate asphyxiated newborn piglets increased carotid vascular resistance and cerebral matrix metalloproteinase-2 activity, there is no detrimental effect observed in this acute model of hypoxia-reoxygenation.

Vasodilator tone in the llama fetus: the role of nitric oxide during normoxemia and hypoxemia

The fetal llama responds to hypoxemia, with a marked peripheral vasoconstriction but, unlike the sheep, with little or no increase in cerebral blood flow. We tested the hypothesis that the role of nitric oxide (NO) may be increased during hypoxemia in this species, to counterbalance a strong vasoconstrictor effect. Ten fetal llamas were operated under general anesthesia. Mean arterial pressure (MAP), heart rate, cardiac output, total vascular resistance, blood flows, and vascular resistances in cerebral, carotid and femoral vascular beds were determined. Two groups were studied, one with nitric oxide synthase (NOS) blocker N(G)-nitro-L-arginine methyl ester (L-NAME), and the other with 0.9% NaCl (control group), during normoxemia, hypoxemia, and recovery. During normoxemia, L-NAME produced an increase in fetal MAP and a rapid bradycardia. Cerebral, carotid, and femoral vascular resistance increased and blood flow decreased to carotid and femoral beds, while cerebral blood flow did not change significantly. However, during hypoxemia cerebral and carotid vascular resistance fell by 44% from its value in normoxemia after L-NAME, although femoral vascular resistance progressively increased and remained high during recovery. We conclude that in the llama fetus: 1) NO has an important role in maintaining a vasodilator tone during both normoxemia and hypoxemia in cerebral and femoral vascular beds and 2) during hypoxemia, NOS blockade unmasked the action of other vasodilator agents that contribute, with nitric oxide, to preserving blood flow and oxygen delivery to the tissues.

Investigation of the effects of naratriptan, rizatriptan, and sumatriptan on jugular venous oxygen saturation in anesthetized pigs: implications for their mechanism of acute antimigraine action.

The effects of naratriptan, rizatriptan, and sumatriptan on arteriovenous oxygen saturation difference and carotid hemodynamics were compared in the anesthetized pig. Oxygen and carbon dioxide partial pressures in systemic arterial and jugular venous blood as well as hemoglobin oxygen saturation were determined by conventional blood gas analysis. Vehicle (n = 19) or naratriptan, rizatriptan, or sumatriptan (0.63, 2.5, 10, 40, 160, 630, and 2,500 microg/kg i.v.; n = 7/group) were infused cumulatively. In naratriptan-, rizatriptan-, and sumatriptan-treated animals, jugular venous oxygen saturation decreased dose dependently (geometric mean ED50 values of 3.1, 17.9, and 16.0 microg/kg, respectively) concomitantly with increases in carotid vascular resistance. Rizatriptan significantly and dose dependently, from 160 microg/kg, increased PvCO2 (P < 0.05 versus vehicle). Naratriptan and sumatriptan also tended to increase PvCO2 albeit nonstatistically significantly. All three triptans consistently evoked quantitatively similar carotid vasoconstriction, whereas decreases in jugular venous oxygen saturation (VOS) and increases in PvCO2 had different magnitudes and occurred only in around one-half of the animals studied. Maximal variations in PvCO2 were found to correlate highly with those in PvO2 (P = 0.002), but maximal variations in carotid resistance failed to correlate with those in PvCO2 (P = 0.76) or PvO2 (P = 0.28). The results demonstrate that the triptans investigated robustly produced carotid vasoconstriction, but elicited less consistent decreases in VOS and increases in jugular PvCO2, possibly suggestive of distinct mechanisms. Collectively, the data suggest that triptan-induced increases in arteriovenous oxygen saturation difference and carbon dioxide partial pressure in venous blood draining the head are class effects.

Donitriptan selectively decreases jugular venous oxygen saturation in the anesthetized pig: further insights into its mechanism of action relevant to headache relief.

The effects of donitriptan on systemic arterial-jugular venous oxygen saturation difference were evaluated in pentobarbitone-anesthetized pigs. Oxygen and carbon dioxide partial pressures in systemic arterial and jugular venous blood as well as hemoglobin oxygen saturation were determined by conventional blood gas analysis. Vehicle (40% polyethyleneglycol in saline, n = 9) or donitriptan (0.01, 0.04, 0.16, 0.63, 2.5, 10, and 40 microg/kg, n = 7) were cumulatively infused over 15 min/dose. The involvement of 5-hydroxytryptamine(1B) (5-HT(1B)) receptors was assessed in the presence of the 5-HT(1B/1D) receptor antagonist, GR 127935. Donitriptan decreased markedly and dose dependently jugular venous oxygen saturation [ED(50) 0.5 (0.3-1.1) microg/kg], in parallel with increases in carotid vascular resistance [ED(50) 0.9 (0.7-1.1) microg/kg]. Since arterial oxygen saturation and partial pressure remained unchanged, donitriptan significantly increased arteriovenous oxygen saturation difference from 0.63 microg/kg (maximal variation: 57 +/- 18%, P < 0.05 compared with vehicle). Unexpectedly, donitriptan from 2.5 microg/kg induced marked and significant increases in carbon dioxide partial pressure (pVCO(2)) in venous blood (maximal increase 18.8 +/- 5.7%; P < 0.05 compared with vehicle). Pretreatment with GR 127935 (0.63 mg/kg, n = 5) abolished the fall in venous oxygen saturation and the increase in carotid vascular resistance and reduced the increases in pVCO(2) induced by donitriptan. The results demonstrate that donitriptan, via 5-HT(1B) receptor activation, decreases the oxygen saturation of venous blood draining the head, concomitantly with cranial vasoconstriction. Since donitriptan also increased pVCO(2), an effect upon cerebral oxygen consumption and metabolism is suggested in addition to cranial vasoconstriction, which may be relevant to its headache-relieving effects.