Measurement of collateral circulation blood flow in anesthetized portal hypertensive rats

AIMS: The aim of this study was to develop a technique to measure collateral blood flow in portal hypertensive rats. METHODS: Morphological techniques included inspection, casts and angiographies of portosystemic shunts. The main hemodynamic measurements were splenorenal shunt blood flow (transit time ultrasound method), percentage of portosystemic shunts and regional blood flows (microsphere method). In study 1, a model of esophageal varices was developed by ligating the splenorenal shunt. In study 2, morphological studies of the splenorenal shunt were performed in rats with portal vein ligation. In study 3, the relationship between splenorenal shunt blood flow with percentage of portosystemic shunts was evaluated in dimethylnitrosamine cirrhosis. In study 4, secondary biliary, CCl4 and dimethylnitrosamine cirrhosis were compared. In study 5, rats with portal vein ligation received acute administration of octreotide. In study 6, rats with dimethylnitrosamine cirrhosis received acute administration of vapreotide. RESULTS: Blood flow of para-esophageal varices could not be measured. SRS blood flow was correlated with the mesenteric percentage of portosystemic shunts (r = 0.74, P < 0.05), splenic percentage of portosystemic shunts (r = 0.54, P < 0.05) and estimated portosystemic blood flow (r = 0.91, P < 0.01). Splenorenal shunt blood flow was 6 to 12 times higher in portal hypertensive rats, e.g., in portal vein ligated rats: 2.8 +/- 2.7 vs 0.3 +/- 0.1 mL.min-1 in sham rats (P < 0.01), and was similar in the different cirrhosis models but was higher in portal vein ligated rats than in cirrhotic rats (1.2 +/- 0.7 vs 0.6 +/- 0.6 mL.min-1.100 g-1, P = 0.05). Octreotide significantly decreased splenorenal shunt blood flow: -23 +/- 20% (P < 0.01) vs -6 +/- 8% (not significant) in placebo rats. The variation of splenorenal shunt blood flow after vapreotide was significant but not that of the splenic percentage of portosystemic shunts compared to placebo. CONCLUSIONS: The splenorenal shunt is the main portosystemic shunt in rats. The measurement of splenorenal shunt blood flow is easy, accurate and reproducible and should replace the traditional measurement of the percentage of portosystemic shunts in pharmacological studies.     

Noninvasive assessment of collateral blood flow of the cerebral hemisphere by Doppler ultrasound

Directional flow in the frontal artery, a terminal branch of the ophthalmic artery, was assessed nonivasively by Doppler ultrasound druing brief digital compression of the ipsilateral common carotid artery in 62 patients. Directional frontal artery flow during carotid compression was compared with mean distal internal carotid back pressure measured at subsequent carotid endarterectomy. Mean carotid back pressure in 28 patients with normal frontal artery flow direction during carotid compression, 68 +/- 14 millimeters of mercury, was significantly higher than that observed in 24 patients in whom frontal artery flow was completely obliterated and ten in whom frontal artery flow was reversed. Distal internal carotid back pressure exceeded 48 millimeters of mercury in all patients with normal frontal artery flow direction during carotid compression. Conversely, carotid back pressure was below 41 millimeters of mercury in all but one patient in whom frontal artery flow was obliterated or bliterated or reversed during carotid compression. The results of this study indicate that Doppler ultrasound assessment of frontal artery flow direction during simultaneous carotid compression provides a rapid, sale noninvasive estimate of the adequacy of collateral hemispheric circulation.     

Hypercapnic cerebral blood flow in spontaneously hypertensive rats

OBJECTIVE: Hypercapnic cerebral vasodilation appears to be endothelium-dependent, as it involves nitric oxide and prostaglandins. Since chronic hypertension has been associated with impaired endothelial function, we designed a study to find out whether hypercapnic cerebral blood flow and its nitric oxide- and prostaglandin-sensitive component is reduced in spontaneously hypertensive rats (SHR) compared with normotensive controls. METHODS: Cerebral blood flow was measured in enflurane-anesthetized SHR (n=53), Wistar-Kyoto (WKY, n=20) and Sprague-Dawley (n=50) rats using the hydrogen clearance method. Cerebral blood flow was measured during eucapnia and hypercapnia; it was also assessed after administering either nonisoform-selective or isoform-selective neuronal nitric oxide synthase inhibitors and during inhibition of prostaglandin production. RESULTS: Hypercapnic cerebral blood flow did not differ among the strains. Nitric oxide synthase inhibition with intracortical N(G)-monomethyl-L-arginine reduced hypercapnic cerebral blood flow in SHR by 23+/-4% and in Sprague-Dawley rats by 23+/-7% without affecting eucapnic flow. Intraperitoneal administration of the inhibitor of neuronal nitric oxide synthase, 7-nitroindazole, reduced eucapnic flow by 18+/-5% in SHR and 27+/-5% in WKY rats, and hypercapnic flow by 48+/-3 and by 51+/-6%, respectively. Indomethacin produced a similar decrease in hypercapnic flow in Sprague-Dawley rats and SHR (49+/-5 and 62+/-4%, respectively). CONCLUSION: Hypercapnic cerebral blood flow was not impaired in SHR. The contribution of nitric oxide- and prostaglandin-dependent vasodilation appeared to be intact Our results are consistent with the hypothesis that neuronal rather than endothelial production of nitric oxide may be responsible for maintaining hypercapnic cerebral vasodilation in SHR.     

Doppler ultrasound determination of average blood flow velocity and flow volume in transjugular intrahepatic portosystemic shunt (TIPS)

We evaluated the acute and chronic experimental toxicity of a water extract of saponins from Argania spinosa following oral and intraperitoneal (i.p.) administration in mice (Iops Ofa) and rats (Wistar). The DL50 obtained were 79 mg/kg for the i.p. route and 1,300 mg/kg for the oral route. For the chronic toxicity studies, we administred 100 and 200 mg/kg orally once a day during a 3 month period. There was a decrease in blood sugar in the third month of each therapy. Blood creatinine levels increased, thus evoking a renal pathology. A slight increase in transaminases levels was not significatif. Hematologic parameters were unchanged during the treatment and the histopathologic study showed hepatic glycogen decrease and a focal renal tube deterioration.     

Systemic and portal vein delivery of human kallikrein gene reduces blood pressure in hypertensive rats

There is an inverse correlation between systemic blood pressure and urinary kallikrein levels in humans and hypertensive animal models, suggesting that the tissue kallikrein-kinin system plays an important role in blood pressure regulation. In this study, we explored the potential of human kallikrein gene delivery on blood pressure reduction in spontaneously hypertensive rats (SHR). The human tissue kallikrein gene or cDNA was placed under the control of following promoters: the metallothionein gene metal response-element (MRE-pHK), albumin gene (ALB-pHK), Rous sarcoma virus 3' long terminal repeat (LTR) (RSV-cHK), and cytomegalovirus (CMV-cHK). A single injection of these kallikrein DNAs results in a significant reduction of blood pressure in SHR, which lasts for 5-6 weeks. Systemic delivery of CMV-cHK, RSV-cHK, and MRE-pHK has a greater effect on blood pressure reduction than ALB-pHK, whereas intraportal vein gene delivery of ALB-pHK is more effective than the other kallikrein DNA constructs. The degree of blood pressure reduction depends on the amount of administered DNA and the age of the animals. Reduction of blood pressure was observed in adult, but not young, SHR. The expression of human tissue kallikrein in rats was identified by an ELISA that is specific for human tissue kallikrein. No antibodies to either human tissue kallikrein or its DNA were detected in rat sera after somatic gene delivery. These results show that somatic gene delivery of human tissue kallikrein causes a lowering effect of systolic blood pressure in genetically hypertensive rats and provide valuable information for kallikrein gene therapy in the treatment of hypertension.     

N-acetylcysteine prevents development of the hyperdynamic circulation in the portal hypertensive rat

Infective endocarditis, defined as pathologically or clinically definite by the Duke criteria, was observed in 14 transplant recipients at our institutions. In addition, we reviewed 32 previously reported cases in solid organ transplant recipients. The spectrum of organisms causing infective endocarditis was clearly different in transplant recipients than in the general population; 50% of the infections were due to Aspergillus fumigatus or Staphylococcus aureus, but only 4% were due to viridans streptococci. Fungal infections predominated early (accounting for six of 10 cases of endocarditis within 30 days of transplantation), while bacterial infections caused most cases (80%) after this time. In 80% (37) of the 46 cases in transplant recipients, there was no underlying valvular disease. Seventy-four percent (34) of the 46 cases were associated with previous hospital-acquired infection, notably venous access device and wound infections. Three patients with S. aureus endocarditis had had an episode of S. aureus bacteremia > 3 weeks prior to the diagnosis of endocarditis and had received treatment for the initial bacteremia of < 14 days' duration. The overall mortality rate was 57% (26 of 46 patients died), with 58% (15) of the 26 fatal cases not being suspected during life. Endocarditis is an underappreciated sequela of hospital-acquired infection in transplant recipients.     

Intrasplenic venous flow patterns demonstrated by Doppler ultrasound in patients with portal hypertension

The flow pattern in the splenic vein has been previously reported in patients with portal hypertension, but with no reference to the flow within the intrasplenic venous radicles. Using Doppler ultrasound, this study describes the intrasplenic venous flow direction in 176 adult patients with intrahepatic portal hypertension. In our series, a normal flow pattern was maintained in all except four patients (2.3%) who had either reversed or dual venous drainage patterns resulting in trans-splenic portosystemic shunts. These abnormal patterns are Doppler signs of portal hypertension which might be associated with a higher risk of oesophageal variceal bleeding. It is recommended that the intrasplenic venous flow pattern should be assessed before surgical intervention involving the spleen in patients with portal hypertension.     

Haemodynamic effects of chronic tetrandrine treatment in portal hypertensive rats

Tetrandrine is a calcium channel antagonist with reported antihypertensive effect. However, the potential role of tetrandrine as a therapeutic agent in portal hypertension has yet to be explored. The present study aimed to investigate the haemodynamic effects of chronic tetrandrine treatment on portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation in Sprague-Dawley rats. Animals were allocated into one of two groups: a tetrandrine group and a vehicle group. Tetrandrine (20 mg/kg) or vehicle was administered by gavage every 12 h for 8 consecutive days, starting 1 day before ligation and continuing thereafter. After 8 days of tetrandrine treatment, systemic haemodynamics, organ blood flow and the degree of portal-systemic shunting were measured after an overnight fast. The portal venous pressure and protal tributary blood flow were significantly decreased, while portal territory as well as hepto-collateral vascular resistance significantly increased in the tetrandrine group compared with the vehicle group. The cardiac index was increased, while systemic vascular resistance was decreased, the the tetrandrine group. Mean arterial pressure, heart rate, portal-systemic shunting and bodyweight were similar between the two groups. Renal blood flow was decreased in the tetrandrine group. In conclusion, long-term treatment of tetrandrine reduced portal venous pressure and alleviated splanchnic hyperaemina in portal hypertensive rats without affecting the portal-systemic shunting.     

Using the POBF as an index of interocular blood flow effects during unilateral vascular stress

Kergoat and Lovasik [(1994). Ophthalmic and Physiological Optics, 14, pp. 401-407] reported that a transient decrease in ocular perfusion pressure (OPP) decreased the neural function in the test eye but increased the responsivity in the contralateral untouched (control) eye. Here the hypothesis tested was that a transient unilateral vascular stress would induce an increase in the Pulsatile Ocular Blood Flow (POBF) in the opposite eye. The POBF was measured in 20 healthy volunteers with normal intraocular pressure (IOP) and brachial blood pressure (BP). The OPP was decreased in the test (right) eye by scleral suction, and a Langham OBF system was used to make four readings of the POBF for each eye for baseline conditions, and when the OPP was decreased in the test eye alone by 20 and 40% for a 2 min period. Each individual, as well as the group averaged data showed a progressive decrease in the POBF in the test eye during a stepwise reduction in the OPP. No change was found for the POBF for the control eyes. Within the limitations of the systems and testing procedures employed, it is concluded that unilateral alterations in the OPP do not cause a change in the POBF in the contralateral eye.     

The hemodynamic effects of AT-112, an analog of ketanserin, in portal hypertensive rats

Proteins that are actively secreted by Mycobacterium tuberculosis generate immune responses in the infected host. This has prompted the characterization of protein components of mycobacterial culture filtrates to develop subunit vaccines and immunodiagnostic reagents. Fractionation of filtrates of M. tuberculosis cultures has yielded an abundant protein called MPT63, which has an apparent molecular mass of 18 kDa. We report the molecular cloning and nucleotide sequence of the mpt63 gene, purification of recombinant MPT63 antigen from Escherichia coli cells, and serological characterization of MPT63. Nucleotide sequence analysis of mpt63 identified an open reading frame encoding a protein of 159 amino acids (aa) consisting of a 29-aa secretion signal peptide and a 130-aa mature MPT63 protein. Recombinant MPT63 protein, purified from E. coli cells, and native MPT63, purified from M. tuberculosis culture filtrates, were indistinguishable in serological assays. Thus, the recombinant protein constitutes a valuable reagent for immunological studies. MPT63 evoked humoral immune responses in guinea pigs infected with virulent M. tuberculosis by the aerosol route. The mpt63 gene is found only in species of the M. tuberculosis complex, as shown by DNA hybridization experiments. Moreover, polyclonal antibody against MPT63 does not cross-react with proteins of a common environmental mycobacterial species, Mycobacterium avium. The absence of cross-reactive epitopes makes MPT63 an attractive candidate as an M. tuberculosis complex-specific diagnostic reagent. In particular, evaluation of MPT63 as an M. tuberculosis complex-specific reagent for diagnostic skin testing is under way.     

Distensibility of portacaval shunts in portal hypertensive cats: index of contractility model

Complete shunting of portal blood flow through portacaval shunts was obtained using a constrictor around the portal vein to gradually produce a total occlusion. After 4 weeks, acute experiments were conducted in anesthetized cats. Blood from the femoral artery was shunted through a pump to supply and control the entire portal blood flow. As shunted portal blood flow was varied over a wide range, the portal shunt resistance showed distensibility. Decreasing portal venous pressure from 15.0 +/- 0.9 to 11.1 +/- 0.6 mmHg (1 mmHg = 133.3 Pa) resulted in elevations of resistance of 58%. The relation between the resistance (R) and the distending pressure (Pd) was a constant, the index of contractility (IC), where IC = R.Pd3. In steady state, the IC was 485 +/- 55 mmHg4.mL-1.min.kg and did not change passively in response to changes in portal blood flow. In conclusion, portacaval shunts are passively distensible, and resistance is altered as a cubic function of the distending pressure. Because resistance is altered both actively and passively, the IC should prove useful to differentiate these alternatives for evaluation of changes in portal hypertensive therapy.     

Omental delivery of prostaglandin E1 effectively increases portal venous blood flow in 66%-hepatectomized rats

BACKGROUND: Contraction-excitation feedback, that is, electrophysiologic changes that are caused or preceded by mechanical changes of the myocardium, has been extensively studied in the ventricles. The role of contraction-excitation feedback in the atria, and more particularly in the genesis and maintenance of atrial fibrillation, has been less adequately investigated. HYPOTHESIS: The aim of the present study was to determine whether increased right atrial pressure (RAP) facilitates the induction of atrial fibrillation (AF) in patients with a history of lone AF. METHODS: Sixteen patients with a history of paroxysmal AF but without structural heart disease were included in the study. All patients underwent electrophysiologic study at both a lower (3.1 +/- 2.0 mmHg) and (in 13 cases) a higher (6.4 +/- 2.5 mmHg) RAP. "Higher" was considered the pressure following rapid (in about 30 min) intravenous administration of normal saline or before the administration of a diuretic. RESULTS: Rapid atrial pacing induced AF in 19 of 29 attempts. At a lower pressure, rapid pacing induced brief (3 s to 3 min) AF in 3 of 16 patients, long-lasting (> 3 min) AF in 3 of 16 patients, and no AF in 10 of 16 patients. At a higher pressure, brief AF was induced in 3 of 10 patients in whom no AF could be induced at a lower pressure, and long-lasting AF in 10 patients in whom either brief AF (3 cases) or no AF (7 cases) was induced at a lower pressure. In 11 patients, in whom Wenckebach periodicity was determined at both higher and lower pressure, the critical cycle length at which atrioventricular block appeared was significantly (p < 0.001, paired t-test) longer (349.1 +/- 44.4 ms, i.e., +15.5 +/- 11.3 ms) at higher than at lower atrial pressure (333.6 +/- 41.0 ms). In nine patients, in whom Wenckebach periodicity was determined and two rhythms occurred at different pressures, the critical cycle length was 332.2 +/- 45.8 ms when associated with sinus rhythm, and significantly (p < 0.01) longer (344.4 +/- 48.0 ms, i.e., +12.2 +/- 8.3 ms) when associated with induction of AF. CONCLUSION: In patients with lone atrial fibrillation, modest increases in atrial pressure may facilitate the induction of atrial fibrillation.     

Activation of 11 beta-hydroxysteroid dehydrogenase by dehydroepiandrosterone sulphate as an anti-hypertensive agent in spontaneously hypertensive rats

The anti-hypertensive properties of dehydroepiandrosterone sulphate (DHEAS) have been investigated by studying its effects on blood pressure, on serum concentrations of corticosterone and dehydrocorticosterone, and on 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) activity in spontaneously hypertensive rats (SHR). SHR were given intraperitoneal injections of DHEAS (10 mg day-1 for 70 days) from six to 16 weeks of age. The blood pressure-time curve was significantly (P < 0.05) suppressed immediately after administration of DHEAS. There was no difference between the heart rates of control and DHEAS groups. Serum concentrations of corticosterone and dehydrocorticosterone in the DHEAS group were significantly (P < 0.05) lower than those of the control group. The dehydrocorticosterone/corticosterone concentration ratio was, however, significantly (P < 0.05) higher in the DHEAS group, suggesting that treatment with DHEAS enhanced the overall interconversion of corticosterone to dehydrocorticosterone. The activity of 11 beta-HSD in specific organs of the DHEAS group was affected, characteristic changes being increases in the kidney (14-58%), decreases in the liver (11-27%) and no change in the testis. Direct addition of DHEAS to 11 beta-HSD preparations from the kidneys of control SHR had the same effect as that observed in the in-vivo experiments. The fall in serum corticosterone in the DHEAS group is considered to be related, at least partly, to increased activity of kidney 11 beta-HSD. The inverse correlation of kidney 11 beta-HSD activity with serum corticosterone and blood pressure (-r = 0.628, P < 0.01, and -r = 0.478, P < 0.05, respectively) suggest that DHEAS delayed the development of hypertension in SHR by selective promotion of kidney 11 beta-HSD activity which in turn resulted in lower serum concentrations of corticosterone and its minimal aldosterone-like activity.     

Doppler ultrasound of blood flow in the hepatic veins

The blood flow in the hepatic veins can normally be studied easily by Doppler ultrasound. The pattern of blood flow in normal individuals is described, and its relation to the cardiac cycle and changing pressure in the right atrium. The blood flow shows variations in healthy persons, and may change in cases of heart disease and hepatic disease. Conditions such as atrial fibrillation, tricuspid regurgitation, abnormal relaxation, restrictive cardiomyopathy, constrictive pericarditis and cardiac tamponade are reflected in the hepatic veins, and the pattern of blood flow may help in diagnosis, and in grading the pathology. In cirrhosis and portal hypertension the heart-synchronous variation in velocity is reduced. This is due to increased resistance to blood flow across the liver and the pressure gradient becoming larger than the variations in pressure in the right atrium.     

Cerebral blood flow in hypertensive patients: an initial report of reduced and compensatory blood flow responses during performance of two cognitive tasks

We asked whether the altered cerebral vasculature associated with essential hypertension might dampen or redirect the regional cerebral blood flow (rCBF) response to cognitive work. Relative rCBF was assessed with [(15)O]water positron emission tomography during a working memory task, a memory span task, and two perceptual control tasks. Unmedicated hypertensive patients and control subjects differed in rCBF response during both memory tasks. Hypertensives showed relatively diminished rCBF responses in right hemisphere areas combined with compensatory activation of homologous areas in the left cerebral cortex. Essential hypertension appears to selectively influence the circulatory reserve of portions of cerebral cortex and secondarily induce recruitment of other cortical areas to process certain tasks.     

Haemodynamic effects of 8-day octreotide and prazosin administration in portal hypertensive rats

Fifty-five novel rat microsatellite markers were isolated from libraries specific for rat chromosomes (Chrs) 1, 2, and 7. The markers were mapped in three backcross rat populations. Thirty of these markers mapped to Chrs 1, 2, or 7, while the other 25 mapped to other chromosomes. New markers for two genes, liver-specific transporter gene (Livtr) and insulin-responsive glucose transporter (Glut4), were also mapped to rat Chrs 9 and 10, respectively. Three provisionally assigned markers from previous studies were also confirmed. Detailed methodologies for the generation and enrichment of clones containing repeat sequences and for the isolation of chromosome-specific markers are presented, since they represent unique combinations and modifications of previous protocols. Such methods and the newly presented markers should be useful for both specific and general mapping studies in the rat.     

Vascular hyporesponsiveness in aorta from portal hypertensive rats: possible sites of involvement

Vascular hyporesponsiveness in portal hypertension has been proposed to be due to postreceptor defect. The present study was aimed to investigate possible sites of involvement in such hyporesponsiveness. Portal hypertension was induced by partial portal vein ligation (PVL). Concentration-response curves to KCI and phenylephrine in both groups showed that the Emax values were significantly lower in the PVL group. The EC50 values were not different between the two groups. In Ca++ free condition, phenylephrine induced a phasic contraction, which was significantly smaller in the aorta from PVL rats. Cumulative readdition of CaCl2 (1.0-2.5 mM) induced tension increases, which were all significantly lower in the PVL group. Basal contents of [3H]inositol phosphates in the aorta were similar between the two groups. Phenylephrine induced concentration-dependent increase of [3H]inositol phosphates in the aorta from both groups. The responses at 10(-8), 10(-7), 10(-6) and 10(-5) M were significantly smaller in the PVL group than in the sham-operated group. Both okadaic acid and phorbol 12,13-dibutyrate induced slowly developing contractile responses in the aorta. The responses were similar between the two groups at all time points. Our results suggested that in the aorta from PVL rats, vascular hyporesponsiveness was observed, together with decreased contractile responses due to: voltage- and receptor-dependent calcium influx as well as intracellular calcium release, and decreased receptor-coupled inositol phosphate formation. Contractile responses due to activation of protein kinase C or phosphatase inhibition were not impaired.     

Improvement of exercise capacity by sarpogrelate as a result of augmented collateral circulation in patients with effort angina

OBJECTIVES: The purpose of this study was to evaluate whether a serotonin blocker, sarpogrelate, improves exercise capacity as a result of vasodilation of coronary collateral channels in patients with effort angina. BACKGROUND: Serotonin has been reported to decrease coronary collateral blood flow by collateral vasoconstriction in a canine model, suggesting that platelet activation in feeding coronary arteries of the collateral network has the potential to cause collateral vasoconstriction. METHODS: The subjects consisted of 22 patients with effort angina and reproducible ischemic threshold (group A, 11 patients with thrombolysis in myocardial infarction (TIMI) grade 2 or 3 flow of the ischemia-related coronary artery and Rentrop's collateral index 0 or 1; group B, 11 patients with TIMI grade 0 or 1 flow and Rentrop's collateral index 2 or 3). We repeated the symptom-limited treadmill exercise test using the Balke-Ware protocol and exercise tetrofosmin myocardial perfusion scintigraphy with and without pretreatment with 200 mg orally administered sarpogrelate. Each exercise test was performed at 9:00 a.m. on different days. The order of tests with and without sarpogrelate was randomized. RESULTS: In group A, sarpogrelate increased neither exercise time at 0.1 mV ST depression nor double product at 0.1 mV ST depression. In contrast, in group B sarpogrelate increased the exercise duration at 0.1 mV ST depression from 181+/-112 (SD) to 248+/-131 s (p < 0.05) and also increased the double product at 0.1 mV ST depression by 21% (p < 0.01). The severity score using myocardial perfusion scintigraphy at the same workload was significantly (p < 0.01) decreased by 37% in group B, but not in group A (11%), due to the sarpogrelate treatment. CONCLUSIONS: Sarpogrelate augments flow reserve of the collateral circulation and improves exercise capacity in anginal patients with well-developed collaterals. These findings indicate that a serotonin blocker, sarpogrelate, is useful not only as an antiplatelet drugs, but as an antianginal drug.     

Sevoflurane selectively increases coronary collateral blood flow independent of KATP channels in vivo

BACKGROUND: Volatile anesthetic agents produce coronary vasodilation via activation of adenosine triphosphate-sensitive potassium (KATP) channels. The authors tested the hypothesis that sevoflurane selectively increases coronary collateral blood flow and assessed the role of KATP channel activation in this process. METHODS: Experiments were conducted in dogs 8 weeks after long-term implantation of a left anterior descending coronary artery (LAD) ameroid constrictor to stimulate coronary collateral growth. Dogs were instrumented for measurement of retrograde LAD blood flow (an index of large coronary collateral blood flow) and LAD tissue flow (via radioactive microspheres; an index of small collateral blood flow). Coronary collateral perfusion and normal (left circumflex coronary artery [LCCA]) zone tissue blood flow were determined in four groups of dogs pretreated with intracoronary glyburide (50 microg/kg) or vehicle in the presence or absence of sevoflurane (1 minimum alveolar concentration). Dose-response relationships to the KATP channel agonist nicorandil were established in each dog using doses (25, 50, and 100 microg/min) previously shown to increase coronary collateral blood flow. RESULTS: Sevoflurane increased blood flow through large and small collaterals and increased collateral vascular conductance in the presence of glyburide but did not affect LCCA blood flow or conductance. In contrast, nicorandil increased blood flow through small but not large collaterals. Nicorandil also increased LCCA blood flow and conductance, actions that were attenuated by glyburide. CONCLUSIONS: The results demonstrate that sevoflurane selectively increases large and small coronary collateral blood flow via mechanism(s) independent of KATP channel activation.