Coronary microvascular responses to reductions in perfusion pressure. Evidence for persistent arteriolar vasomotor tone during coronary hypoperfusion

The goals of this study were to test the following hypotheses: 1) Coronary autoregulatory adjustments to decreases in perfusion pressure occur primarily in coronary arterioles (less than 150 microns in diameter). 2) Small coronary arteries (greater than 150 microns in diameter) can be recruited to participate in the autoregulatory adjustments as perfusion pressure is progressively lowered. 3) Small arterioles are the location of vasodilator reserve in the coronary microcirculation during hypoperfusion. Studies were performed in anesthetized open-chest dogs in which coronary perfusion pressures were reduced to 80, 60, 40, and 30 mm Hg. During reductions in coronary perfusion pressure, measurements were made of systemic hemodynamics, myocardial blood flow (radioactive microspheres), and coronary microvascular diameters. Arterial pressure and heart rate were largely unchanged during the experimental maneuvers. Measurements of microvascular diameters in the beating heart were performed during epi-illumination via a stroboscopic light source synchronized to the cardiac cycle using fluorescence intravital microscopy. Coronary autoregulatory adjustments were evident during reductions in perfusion pressure from control (96 mm Hg) to 80 and 60 mm Hg. Blood flow was unchanged from control, and active vasodilation of coronary arterioles was observed. At 80 mm Hg, only coronary arterioles dilated (4.4 +/- 1.2%), whereas at 60 mm Hg both small arteries (4.9 +/- 2.2%) and arterioles (6.9 +/- 1.2%) demonstrated significant vasodilation (p less than 0.05). The magnitude of dilation (i.e., percent increase in diameter) was inversely related to the initial diameter; that is, the arterioles dilated to a greater extent, percentage wise, than the small arteries. At 40 mm Hg, myocardial blood flow decreased slightly from that under control conditions, but coronary arterioles dilated to a greater extent than at 60 mm Hg (8.1 +/- 1.6%); yet, microvessels were incompletely vasodilated, because adenosine produced a further increase in microvessel diameter (12.5 +/- 2.1%) (p less than 0.05). At a perfusion pressure of 30 mm Hg, arterioles demonstrated a decrease in vascular diameter (-0.2 +/- 2.1%), which was reversed by adenosine (11.1 +/- 3.1%). From these results we concluded the following: 1) Coronary autoregulatory adjustments involve primarily coronary arteriolar vessels, but small coronary arteries can be recruited to participate in the autoregulatory response. 2) The magnitude of vessel dilation appears to be inversely related to vascular diameter. 3) Coronary arterioles are not maximally vasodilated during coronary hypoperfusion, and these vessels may be the source of persistent vasomotor tone during coronary insufficiency.     

Effect of ATP-sensitive potassium channel inhibition on resting coronary vascular responses in humans

Experimental data suggest that vascular ATP-sensitive potassium (K(ATP)) channels regulate coronary blood flow (CBF), but their role in regulating human CBF is unclear. We sought to determine the contribution of K(ATP) channels to resting conduit vessel and microvascular function in the human coronary circulation. Twenty-five patients (19 male/6 female, aged 56 +/- 12 years) were recruited. Systemic and coronary hemodynamics were assessed in 20 patients before and after K(ATP) channel inhibition with graded intracoronary glibenclamide infusions (4, 16, and 40 microg/min), in an angiographically smooth or mildly stenosed coronary artery following successful elective percutaneous coronary intervention to another vessel. Coronary blood velocity was measured with a Doppler guidewire and CBF calculated. Adenosine-induced hyperemia was determined following bolus intracoronary adenosine injection (24 microg). Time control studies were undertaken in 5 patients. Compared with vehicle infusion (0.9% saline), glibenclamide reduced resting conduit vessel diameter from 2.5 +/- 0.1 to 2.3 +/- 0.1 mm (P<0.01), resting CBF by 17% (P=0.05), and resting CBF corrected for rate pressure-product by 18% (P=0.01) in a dose-dependent manner. A corresponding 24% increase in coronary vascular resistance was noted at the highest dose (P<0.01). No alteration to resting CBF was noted in the time control studies. Glibenclamide reduced peak adenosine-induced hyperemia (P=0.01) but did not alter coronary flow reserve. Plasma insulin increased from 5.6 +/- 1.2 to 7.6 +/- 1.3 mU/L (P=0.02); however, plasma glucose was unchanged. Vascular K(ATP) channels are involved in the maintenance of basal coronary tone but may not be essential to adenosine-induced coronary hyperemia in humans.     

Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs.

Single or multiple brief periods of ischemia (preconditioning) have been shown to protect the myocardium from infarction after a subsequent more prolonged ischemic insult. To test the hypothesis that preconditioning is the result of opening ATP-sensitive potassium (KATP) channels, a selective KATP channel antagonist, glibenclamide, was administered before or immediately after preconditioning in barbital-anesthetized open-chest dogs subjected to 60 minutes of left circumflex coronary artery (LCX) occlusion followed by 5 hours of reperfusion. Preconditioning was elicited by 5 minutes of LCX occlusion followed by 10 minutes of reperfusion before the 60-minute occlusion period. Glibenclamide (0.3 mg/kg i.v.) or vehicle was given 10 minutes before the initial ischemic insult in each of four groups. In a fifth group, glibenclamide was administered immediately after preconditioning. In a final series (group 6), a selective potassium channel opener, RP 52891 (10 micrograms/kg bolus and 0.1 micrograms/mg/min i.v.) was started 10 minutes before occlusion and continued throughout reperfusion. Transmural myocardial blood flow was measured at 30 minutes of occlusion, and infarct size was determined by triphenyltetrazolium staining and expressed as a percent of the area at risk. There were no significant differences in hemodynamics, collateral blood flow, or area at risk between groups. The ratio of infarct size to area at risk in the control group (28 +/- 6%) was not different from the group pretreated with glibenclamide in the absence of preconditioning (31 +/- 6%). Preconditioning produced a marked reduction (p less than 0.002) in infarct size (28 +/- 6% to 6 +/- 2%), whereas glibenclamide administered before or immediately after preconditioning completely abolished the protective effect (28 +/- 6% and 30 +/- 8%, respectively). RP 52891 also produced a significant (p less than 0.03) reduction (28 +/- 6% to 13 +/- 3%) in infarct size. These results suggest that myocardial preconditioning in the canine heart is mediated by activation of KATP channels and that these channels may serve an endogenous myocardial protective role.     

Effect of hypertension and hypertrophy on coronary microvascular pressure.

We tested the hypothesis that transmural differences in coronary microvascular pressures may be greater in the setting of hypertension and left ventricular hypertrophy. Epicardial and endocardial microvascular pressures were measured in isolated lidocaine-arrested hearts during adenosine vasodilation. In both normotensive (n = 19) and hypertensive (one clip, one kidney, n = 10) dogs, microvascular pressures in endocardial arterioles at 60, 70, 80, 90, and 100 mm Hg of left main coronary perfusion pressures were lower than in epicardial arterioles (p less than 0.05 at all perfusion pressures). The pressures in epicardial arterioles as a percentage of the left main coronary perfusion pressure were similar in normotensive versus hypertensive hearts at all perfusion pressures. In contrast, the pressures in endocardium at 90 and 100 mm Hg of perfusion pressure were significantly (p less than 0.05) lower in dogs with hypertension and hypertrophy than in the controls (41 +/- 4 versus 50 +/- 2 and 40 +/- 4 versus 50 +/- 3 mm Hg at 90 and 100 mm Hg of perfusion pressure, respectively). Thus, there is a greater transmural resistance to microvascular perfusion in hearts with myocardial hypertrophy secondary to hypertension. This is likely due to differences in the vascular anatomy, secondary to hypertension and hypertrophy, and may contribute to vulnerabilities in subendocardial ischemia encountered in this condition.     

Coronary vascular K+ATP channels contribute to the maintenance of myocardial perfusion in dogs with pacing-induced heart failure

The functional role of coronary vascular ATP-sensitive potassium (K+ATP) channels in the regulation of coronary blood flow (CBF) has not been determined in chronic heart failure (CHF). To test the hypothesis that K+ATP channels contribute to myocardial perfusion in HF, we examined the effects of intracoronary infusion of glibenclamide, an inhibitor of K+ATP channels, on basal CBF in control and CHF dogs. CHF was produced in mongrel dogs by pacing the right ventricle for 4 weeks. Under anesthesia, CBF in the left anterior descending coronary artery, other hemodynamic and metabolic parameters, or regional myocardial blood flow were measured. Basal CBF was less in CHF dogs than in controls. Glibenclamide at the graded doses (5, 15 and 50 microg x kg(-1) x min(-1) decreased CBF in both control and CHF dogs. The percentage decrease in CBF with glibenclamide at 50 microg x kg(-1) x min(-1) was greater (p<0.01) in CHF dogs than in controls. The greater decrease in CBF with glibenclamide at 50microg x kg(-1) x min(-1) was associated with myocardial ischemia. Glibenclamide decreased myocardial blood flow in each sublayer of the myocardium in the 2 groups. These results suggest that the basal activity of coronary vascular K+ATP channels is increased in CHF dogs but not in controls. This may contribute to the maintenance of myocardial perfusion in CHF.     

Blockade of the ATP-sensitive potassium channel modulates reactive hyperemia in the canine coronary circulation.

The mechanism of reactive hyperemia remains unknown. We hypothesized that reactive hyperemia was related to the opening of ATP-sensitive potassium channels during coronary occlusion. The resulting hyperpolarization of the smooth muscle cell plasma membrane might reduce calcium influx through voltage-dependent calcium channels and result in relaxation of smooth muscle tone and vasodilation. In eight open-chest, anesthetized dogs, 30-second coronary occlusions resulted in an average flow debt repayment of 200 +/- 41%. After low-dose (0.8 mumol/min) and high-dose (3.7 mumol/min) infusion of intracoronary glibenclamide, flow debt repayment fell to 76 +/- 14% and 50 +/- 8%, respectively (p less than 0.05 compared with control for both). The decline in flow debt repayment was due to a significant reduction both in maximum coronary conductance during reactive hyperemia and in its duration. In addition, there was a significant decline in the sensitivity of the coronary circulation to adenosine-induced vasodilation after glibenclamide. While more variable, there was no overall change in the sensitivity of the coronary vasculature to acetylcholine-induced vasodilation after glibenclamide. We conclude that reactive hyperemia is determined in a large part by the ATP-sensitive potassium channel, probably through its effect on membrane potential and voltage-sensitive calcium channels. Because reactive hyperemia was never fully abolished at the highest doses of glibenclamide tested, it is possible that additional mechanisms are involved in the genesis of this complex phenomenon.     

Reversal of glibenclamide-induced coronary vasoconstriction by enhanced perfusion pulsatility: possible role for nitric oxide

OBJECTIVES: ATP-sensitive potassium channels (K+ATP) prominently contribute to basal coronary tone; however, flow reserve during exercise remains unchanged despite channel blockade with glibenclamide (GLI). We hypothesized that increasing perfusion pulsatility, as accompanies exercise, offsets vasoconstriction from K+ATP-channel blockade, and that this effect is blunted by nitric oxide synthase (NOS) inhibition. METHODS: In 31 anaesthetized dogs the left anterior descending artery was blood-perfused by computer-controlled servo-pump, with real-time arterial perfusion pulse pressure (PP) varied from 40 and 100 mm Hg at a constant mean pressure and cardiac workload. RESULTS: At control PP (40 mm Hg), GLI (50 micrograms/min/kg, i.c.) lowered mean regional coronary flow from 37 +/- 5 to 25 +/- 4 ml/min (P < 0.001). However, this was not observed at 100 mm Hg PP (41 +/- 2 vs. 45 +/- 4). NOS inhibition by NG-monomethyl-L-arginine (L-NMMA) did not alter basal flow at 40 mm Hg PP, but modestly lowered flow (-5%, P < 0.001) at higher PP (100 mm Hg), reducing PP-flow augmentation by -36%, and acetylcholine (ACh) induced flow elevation by -39%. Co-infusion of L-NMMA with GLI resulted in net vasoconstriction at both PP levels (-60% and -40% at 40 and 100 mm Hg PP, respectively). Unlike GLI, vasoconstriction by vasopressin (-43 +/- 3% flow reduction at 40 mm Hg PP) or quinacrine (-23 +/- 7%) was not offset at higher pulsatility (-44 +/- 4 and -23 +/- 6%, respectively). Neither of the latter agents inhibited ACh- or PP-induced flow responses, nor did they modify the effect of L-NMMA on these responses. CONCLUSIONS: Increased coronary flow pulsatility offsets vasoconstriction from K+ATP blockade by likely enhancing NO release. This mechanism may assist exercise-mediated dilation in settings where K+ATP opening is partially compromised.     

Effect of the oral hypoglycaemic sulphonylurea glibenclamide, a blocker of ATP-sensitive potassium channels, on walking distance in patients with intermittent claudication.

AIMS: The oral hypoglycaemic sulphonylurea glibenclamide stimulates endogenous insulin secretion through blockade of ATP-sensitive potassium (KATP) channels on pancreatic beta cells, but also blocks cardiovascular KATP channels, leading to increased peripheral vascular resistance and reduced peripheral blood flow in non-diabetic subjects. Therefore, this study examined whether a single oral dose of glibenclamide adversely affected the pain-free or maximal walking distance in patients with intermittent claudication. METHODS: In a double-blind, randomized crossover study, 12 non-diabetic patients with intermittent claudication were given a single oral dose of glibenclamide (5.25 mg) or placebo separated by a washout period of 1 week. A treadmill test was carried out 180 min after glibenclamide/placebo intake for determination of pain-free and maximal walking distance. Plasma glucose concentrations were kept constant by an euglycemic clamp. Changes in ankle/brachial blood pressure index (ABI), serum insulin, and serum glibenclamide were also assessed. RESULTS: The pain-free walking distance was 62.8 +/- 9.8 metres (mean +/- sem) after glibenclamide and 52.6 +/- 5.9 metres after placebo (P = 0.52). The maximal walking distance was 142.7 +/- 18.7 metres after glibenclamide and 132.6 +/- 16.6 metres after placebo (P = 0.23). The ABI was not significantly changed by glibenclamide compared with placebo. Serum glibenclamide was 0.51 +/- 0.08 microm 180 min after administration of the drug. Glibenclamide produced an 8-fold increase in circulating insulin compared with placebo (P < 0.001). CONCLUSIONS: Glibenclamide given as a single oral dose commonly used in glucose-lowering drug therapy does not reduce pain-free or maximal walking distance in non-diabetic patients with intermittent claudication.     

Nonuniform vasomotor responses of the coronary microcirculation to serotonin and vasopressin

Large-conduit coronary arteries respond to vasoactive stimuli differently than smaller coronary arterioles, but the quantitative effects of many vasoactive stimuli at various levels of the microvasculature remain unknown. To determine the site of constriction or dilation to serotonin and vasopressin in the coronary microcirculation, we studied microvascular responses in the left ventricle of anesthetized cats (n = 36). To compensate for motion due to contraction of the heart, the epicardium was visualized with stroboscopic epi-illumination controlled by a computer to flash once per cardiac cycle in mid-diastole, making the vessels appear stationary. Serotonin (16 micrograms/kg/min) or vasopressin (0.5 units/min) was infused into the left atrium while maintaining aortic pressure constant with a snare on the descending aorta or inferior vena cava. Myocardial blood flow was measured with radioactive microspheres. During infusion of serotonin, aortic pressure and heart rate did not change, but myocardial perfusion increased 90 +/- 38% (mean +/- SEM) from a control value of 159 +/- 27 ml/min.100 g. Arteries and arterioles larger than 90 microns constricted in response to serotonin (control 159 +/- 12 microns; percent change -18 +/- 3; range -41 to 10%) while arterioles less than 90 microns dilated to serotonin (control 54 +/- 7 microns; percent change 22 +/- 9; range -10 to 62%). During infusion of vasopressin, aortic pressure and heart rate did not change, and myocardial perfusion decreased 16 +/- 7% (control, 147 +/- 18 ml/min.100 g).(ABSTRACT TRUNCATED AT 250 WORDS)     

Afferent arteriolar reactivity to angiotensin II is enhanced during the early phase of angiotensin II hypertension

Increased renal microvascular reactivity may contribute to the blunted pressure natriuretic response and increase in blood pressure during the development of angiotensin II hypertension. The current studies were performed to determine renal microvascular reactivity during the early phases of angiotensin II-infused hypertension. Male-Sprague Dawley rats received angiotensin II (60 ng/min) or vehicle via an osmotic minipump. Normotensive and angiotensin II hypertensive rats were studied 1 and 2 weeks after implantation of the minipump. Systolic blood pressure averaged 117 +/- 4 mm Hg (n = 31) before pump implantation. Angiotensin II infusion increased systolic blood pressure to 149 +/- 3 and 187 +/- 5 mm Hg on infusion days 6 and 12, respectively. Renal microvascular responses to angiotensin II and norepinephrine at renal perfusion pressures of 100 and 150 mm Hg were observed using the in vitro juxtamedullary nephron preparation. Afferent arteriolar diameters of 1-week normotensive animals averaged 22 +/- 1 microm and after 2 weeks of vehicle infusion averaged 21 +/- 1 microm at a perfusion pressure of 100 mm Hg. In animals infused with angiotensin II for 1 or 2 weeks, diameters of the afferent arterioles perfused at a pressure of 100 mm Hg were 20% and 9% smaller, respectively. Additionally, 1- and 2-week hypertensive animals had an enhanced responsiveness of the renal microvasculature to angiotensin II. At a perfusion pressure of 100 mm Hg, angiotensin II (10 nmol/L) decreased afferent arteriolar diameter by 26 +/- 5% and 22 +/- 3% in the 1- and 2-week angiotensin II hypertensive rats, respectively. In 1- and 2-week normotensive animals, angiotensin II (10 nmol/L) decreased afferent arteriolar diameter by 18 +/- 2% and 15 +/- 2%, respectively, at a perfusion pressure of 100 mm Hg. In contrast, the afferent arteriolar response to norepinephrine was not altered in angiotensin II hypertensive rats. These data demonstrate an elevated renal microvascular resistance and enhanced vascular reactivity that is selective for angiotensin II in the early phases of hypertension development after infusion of angiotensin II. Thus, an alteration in renal microvascular function contributes to the blunted pressure natriuretic response and progressive development of hypertension.     

Coronary microcirculatory vasoconstriction during ischemia in patients with unstable angina

OBJECTIVE: To verify the behavior of coronary microvascular tone during spontaneous ischemia in patients with unstable angina (UA). BACKGROUND: In UA, the pathogenetic role of vasoconstriction is classically confined at the stenotic coronary segment. However, microcirculatory vasoconstriction has been also suggested by previous experimental and clinical studies. METHODS: The study included 10 patients with UA (recent worsening of anginal threshold and appearance of angina at rest) and single-vessel CAD. Blood flow velocity was monitored by a Doppler catheter in the diseased artery. Transstenotic pressure gradient was monitored by aortic and distal coronary pressure monitoring. Stenosis resistance was calculated as the ratio between pressure gradient and blood flow, microvascular resistance as the ratio between distal pressure and blood flow. Measurements were obtained at baseline, following intracoronary adenosine (2 mg) and during transient ischemia. Aortic and distal coronary pressures were also measured during balloon coronary occlusion. RESULTS: Adenosine did not affect stenosis resistance, while it decreased (p < 0.05) microvascular resistance to 52 +/- 22% of baseline. Angina and ischemic ST segment shift were associated with transient angiographic coronary occlusion in 7 of 10 patients; however, in no case was ischemia associated with interruption of flow. Despite markedly different flow values, distal coronary pressure was similar during adenosine and during spontaneous ischemia (48 +/- 15 vs. 46 +/- 20 mm Hg, respectively, NS). During ischemia, a marked increase in the resistance of both coronary stenosis and coronary microcirculation was observed (to 1,233% +/- 1,298% and 671% +/- 652% of baseline, respectively, p < 0.05). Distal coronary pressure was markedly reduced during balloon coronary occlusion (14 +/- 7 mm Hg, p < 0.05 vs. both adenosine and ischemia), suggesting the absence of significant collateral circulation. CONCLUSIONS: In patients with UA, transient myocardial ischemia is associated with vasoconstriction of both stenotic arterial segment and downstream microcirculation.     

Adaptation to high altitude hypoxia protects the rat heart against ischemia-induced arrhythmias. Involvement of mitochondrial K(ATP) channel.

The aim was to determine whether adaptation to chronic hypoxia protects the heart against ischemic arrhythmias and whether ATP-dependent potassium channels (K(ATP)) play a role in the antiarrhythmic mechanism. Adult male rats were adapted to intermittent high altitude hypoxia (5000 m, 4 h/day) and susceptibility to ischemia-induced ventricular arrhythmias was evaluated in the Langendorff-perfused hearts subjected to either an occlusion of the coronary artery for 30 min or pre-conditioning by brief occlusion of the same artery prior to 30-min reocclusion. In separate groups, either a K(ATP) blocker, glibenclamide (10 micromol/l), or a mitochondrial K(ATP) opener, diazoxide (50 micromol/l), were added to a perfusion medium 20 min before the occlusion. Adaptation to hypoxia reduced the total number of ventricular arrhythmias by 64% as compared with normoxic controls. Preconditioning by a single 3-min coronary artery occlusion was antiarrhythmic only in the normoxic group, while two occlusion periods of 5 min each were needed to pre-condition the hypoxic hearts. Glibenclamide increased the number of arrhythmias in the normoxic hearts from 1316+/-215 to 2091+/-187 (by 59%) and in the hypoxic group from 636+/-103 to 1777+/-186 (by 179%). In contrast, diazoxide decreased the number of arrhythmias only in the normoxic group from 1374+/-96 to 582+/-149 (by 58%), while its effect in the hypoxic group was not significant. It is concluded that long-term adaptation of rats to high altitude hypoxia decreases the susceptibility of their hearts to ischemic arrhythmias and increases an antiarrhythmic threshold of pre-conditioning. The mitochondrial K(ATP) channel, rather than the sarcolemmal K(ATP) channel, appears to be involved in the protective mechanism afforded by adaptation.     

Dopamine and somatostatin inhibition of prolactin secretion from MMQ pituitary cells: role of adenosine triphosphate-sensitive potassium channels.

The sulfonylurea glibenclamide, which is known to block ATP-sensitive potassium channels, increases, in a dose-dependent manner, the release of PRL from MMQ pituitary cells. Glibenclamide does not reduce the dopaminergic inhibition of forskolin-stimulated PRL secretion; conversely it almost completely abolishes the inhibitory effect of somatostatin (SRIF) on this parameter. The sulfonylurea dose dependently increases basal [Ca++]i, without affecting the increase in [Ca++]i induced by high concentrations of extracellular potassium. Glibenclamide does not modify dopamine-induced [Ca++]i reduction, whereas it abolishes the inhibitory effect of SRIF on basal [Ca++]i. In the presence of diazoxide, an opener of ATP-sensitive potassium channels, which lowers basal [Ca++]i, dopamine still reduces [Ca++]i whereas SRIF does not induce a further decrease. Glibenclamide induces the depolarization of the cell membrane and prevents the SRIF-evoked hyperpolarization. The hyperpolarization of the cell membrane induced by dopamine is not modified by glibenclamide. Diazoxide induces a cell membrane hyperpolarization that is enhanced by dopamine but not by SRIF. Finally, glibenclamide does not affect basal and stimulated adenylate cyclase activity. In conclusion, our findings show that, in MMQ cells, glibenclamide stimulates PRL release, suggesting an involvement of ATP-sensitive potassium channels in the regulation of PRL secretion. The reversal by glibenclamide of the effects of SRIF on calcium homeostasis, membrane potential, and PRL release suggests that this type of potassium channel participates to the somatostatinergic inhibition of PRL secretion. Conversely, we found that glibenclamide does not modify the dopaminergic inhibition of PRL secretion and second messenger systems, suggesting that ATP-sensitive potassium channels may not be involved in the inhibitory effect of dopamine on PRL release.     

Coronary microvascular resistance in hypertensive cats.

Chronic systemic hypertension has been shown to alter the distribution of vascular resistance in many microvascular beds. The purposes of this study were to assess the effects of chronic systemic hypertension on the pressure distribution in the coronary microcirculation and to determine the microvascular site where coronary vascular resistance is increased. Cats were made hypertensive using a one-kidney, one-wrap model (Page model). A servonulling system was used to directly measure pressures in the epimyocardial microvessels of the beating left ventricle in normotensive and hypertensive cats. In chronically hypertensive cats, mean arterial pressure was 153 +/- 5 mm Hg compared with 98 +/- 3 mm Hg in normotensive cats (p less than 0.05). Left ventricular mass was increased approximately 34% in hypertensive cats (9.4 +/- 0.3 versus 7.0 +/- 0.3 g, p less than 0.05). Myocardial perfusion measured using radiolabeled microspheres was not different between hypertensive and normal cats. Coronary vascular resistance of the left ventricle was increased in hypertensive cats (0.90 +/- 0.08 versus 0.66 +/- 0.05 mm Hg x min x 100 g/ml, p less than 0.05). Microvascular pressures were measured in three groups of microvessels: small, less than 200 microns; medium, 200-300 microns; and large, greater than or equal to 300 microns. Mean microvascular pressures of large, medium, and small arterial microvessels in hypertensive cats were 144 +/- 8, 127 +/- 6, and 115 +/- 7 mm Hg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of K(ATP) channel blockade by glibenclamide on the warm-up phenomenon.

AIMS: The increased tolerance to myocardial ischaemia observed during the second of two sequential exercise tests, i.e. the warm-up phenomenon, has been proposed as a clinical model of ischaemic preconditioning. As ATP-sensitive K+ channels appear to be a mediator of ischaemic preconditioning in both experimental and clinical studies, the aim of this study was to investigate the role of K(ATP) channels in the warm-up phenomenon. METHODS AND RESULTS: Twenty-six patients with coronary artery disease were randomized to receive 10 mg oral glibenclamide, a selective ATP-sensitive K+ channel blocker, or placebo. Sixty minutes after glibenclamide or placebo administration, patients were given an infusion of 10% dextrose (8 ml x min(-1)) to correct glucose plasma levels or, respectively, an infusion of saline at the same infusion rate. Thirty minutes after the beginning of the infusions, both patient groups underwent two consecutive treadmill exercise tests, with a recovery period of 15 min to re-establish baseline conditions. Before exercise tests, blood glucose levels were similar in placebo and glibenclamide groups (96 +/- 10 vs 105 +/- 22 mg x 100 ml(-1), P=ns). After placebo administration, rate-pressure product at 1.5 mm ST-segment depression significantly increased during the second exercise test compared to the first (220 +/- 41 vs 186 +/- 29 beats x min(-1) x mmHg x 10(2), P<0.01), but it did not change after glibenclamide (191 +/- 34 vs 187 +/- 42 beats x min(-1) x mmHg x 10(2), P=ns), with a significant drug-test interaction (P=0.0091, at two-way ANOVA). CONCLUSIONS: Glibenclamide, at a dose previously shown to abolish ischaemic preconditioning during coronary angioplasty, prevents the increase of ischaemic threshold observed during the second of two sequential exercise tests. These findings confirm that ischaemic preconditioning plays a key role in the warm-up phenomenon and that in this setting is, at least partially, mediated by activation of ATP-sensitive K+ channels.     

Effects of glibenclamide on ventricular arrhythmias and cardiac function in ischaemia and reperfusion in isolated rat heart.

OBJECTIVE: The aim was to investigate the effects of glibenclamide, a specific blocker of the ATP sensitive potassium channel, on the incidence of ventricular arrhythmias and the functional changes occurring during myocardial ischaemia and reperfusion. METHODS: Hearts (n = 10 per group) were obtained from male Wistar rats, weight 250-300 g. The study was performed in isolated Langendorff perfused rat hearts subjected to ligation of the left coronary artery and reperfusion. Because of the occurrence of arrhythmias, cardiac function was not evaluated during reperfusion. Glibenclamide (1 or 10 microM) was added to the perfusion solution before the coronary artery occlusion, during ischaemia or after reperfusion. In some experiments the incidence of various durations of ischaemia (5, 10, 15, and 30 min) was evaluated. RESULTS: During the preischaemic period, glibenclamide induced a marked reduction in coronary flow, with a slight decrease in heart rate and left ventricular pressure. The ischaemia induced decrease in left ventricular pressure was markedly attenuated when glibenclamide was given before ischaemia. Thus the isovolumetric left ventricular pressure measured after 15 min ischaemia, which represents 59(SEM 6)% of the preischaemic value in the control group, was increased to 82(9) and 94(8)% in presence of glibenclamide (1 and 10 microM, p < 0.05 respectively). The effect was less pronounced when glibenclamide was added to the perfusion fluid during the ischaemic period. None of the hearts showed ventricular fibrillation during the ischaemic period. Glibenclamide (1 and 10 microM) did not reduce the incidence of reperfusion induced ventricular fibrillation. However, a defibrillatory action was observed since glibenclamide reduced the duration of ventricular fibrillation during reperfusion. CONCLUSIONS: Glibenclamide may increase the probability of spontaneous termination of ventricular fibrillation and facilitate the restoration of the myocardial function during regional ischaemia.     

Blockade of ATP-sensitive K+ channels by glibenclamide reduces portal pressure and hyperkinetic circulation in portal hypertensive rats.

Certain results of in vitro studies raise the possibility that blockade of ATP-sensitive K+ channels by glibenclamide may induce vasoconstriction. Therefore, this substance might decrease portal pressure and hyperkinetic circulation in animals with portal hypertension. Thus, systemic and regional hemodynamics (radioactive microspheres) were measured before and 20 min after a bolus intravenous injection of glibenclamide (20 mg/kg) in conscious rats with portal vein stenosis. Blood pressure decreased significantly from 14.5 +/- 1.5 to 12.2 +/- 1.2 (mean +/- SE). Cardiac index significantly decreased by 24%, portal tributary blood flow by 31%, and hepatic artery blood flow by 35%. Systemic vascular resistance significantly increased by 38%, portal territory vascular resistance and hepatic artery vascular resistance by 61%, each, and renal vascular resistance by 17%. Arterial pressure, heart rate, and renal blood flow were unchanged. Moreover, glibenclamide blunted the vasodilating action of diazoxide (an ATP-sensitive K+ channel opener). These results show that in rats with extrahepatic portal hypertension the blockade of ATP-sensitive K+ channels by glibenclamide reduces portal pressure and hyperkinetic circulation.     

Mechanics of cerebral arterioles in hypertensive rats

Chronic hypertension is associated with hypertrophy of cerebral blood vessels. Previous studies of the mechanical properties of cerebral vessels in chronic hypertension have examined large cerebral arteries. The goals of this study were first to develop a method to examine vascular mechanics of cerebral arterioles in vivo and second to determine whether the stiffness of cerebral arterioles is altered in the presence of chronic hypertension. We calculated circumferential stress and strain of pial arterioles in age-matched, anesthetized stroke-prone spontaneously hypertensive rats (SHRSP) and in Wistar Kyoto rats (WKY) from measurements of pial arteriolar pressure, inner diameter, and wall thickness. Pial arteriolar pressure was measured with a servonull system. Smooth muscle of pial arterioles was deactivated with ethylenediaminetetraacetic acid (EDTA), and pressure-diameter relations were examined during step-wise reductions in pressure. Prior to deactivation of smooth muscle in 3-4-month-old rats, pial arteriolar pressure was greater in SHRSP than in WKY (110 +/- 4 versus 75 +/- 2 mm Hg [mean +/- SE]; p less than 0.05). Pial arteriolar diameter, which was measured at prevailing levels of pial arteriolar pressure, was less in SHRSP than in WKY (52 +/- 5 versus 63 +/- 3 microns; p less than 0.05). Following deactivation of smooth muscle, diameter of pial arterioles at 70 mm Hg of pial arteriolar pressure was similar in the two groups: 104 +/- 6 microns in SHRSP and 109 +/- 3 microns in WKY (p greater than 0.05). Wall thickness was 4.5 +/- 0.2 microns in SHRSP and 4.1 +/- 0.1 microns in WKY (p greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of antihypertensive therapy on mechanics of cerebral arterioles in rats.

The purpose of this study was to examine effects of antihypertensive treatment on structure and mechanics of cerebral arterioles and the incidence of stroke in stroke-prone spontaneously hypertensive rats (SHRSP). Treatment of hypertension was begun at 3 months of age with cilazapril (45 mg/kg/day), an angiotensin converting enzyme (ACE) inhibitor, or with hydralazine (18 mg/kg/day). Cilazapril and hydralazine reduced systolic arterial pressure (from 195 +/- 8 to 125 +/- 5 and 148 +/- 3 mm Hg, respectively [mean +/- SEM]; p less than 0.05). To examine structure and mechanics of cerebral arterioles, we measured pressure (servonull), external diameter, and cross-sectional area of the vessel wall (histologically) in pial arterioles of normotensive Wistar-Kyoto (WKY) rats and SHRSP that were untreated or that were treated for 3 months with cilazapril or with hydralazine. Arterioles were maximally dilated with EDTA. In WKY rats, cilazapril and hydralazine did not alter pial arteriolar pressure, external diameter, or cross-sectional area of the vessel wall. In SHRSP, both cilazapril and hydralazine reduced cross-sectional area of the vessel wall to levels not significantly different from WKY rats (from 1,911 +/- 155 to 1,244 +/- 101 and 1,388 +/- 59 microns 2, respectively, compared with 1,405 +/- 95 microns 2 for untreated WKY rats). Cilazapril was more effective than hydralazine in reducing pial arteriolar pressure (from 110 +/- 6 to 62 +/- 2 mm Hg with cilazapril versus 79 +/- 5 mm Hg for hydralazine compared with 60 +/- 4 mm Hg for untreated WKY rats). Cilazapril, but not hydralazine, attenuated reductions in external diameter of pial arterioles (from 91 +/- 4 to 100 +/- 4 microns for cilazapril versus 91 +/- 3 microns for hydralazine compared with 107 +/- 3 microns for untreated WKY rats).(ABSTRACT TRUNCATED AT 250 WORDS)     

Collateral conductance changes during a brief coronary occlusion in awake dogs

Function of the coronary collateral circulation during the course of a single abrupt coronary occlusion was evaluated in awake dogs instrumented over the long term. Studies were performed approximately 2 weeks after collateral development had been stimulated in the dogs by partial stenosis of the proximal left circumflex coronary artery. The pressure drop from the central aorta to the distal circumflex coronary artery was measured continuously. Under control conditions and at 30 sec and 4 min of a single abrupt complete circumflex occlusion, myocardial blood flow was determined by a radioactive microsphere technique. Coronary collateral conductance was calculated as mean collateral blood flow divided by the mean drop in pressure. The following was noted in dogs that developed collateral vessels: during the coronary occlusion, mean distal circumflex coronary pressure increased from 42 +/- 9 to 49 +/- 10 mm Hg (p less than or equal to .01); mean collateral flow increased from 0.78 +/- 0.30 to 0.84 +/- 0.33 ml/min/g (p less than or equal to .05); the endocardial/epicardial flow ratio increased from 0.77 +/- 0.36 to 1.04 +/- 0.25 (p less than or equal to .01); and the coronary collateral conductance increased significantly from 0.017 +/- 0.017 to 0.021 +/- 0.021 (ml/min/g)/mm Hg (p less than or equal to .005). These data suggest that during a brief occlusion of a major coronary artery, immature coronary collateral channels do not reach maximal function immediately after the occlusion. Rather, coronary collateral conductance increases with time and may be associated with improved transmural perfusion of the myocardium.