Increase In Coronary Blood Flow Research Articles

Attenuation of angiotensin II-mediated coronary vasoconstriction and vasodilatory action of angiotensin-converting enzyme inhibitor in pacing-induced heart failure in dogs

OBJECTIVESWe investigated the changes in coronary vascular resistance caused by angiotensin II, angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 or 2 receptor (AT1R and AT2R, respectively) antagonists in chronic heart failure (CHF).BACKGROUNDAngiotensin II is an intense vasoconstrictor, and increased angiotensin II in CHF might exert significant vasoconstriction.METHODSEleven dogs were studied. Before and after three and five weeks of rapid pacing, coronary flow dynamics were evaluated by the coronary pressure–flow relationship (PFR) in long diastole, before and after intracoronary injection of angiotensin II, the ACE inhibitor enalaprilat, the AT1R antagonist L158,809 or the AT2R antagonist PD123319.RESULTSBefore rapid pacing, angiotensin II reduced the slope of PFR (1.16 ± 0.08 to 0.81 ± 0.07 ml/min/100 g left ventricular mass per mm Hg; p < 0.01) and increased the perfusion pressure at which coronary flow ceased (zero-flow pressure [Pf= 0]), whereas enalaprilat did not change either of them. After rapid pacing, angiotensin II did not change the slope or Pf= 0. In contrast, enalaprilat increased the slope (three weeks: 1.20 ± 0.05 to 1.50 ± 0.03; five weeks: 1.25 ± 0.19 to 1.37 ± 0.08; both p < 0.05) and decreased Pf= 0 after three weeks of pacing, but not after five weeks. Pretreatment with the bradykinin antagonist HOE-140 attenuated the enalaprilat-induced increase in coronary blood flow. L158,809 and PD123319 had no effect both before and after rapid pacing.CONCLUSIONSThis suggests that the coronary vasoconstrictive effect of angiotensin II would disappear and the vasodilatory effect of the ACE inhibitor, partly through bradykinin, would be enhanced in the early stage of CHF.

Myocardial and coronary effects of propofol in rabbits with compensated cardiac hypertrophy.

Myocardial effects of propofol have been previously investigated but most studies have been performed in healthy hearts. This study compared the cardiac effects of propofol on isolated normal and hypertrophic rabbits hearts. The effects of propofol (10-1,000 microM) on myocardial contractility, relaxation, coronary flow and oxygen consumption were investigated in hearts from rabbits with pressure overload-induced left ventricular hypertrophy (LVH group, n = 20) after aortic abdominal banding and from sham-operated control rabbits (SHAM group, n = 10), using an isolated and erythrocyte-perfused heart model. In addition, to assess the myocardial and coronary effects of propofol in more severe LVH, hearts with a degree of hypertrophy greater than 140% were selected (severe LVH group, n = 7). The cardiac hypertrophy model induced significant left ventricular hypertrophy (136+/-21%, P < 0.05). The pressure-volume relation showed normal systolic function but an altered diastolic compliance in hypertrophic hearts. Propofol only decreased myocardial contractility and relaxation at supratherapeutic concentrations (> or = 300 microM) in SHAM and LVH groups. The decrease in myocardial performances was not significantly different in SHAM and LVH groups. Propofol induced a significant increase in coronary blood flow which was not significantly different between groups. In severe LVH group, the degree of hypertrophy reached to 157+/-23%. Similarly, the effects of concentrations of propofol were not significantly different from the SHAM group. Propofol only decreased myocardial function at supratherapeutic concentrations. The myocardial and coronary effects of propofol were not significantly modified in cardiac hypertrophy.

Tetrahydrobiopterin improves endothelial dysfunction in coronary microcirculation in patients without epicardial coronary artery disease

OBJECTIVES We aimed to determine whether intracoronary supplementation with nitric oxide (NO) synthase co-factor tetrahydrobiopterin (BH4) improves NO-dependent coronary microvascular dilation in patients with coronary risk factors but no significant organic stenosis. BACKGROUND Impaired coronary microvascular dilator reserve attributable to endothelial dysfunction plays an important role in the regulation of coronary blood flow (CBF). METHODS Fifteen patients were measured for CBF (Doppler-wire and quantitative coronary angiography). Stimulated release of NO in the coronary microcirculation was evaluated by percent increase in CBF (%ΔCBF) at graded doses of intracoronary acetylcholine (1, 3, 10 and 30 μg/min). Measurements were repeated after intracoronary co-infusion of BH4 (4 mg/min) and acetylcholine. RESULTS The patients were divided into two groups on the basis of CBF responses to acetylcholine: those with “diminished” (%ΔCBF <300%, n = 8) and “normal” (%ΔCBF >300%, n = 7) flow responses. Tetrahydrobiopterin significantly (p < 0.0001) improved acetylcholine-induced increases in CBF in patients with diminished flow responses, but exerted no effect in those with normal flow responses. Among the 15 studied patients, the magnitude of flow improvement by BH4 was inversely correlated with baseline flow responses (p < 0.02). Microvascular dilator response to direct NO donor (isosorbide dinitrate) was not affected by BH4. CONCLUSIONS We demonstrated for the first time that intracoronary BH4 improved acetylcholine-induced microvascular dilator responses in patients with endothelial dysfunction in vivo. Thus, supplementation with BH4 may be a novel therapeutic means to increase NO availability for patients with coronary microvascular disease.

Fetal cerebral and peripheral circulatory responses to hypoxia after nitric oxide synthase inhibition.

The increase in cerebral blood flow (CBF) during hypoxia in fetal sheep at 0.6 gestation is less than the increase at 0.9 gestation when normalized for differences in baseline CBF and oxygen consumption. Nitric oxide (NO) synthase (NOS) catalytic activity increases threefold during this period of development. We tested the hypothesis that administration of the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) decreases the CBF response to systemic hypoxia selectively at 0.9 gestation. We also tested whether any peripheral vasoconstriction during hypoxia is potentiated by L-NAME at 0.9 gestation. Administration of L-NAME increased arterial blood pressure and decreased microsphere-determined CBF during normoxia in fetal sheep at both 0.6 and 0.9 gestation. With subsequent reduction of arterial oxygen content by approximately 50%, the percent increase in forebrain CBF in a control group (57 +/- 11%; +/- SE) and L-NAME-treated group (51 +/- 6%) was similar at 0.6 gestation. Likewise, at 0.9 gestation, the increase in CBF was similar in control (90 +/- 25%) and L-NAME (80 +/- 28%) groups. At 0.9 gestation, L-NAME treatment attenuated the increase in coronary blood flow and increased gastrointestinal vascular resistance during hypoxia. We conclude that NO exerts a basal vasodilatory influence in brain as early as 0.6 gestation in fetal sheep but is not an important mechanism for hypoxic vasodilation in brain at either 0.6 or 0.9 gestation. Thus the developmental increase in NOS catalytic capacity does not appear to be responsible for developmental increases in the CBF response to hypoxia during this period. In contrast, NO modulates the vascular response to hypoxia in heart and gastrointestinal tract.

Selective blockade of mitochondrial K(ATP) channels does not impair myocardial oxygen consumption.

Opening of mitochondrial ATP-sensitive potassium (K(ATP)) channels has been postulated to prevent inhibition of respiration resulting from matrix contraction during high rates of ATP synthesis. Glibenclamide, which blocks K(ATP) channels on the sarcolemma of vascular smooth muscle cells and myocardial myocytes as well as on the inner mitochondrial membrane, results in a decrease of myocardial oxygen consumption (MVO2) both at rest and during exercise. This study examined whether this represents a primary effect of blockade of mitochondrial K(ATP) channels or occurs secondary to coronary resistance vessel constriction with a decrease of coronary blood flow (CBF) and myocardial oxygen availability. MVO2 was measured at rest and during treadmill exercise in 10 dogs during control conditions, after selective mitochondrial K(ATP) channel blockade with 5-hydroxydecanoate (5-HD), and after nonselective K(ATP) channel blockade with glibenclamide. During control conditions, exercise resulted in progressive increases of CBF and MVO2. Glibenclamide (50 microg x kg(-1) x min(-1) ic) resulted in a 17 +/- 6% decrease of resting CBF with a downward shift of CBF during exercise and a decrease of coronary venous PO2, indicating increased myocardial oxygen extraction. In contrast with the effects of glibenclamide, 5-HD (0.7 mg x kg(-1) x min(-1) ic) had no effect on CBF, MVO2, or myocardial oxygen extraction. These findings suggest that glibenclamide decreased MVO2 by causing resistance vessel constriction with a decrease of CBF and oxygen available to the myocardium rather than to a primary reduction of mitochondrial respiration.

Influence of L-carnitine and its derivatives on myocardial metabolism and function in ischemic heart disease and during cardiopulmonary bypass.

Carnitine and its derivatives have recently been shown to protect cardiac metabolism and function in ischemic heart disease and other clinical conditions of myocardial ischemia. Potential mechanisms of this effect include an increase in glucose metabolism, a reduction of toxic effects of long-chain acyl-CoA and acyl-carnitine in myocytes, an increase in coronary blood flow and anti-arrhythmic effect. It has also been shown that propionyl-L-carnitine which penetrates faster than carnitine into myocytes is effective in inhibiting production of free radicals. Beneficial effects of carnitine supplementation have been demonstrated under a variety of clinical conditions such as acute cardiac ischemia, during extracorporeal circulation, in carnitine-dependent cardiomyopathy as well as in patients with chronic circulatory failure and in cardiogenic shock. However, further studies are required before carnitine administration could be recommended as a routine procedure in ischemic heart disease or before cardiopulmonary bypass.

Impairment of coronary microvascular dilation in response to cold pressor--induced sympathetic stimulation in type 2 diabetic patients with abnormal stress thallium imaging.

Coronary microcirculation dysfunction may be associated with myocardial perfusion defects on thallium imaging in diabetic patients without coronary artery stenosis. Microvascular coronary adaptation to increased myocardial oxygen demand in response to sympathetic stimulation evoked by the cold pressor test was examined in 22 type 2 diabetic patients with thallium imaging defects and in 15 control subjects. Both the diabetic patients and control subjects had angiographically normal coronary arteries and no other risk factors. Despite a similar increase in the rate-pressure product in the two groups (22.6 +/- 12.4% in diabetic patients and 31.8 +/- 8.2% in control subjects, NS), coronary blood flow increase in the left anterior descending artery (mean flow velocity measured by intracoronary Doppler multiplied by the cross-sectional area measured by digital angiography) was significantly lower in diabetic patients than in control subjects (14.7 +/- 19.8 vs. 75.5 +/- 13.5%, respectively; P = 0.0001). In addition, when there was a positive correlation between the two parameters in control subjects (r = 0.651, P < 0.01), there was no relationship in diabetic patients (r = 0.054). In conclusion, vasodilation of the coronary microcirculation in response to sympathetic stimulation evoked by the cold pressor test is impaired in type 2 diabetic patients without epicardial artery lesions. This microvascular impairment during sympathetic stimulation may explain exercise-induced myocardial perfusion abnormalities observed in these patients and may impair microcirculatory coronary vasodilation during current life stress episodes such as exercise, mental stress, or cold exposition.

Bradykinin stimulates the release of tissue plasminogen activator in human coronary circulation: effects of angiotensin-converting enzyme inhibitors

OBJECTIVESThe goal of this study was to determine: 1) whether bradykinin (BK) directly stimulates tissue plasminogen activator (tPA) secretion in human coronary circulation, and 2) whether angiotensin-converting enzyme (ACE) inhibition favorably alters the fibrinolytic balance regulated by BK.BACKGROUNDBradykinin is a potent stimulator of tPA secretion in endothelial cells; however, the effect of BK on tPA release in the human coronary circulation has not been studied.METHODSFifty-six patients with atypical chest pain were randomly assigned to two groups: 25 patients were treated with the ACE inhibitor enalapril (ACE inhibitor group), and 31 were not treated with ACE inhibitors (non-ACE inhibitor group). Graded doses of BK (0.2, 0.6, 2.0 μg/min), acetylcholine (ACh) (30 μg/min) and papaverine (PA) (12 mg) were administered into the left coronary artery. Coronary blood flow (CBF) was evaluated by Doppler flow velocity measurement. Blood samples were taken from the aorta (Ao) and the coronary sinus (CS).RESULTSBradykinin induced similar increases in CBF in both groups. The net tPA release induced by BK was dose-dependently increased in both groups, and the extent of that increase in the ACE inhibitor group was greater than that in the non-ACE inhibitor group. Bradykinin did not alter plasminogen activator inhibitor-1 (PAI-1) levels in the Ao or CS in either group. Neither ACh nor PA altered tPA levels or PAI-1 levels in either group.CONCLUSIONSIntracoronary infusion of BK stimulates tPA release without causing any change in PAI-1 levels in the human coronary circulation. In addition, this effect of BK is augmented by an ACE inhibitor.

Hemodynamic response to tibolone in reproductive and nonreproductive tissues in the sheep

Objective: We sought to determine the hemodynamic effects of tibolone in reproductive and nonreproductive tissues in the nonpregnant ovariectomized sheep. Study Design: Six ewes were chronically instrumented for measurement of mean arterial pressure, heart rate, cardiac output, and coronary and uterine blood flow. A dose response curve was generated for intravenous tibolone (1.25, 2.5, and 5 mg) and compared with intravenous 17β-estradiol (1 μg/kg body weight). To determine whether tibolone-related cardiovascular responses were estrogen receptor mediated and produced by nitric oxide, animals were treated on separate days with either estrogen receptor antagonist ICI 182,780 or the nitric oxide synthase inhibitor, L -nitroarginine methyl ester. Results: Tibolone significantly increased coronary blood flow in a dose-related fashion by 5% ± 3%, 9% ± 2%, and 11% ± 2% for the 1.25, 2.5, and 5 mg doses, respectively. Uterine blood flow was also increased significantly in a dose-dependent manner by 98 ± 15, 216 ± 59, and 303 ± 56 mL/min, for the 1.25, 2.5, and 5 mg doses, respectively. L -Nitroarginine methyl ester attenuated tibolone-induced increases in uterine blood flow by 84% ± 4% and abolished the increase in coronary blood flow. ICI 182,780 inhibited all tibolone-induced cardiovascular responses. Conclusion: Tibolone significantly increases coronary and uterine blood flow in ovariectomized ewes. The coronary and uterine vascular responses are mediated via an estrogen receptor–dependent mechanism and are produced mainly by nitric oxide. (Am J Obstet Gynecol 2001;184:544-51.)

The endothelium: Dysfunction and beyond

Since its anatomic discovery in the 19th century, the endothelium was considered to fulfill no other purpose than that of a physical barrier between blood and tissue, until Furchgott and colleagues defined endothelium-dependent vasoreactivity in the late 1970s. Henceforth, a functional paradigm defined the balance between endothelium-derived relaxing factors and endothelium-derived contracting factors as the hallmark of endothelial cell integrity. As a consequence, any reflection of a deviation from this state was defined as endothelial dysfunction, most notably the impairment of vasorelaxation in response to pharmacologic stimuli such as acetylcholine or nonpharmacologic stimuli such as shear stress and cold pressor. Within the coronary artery tree these alterations have been recognized before the development of obstructive coronary artery disease, affecting the microcirculation before the epicardial conduit vessel. Furthermore, recent clinical trials outlined the prognostic significance of these changes, whereby impairment of increase in coronary blood flow in response to endothelium-dependent stimuli seemed to be of utmost importance. Thus it is intriguing to speculate on the evolving role of myocardial perfusion imaging in combination with pharmacologic and nonpharmacologic stimuli for the noninvasive assessment of coronary endothelial dysfunction in patients at risk for future adverse events. At a minimum, this review aims to put endothelial dysfunction into an imaging perspective beyond the scope of the conventional approach. (J Nucl Cardiol 2001;8:197-206.)

Altered effects of potassium channel modulation in the coronary circulation in experimental hypercholesterolemia

Objective: To evaluate the role of potassium channels in the regulation of coronary hemodynamics in experimental hypercholesterolemia. Background: Potassium (K +) channels play an important role in coronary vasoregulation. It has previously been demonstrated that experimental hypercholesterolemia is associated with altered coronary vasomotion; however, the role of K + channels in modulating coronary blood flow in this pathophysiologic state has not been evaluated. Methods and results: Pinacidil (group 1, n=5) at 2 μg/kg per min, glibenclamide (group 2, n=5), or N-monomethyl- l-arginine (LNMMA) (group 3, n=4) at 50 μg/kg per min were infused into the left anterior descending artery of pigs prior to and following 10 weeks of 2% cholesterol diet. After 10 weeks of cholesterol feeding, intracoronary pinacidil resulted in a significant increase in coronary blood flow (CBF) and coronary artery diameter (CAD) compared to the normolipidemic state (111±10 versus 59±12%, and 6±1.1 versus 2.7±1.0%, respectively, P<0.05 for both comparisons), whereas intracoronary glibenclamide resulted in a significant decrease in CBF and CAD compared to the normolipidemic state (−17±5 versus 5±6%, and −0.8±1.4 versus 3.6±1.6%, respectively, P<0.05 for both comparisons). The effect of intracoronary LNMMA on CBF and CAD was significantly attenuated after 10 weeks of cholesterol feeding as compared to the normolipidemic state (−47±5.4 versus −0.8±6.8%, and −19.4±5.7 versus −2.3±3.3%, respectively, P<0.05 for both comparisons). Furthermore, pretreatment with intracoronary LNMMA did not alter the CBF response to pinacidil in normal pigs (group 4, n=4) (57.4±19 versus 59±12%, P=NS). Conclusions: The current study demonstrates an enhanced effect of coronary K + channel modulation and confirms the attenuated basal NO activity previously reported in experimental hypercholesterolemia. Acute withdrawal of basal NO activity alone, however, does not explain the enhanced effect of coronary K + channel modulation. These findings underscore the importance of the K + channel pathway in the regulation of coronary vasomotor tone in pathophysiologic states.

Role of Nitric Oxide in Regulation of Coronary Blood Flow in Response to Increased Metabolic Demand in Dogs With Pacing-Induced Heart Failure.

The role of endothelium-derived nitric oxide (NO) in the metabolic control of coronary blood flow (CBF) in heart failure (HF) is poorly understood, so the present study investigated the effects of inhibitors of NO synthesis on the response of CBF to changes in myocardial oxygen consumption (MVO2) in dogs with HF produced by rapid ventricular pacing and in control dogs. The CBF, MVO2, and other hemodynamic parameters were measured in anesthetized animals. Before infusion of Nomega-nitro-L-arginine methyl ester (L-NAME), the increases in CBF and MVO2 during pacing tachycardia were not significantly different between the control and HF dogs. Intracoronary infusion of L-NAME did not alter the responses of CBF or MVO2 to pacing tachycardia in the control dogs, but in the HF dogs, it reduced the CBF response to pacing tachycardia without altering the tachycardia-induced changes in MVO2. Intracoronary infusion of L-arginine reversed the effect of L-NAME. These results suggest that in HF dogs NO contributes to the regulation of CBF in response to an increased metabolic demand.

The Effect of Progesterone on Coronary Blood Flow in Anaesthetized Pigs

The present study was designed to investigate the effect of progesterone on the coronary circulation and to determine the mechanisms involved. In pigs anaesthetized with sodium pentobarbitone, changes in left circumflex or anterior descending coronary blood flow caused by intravenous infusion of progesterone at constant heart rate and arterial blood pressure were assessed using an electromagnetic flowmeter. In 14 pigs, infusion of 1 mg h(-1) of progesterone caused an increase in coronary blood flow without affecting left ventricular dP/dtmax (rate of change of left ventricular systolic pressure) and filling pressures of the heart. In a further four pigs, this vasodilatory coronary effect was enhanced by graded increases in the dose of the hormone of between 1, 2 and 3 mg h(-1). The mechanisms of the above response were studied in the 14 pigs by repeating the experiment after haemodynamic variables had returned to the control values observed before infusion. In six pigs, blockade of muscarinic cholinoceptors and adrenoceptors with atropine, propranolol and phentolamine did not affect the coronary vasodilatation caused by progesterone. In the remaining eight pigs, this response was abolished by intracoronary injection of N(omega)-nitro-L-arginine methyl ester (L-NAME) even when performed after reversing the increase in arterial blood pressure and coronary vascular resistance caused by L-NAME with continuous intravenous infusion of papaverine. The present study showed that intravenous infusion of progesterone primarily caused coronary vasodilatation. The mechanism of this response was shown to involve the endothelial release of nitric oxide.

Blood Pressure and Cardiovascular Tone: Role of CGRP Family of Peptides

Calcitonin gene-related peptide (CGRP) belongs to a family of peptides (adrenomedullin, amylin and calcitonin), most of which have significant effects on the cardiovascular system[1]. CGRP is the most potent endogenous vasodilatory peptide and is the most studied of the peptides in this family[2]. CGRP and its receptors are widely distributed throughout the vascular system. Localization of i-CGRP and its receptors in the heart, correlates well with the postulated functions of this peptide (i.e., increase in heart rate, atrial contractility, and increase in coronary blood flow). CGRP and ADM have direct effects on capacitance blood vessels, and administration leads to peripheral vasodilation and reduced vascular resistance. Injection or an infusion of physiological doses of CGRP and ADM has both significant effects on the blood pressure; cardiac performance, and blood supply to critical organs. Effects of CGRP (and its antagonists) have been examined as potential therapeutic agents in controlling hypertension, cardiac failure, cardiac arrhythmia, migraine headaches, Renaud’s syndrome, preeclampsia, etc. Animal studies have revealed that in the presence of progesterone, administration of CGRP can alleviate both premature delivery and preeclampsia-like syndrome. The role of CGRP as a potential therapeutic agent and its mechanism of actions in alleviating pregnancy-induced hypertension will be discussed in detail[3].

Coronary vasomotor responses to bradykinin and acetylcholine in patients with coronary spastic angina.

It is unclear whether coronary endothelial function is linked to the pathogenesis of coronary spastic angina (CSA), so the present study examined the coronary vasomotor responses to acetylcholine (ACh) and bradykinin (BK) in 23 patients with CSA, 26 patients with CSA+coronary artery disease (CAD), and 21 control patients. Acetylcholine induced vasospasm of the left coronary artery in all of the patients with CSA, but not in any of the control patients. The changes in dilatation of the left coronary artery in response to bradykinin at doses of 0.2, 0.6 and 2.0 microg/min in the CSA group were significantly greater than those in the other 2 groups. The ratio of epicardial coronary vasodilations induced by BK to those induced by nitroglycerin did not differ among any of the groups. Bradykinin caused a similar increase in coronary blood flow in the control group and CSA group, but had less of an effect in the CSA+CAD group. In conclusion, the vasorelaxing effect of BK was preserved not only in epicardial spasm coronary arteries induced by ACh, but also in resistance coronary arteries distal to the spasm arteries in patients with CSA. The coronary vasodilation response induced by BK may not deteriorate until coronary atherosclerosis advances in patients with CSA.

The physiological role of endogenous endothelin in the regulation of human coronary vasomotor tone

OBJECTIVESThe study was done to investigate the physiological role of endogenous endothelin-1 in the human coronary circulation by studying the effect of an intracoronary infusion of the specific endothelin receptor subtype A (ETA) receptor antagonist BQ123 on coronary vasomotor tone.BACKGROUNDEndothelin-1 contributes to the maintenance of peripheral vascular tone in humans. However, its physiological role in the human coronary vasculature is unknown.METHODSWe studied 12 patients (mean age 54.7 ± 2.5 years, 3 men) undergoing cardiac catheterization for investigation of atypical chest pain, with angiographically normal coronary arteries. Coronary artery cross-sectional area was measured with digital quantitative coronary angiography, and coronary blood flow was assessed with an intracoronary Doppler flow wire. Flow-mediated (adenosine, 18 μg) and agonist-mediated (substance P, 20 pmol/min for 2 min) endothelial responses were measured prior to study. BQ123 (40 nmol/min for 15 min and monitored for a further 15 min) was infused into the left coronary artery.RESULTSThe BQ123 caused significant dilation of the proximal (artery cross-sectional area: 8.08 ± 0.9 to 8.88 ± 0.9 mm2; p < 0.05), mid (5.32 ± 0.8 to 6.49 ± 0.8 mm2; p < 0.001) and distal study vessel (2.11 ± 0.2 to 2.50 ± 0.2 mm2; p < 0.05). There was an increase in coronary blood flow (26.8 ± 2.8 to 32.8 ± 3.4 ml/min; p < 0.001) but no change in systemic hemodynamics. Baseline flow- or substance P-induced epicardial vasodilation did not correlate with the degree of vasodilation induced by BQ123.CONCLUSIONSThese data uncover a role of endogenous endothelin-1 in the maintenance of basal vasomotor tone in patients with angiographically normal coronary arteries.

Influence of dual ET(A)/ET(B)-receptor blockade on coronary responses to treadmill exercise in dogs.

We hypothesized that endothelin (ET) release during exercise may be triggered by alpha-adrenergic-receptor activation and thereby influence coronary hemodynamics and O(2) metabolism in dogs. Exercise resulted in coronary blood flow increases (to 1.88+/-0.26 from 1.10+/- 0.12 ml x min(-1) x g(-1)) and in a fall (P<0.01) in coronary sinus O(2) saturation (17.4+/-1.5 to 9.6+/-0.7 vol%), whereas myocardial O(2) consumption (MVO(2)) increased (109+/-13% from 145+/-16 microl O(2) min(-1) x g(-1)). Tezosentan, a dual ET(A)/ET(B)-receptor blocker, slightly reduced mean arterial pressure (MAP) and increased heart rate throughout exercise. The relationship between coronary sinus O(2) saturation and MVO(2) was shifted upward (P<0.05) after tezosentan administration; i.e., as MVO(2) increased during exercise, coronary sinus O(2) saturation was disproportionately higher after ET-receptor blockade. After propranolol, tezosentan resulted in significant decreases (P<0.05) in left ventricular pressure, the first derivative of left ventricular pressure over time, and MAP during exercise. As MVO(2) increased during exercise, coronary sinus O(2) saturation levels after tezosentan became superimposable over those observed before ET-receptor blockade. Thus dual blockade of ET(A)/ET(B) receptors alters coronary hemodynamics and O(2) metabolism during exercise, but ET activity failed to increase beyond baseline levels.

The insertion/deletion polymorphism of the angiotensin-converting enzyme gene determines coronary vascular tone and nitric oxide activity

OBJECTIVESWe investigated whether the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene modulates vasomotor tone and endothelial function.BACKGROUNDThe deletion allele of the ACE I/D polymorphism has been associated with increased incidence of cardiovascular pathology. The risk is synergistically increased in patients who also possess the C allele at position 1,166 of the angiotensin type I (AT1) receptor gene.METHODSIn 177 patients with coronary atherosclerosis or its risk factors, we investigated endothelial function with intracoronary acetylcholine (ACH), endothelium-independent smooth muscle function with sodium nitroprusside (SNP) and basal nitric oxide activity with L-NG monomethyl arginine.RESULTSCompared with ACE II genotype, patients with the ACE DD genotype had lower coronary microvascular and epicardial responses with SNP (coronary blood flow increase 196 ± 26% vs. 121 ± 11%, p = 0.003, and diameter increase 21.9 ± 2% vs. 17 ± 1%, p = 0.03, ACE II vs. DD, respectively). L-NG monomethyl arginine induced greater constriction in patients with the ACE DD compared with ACE II genotype (coronary blood flow −10 ± 4% vs. 11 ± 5%, p = 0.003, ACE DD vs. II and diameter constriction −6.3 ± 1.2% vs. −1.9 ± 1.2%, p = 0.01, respectively, in patients with atherosclerosis). No difference in ACH-mediated vasomotion was detected between the three ACE genotypes. The AT1 receptor polymorphism did not influence responses to either SNP or ACH.CONCLUSIONSPatients possessing the D allele of the ACE gene have increased vascular smooth muscle tone. The enhanced tone appears to be counterbalanced by an increase in basal nitric oxide activity in patients with atherosclerosis.

Interaction of isoflurane and cromakalim, a KATP channel opener, on coronary and systemic haemodynamics in chronically instrumented dogs.

Although isoflurane has been shown to cause coronary and systemic vasodilation through KATP channel activation, the interaction of KATP channel openers and isoflurane has not been fully investigated. The present study was carried out to determine the haemodynamic actions of cromakalim, a KATP channel opener, under the conscious state and during isoflurane anaesthesia in chronically instrumented dogs. Fourteen dogs were chronically instrumented to measure systemic and coronary haemodynamics. Each dog was randomly assigned to receive doses of either cromakalim, 4 and 10 microg x kg(-1) i.v., or isoflurane, 2.1% end-tidal (1.5 MAC), plus cromakalim, 4 and 10 microg x kg(-1) i.v. Cromakalim dose-relatedly decreased mean arterial pressure and systemic vascular resistance and increased coronary blood flow in both conscious and anaesthetized states. With isoflurane, the duration of effects of cromakalim were prolonged. Isoflurane exerted an additive effect on the increase in coronary blood flow induced by a low-dose cromakalim, whereas it did not influence the effect of a high-dose cromakalim. The maximum rate of increase in left ventricular pressure and segment shortening were increased by cromakalim in the conscious state but unchanged during isoflurane anaesthesia. The results suggest that the coronary vasodilating effects of isoflurane and cromakalim are basically additive until cromakalim exerts the maximal effect, and that the action of cromakalim on the coronary vasculature is prolonged by isoflurane.

ANALYTICAL METHODS TO DETECT THE AUTOOXIDATION OF ADRENOLUTIN AS A STEP IN CATECHOLAMINE METABOLISM

The acute hemodynamic effects of organophosphate (OP) intoxication include positive chronotropic and inotropic changes along with increases in intraventricular pressure and coronary blood flow. These observations are consistent with an enhanced sympathetic tone that correlates neurogenic cardiomyopathy to adrenergic overactivity and subsequent, focal catecholamine (CA) release and cellular oxidative stress. Several mechanisms have been proposed to explain the cardiotoxicity associated with elevated CA concentrations. However, it is suggested that the oxidative metabolites of CA's, rather than (or in addition to) the parent CA's per se, may initiate or be in part responsible for the cardiotoxicity. The chromatographic profile of adrenochrome (1) and adrenolutin (2) (Figure 1) are described in this study in an isocratic, reverse phase HPLC method using UV/VIS and electrochemical (EC) detection. The aqueous adrenochrome standard shows a retention time of 1.9 minutes under employed conditions. Furthermore, us...