Changes In Coronary Flow Research Articles

Higher viscosity participates in the regulation of coronary flow via nitric oxide and indomethacin-sensitive contracting factor

Few studies have reported on the association of viscosity with coronary circulation. We evaluated the change in coronary flow after dextran was added to a perfusion solution to increase viscosity in isolated rat hearts. We also measured NOx- production induced by the change in shear stress in the coronary effluent, as a marker of NO synthesis. The baseline coronary flow was not influenced by the presence of either the cyclooxygenase inhibitor indomethacin, the thromboxane A2 (TXA2)-prostaglandin H2 (PGH2) receptor antagonist ONO-3708, or the TXA2 synthase inhibitor OKY-046. After exposure to solution containing 0.5% dextran, the coronary flow first decreased and then gradually increased until 10 min. The initial decrease in coronary flow was inhibited by indomethacin, ONO-3708, and OKY-046 individually. The gradual increase was completely inhibited by the NO inhibitor L-NAME, but not by indomethacin or ONO-3708. OKY-046 partially inhibited the increase. NOx- levels in the effluent were higher after the dextran solution was administered, and the increased NOx- levels were inhibited by L-NAME. The increased NOx- levels were not inhibited by inhibitors of the cyclooxygenase pathway. It appears that a higher viscosity of perfusion solution induced a gradual increase in NO production and was associated with increased production of indomethacin-sensitive contracting factor.

Effect of Long-term Hormone Replacement Therapy on Coronary Endothelial Function in Postmenopausal Women

To determine the difference in endothelial function between premenopausal and postmenopausal women and to determine whether hormone replacement therapy (HRT) is associated with an improvement in coronary endothelial function. Women undergoing coronary physiology studies for chest pain at the Mayo Clinic In Rochester, Minn, between December 1992 and April 2002 underwent assessment of coronary endothelium-independent and -dependent function with intracoronary administration of adenosine and acetylcholine, respectively. The coronary diameters, coronary blood flows, and coronary velocity reserves were measured. A total of 270 women (89 premenopausal and 181 postmenopausal) participated in the study. Endothelium-dependent coronary blood flow change (baseline to peak flow) in response to acetylcholine (10(-4), 10(-5), and 10(-4) mol/L) was lower in postmenopausal women compared with premenopausal women (39.7% vs 72.9%, P = .03). There was no significant difference between the postmenopausal women receiving and not receiving HRT with regard to percent change in coronary diameter (-21.8% vs -13.9%, P = .15), percent change in coronary blood flow (37.3% vs 42.7%, P = .74), or coronary velocity reserve (2.7 vs 2.7, P = .82). This study shows that the postmenopausal state is associated with a greater abnormality in coronary endothelial function at the level of the microcirculation. Moreover, HRT status was not associated with an improvement in coronary endothelial function in postmenopausal women.

Nitric oxide regulation of myocardial O2 consumption and HEP metabolism.

NO and O(2) compete at cytochrome-c oxidase, thus potentially allowing NO to modulate mitochondrial respiration. We previously observed a decrease of myocardial phosphocreatine (PCr)/ATP during very high cardiac work states, corresponding to an increase in cytosolic free ADP. This study tested the hypothesis that NO inhibition of respiration contributes to this increase of ADP. Infusion of dobutamine + dopamine (DbDp, each 20 microg.kg(-1).min(-1) iv) to more than double myocardial oxygen consumption (MVo(2)) in open-chest dogs caused a decrease of myocardial PCr/ATP measured with (31)P NMR from 2.04 +/- 0.09 to 1.85 +/- 0.08 (P < 0.05). Inhibition of NO synthesis with N(omega)-nitro-L-arginine (L-NNA), while catecholamine infusion continued, caused PCr/ATP to increase to the control value. In a second group of animals, L-NNA administered before catecholamine stimulation (reverse intervention of the first group) increased PCr/ATP during basal conditions. In these animals L-NNA did not prevent a decrease of PCr/ATP at the high cardiac work state but, relative to MVo(2), PCr/ATP was significantly higher after L-NNA. In a third group of animals, pharmacological coronary vasodilation with carbochromen was used to prevent changes in coronary flow that might alter endothelial NO production. In these animals L-NNA again restored depressed myocardial PCr/ATP during catecholamine infusion. The finding that inhibition of NO production increased PCr/ATP suggests that during very high work states NO inhibition of mitochondrial respiration requires ADP to increase to drive oxidative phosphorylation.

The decrease of plaque volume during percutaneous coronary intervention has a negative impact on coronary flow in acute myocardial infarction: A major role of percutaneous coronary intervention-induced embolization

ObjectivesThe aim of this study was to evaluate how decreased plaque volume during percutaneous coronary intervention (PCI) affects coronary flow in patients with acute myocardial infarction (AMI). BackgroundCoronary flow after reperfusion therapy is a major determinant of clinical outcomes in patients with AMI. However, little is still known about the changes in coronary flow that appear after PCI in response to the decreased plaque during the procedure. MethodsThe study group comprised 60 patients with AMI who underwent pre- and post-PCI intravascular ultrasound (IVUS). Qualitative and quantitative analyses were performed on all IVUS procedures. External elastic membrane volume (EEMV), lumen volume (LV), and plaque volume (PV) were measured every 1.0 mm to include the lesion and reference segments 3.0 mm proximal and distal to the lesion. The difference between pre- and post-PCI PV was defined as the index of the decrease in plaque volume (ΔPV). The corrected TIMI frame count (CTFC) was used to evaluate coronary flow after PCI. ResultsPlaque volume was decreased at post-PCI IVUS in all 60 patients. Inadequate reflow (CTFC >40) was observed in 13 patients (21.7%). The decrease in PV was significantly larger in patients with inadequate reflow than in those with reflow (49.4 ± 18.9 vs. 31.7 ± 15.5 mm3, p = 0.0010). Also, ΔPV was significantly correlated with CTFC after PCI (r = 0.415, p = 0.0012). ConclusionsThe decrease in PV during PCI has a negative impact on coronary flow after PCI in patients with AMI. Embolization induced by PCI may occur in all patients with AMI.

Impairment of coronary flow reserve and left ventricular function in the brain-dead canine heart

The mechanisms of cardiac dysfunction after brain death, which are thought to be mainly associated with massive catecholamine release, have not been fully elucidated, especially with respect to the coronary circulation. The aim of this study was to investigate the changes in function of the coronary artery and its contribution to hemodynamic deterioration in a canine brain death model. Brain death was induced by rapid inflation of a subdurally placed balloon catheter. Hemodynamic measurements including assessment of left ventricular contractility using pressure-volume relations and biochemical analyses of blood samples were performed in seven dogs. Coronary flow reserve in the same brain death model was assessed by changes in coronary flow and resistance induced by administering a vasodilator directly into the coronary artery in another eight dogs. A hyperdynamic response was transiently observed after induction of brain death, followed by decreases in arterial pressure, cardiac output, and coronary blood flow. Parameters of left ventricular contractility as measured by pressure-volume relations had significantly deteriorated by 60 min after brain death. Percent changes in coronary flow by administration of acetylcholine and sodium nitroprusside were 272 and 209%, respectively, before brain death; these were decreased to 178 and 145% at 30 min after brain death, and to 192 and 153% at 60 min. Coronary resistance ratios were also significantly increased at 30 and 60 min after brain death. Impairment of coronary flow reserve was found in the brain-dead canine heart. This impaired coronary circulation may constitute a disadvantage of prevention and recovery of cardiac dysfunction after induction of brain death.

Effects of first and second generation calcium channel blockers on diastolic function of the failing hamster heart: relationship with coronary flow changes.

Calcium channel blockers (CCBs) have variable efficacy in the treatment of heart failure. We hypothesized that modulation of left ventricular diastolic pressure (LVDP) may play a role in the variable efficacy of CCBs in this condition. Isolated perfused hearts from 200- to 250-day-old UM-X7.1 cardiomyopathic hamsters (failing hearts) and age-matched Syrian hamsters (normal hearts) were studied. After recording of heart rate, coronary flow (CF), LVDP and left ventricular systolic pressure (LVSP), hearts were exposed either to verapamil or diltiazem (1 nM-10 microM), mibefradil (1 nM-1 microM) or clentiazem (1 nM-10 microM). Mechanical increase in CF (+2 to +10 ml/min) was carried out using a roller pump. Mechanically-augmented flow led to an increase in coronary perfusion pressure (+40 to +90 mm Hg), LVSP (+5 to +40 mm Hg) and LVDP (+5 to +25 mm Hg). CCBs-induced increment of coronary flow led to a difference in their cardiac response. In normal hearts, the negative inotropic response was more important with diltiazem and verapamil. Failing hearts did not demonstrate increased inotropic sensitivity to first-generation CCBs. On the contrary, at clinically relevant concentrations, verapamil resulted in the most pronounced impairment of LVDP followed by diltiazem while mibefradil and clentiazem, at clinically relevant concentrations, preserved LVDP. Such findings provide an additional explanation for the variable efficacy of CCBs in heart failure.

Effect of PDE5 inhibition on coronary hemodynamics in pacing-induced heart failure.

Inhibition of phosphodiesterase type 5 (PDE5) can relax systemic and coronary vessels by causing accumulation of cGMP. Both the endothelial dysfunction with decreased nitric oxide production and increased natriuretic peptide levels in congestive heart failure (CHF) have the potential to alter cGMP production, thereby influencing the response to PDE5 inhibition. Consequently, this study examined the effects of PDE5 inhibition with sildenafil in dogs with CHF produced by rapid ventricular pacing. CHF resulted in decreases of left ventricular (LV) systolic pressure, coronary blood flow, and the maximal first time derivative of LV pressure (LV dP/dt(max)) at rest and during treadmill exercise compared with normal, whereas resting LV end-diastolic pressure increased from 10 +/- 1.4 to 23 +/- 1.4 mmHg. Sildenafil (2 and 10 mg/kg per os) caused a 5- to 6-mmHg decrease of aortic pressure (P < 0.05), with no change of heart rate, LV systolic pressure, or LV dP/dt(max). Sildenafil caused no change in coronary flow or myocardial oxygen consumption in animals with CHF at rest or during exercise. In contrast to findings in normal animals, sildenafil did not augment endothelium-dependent coronary vasodilation in response to acetylcholine in animals with CHF. Furthermore, Western blotting showed decreased PDE5 protein expression in myocardium from failing hearts. These findings demonstrate that PDE5 contributes little to regulation of coronary hemodynamics in CHF.

Myocardial protection of immature rabbits: polarizing versus depolarizing

Background. This study was designed to identify the potassium-channel opener pinacidil as a cardioplegic agent vs hyperkalemic cardioplegia in terms of its efficacy in immature cardioprotection. Methods. By a Langendorff model, 21 hearts of 21- to 28-day-old New Zealand rabbits underwent 90 min of global hypothermic (15°C) ischemia protected with a different single dose of hypothermic (4°C) cardioplegia (pinacidil [50 μmol/l], St. Thomas’ solution combined with pinacidil [50 μmol/l], and St. Thomas’ solution). The percent recovery of the cardiac function, creatine kinase release, and cellular ultrastructure were compared. Results. Pinacidil (50 μmol/l) provided significantly the best postreperfused percentage recovery of the function than the other groups; pinacidil cardioplegia showed a significant reduction of creatine kinase release in the coronary flow compared with the other groups; St. Thomas’ solution combined with pinacidil showed the highest release. Percentage recovery of the coronary flow, water contents, and ultrastructural changes were similar between the groups. Conclusions. Pinacidil provided better protection during ischemia-reperfusion in the immature rabbit heart than St. Thomas’ solution, whereas pinacidil combined with St. Thomas’ solution showed the worst protective effects in immature hearts.

Decreased contractility of the left ventricle is induced by the neurotransmitter acetylcholine, but not by vagal stimulation in rats.

There is still controversy with respect to how an increase in vagal tone changes left ventricular (LV) contractility. It is possible that a difference in LV vagal innervation density may affect the inotropic effect. To test this, we examined the effects of vagal stimulation and acetylcholine (ACh) infusion on the rat ventricle, in which LV vagal innervation density is sparse and a negative force-frequency relationship is uniquely observed. To evaluate LV contractility, we developed an in situ Langendorff preparation, in which the effects of changes in afterload, preload, and coronary flow during an intervention were minimized. Both vagal stimulation and ACh infusion significantly increased LV systolic pressure (34 +/- 16%: 36 +/- 22%. respectively) and its maximum positive first derivative with slowing of heart rate (51 +/- 17%: 46 +/- 18%). These effects of vagal stimulation were abolished by pretreatment with atropine. During a fixed heart rate, LV systolic pressure was not changed by vagal stimulation, however, it was decreased slightly but significantly (11 +/- 8%) by ACh infusion. In conclusion, LV contractility changes due to ACh release during vagal stimulation were negligibly small, presumably due to a sparse vagal innervation density in rats, and therefore, a bradycardia-dependent indirect positive inotropic effect may be dominant compared to a direct negative inotropic action during vagal stimulation. Thus, the integrated effect of vagal nerve stimulation on LV contractility is different among species, because it is determined by a direct negative inotropic effect, which depends on the vagal innervation density in the left ventricle, as well as by bradycardia-dependent indirect inotropic changes.

Role of endothelin during experimental Trypanosoma cruzi infection in rats.

Chagas' disease is caused by the intracellular protozoan Trypanosoma cruzi. Here we have investigated the role of endothelin-1 in T. cruzi acute infection in rats, using the orally active ET(A) receptor antagonist BSF-461314. Treatment with BSF-461314 markedly increased parasitaemia, but animals managed to control the infection by day 15. Histopathological analysis of heart tissue at the end of the acute phase showed greater numbers of parasite nests in BSF-461314-treated animals. The perfusion of isolated rat hearts from infected animals with bradykinin failed to induce an increase, and actually reduced, coronary blood flow. Pretreatment with BSF-461314 prevented changes in coronary flow induced by T. cruzi infection. Together these results demonstrate that endothelin-1, through ET(A) receptor activation, contributes to the protective immune response against acute T. cruzi infection. Moreover, these data suggest that endothelin-1 is a mediator of impaired endothelium-dependent vasomotion in the coronary microcirculation associated with acute T. cruzi infection.

Targeted deletion of adenosine A(3) receptors augments adenosine-induced coronary flow in isolated mouse heart.

To determine whether adenosine A(3) receptors participate in adenosine-induced changes in coronary flow, isolated hearts from wild-type (WT) and A(3) receptor knockout (A(3)KO) mice were perfused under constant pressure and effects of nonselective and selective agonists were examined. Adenosine and the selective A(2A) agonist 2-[p-(2-carboxyethyl)]phenylethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680) produced augmented maximal coronary vasodilation in A(3)KO hearts compared with WT hearts. Selective activation of A(3) receptors with 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA) at nanomolar concentrations did not effect coronary flow, but at higher concentrations it produced coronary vasodilation both in WT and A(3)KO hearts. Cl-IB-MECA-induced increases in coronary flow were susceptible to both pharmacological blockade and genetic deletion of A(2A) receptors. Because deletion or blockade of adenosine A(3) receptors augmented coronary flow induced by nonselective adenosine and the selective A(2A) receptor agonist CGS-21680, we speculate that this is due to removal of an inhibitory influence associated with the A(3) receptor subtype. These data indicate that the presence of adenosine A(3) receptors may either inhibit or negatively modulate coronary flow mediated by other adenosine receptor subtypes.

Does nitric oxyde synthase inhibitor influence on coronary flow and nitrite outflow changes induced by different phosphodiesterase (PDEs) inhibitors in isolated rat heart?

Does nitric oxyde synthase inhibitor influence on coronary flow and nitrite outflow changes induced by different phosphodiesterase (PDEs) inhibitors in isolated rat heart?

Intrinsic changes on automatism, conduction, and refractoriness by exercise in isolated rabbit heart.

We have studied the intrinsic modifications on myocardial automatism, conduction, and refractoriness produced by chronic exercise. Experiments were performed on isolated rabbit hearts. Trained animals were submitted to exercise on a treadmill. The parameters investigated were 1) R-R interval, noncorrected and corrected sinus node recovery time (SNRT) as automatism index; 2) sinoatrial conduction time; 3) Wenckebach cycle length (WCL) and retrograde WCL, as atrioventricular (A-V) and ventriculoatrial conduction index; and 4) effective and functional refractory periods of left ventricle, A-V node, and ventriculoatrial retrograde conduction system. Measurements were also performed on coronary flow, weight of the hearts, and thiobarbituric acid reagent substances and glutathione in myocardium, quadriceps femoris muscle, liver, and kidney, to analyze whether these substances related to oxidative stress were modified by training. The following parameters were larger (P < 0.05) in trained vs. untrained animals: R-R interval (365 +/- 49 vs. 286 +/- 60 ms), WCL (177 +/- 20 vs. 146 +/- 32 ms), and functional refractory period of the left ventricle (172 +/- 27 vs. 141 +/- 5 ms). Corrected SNRT was not different between groups despite the larger noncorrected SNRT obtained in trained animals. Thus training depresses sinus chronotropism, A-V nodal conduction, and increases ventricular refractoriness by intrinsic mechanisms, which do not involve changes in myocardial mass and/or coronary flow.

Obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries

OBJECTIVESThis study evaluates the impact of obesity on coronary endothelial function in patients with normal or mild coronary artery disease.BACKGROUNDThe American Heart Association (AHA) has recently classified obesity as a modifiable risk factor for coronary heart disease.METHODSA total of 397 consecutive patients with normal or mildly diseased coronary arteries at angiography underwent coronary vascular reactivity evaluation using intracoronary adenosine, acetylcholine and nitroglycerin. Patients were divided into three groups based on the body mass index (BMI): Group 1, patients with a BMI <25 (n = 117, normal weight); Group 2, patients with a BMI 25–30 (n = 149, overweight) and Group 3, patients with a BMI >30 (n = 131, obese).RESULTSThere were no significant differences among the groups in regard to other cardiovascular risk factors, except that overweight but not obese patients were significantly older than normal-weight patients (47 ± 1 years in Group 1, 53 ± 1 years in Group 2 and 50 ± 1 years in Group 3, p < 0.001). The percent change of coronary blood flow to acetylcholine (%Δ CBF Ach) was significantly lower in the obese patients than in the normal-weight group (85.2 ± 12.0% in Group 1, 63.7 ± 10.0% in Group 2 and 38.1 ± 9.6% in Group 3, p = 0.009). By multivariate analysis, overweight (odds ratio, 1.55; 95% confidence interval, 1.2–2.0) and obesity (odds ratio, 2.41; 95% confidence interval, 1.5–4.0) status were independently associated with impaired coronary endothelial function.CONCLUSIONSThe study demonstrates that obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries.

Deterioration of the protein kinase C–K ATP channel pathway in regulation of coronary flow in hypercholesterolaemic rabbits

We studied the effect of experimental hypercholesterolaemia/atherosclerosis on changes in coronary flow and cardiac function, induced by protein kinase C and ATP-sensitive K + (K ATP) channel modulators in isolated Langendorff-perfused rabbit hearts. Both phorbol 12-myristate-13-acetate (PMA) and phorbol 12,13-dibutyrate (PDB, 0.1 μM each), activators of protein kinase C, decreased, whereas staurosporine, (0.1 μM), a protein kinase C inhibitor, increased coronary flow and left ventricular d P/d t, an index of ventricular contractility. Glyburide (5–50 μM), a K ATP channel inhibitor, blocked the effect of staurosporine. The phorbol esters were without effect in the presence of pinacidil (5 μM), a K ATP channel activator. Neither the protein kinase C modulators nor glyburide produced any effect on coronary flow and left ventricular contractility, when the hearts were prepared from animals either maintained on a cholesterol (1.5%)-enriched diet or treated with lovastatin (5 mg/kg/day per os). Treatment with farnesol (1 mg/kg twice a day for 7 days intravenously) restored the reactivity of hearts from either hypercholesterolaemic or lovastatin-treated animals to protein kinase C modulators. We conclude that non-cholesterol mevalonate products are necessary for the functional integrity of the protein kinase C–K ATP channel pathway in the rabbit heart.

Isolated working rat heart adaptation after abrupt changes in extracellular Ca2+ concentration.

In isolated working rat hearts, a rapid up- or downward change in perfusate Ca2+ concentration by the factors 2, 4, or 8 in the range between 1.25 and 10 mM resulted within 1 min in the well-known change of left ventricular contractility as evaluated by maximum left ventricular pressure change velocity (LVdP/dt max) and left ventricular end-diastolic pressure (LVEDP). However, within about 10 min thereafter, contractility showed an adaptive behaviour opposite to the initial change, with t 1/2 values for LVdP/dt max between 1.45 and 2.8 min. The adaptive LVdP/dt max reactions amounted to 10-35% of the initial change. With an abrupt fall from 10 mM to 1.25 mM Ca2+ (not tolerated by all hearts), LVdP/dt max decreased initially by 4.260 mmHg/s (LVEDP +9.7 mmHg) and increased thereafter by 524 mmHg/s (LVEDP -6.8 mmHg). The adaptive inotropic behaviour cannot be related to changes in heart rate or coronary flow and is not affected by thapsigargin (1 microM) or the amiloride derivative benzamil (10 microM). This suggests that sarcoplasmatic Ca2+-ATPase and sarcolemmal Na+-Ca2+ exchange do not play a decisive role in this adaptive behaviour. In conclusion, an intrinsic regulatory mechanism of the myocardium attenuates the inotropic effect of acute changes in Ca2+ concentration. This phenomenon might protect the heart against Ca2+ overload after an acute rise in catecholamine concentration.

Direct coronary artery perfusion from the left ventricle

Objectives: Trends in coronary bypass surgery require less invasive techniques and more conduits. We investigated the ability of direct coronary perfusion from the left ventricle to support regional and global cardiac function. Methods: A conduit was established between the left ventricle and left anterior descending coronary artery (n = 6) with an interposed Starling resistor that allowed for graded regulation of backward flow. Changes of coronary flow, regional function in the territory of the left anterior descending coronary artery, and reactive hyperemia were studied. In 3 separate dogs, functional tolerance to increased heart rate was tested. In another 3 dogs, left ventricle–left anterior descending and left ventricle–left circumflex coronary artery conduits were established simultaneously (double conduit), and global function was tested. Results: Without flow regulation, flow through the left ventricle–left anterior descending conduit exhibited high peaking (102 ± 35 mL/min), midsystolic forward flow, and large pandiastolic backward flow (peaking at –47 ± 22 mL/min). Mean coronary flow and regional function were maintained at 46.0% ± 7.1% (35.8%-54.2%) and 45.3% ± 29.1% (–1.8%-74.2%) of their respective normal values. When the Starling resistor was used to regulate backward flow, these values increased to 70.8% ± 12.5% (56.8%-90.4%) and 70.2% ± 27.8% (23.6%-107.7%), respectively. Coronary and functional reserve with a left ventricle–left anterior descending conduit were not observed. With the double conduit, global ventricular contractility indexed by end-systolic pressure-volume relation averaged 46% ± 35% of its normal value. Conclusions: A left ventricle–coronary artery conduit supplied approximately 45% of normal blood flow and regional function, and both were improved by regulation of backward flow. Therefore, a conduit from the left ventricle to an epicardial vessel could serve as a rapidly deployable means of revascularizing totally occluded coronary vessels for which suitable natural conduits are not available. (J Thorac Cardiovasc Surg 2001;121:307-15)

Impaired nitric oxide production and enhanced autoregulation of coronary circulation in young spontaneously hypertensive rats at prehypertensive stage.

In the current study, we investigated the NO-generation pathway in response to mechanical stimuli in SHR at the prehypertensive stage. To examine the role of NO in coronary autoregulation, we evaluated the effects of L-NAME on the coronary flow in SHR at both the prehypertensive and hypertensive stages. Isolated perfused hearts from 5- and 15-week-old SHR and from age-matched Wistar-Kyoto rats (WKY) were used. After stabilization at 60 mmHg, perfusion pressure was immediately raised to 90 mmHg to record the change in coronary flow for 10 min without (control) or with NO synthesis blockade by Nomega-nitro-L-arginine methyl ester (L-NAME). NOx- (nitrite/nitrate) was measured in coronary effluent. At 5 weeks of age, SHR did not have hypertension, while the coronary autoregulation was enhanced. L-NAME did not affect this enhanced autoregulation in 5-week-old SHR. At perfusion pressures of both 60 and 90 mmHg, 5-week-old SHR showed less coronary NOx- production than age-matched WKY. At 15 weeks, SHR showed a higher blood pressure than WKY. The coronary autoregulation in SHR remained higher than that in WKY, but was below that in 5-week-old SHR. NOx- production in 15-week-old SHR recovered to the level of age-matched WKY. These results indicate that NOx- production induced by mechanical stimulation was markedly reduced in 5-week-old SHR at the prehypertensive stage, which may have enhanced coronary autoregulation. An impaired nitric oxide production may precede the onset of hypertension in SHR.

Short ischemia causes endothelial dysfunction in porcine coronary vessels in an in vivo model

Background. The aim of this study was to evaluate the effects of a short period of ischemia (10 mins) and a prolonged period of ischemia (60 mins) followed by reperfusion on coronary flow changes induced by acetylcholine (ACh), adenosine (ADO), and endothelin (ET). Methods. The left anterior descending coronary artery in anesthetized pigs was occluded for 10 or 60 minutes followed by 120 minutes reperfusion. Thereafter, the flow changes in the left anterior descending coronary artery were studied after intracoronary infusion of ACh, ADO, and ET. Results. Short-term ischemia (10 minutes) caused a decrease in vasodilatation, but not the vasoconstriction response to ACh. Prolonged ischemia (60 minutes) impaired ADO induced vasodilatation and aggravated ET evoked vasoconstriction. Conclusions. The present findings suggest that a short period of ischemia (10 minutes) causes disturbances of the endothelial regulation of coronary vascular tone and that this endothelial regulation is more sensitive, and precedes changes in vascular smooth muscle function after ischemia and reperfusion.

Heart function challenged with beta-receptor agonism or antagonism in a heart failure model.

We have shown that chronic treatment with carteolol, a non-selective beta-adrenergic receptor antagonist, improved left ventricular (LV) function and survival in an avian model of dilated cardiomyopathy (DCM). The aim of the present study was to compare ex vivo heart function with and without beta-agonist and antagonist challenge. We investigated whether intracoronary infusion of a beta-blocker, carteolol or beta-agonist, isoproterenol decreased contractility. In the DCM group, isoproterenol resulted in a significantly greater increase in heart rate (71% vs. 28% compared to control hearts). To investigate the mechanism for the increase in heart rate, we exposed spontaneously beating neonatal cardiomyocytes to serum immunoglobulin (IgG) isolated from DCM animals. Serum IgG resulted in a significant increase in spontaneous beating rate in neonatal rat cardiomyocytes that was blocked by pre-treatment with a beta-blocker. Carteolol challenge did not significantly change heart rate but did significantly increase LV peak pressure in DCM hearts (62%) while coronary artery flow remained unchanged (2.7+/-0.1 vs 2.7+/-0.5 ml/min/g). These results show that 1) beta-receptor stimulation results in a greater tachycardic response in DCM animals, and 2) carteolol challenge improves myocardial contractility in hearts from DCM animals independent of heart rate or changes in coronary artery flow.