Relative quantification of plasma N-glycans in type II congenital disorder of glycosylation patients by mass spectrometry.

BACKGROUND: Type II Congenital Disorders of Glycosylation (CDG-II) are a group of diseases with challenging diagnostics characterized by defects in the processing of glycans in the Golgi apparatus. Mass Spectrometry (MS) has been a valuable tool in the definition of CDG-II subtypes. While some CDG-II subtypes are associated with specific N-glycan structures, others only produce changes in relative levels, reinforcing the demand for quantification methods. METHODS: Plasma samples from control individuals were pooled, derivatized with deuterated iodomethane (I-CD3), and used as internal standards for controls and patients whose glycans were derivatized with iodomethane (I-CH3), followed by MALDI MS, LC-MS and -MS/MS analyses. RESULTS: Total N-glycans from fifteen CDG-II patients were evaluated, and 4 cases with molecular diagnosis were considered in detail: 2ATP6V0A2-CDG siblings, and 2 MAN1B1-CDG patients, one of them carrying a previously undescribed p.Gly536Val mutation. CONCLUSIONS: Our methodology offers a feasible alternative to the current methods for CDG-II diagnosis by MS, which quantify glycan structures as fractions of the total summed signal across a mass spectrum, a strategy that lowers the variability of minor components. Moreover, given its sensitivity for less concentrated yet biologically relevant structures, it might assist the uncovering of novel diagnostic glycans in other CDG-II subtypes.

Heart rate, heart rate variability, and blood pressure during perioperative stressor events in abdominal surgery.

STUDY OBJECTIVE: To define the behavior of power spectral heart rate variability (PSHR) during potentially stressful events in the perioperative period, and relate it to changes in blood pressure (BP) and heart rate (HR). DESIGN: Longitudinal clinical study. SETTING: Operating room and recovery suites of a large tertiary care referral center. PATIENTS: 26 ASA physical status I, II, and III patients undergoing elective abdominal surgery. INTERVENTIONS: Anesthesia was induced with thiopental sodium and fentanyl, and maintained with isoflurane/nitrous oxide (N2O)/relaxant or enflurane/N2O/relaxant. The trachea was intubated and intraabdominal surgery was performed. MEASUREMENTS AND MAIN RESULTS: Observations consisted of HR, noninvasive blood pressure, and PSHR. They were made before and after induction of anesthesia, tracheal intubation, and surgical incision, and during maximal surgical stimulation and skin closure. HR and mean arterial pressure (MAP) maxima were also recorded for one hour before and after emergence from anesthesia. PSHR was obtained using a special algorithm and data acquisition system for real time spectral analysis of the instantaneous HRversus time function. The HR power spectrum parameters analyzed were low-frequency (LFA; powerband = 0.04 to 0.10 Hz), respiratory-induced frequency (RFA; powerband = respiratory frequency +/- 0.06 Hz), and the ratio of LFA to RFA. With induction of anesthesia, only RFA power decreased significantly. LFA power reduction became significant only after intubation and continued so until after incision. Immediately after induction, the decline in RFA power (vs. preinduction) was more pronounced when compared with the decline in LFA power (76% vs. 34%; p = 0.01). Hence, the ratio LFA/RFA increased significantly after induction of anesthesia. It was significantly higher than at postintubation, preincision, or skin closure. A significant elevation in LFA, LFA/RFA ratio, and BP occurred with maximal abdominal surgical stimulation. Only preinduction LFA, RFA, and LFA/ RFA ratio were predictive of MAP changes with induction of anesthesia (p = 0.006). In 8 of the 15 patients who had MAP changes of at least 10 mmHg with induction, PSHR indices correctly predicted a change of this magnitude. Late intraoperative HR maxima were positively correlated with the change in HR and incision (r2 = 0.58; p < 0.01). The change in BP with incision was positively correlated with early postoperative HR maxima (r2 = 0.60; p < 0.01). CONCLUSIONS: On anesthetic induction, preoperative, but not intraoperative, spectral indices were predictive of BP changes. Power spectral analysis of HR may provide information about the autonomic state that is not evident from BP or HR. The HR power spectrum, in particular, indicated a striking autonomic imbalance immediately after the induction of anesthesia despite stable HR and BP. LFA and LFA/RFA ratio appeared to track sympathetic autonomic activation during abdominal surgical stimulation, but not during other perioperative stressor events.

Sigma receptor activation does not mediate fentanyl-induced attenuation of muscarinic coronary contraction.

Our overall goal was to investigate the mechanism by which fentanyl attenuates acetylcholine-induced contraction in porcine coronary artery. We tested the hypothesis that fentanyl attenuates muscarinic coronary contraction via sigma receptor activation. Left coronary artery vascular rings were isolated from porcine hearts and were suspended in organ chambers for isometric tension recording. In untreated coronary vascular rings, acetylcholine administration resulted in dose-dependent contraction. Fentanyl attenuated acetylcholine-induced contraction. The sigma ligands--(+)-pentazocine, (+)-cyclazocine, haloperidol, and 1,3-di-o-tolylguanidine--also inhibited acetylcholine-induced contraction. In contrast, the selective sigma ligand, (+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine failed to have an inhibitory effect on acetylcholine-induced contraction. Moreover, metaphit (1-[1(3-isothiocyanatophenyl)cyclohexyl]piperidine), which causes irreversible acylation of sigma receptors, only inhibited acetylcholine-induced contraction when it was present in the organ chamber. We also assessed the effects of inhibiting various points in the signal transduction pathway distal to naloxone-sensitive opioid receptor activation on acetylcholine-induced contraction. Selective (glybenclamide) and nonselective (tetraethylammonium) K(+)-channel inhibition, guanosine triphosphate-binding protein inactivation (pertussis toxin), and Type 1 and Type 2 dopamine receptor inhibition all failed to alter the attenuating effect of fentanyl on acetylcholine-induced contraction. Thus, neither sigma or opioid receptor activation is a prerequisite for fentanyl-induced inhibition of muscarinic coronary contraction.

Role of nitric oxide in systemic hemodynamic responses to dobutamine, epinephrine, and amrinone.

OBJECTIVE: This study was designed to investigate the extent to which the systemic vasodilator effects of dobutamine, epinephrine, and amrinone are modulated by the endothelium-derived relaxing factor, nitric oxide (NO). DESIGN: This was a prospective study of low and high doses of the agonists before and after inhibition of NO synthesis. SETTING: Experiments were performed in the basic research laboratories of the Center for Anesthesiology Research. PARTICIPANTS: Pentobarbital-anesthetized, intact Sprague-Dawley rats were studied in seven separate groups of eight rats each. INTERVENTIONS: The systemic vasodilator responses to the agonists were assessed before and after the administration of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester. MEASUREMENTS AND MAIN RESULTS: Decreases in systemic vascular resistance in response to dobutamine and epinephrine were not observed after inhibition of NO synthesis, whereas the decrease in systemic vascular resistance in response to amrinone was still apparent. CONCLUSIONS: The results suggest that dobutamine and epinephrine produce systemic vasodilation through the release of NO, whereas amrinone produces vasodilation independent of NO release.

Mechanism of systemic vasodilation during normovolemic hemodilution.

In the nonfailing heart, normovolemic hemodilution increases cardiac output and decreases total peripheral resistance (TPR). Putative mechanisms mediating the decrease in TPR include reflex vasodilation and changes in the local regulation of blood flow. Our objectives were to determine whether ablation of reflex neural mechanisms or the inhibition of nitric oxide (NO) synthase, the enzyme responsible for the synthesis of the endothelium-derived relaxing factor (EDRF-NO), modulates the systemic vasodilator response to normovolemic hemodilution. Three groups of male Sprague-Dawley rats were subjected to acute normovolemic hemodilution, which was achieved by exchanging a volume of blood equivalent to 3.8% of body weight with hydroxyethyl starch. Hemodilution increased cardiac output and decreased TPR. Subsequent administration of the NO synthase inhibitor, L-nitroarginine (LNA), returned both cardiac output and TPR to control values. Pretreatment with LNA prior to hemodilution increased TPR, an effect that was partially reversed by the NO donor, sodium nitroprusside. In this setting, hemodilution failed to decrease TPR. After spinal cord destruction by "pithing," hemodilution decreased TPR to the same extent as that observed in intact rats. This hemodilution-induced decrease in TPR was abolished by the subsequent administration of LNA. These results indicate that neural reflexes do not modulate the systemic vascular response to hemodilution. Moreover, the systemic vasodilator response to hemodilution is abolished after inhibition of endogenous NO synthesis.

Effect of cocaine on the contracture response to 1% halothane in patients undergoing diagnostic muscle biopsy for malignant hyperthermia.

Two case reports have cited the recreational use of cocaine as possible trigger of a malignant hyperthermia (MH) crisis. We evaluated whether toxic concentrations of cocaine altered the in vitro muscle response to halothane during contracture tests for MH. Twenty-two patients were studied. Muscle biopsies were obtained and first tested for MH susceptibility with 3% halothane and caffeine contracture testing. Ten patients were diagnosed as MH-susceptible and 12 as MH non-susceptible, in accordance with the North American Malignant Hyperthermia Group protocol. Then, muscle strips were exposed to 1% halothane in the presence and absence of 0.1 mmol.L-1 cocaine. Cocaine alone did not affect baseline muscle tension in either group. With 1% halothane, MH non-susceptible muscle showed no contracture with or without cocaine. In contrast, in the presence of 1% halothane, MH-susceptible muscle showed either no change in contracture (six patients), an increase (two patients), or a decrease (two patients) when exposed to cocaine. However, the overall effect of cocaine on muscle contracture in the presence of 1% halothane was insignificant in both groups. We conclude that cocaine, even at toxic levels, does not have a direct effect on skeletal muscle contractility and thus is safe for MH-susceptible patients.

Vasodilation and mechanism of action of propofol in porcine coronary artery.

BACKGROUND: A decrease in myocardial perfusion pressure may reduce myocardial blood flow. However, it may not significantly affect myocardial perfusion when in presence of a concurrent coronary artery vasodilation. However, the effects of propofol in coronary arteries are not well determined. In this study, the effects of propofol on porcine coronary artery responses to vasoactive agents that operate through voltage- and receptor-mediated calcium mechanisms were investigated. METHODS: Hearts of adult pigs (n = 103) were obtained from a slaughter house, and the left anterior descending coronary arteries were dissected. The arteries were cut into vessel rings and prepared with and without the endothelium organ chambers filled with buffered salt solution. The effect of propofol (10(-7), 10(-6), 10(-5), and 10(-4) M) on vascular smooth muscle contraction caused by intracellular Ca(2+)-influx through voltage- and receptor-mediated mechanism also was studied at a cellular level. RESULTS: Propofol relaxed coronary rings that were contracted by KCl, norepinephrine (NE), serotonin (5-HT), or carbachol (CCh). The minimal concentrations of propofol that produced significant vasorelaxation ranged from 3.16 x 10(-7) M to 3.16 x 10(-6) M. Vasodilation was more pronounced in rings contracted by NE, 5-HT, and CCh than by KCl. Propofol (10(-5) M) attenuated coronary vasoconstriction in response to cumulative concentrations of KCl, NE, 5-HT, and acetylcholine. Maximal contractions produced by NE and 5-HT were inhibited to a greater degree than contractions produced by KCl. Propofol at concentrations of 10(-5) M and higher attenuated a contraction in response to CaCl2 in vascular rings depolarized by KCl, but concentrations of 10-M did not attenuate contractions. Vasoconstriction in response to calcium entry in the presence of NE (and nifedipine 10(-6) M) was attenuated by propofol at concentrations of 10(-6) M and higher. Caffeine-induced contraction, caused by intracellular calcium release, was attenuated only at 10(-4) M of propofol. CONCLUSIONS: Propofol possesses vasodilator effect and attenuates the effects of vasoconstrictor agents in porcine coronary artery. Further, an antagonism of calcium channels may be responsible for these effects of propofol.

Fentanyl attenuates porcine coronary arterial contraction through M3-muscarinic antagonism.

The "antimuscarinic effect" of fentanyl and its dependence on subtypes of receptors were characterized in isolated porcine coronary arteries. Left anterior descending coronary arteries were dissected from the hearts of 60 adult pigs obtained at a slaughterhouse and prepared for isometric tension studies. The effects of fentanyl on the cumulative concentration-response curve for acetylcholine were obtained in the presence and absence of muscarinic blockade by atropine. Fentanyl shifted the concentration-response curve to the right in a concentration-dependent fashion. Atropine shifted the concentration-response curve to the right, and no further shift was caused by fentanyl. To investigate the dependence on muscarinic receptor subtypes, the effect of fentanyl on acetylcholine-induced contraction was examined in the presence of specific M1-, M2-, and M3-muscarinic antagonists. The pA2 values for fentanyl decreased significantly in the presence of atropine (a nonspecific antagonist) and also in the presence of p-F-HHSiD (an M3-antagonist). In contrast, no significant change of pA2 value for fentanyl was observed in the presence of both pirenzepine (an M1-antagonist) and methoctramine (an M2-antagonist). We conclude that fentanyl has an antimuscarinic effect, and that this antagonism occurs in a competitive manner. Furthermore, the significant decrease of the pA2 value for fentanyl in the presence of M3-, but not in the presence of M1 + M2-antagonists, suggests that the attenuation of cholinergic contraction of porcine coronary arteries by fentanyl is mediated through the M3-muscarinic receptor subtype.

Analysis of heart rate variability to assess hemodynamic alterations following induction of anesthesia.

Extensive changes in hemodynamics and cardiac rhythm during induction of anesthesia may be mediated by altered responses of the autonomic nervous system to anesthetic agents. Analysis of the power spectrum of the heart rate (PSHR) variability can supply information about the autonomic nervous system, and may be used in order to assess this phenomenon. In this study, 78 patients undergoing coronary artery bypass graft surgery were evaluated. Anesthesia was induced with sufentanil, and neuromuscular blockade with vecuronium, a combination that may cause a decrease in heart rate. Before and after induction of anesthesia, the heart rate (HR), blood pressure (BP), cardiac output (CO), cardiac index (CI), and PSHR components were recorded. PSHR was obtained by using a special algorithm and data acquisition system for real-time spectral analysis. A low-frequency component (LFa, mainly sympathetic) was analyzed from a band of 0.04 Hz to 0.1 Hz. A high-frequency component (RFa, parasympathetic) was identified by the respiratory frequency spectrum. Alterations of the heart rate after induction of anesthesia were defined in order to separate the patient population into two groups: slow heart rate (slow-HR) and stable heart rate (stable-HR). Slow heart rate was defined as a decrease in HR of more than 20% of the baseline value. The variables were analyzed and compared between the slow-HR (n = 25) and stable-HR (n = 53) groups in order to verify the possibility of identifying patients prone to hemodynamic changes after anesthesia induction. There were no differences in preoperative HR, BP, CO, or CI between groups before anesthesia induction.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of opioids on vasoresponsiveness of porcine coronary artery.

Myocardial ischemia during surgery can be caused by coronary vasospasm. Neurohumoral mechanisms are involved in this phenomenon, and various substances have been suggested as possible causes, including acetylcholine, histamine, and norepinephrine. The responses of isolated porcine coronary arteries (from 117 pig hearts) with (E+) and without (E-) endothelium to these agents were investigated in the presence of fentanyl, sufentanil, and morphine. Fentanyl significantly shifted to the right, in a concentration-dependent fashion, the concentration-response curve to acetylcholine. This effect was not different between E+ and E- rings. Neither sufentanil nor morphine altered acetylcholine-induced contraction of porcine coronary arteries. Naloxone did not antagonize the suppressive effect of fentanyl on acetylcholine-induced contraction. The response of porcine coronary arteries to norepinephrine was decreased only at very high concentrations of fentanyl. Neither sufentanil nor morphine altered norepinephrine-induced contraction of porcine coronary arteries. Fentanyl, sufentanil, and morphine had no effect on histamine-induced contraction. We conclude that fentanyl antagonized acetylcholine-induced contraction of porcine coronary arteries. This effect of fentanyl seems to be caused by a direct effect on smooth muscle cells and is not opioid-receptor mediated.

Exercise training and responsiveness of isolated coronary arteries.

Exercise is associated with release of catecholamines and vasoactive intestinal polypeptides. Recurrent exposure to catecholamines modifies the sensitivity of adrenoceptors. To test the hypothesis that exercise training may affect the sensitivity of the epicardial coronary arteries, we performed studies on isolated coronary arteries from male dogs capable of running on a treadmill. The animals were separated randomly into two groups: sedentary and exercise training. After 11 wk, rings of left circumflex and left anterior descending coronary arteries were studied in vitro. Contractions to alpha 1-adrenergic agonists (norepinephrine and phenylephrine) were not affected by exercise training. During contractions with prostaglandin F2 alpha, endothelium-dependent relaxations to alpha 2-adrenergic agonists (norepinephrine and UK 14304) were not reduced significantly by exercise training. The concentration-relaxation curves to beta-adrenergic agonists (norepinephrine, isoproterenol, and epinephrine) were shifted to the right after training. The concentration-response curves to vasoactive intestinal polypeptide, but not that to substance P, were shifted to the right in rings with endothelium from exercise-trained animals. These findings demonstrate a decrease in responsiveness of canine vascular smooth muscle to beta-adrenergic agonists and to vasoactive intestinal polypeptide after exercise training.

Attenuated vascular reactivity in dogs with anteroventral third ventricle lesions.

Lesion of the anteroventral portion of the third cerebral ventricle causes hypernatremia, adipsia, and attenuation of the pressor response to intravenous administration of angiotensin II and norepinephrine. In addition, these lesions prevent the development of several experimental models of hypertension. In this study, a lesion of the third cerebral ventricle region was made in 14 dogs. In seven dogs in which hypernatremia developed the lesions included the organum vasculosum of the lamina terminalis; seven animals in which the circumventricular organ was spared by the lesion remained normonatremic. Vascular responsiveness of isolated right carotid artery rings to angiotensin II and phenylephrine was assessed 3 days after lesioning the anteroventral portion of the third cerebral ventricle. In endothelium-denuded ring vessels, vasoconstrictor responses to phenylephrine were significantly decreased in animals both with and without inclusion of the organum vasculosum of the lamina terminalis. A similar effect was observed in intact vessels of dogs in which the circumventricular organ was spared but not in those with lesions that included this area. In contrast, angiotensin II-induced vasoconstriction was significantly decreased in the arteries with intact endothelium of both groups of lesioned animals. These data show that lesion of the anteroventral third ventricle area alters alpha 1-adrenergic and angiotensin II vascular responsiveness in isolated carotid artery rings with the possible participation of the endothelium.

Neurovascular mechanisms and sodium balance in the pathogenesis of hypertension.

Physiological studies have clarified the role that the brain has in the interplay between salt balance and hypertension. Neural mechanisms and endocrine secretions play a pivotal role in the adaptation of mammals to changes in the intake and excretion of sodium. Maneuvers that alter the concentration of sodium in the plasma modify the sensitivity of baroreceptor reflexes and alter vascular reactivity. These changes may be mediated in part by the release of vasopressin. The research also suggests that the brain indirectly modulates the ability of the vascular endothelium to release vasoactive factors. Collectively, these studies illustrate the multiple effects of the sodium ion on the peripheral neural and central endocrine mechanisms that participate in the regulation of arterial pressure.

The renin-angiotensin system during acute myocardial ischemia in dogs.

We used the technique of high-performance liquid chromatography combined with radioimmunoassay to establish the profile of angiotensin peptides in the periphery and across the circulation of the dog's heart. Data were obtained before and after blockade of angiotensin converting enzyme, and after acute myocardial ischemia produced by occlusion of the left anterior descending coronary artery. Baseline values of plasma renin activity and immunoreactive angiotensin II were higher in the aortic root than in the coronary sinus but concentrations of angiotensin I and angiotensin-(1-7) were similar. In untreated animals, coronary occlusion produced significant increases in renin activity and arterial and venous levels of angiotensin I and angiotensin II. Inhibition of converting enzyme with benazeprilat (CGS-14,831) increased baseline circulating levels of angiotensin I, whereas angiotensin II and its carboxyl terminal fragments were reduced markedly. Baseline plasma levels of angiotensin-(1-7) and its fragments did not change. Myocardial ischemia in benazeprilat-treated dogs increased plasma renin activity and circulating levels of angiotensin I. Concentrations of angiotensin II and angiotensin-(1-7) did not change either in peripheral blood or across the coronary circulation. These results indicate that angiotensin peptides can be formed endogenously by enzymatic pathways alternate to converting enzyme. Furthermore, these data provide the basis for a further understanding of the role of the renin-angiotensin system after myocardial ischemia.

Effect of Na+/H+ exchange inhibitors on agonist-induced contraction of rat aorta.

A number of vasoconstrictor agonists activate the Na+/H+ antiport system in vascular smooth muscle, leading to alkalinization of the cytosol and influx of Na+. It is believed that agonist-induced Na+/H+ exchange may play an important role in contraction. We have evaluated this hypothesis by determining the effect of inhibition of Na+/H+ exchange on phenylephrine (PE)-induced contraction of rat aorta. Preincubation of rat aorta with the Na+/H+ exchange inhibitor amiloride (0.5 mM) inhibited subsequent PE-induced contraction. However, the more potent and specific Na+/H+ exchange inhibitor hexamethylene amiloride (10 microM) did not inhibit PE-induced contraction. Inhibition of Na+/H+ exchange by removal of extracellular Na+ and substitution with N-methyl-D-glucamine only moderately reduced PE-induced contraction. Hexamethylene amiloride (10 microM) and methyl-isobutyl amiloride (30 microM), another potent and specific inhibitor of Na+/H+ exchange, caused a slow, sustained and reversible contraction of rat aorta which was 114.7 and 86.6%, respectively, of maximal PE-induced contraction. Hexamethylene amiloride-induced contraction was dose-dependent, dependent on extracellular calcium and inhibited by nifedipine. We conclude that the vasorelaxant effects of amiloride are unrelated to inhibition of Na+/H+ exchange, and may be mediated by inhibition of kinases involved in contraction. These results demonstrate that inhibition of Na+/H+ exchange has no major effect on agonist-induced contraction of rat aorta, and suggest that vasoconstrictor activation of Na+/H+ exchange does not play a major role in agonist-induced contraction of rat aorta.

A simple technique for producing supravalvular aortic stenosis in animals.

A safe and reproducible technique to create supravalvular aortic stenosis was developed, which avoids many of the difficulties encountered in the production of aortic stenosis. Dogs were anaesthetised and artificially ventilated. The chest was opened and the venae cavae were encircled with umbilical tapes. The ascending aorta was then encircled by a 1.5-2 cm wide, 6-7 cm long dacron patch, venous return was stopped by tightening the tapes, and a J-shaped clamp applied to the ascending aorta at the dacron patch. Two layers of continuous mattress suture were placed adjacent to the clamp, plicating the aortic diameter by about 50%. After releasing the clamp and restoring normal venous return, left ventricular (LV) and aortic (AO) pressures were measured. Subsequently, one or two deep mattress sutures were placed below the running mattress sutures to increase the stenosis and to obtain the desired gradient. The LV-AO systolic pressure gradients obtained immediately after the operation ranged from 40 to 75 mm Hg. Two to 6 months after the operation the pressure gradients ranged from 50 to 200 mm Hg. Left ventricular to body weight ratios were 6.41 (SEM 0.26) v 4.24(0.20) for the controls. Heart weight to body weight ratios were 8.37(0.35) v 5.65(0.33). LV end diastolic pressures were normal. This technique can be used either in puppies or adult animals. The problem of aortic rupture is eliminated. The pressure gradient can be easily controlled during the operation and reproducible LV hypertrophy can be obtained in a shorter time than with aortic banding of puppies.

Energy production, O2 consumption, and blood flow reserve in experimental aortic valve disease.

Left ventricular energy production and its relation to myocardial O2 consumption and blood flow reserve were studied in 11 dogs with surgically produced valvular aortic stenosis (AS, 6 of 11) or combined stenosis and insufficiency (AS + AI, 5 of 11), and 7 dogs undergoing sham operation (S). Two months after operation the combined AS + AI group had the highest left ventricular mass (S, 4.85 +/- 0.53; AS, 6.38 +/- 0.90; AS + AI, 7.23 +/- 0.39 g/kg), left ventricular end-diastolic pressure (S, 2.1 +/- 1.6; AS, 6.3 +/- 1.7; AS + AI, 8.6 +/- 3.1 mmHg), left ventricular end-diastolic volume (S, 61.1 +/- 8.5; AS, 73.0 +/- 7.8; AS + AI, 95.8 +/- 20.9 ml), and stroke work. At rest, total left ventricular myocardial blood flow was increased in AS and AS + AI compared with sham (S, 89 +/- 8; AS, 135 +/- 19; AS + AI, 164 +/- 9 ml/min, P less than 0.05); and coronary resistance was lower in both AS and AS + AI groups. Peak-to-resting flow ratio determined by adenosine vasodilation was reduced in AS and AS + AI despite normal resting function (peak-to-resting flow ratio: S, 6.78 +/- 2.24; AS, 3.19 +/- 0.58, AS + AI, 3.99 +/- 0.84, P less than 0.02). Peak-to-resting flow ratio was inversely proportional to left ventricular mass. In turn the degree of hypertrophy correlated with the total power requirement of the left ventricle, regardless of the type of overload lesion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of thromboxane analog U46619 on endothelial damaged canine coronary arteries in vivo.

We studied the effects of the thromboxane analog, U46619, infused into the left anterior descending (LAD) artery of intact dogs before and after producing endothelial denudation of the mid portion of the LAD. Proximal artery cross-sectional area (CSA) decreased by 47% with 0.1 microgram/min infusion of U46619 with intact and denuded endothelium, while resting CSA reduced spontaneously following denudation. Coronary resistance vessels demonstrated a marked constrictor response to U46619 with a rise in resistance and a fall in flow and myocardial O2 consumption. U46619 produces significant narrowing of proximal epicardial coronary arteries as well as resistance coronary vessels. This effect could cause ischemia in patients with moderate coronary atherosclerosis.

Substance P distribution and effects in the canine epicardial coronary arteries.

Substance P (SP), a vasoactive neuropeptide detected in animal and human hearts has been reported to increase coronary blood flow in animals. However, no data are available on SP effects on epicardial coronary arteries, the site of coronary disease. To determine the amount and distribution of SP and its action in the large coronary vessels, we studied two groups of dogs. One group was anesthetized for collecting three 1 cm segments of the circumflex coronary artery (CX) and left anterior descending artery (LAD) through a left thoracotomy. These segments represented proximal (I), middle (II), and distal (III) portions of the two arteries. Concentrations (ng/g) of SP-like immunoreactivity (SP-LI) were determined by radioimmunoassay. SP-LI was present in LAD (I: 1.17 +/- 0.20, II: 1.08 +/- 0.36, III: 1.14 +/- 0.25) and CX (I: 1.44 +/- 0.38, II: 1.51 +/- 0.47, III: 0.70 +/- 0.20). SP differences among segments of LAD and segments I and II of CX were not significant, but there was a significant difference between segment III of CX and the others. In the second group of closed chest anesthetized dogs, we examined the effects of intracoronary SP infusion before and during administration of serotonin (5HT). LAD and CX artery responses (% area change) to SP and to SP plus 5HT were examined using quantitative coronary angiography. Intracoronary 133Xe in saline provided coronary flow data. SP infusion produced significant vasodilation in segment II (15% area increase) and III (17%) during the highest dose (1 microgram/min). The three SP doses infused with 5HT (0.05 mg/min) did not produce vasodilation, although LAD segment III constriction from 5HT was abolished during the highest dose of SP infusion. The presence of SP, and its dilatory effect on the coronary arteries, suggests a role in maintaining vasodilator tone in the coronary arteries.