Effect of pediatric surgical practice on the treatment of children with appendicitis.

OBJECTIVE: Acute appendicitis in children is managed by both general surgeons (GSs) and pediatric surgeons (PSs). Our objective was to investigate the economics of surgical care provided by either GSs or PSs for appendicitis. METHODS: The outcome of children within our state who underwent operative treatment for appendicitis (January 1994 to June 1997) by board-certified GSs were compared with the results of PSs. Data were sorted according to patient age and diagnosis according to the International Classification of Diseases, Ninth Revision. Analysis of variance was performed on continuous data, and chi(2) analysis was performed on nominal data; data are depicted as mean +/- standard error of the mean. RESULTS: GSs (n = 2178) managed older children when compared with PSs (n = 1018; 11.0 +/- 0.1 vs 9.1 +/- 0.1 years) and less frequently treated perforated appendicitis (18.8% vs 31.9%). Independent of diagnosis (simple or perforated appendicitis), younger children (0-4 years, 5-8 years, and 9-12 years) who were treated by PSs had a significantly shorter hospital stay and/or decreased hospital charge when compared with those who were treated by GSs. However, older children (13-15 years) seemed to have comparable outcomes. CONCLUSIONS: Younger children with appendicitis have reduced hospital days and charges when they are treated by PSs.

Prenatal diagnosis of esophageal atresia using sonography and magnetic resonance imaging.

BACKGROUND: The diagnosis of esophageal atresia may be suspected on prenatal ultrasound scan in fetuses with a small or absent stomach or unexplained polyhydramnios. However, these findings are thought to have a low positive predictive value and clinical decisions affecting timing or site of delivery may be made erroneously. The authors evaluated the accuracy of fetal sonography followed by magnetic resonance imaging (MRI) for the diagnosis of this lesion. METHODS: Fetuses considered to be at risk for esophageal atresia based on detailed obstetric sonography underwent fetal MRI using a single-shot rapid-acquisition technique, and the T(2)-weighted images were evaluated prospectively. Scans were considered to be positive if the proximal esophagus was dilated, and the distal esophagus was not seen and negative if the esophagus was visualized throughout its length. RESULTS: Ten fetuses underwent MRI scanning. All had a small or absent stomach bubble with unexplained polyhydramnios. Four scans were considered to be negative for esophageal atresia; all 4 were found to have a normal esophagus after delivery. Six scans were considered to be positive; 5 had esophageal atresia (2 with tracheoesophageal fistula and 3 without), and one had a neurologic syndrome with a normal esophagus. CONCLUSIONS: Magnetic resonance imaging appears to be accurate for establishing or ruling out a prenatal diagnosis of esophageal atresia, and should be considered in fetuses who are at high risk based on ultrasound findings.

A prospective study of botulinum toxin for internal anal sphincter hypertonicity in children with Hirschsprung's disease.

BACKGROUND: Internal anal sphincter hypertonicity with nonrelaxation can cause persistent constipation and obstructive symptoms in children after surgery for Hirschsprung's disease. Intractable symptoms traditionally have been treated with anal myectomy, which may be ineffective or complicated by long-term incontinence. The authors evaluated prospectively the use of intrasphincteric botulinum toxin for these patients. METHODS: Eighteen children were studied (age 1 to 13; median, 4 years). Botulinum toxin was injected (total dose 15 to 60 U) into 4 quadrants of the sphincter. Resting sphincter pressure was measured in 14 patients before and after injection. Ten have had 1 to 5 additional injections (total dose, 30 to 60 U per injection). RESULTS: Four patients had no improvement in bowel function, 2 had improvement for less than 1 month, 7 had improvement for 1 to 6 months, and 5 had improvement more than 6 months. Nine of those with symptomatic improvement longer than 1 month had pressures measured, with a documented decrease in 8. Five with no significant clinical improvement had pressure measurements, with a decrease in 3. There were no adverse effects associated with botulinum toxin injection. Four children had new encopresis postinjection, which was mild and resolved in each case. CONCLUSIONS: Intrasphincteric botulinum toxin is a safe and less-invasive alternative to myectomy for symptomatic internal sphincter hypertonicity. Persistent symptoms, despite a fall in sphincter pressure, suggest a nonsphincteric etiology. Repeat injections often are necessary for recurrent symptoms.

Pediatric surgery on the Internet: is the truth out there?

BACKGROUND: The enormous amount of unmonitored medical information on the Internet prompted this investigation into the quality of pediatric surgery information on the Internet. METHODS: The Internet was searched for information on diaphragmatic hernia (CDH), abdominal wall defects (AWD), pediatric inguinal hernia (IH), and pectus excavatum (PE). Websites were characterized, classified, and evaluated for completeness, accuracy and bias toward or against the medical profession. RESULTS: A total of 141 websites were evaluated (N(CDH) = 37, N(AWD) = 49, N(IH) = 26, N(PE) = 29). A total of 59.6% targeted medical professionals, and 46.8% targeted the lay population. A total of 58.2% described symptoms and diagnosis. Etiology, pathology, surgery, postoperative course, and prognosis each were addressed by under 40%. A total of 58.2% were accountable for the information presented. A total of 93.1% were incomplete, 75.7% contained accurate information, and 97.7% were positive or neutral toward medical treatment. Among diagnoses, CDH had the highest percentage of websites owned by academic institutions. PE had the highest percentage of websites owned by lay people. PE websites also were the least accurate. CONCLUSIONS: Internet information on pediatric surgery varies significantly in quality. Lay people own most websites targeted at the lay audience, and the information may not reflect the opinions of most pediatric surgeons. Increasing use of the Internet by parents seeking medical information warrants an organized approach to ensure complete and accurate information online.

One-stage Soave pull-through for Hirschsprung's disease: a comparison of the transanal and open approaches.

PURPOSE: The authors reviewed their experience using the transanal Soave technique, to determine (1) if it offers any advantages over the standard open approach and (2) whether routine laparoscopic visualization is necessary. METHODS: The case reports of 37 consecutive children less than 3 years old undergoing Soave pull-through were reviewed. Patients were excluded from analysis if they had total colon disease or had a previous colostomy. The patients were divided into 3 groups: open Soave (OS, n = 13), transanal Soave with routine laparoscopic visualization (LVS, n = 9), and transanal Soave with selective laparoscopy or minilaparotomy (TAS, n = 15). Cost was calculated based on hospital stay, operating room time, and use of laparoscopic equipment. RESULTS: In the TAS group, suspicion of a longer segment led to the selective use of laparoscopy with or without biopsy in 2 children, and the use of a small umbilical incision for mobilization of the splenic flexure in 2. There were no differences among groups with respect to age, weight, gender, transition zone, operating time, blood loss, intraoperative complications, enterocolitis, or stricture or cuff narrowing. Hospital stay was significantly longer in the OS group (median, 7 days; range, 3 to 47) than the LVS (median, 1; range 1 to 6) or TAS (median, 1, range, 1 to 3) groups. Cost (in thousands of dollars) was also higher in the OS group (median, 6.9; range, 3.9-25.7) than the LVS (median, 3.9; range, 3.6 to 6.4) or TAS (median, 3.4; range, 2.2 to 9.4) groups. Repeat surgery was necessary for 4 OS patients: 2 adhesive small bowel obstructions (1 of whom died), 1 twisted pull-through, and 1 recurrent aganglionosis. Three TAS patients required repeat surgery: 1 twisted pull-through, 1 anastomotic leak, and 1 cuff narrowing. CONCLUSIONS: These data suggest that the transanal pull-through is associated with a significantly shorter hospital stay and lower cost than the open approach, without an increased risk of complications. Because there is no intraabdominal dissection, there probably is a lower incidence of adhesive bowel obstruction. Routine laparoscopic visualization or minilaparotomy is not necessary but should be used in children who are at higher risk for long segment disease.

Routine insertion of a silastic spring-loaded silo for infants with gastroschisis.

BACKGROUND/PURPOSE: Gastroschisis traditionally is managed by emergency operating room closure (EC), with a silo reserved for cases that cannot be closed primarily. The authors recently began using routine insertion of a SILASTIC (Dow Corning, Midland, MI) spring-loaded silo (SLS), followed by elective closure. METHODS: A total of 43 consecutive neonates with gastroschisis were treated between 1993 and 1998. RESULTS: Thirty patients underwent EC, and 13 underwent closure after insertion of a SLS (10 at bedside, 3 in the operating room). Eight infants treated by EC required staged repair. There were no differences with respect to gestational age, birth weight, gender, Apgar score, maternal age, or mode of delivery. Median length of stay was 32 days for EC and 25 days for SLS (P = .05). The SLS group required fewer days on a ventilator (4 v 6 days, P = .03) and had lower intraoperative (28 v 21, P = .02) and early postoperative peak airway pressures. The time to tolerate full feedings was 21 days for SLS and 27 days for EC (P = .07). The SLS group had fewer complications and a lower median hospital charge ($71,498 v $85,147; P = .05). CONCLUSION: SLS followed by elective repair permits gentle, gradual reduction of the viscera. When compared with EC, SLS is associated with significantly lower airway pressures, earlier extubation, fewer complications, and decreased length of stay and hospital charges.

Laparoscopic versus open splenectomy in children.

BACKGROUND: The authors have reviewed their initial experience with laparoscopic splenectomy (LS) to identify the indications, success rate, and complications associated with this procedure compared with a series of children undergoing open splenectomy (OS) during the same time period. METHODS: The records of 51 children who underwent splenectomy from 1993 through 1998 were reviewed retrospectively. RESULTS: Thirty-five patients aged 1 to 17 years (mean, 9.4 years) underwent LS for the following indications: ITP (n = 20), sickle cell disease or thalassemia (n = 6), hereditary spherocytosis (n = 5), other hematologic disorders (n = 4). Seventeen patients aged 2 to 17 years (mean, 11.8 years) underwent OS during the same time period for ITP (n = 4), sickle cell disease or thalassemia (n = 4), hereditary spherocytosis (n = 5), and other indications (n = 4). Concomitant cholecystectomy was performed in 4 of 35 LS and 4 of 17 OS. Accessory spleens were identified in 10 of 35 LS and 2 of 17 OS cases. Eleven spleens were enlarged in the LS group, and 8 were enlarged in the OS group. One LS required conversion to an open procedure because the spleen did not fit in the bag. No other cases were converted. Median estimated blood loss was 50 mL for both the LS and OS groups. The only intraoperative complication in the LS group was a splenic capsular tear, which had no effect on the successful laparoscopic removal of the spleen. No patient in either group required a blood transfusion. The LS patients had a shorter length of hospital stay (1.8 +/- 1 versus 4.0 +/- 1 day, P = .0001). Total hospital charges were not significantly different. Follow-up ranged from 6 to 40 months. One LS patient died 47 days postoperatively from unrelated causes. Two LS patients had recurrent ITP; accessory spleens were found in one and resected laparoscopically. CONCLUSION: LS in children can be performed safely with a low conversion rate (2.9%) and is associated with a shorter hospital stay and comparable total hospital cost when compared with OS.

Intestinal obstruction after lung transplantation in children with cystic fibrosis.

BACKGROUND/PURPOSE: Distal intestinal obstruction syndrome (DIOS) occurs in 15% of patients with cystic fibrosis (CF). The authors reviewed their experience to determine the incidence, risk factors, and natural history of adhesive intestinal obstruction and DIOS after lung transplantation. METHODS: Eighty-three bilateral transplants were performed in 70 CF patients between January 1990 and September 1998. All were on pancreatic enzymes preoperatively, and none had preoperative bowel preparation. Fifty-six patients (80%) had prior gastrostomy (n = 54) or jejunostomy (n = 2). Eighteen patients (25.7%) had a previous laparotomy for meconium ileus (n = 8), fundoplication (n = 4), liver transplant (n = 1), jejunal atresia (n = 1), Janeway gastrostomy takedown (n = 1), pyloromyotomy (n = 1), free air (n = 1), or appendectomy (n = 1). RESULTS: After lung transplantation, 7 patients (10%) required laparotomy for bowel obstruction (6 during the same hospitalization, and 1 during a subsequent hospitalization). The causes of obstruction were adhesions only (n = 1), DIOS only (n = 2), and a combination of DIOS and adhesions (n = 4). Adhesiolysis was performed in the 5 patients with adhesions, and a small bowel resection was also performed in 1 patient. DIOS was treated by milking secretions distally without an enterotomy (n = 3) with an enterotomy and primary closure (n = 1) or with an end ileostomy and mucus fistula (n = 2). Five had recurrent DIOS early postoperatively. One resolved with intestinal lavage, 2 were treated successfully with hypaque disimpaction, and 2 underwent reoperation; 1 required an ileostomy. The most important risk factor for posttransplant obstruction was a previous major abdominal operation. Obstruction occurred in 7 of 18 (39%) who had undergone a prior laparotomy versus 0 of 52 who had not (P < .001, chi2). CONCLUSIONS: (1) The incidence of intestinal obstruction is high after lung transplantation in children with CF. (2) Previous laparotomy is a significant risk factor. (3) Recurrent obstruction after surgery for this condition is common. (4) Preventive measures such as pretransplant bowel preparation and early postoperative bowel lavage may be beneficial in these patients.

Transanal one-stage Soave procedure for infants with Hirschsprung's disease.

PURPOSE: Many centers perform a one-stage pull-through procedure for Hirschsprung's disease (HD) diagnosed in infancy. The authors have developed a one-stage pullthrough procedure using a transanal approach that eliminates the need for intraabdominal dissection. METHODS: Nine children aged 3 weeks to 18 months with biopsy-proven HD underwent a transanal pull-through procedure over a 13-month period. A rectal mucosectomy was performed starting 0.5 cm proximal to the dentate line, and extending proximally to the level of the intraperitoneal rectum. In the first eight children, intraperitoneal position was confirmed with a laparoscope placed through a 3- to 5-mm port in the base of the umbilicus. The muscular sleeve was divided circumferentially to allow full-thickness mobilization of the rectosigmoid junction. Manual transanal traction permitted direct visualization and division of mesenteric vessels with transanal mobilization above the transition zone. Ganglion cells were confirmed by frozen section, and the bowel was transected. The rectal muscular cuff was divided longitudinally, and the anastomosis was completed. The laparoscope confirmed orientation and adequate hemostasis. In a ninth patient, the identical procedure was performed, but with the laparoscope used only for confirmation at the end of the procedure. RESULTS: Operative time, including frozen sections, averaged 194 minutes (range, 169 to 250 minutes), and the average length of bowel resected was 12 cm (range, 7.5 to 22 cm). Four of the nine patients were discharged on postoperative day (POD) 1, four on POD 2, and one patient with Down's syndrome was discharged on POD 6. Median follow-up was 6 months (range, 3 to 14 months). One death occurred 2.5 months postoperatively secondary to sudden infant death syndrome. Complications included postoperative apnea spells (n = 1), mild enterocolitis (n = 2), constipation (n = 1), anastomotic stricture(n = 1), and muscularcuff narrowing (n = 1); each responded to nonoperative management. Stool output has ranged from four to eight per day. CONCLUSION: A one-stage pull-through for HD can be performed successfully using a transanal approach without intraperitoneal dissection. This procedure is associated with excellent clinical results and permits early postoperative feeding, early hospital discharge, and no visible scars.

Role of K+ATP channels and EDRF in reactive hyperemia in the hindquarters vascular bed of cats.

The mechanism underlying reactive hyperemia was investigated in the feline hindquarters vascular bed under natural- and constant-flow conditions. A 30-s occlusion of the distal aorta produced a marked hyperemic increase in distal aortic blood flow that was attenuated by the ATP-sensitive K+ (K+ATP) channel blocking agent, glibenclamide. When blood flow to the hindquarters vascular bed was held constant with a pump, interruption of blood flow for 5- to 90-s periods produced reactive vasodilator responses that increased in magnitude and duration as the period of ischemia increased. The magnitude and duration of the reactive vasodilator responses were reduced by K+ATP channel antagonists and an inhibitor of nitric oxide synthase, whereas indomethacin had no significant effect. In the pulmonary vascular bed, under constant-flow, elevated tone conditions, a 30-s period of ischemia produced a small reactive vasodilator response and a larger secondary vasoconstrictor response. The present data suggest that reactive hyperemia in the hindquarters vascular bed is mediated by the opening of K+ATP channels and nitric oxide release and that the reactive hyperemic response is not pronounced in the pulmonary circulation.

Differential responses to angiotensin-(1-7) in the feline mesenteric and hindquarters vascular beds.

Regional vascular responses to angiotensin (Ang)-(1-7), a heptapeptide derivative of Ang II were investigated in the feline hindquarters and mesenteric vascular beds under conditions of controlled flow. In the mesenteric vascular bed, injections of Ang-(1-7) in doses of 1, 3 and 10 micrograms produced dose-dependent decreases in mesenteric perfusion pressure whereas at doses of 30 and 100 micrograms, increases were observed. In contrast, in the hindquarters circulation, low doses produced increases while high doses produced decreases in perfusion pressure. In both vascular beds the degree of vasoconstriction was weak, being less than 1% of that elicited by Ang II. The vasoconstrictor effect of Ang-(1-7) in both the mesenteric and hindquarters vascular bed was blocked by DuP 753 (1 mg/kg i.v.), an Ang receptor subtype 1 (AT1) antagonist. The vasodilator responses in both vascular beds were partially blocked by the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (100 mg/kg i.v.) but were unaffected by the cyclooxygenase inhibitor, meclofenamate (2.5 mg/kg i.v.). The present results show that in the peripheral vascular bed of the cat, Ang-(1-7) causes vasodilation or modest vasoconstriction, depending on the dose and the regional vascular bed studied. The present data also suggest that the vasodilator effect of the peptide may be mediated in part by the release of endothelium-derived relaxing factor and the vasoconstrictor effect by activation of the AT1 receptor subtype.

Analysis of the inhibitory effects of DuP 753 and EXP 3174 on responses to angiotensin II in the feline hindquarters vascular bed.

The effects of DuP 753 and EXP 3174, nonpeptide angiotensin II type 1 antagonists, on responses to angiotensin II were investigated in the hindquarters vascular bed of the cat. Under constant flow conditions, injections of angiotensin II into the hindquarters perfusion circuit elicited dose-dependent increases in perfusion pressure. Responses to the peptide were stable with respect to time, did not exhibit tachyphylaxis, and 2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)biph eny l-4-yl]methyl]methyl]imidazole (DuP 753) in doses of 1 and 2.5 mg/kg decreased vasoconstrictor responses to angiotensin II in a competitive manner, with a longer duration of action at the higher dose. DuP 753 had no significant effect on vasoconstrictor responses to vasopressin, norepinephrine, neuropeptide Y or 11 alpha,6 alpha-epoxymethano-9 alpha,11 alpha-dideoxy-prostaglandin F2 alpha, on biphasic responses to endothelin-1, or on vasodilator responses to acetylcholine. 2-n-Butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]im idazole-5-carboxylic acid (EXP 3174) also decreased responses to angiotensin II without altering responses to norepinephrine, vasopressin, U46619 or endothelin-1. The inhibitory effect of EXP 3174 was surmountable; however, large doses of angiotensin II were required, and the blockade was long in duration. The effects of DuP 753 and EXP 3174 on responses to angiotensin II and angiotensin III were similar, and when EXP 3174 was administered in doses of 0.1 and 0.05 mg/kg i.v., the blockade was overcome and the dose-response curves for angiotensin II were shifted to the right in a parallel manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Penile erections induced by vasoactive intestinal peptide and sodium nitroprusside.

The use of vasoactive intestinal peptide (VIP), sodium nitroprusside (SNP), and the reference combination of papaverine, prostaglandin E1, and phentolamine was studied in 22 adult cats. The maximal erectile response (intracavernous pressure, penile length, and rigidity) was produced by intracavernous injection of a combination of 1.65 mg papaverine, 0.5 micrograms PGE1, and 25 micrograms phentolamine. This combination was considered as "control" in order to compare the effect of other agents. VIP and SNP increased the intracavernous pressure and caused erection in a dose-dependent manner with a maximal response obtained with 5 micrograms VIP or 10 micrograms SNP. The duration of peak erection and the total duration of drug effect were significantly shorter with VIP and SNP than with the reference combination (P < 0.01). Epinephrine (30 micrograms) reversed the effects of SNP and significantly shortened the duration of peak action and total effect (P < 0.05). This study supports the use of an in vivo feline model for the evaluation of vasoactive agents and demonstrates that the intracavernous injection of either VIP or SNP can induce penile erection in the adult cat.

Analysis of systemic and pulmonary vascular responses to PACAP and VIP: role of adrenal catecholamines.

Systemic and pulmonary vascular responses to pituitary adenylate cyclase-activating polypeptide (PACAP), a novel peptide with 68% sequence homology to vasoactive intestinal peptide (VIP), were investigated in the anesthetized cat. Intravenous injections of PACAP in doses of 0.1-3.0 nmol/kg produced decreases in arterial pressure (AP) at low doses and biphasic changes (decreases followed by increases) at higher doses, which were accompanied by increases in central venous pressure (CVP) and cardiac output (CO), and decreases and biphasic changes in systemic vascular resistance (SVR). In contrast, VIP in doses of 0.1-3.0 nmol/kg produced only dose-dependent decreases in AP and SVR and produced little change in CVP and CO. PACAP produced increased pulmonary arterial pressure (PAP), left atrial pressure (LAP), and increases in pulmonary vascular resistance (PVR). PACAP increased heart rate (HR) and right ventricular contractile force (RVCF), while VIP had no effect. Increases in AP and SVR in response to PACAP were changed to decreases following the administration of phentolamine or after adrenalectomy. Under constant flow conditions, PACAP and VIP produced dose-dependent decreases in lobar arterial pressure when tone was elevated, with PACAP being threefold more potent than VIP. Meclofenamate and nitro-L-arginine methyl ester (L-NAME) had no effect on pulmonary responses to the peptides. PACAP produced dose-dependent biphasic changes in hindquarters perfusion pressure, whereas VIP produced only decreases that were unchanged by indomethacin, L-NAME, and glibenclamide. Phentolamine and adrenalectomy eliminated the hindquarters pressor response to PACAP and D-Phe2-VIP, a VIP antagonist, reduced responses to VIP but not to PACAP. These data suggest that responses to PACAP and VIP are mediated by distinct receptors and that pressor responses to PACAP are due to the release of catecholamines from the adrenal gland.

Inhibitory effects of DuP 753 and EXP3174 on responses to angiotensin II in pulmonary vascular bed of the cat.

The effects of the non-peptide antagonist DuP 753 and its metabolite EXP3174 on responses to angiotensin II were investigated in the pulmonary vascular bed of the intact-chest cat. Under conditions of controlled blood flow and constant left atrial pressure, injections of angiotensin II into the perfused lobar artery caused dose-related increases in lobar arterial pressure. Responses to angiotensin II were reproducible and were not changed by meclofenamate or prazosin, indicating that prostaglandin or norepinephrine release does not mediate or modulate pulmonary vascular responses to the peptide. DuP 753 (1-5 mg/kg iv) decreased responses to angiotensin II in a competitive manner, and the duration of the blockade was related to dose of the antagonist. DuP 753 had no significant effect on responses to U-46619, norepinephrine, serotonin, endothelin-1, vasopressin, or BAY K 8644. EXP3174 also decreased responses to angiotensin II without altering responses to agents that act by a variety of mechanisms. The inhibitory effect of EXP3174 (1 mg/kg iv) was not overcome by angiotensin II in the range of doses studied, and the shift to the right of the dose-response curve was nonparallel, suggesting that the blockade was noncompetitive. The blockade was long in duration, and, when the dose of EXP3174 was decreased to 0.1 mg/kg iv, the blockade was surmounted and the shift to the right of the dose-response relationship was parallel. DuP 753 and EXP3174 had little effect on mean baseline pressures in the cat.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative effects of endothelin (ET-1) and U46619 on human saphenous vein and gastroepiploic artery, sources of human autologous grafts.

The effects of endothelin (ET-1) on smooth muscle contractile activity were investigated and compared in human saphenous vein and gastroepiploic artery, vessels frequently used in revascularization procedures. ET-1 contracted saphenous vein and gastroepiploic artery in a concentration-dependent manner. The peptide produced a greater maximal effect in the vein than in the artery and, in both preparations, ET-1 was less efficacious than U46619, an agent which mimics the actions of thromboxane A2 at the thromboxane A2/prostaglandin H2 receptor. The contractile response to ET-1 declined spontaneously at a more rapid rate in the artery than in the vein. The present data indicate that ET-1 has significant contractile activity in both vessels which are used for coronary arterial bypass surgery and suggest that although, a weaker vasoconstrictor than U46619, the peptide could induce vasospasm in both graft vessels.

Analysis of responses to big endothelin in the hindquarters vascular bed of the cat.

OBJECTIVE: To investigate vascular responses to the endothelin-1 (ET-1) precursor, human big endothelin 1-38 (big ET), in the peripheral vascular bed of the cat. DESIGN: These studies were designed to investigate the hypothesis that bit ET is converted to an active peptide with properties similar to ET-1. SETTING: Hindquarters vascular bed of the cat under conditions of controlled bloodflow; changes in perfusion pressure reflect changes in vascular resistance. ANIMALS: Fifty-four adult mongrel cats. INTERVENTIONS: Big ET, ET-1, the peptidases chymotrypsin, pepsin and cathepsin-D, and the metalloprotease inhibitor phosphoramidon. MAIN RESULTS: Intra-arterial injections of big ET induced a slow-developing and sustained increase in hindquarters perfusion pressure which could be blocked by phosphoramidon. ET-1 (0.3 nmol), administered as a slow infusion over a 10-min period, produced a slowly developing increase in hindquarters perfusion pressure in a manner similar to that observed in response to injection of big ET. A bolus injection of ET-1 produced a biphasic response characterized by a transient decrease in pressure followed by an increase which was significantly greater in magnitude and more rapid in onset than the pressor response to big ET (0.3 nmol). After incubation of big ET with chymotrypsin, pepsin and cathepsin-D (each 5% weight/weight) for 30 mins at 37 degrees C, injection of activated big ET produced a biphasic response characteristic of the response to ET-1 with an initial transient decrease in pressure followed by a secondary increase in hindquarters perfusion pressure. CONCLUSIONS: Big ET produces a phosphoramidon-sensitive pressor response which is similar to that produced by an infusion of ET-1. These data suggest that chymotrypsin, pepsin and cathepsin-D can convert big ET to an active peptide which elicits a biphasic response similar to that produced by ET-1.

Analysis of pulmonary and systemic vascular responses to platelet-activating factor in the cat.

Pulmonary and systemic vascular responses to platelet-activating factor (PAF) were investigated in the anesthetized cat. Intravenous injections of PAF decreased arterial pressure, increased pulmonary arterial pressure, and caused small but significant decreases in right and left atrial pressures. A transient increase in cardiac output was followed by a secondary decrease, and heart rate was increased. Pulmonary vascular resistance (PVR) was increased, systemic vascular resistance (SVR) was reduced, and changes in PVR and SVR in response to PAF were blocked by the novel PAF receptor antagonist, BN 50730. Under constant-flow conditions PAF dilated the hindlimb vascular bed in a dose-related manner, whereas in the pulmonary lobar vascular bed, PAF caused dose-related increases in perfusion pressure. Hindlimb and lobar vascular responses to PAF were blocked by BN 50730 in a selective manner, whereas cyclooxygenase inhibitors had no effect on responses to the phospholipid mediator. Hindlimb vasodilator responses to PAF were reduced by N omega-nitro-L-arginine in a dose that blocked the response to acetylcholine but did not decrease responses to prostaglandin E1 or nitroprusside. Increases in lobar arterial pressure in response to PAF were not altered by treatment with a thromboxane receptor antagonist, when the lung was perfused with a low-molecular-weight dextran solution, or when ventilation to the lobe was interrupted. These data suggest that the release of cyclooxygenase products, activation of thromboxane A2 receptors, cellular aggregation, release of leukocyte or platelet mediators, or changes in bronchomotor tone do not contribute to the pulmonary vasoconstrictor response to PAF and that the hindlimb vasodilator response to the phospholipid mediator is dependent in part on the release of endothelium-derived relaxing factor.

Differential effects of PACAP and VIP on the pulmonary and hindquarters vascular beds of the cat.

Responses to pituitary adenylate cyclase-activating polypeptide (PACAP), a novel peptide derived from ovine hypothalamus with 68% sequence homology with vasoactive intestinal polypeptide (VIP), were investigated in the pulmonary and hindquarters vascular beds of the anesthetized cat under conditions of controlled blood flow. Injection of the peptide into the perfused lung lobe under elevated tone conditions produced dose-dependent decreases in lobar arterial pressure that were accompanied by biphasic changes in systemic arterial pressure characterized by an initial decrease followed by a secondary increase in pressure. When compared with other vasodilator agents in the pulmonary vascular bed, the relative order of potency was isoproterenol greater than PACAP greater than acetylcholine greater than calcitonin gene-related peptide greater than VIP. In the hindquarters vascular bed, intra-arterial injections of PACAP produced biphasic changes in hindquarters perfusion pressure characterized by initial decreases followed by secondary increases, which were accompanied by biphasic changes in systemic arterial pressure. In terms of relative vasodilator activity in the hindlimb, the order of relative potency was isoproterenol greater than acetylcholine greater than calcitonin gene-related peptide greater than VIP greater than PACAP. PACAP was the only agent that caused a secondary vasoconstrictor response in the hindlimb and produced biphasic changes in systemic arterial pressure. D-Phe2-VIP, a VIP receptor antagonist, blocked the hindquarters vasodilation in response to VIP but had no effect on responses to PACAP. The present investigation shows that PACAP produces pulmonary vasodilation, as well as dilation, and vasoconstriction in the systemic (hindlimb) vascular bed.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of responses to sarafotoxins 6a and 6c in pulmonary and systemic vascular beds.

Cardiovascular and pulmonary responses to sarafotoxin (S) 6a and S6c were investigated in the anesthetized cat. Intravenous injections of the peptides in doses of 0.1-1.0 nmol/kg caused decreases or biphasic changes in arterial pressure (AP) and increases in central venous pressure, pulmonary arterial pressure (PAP), and cardiac output (CO). Secondary decreases in CO were observed in response to higher doses, and biphasic changes in systemic (SVR) and pulmonary (PVR) vascular resistances were observed. Under constant-flow conditions, the peptides only increased pulmonary lobar arterial perfusion pressure and lobar vascular resistance. AP responses to S6a, S6c, endothelin (ET)-1, ET-2, vasoactive intestinal contractor (VIC), and Lys7-ET-1 were similar, whereas AP responses to S6b and ET-3 were similar. S6a, S6b, S6c, ET-1, ET-2, ET-3, VIC, Lys7-ET-1, and big ET-1 increased PAP. S6a and S6c increased distal aortic and superior mesenteric arterial (SMA) blood flow and caused biphasic changes at the highest doses. Under constant-flow conditions, S6a and S6c produced dose-dependent biphasic changes in hindquarters perfusion pressure. Changes in SVR and PVR in response to the peptide were not affected by hexamethonium, glyburide, or meclofenamate, indicating that responses are independent of autonomic reflexes, activation of ATP-regulated K+ channels, or release of cyclooxygenase products. In contrast, N-nitro-L-arginine methyl ester decreased hindquarters vasodilator response to S6a and S6c. The present data show that S6a and S6c produce both vasodilation and vasoconstriction in the systemic vascular bed and increase lobar vascular resistance and that hindquarters vasodilator responses are mediated, in part, by the release of endothelium-derived relaxing factor.