Antifibrinolytic activity of apolipoprotein(a) in vivo: human apolipoprotein(a) transgenic mice are resistant to tissue plasminogen activator-mediated thrombolysis.

The extensive homology between apolipoprotein(a) and plasminogen has led to the hypothesis that the increased risk for atherosclerosis, cardiac disease and stroke associated with elevated levels of apolipoprotein(a) may reflect modulation of fibrinolysis. We have investigated the role of apolipoprotein(a) on clot lysis in transgenic mice expressing the human apolipoprotein(a) gene. These mice develop fatty streak lesions resembling early lesions of human atherosclerosis. Pulmonary emboli were generated in mice by injection, through the right jugular vein, of a human platelet-rich plasma clot radiolabelled with technetium-99m-labelled antifibrin antibodies. Tissue plasminogen activator was introduced continuously via the right jugular vein. Clot lysis, determined by ex vivo imaging, was depressed in mice carrying the apolipoprotein(a) transgene relative to their sex-matched normal littermates. These results directly demonstrate an in vivo effect of apolipoprotein(a) on fibrinolysis, an effect that may contribute to the pathology associated with elevated levels of this protein.

Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice.

The atheroprotective effects of estrogen in women are well recognized, but the underlying mechanisms responsible are not well understood. Blood vessel cells express the classic estrogen receptor, ER alpha (ref. 2-6), and are directly affected by estrogen, which inhibits the development of atherosclerotic and injury-induced vascular lesions. We have generated mice in which the ER alpha gene is disrupted and have used a mouse model of carotid arterial injury to compare the effects of estrogen on wild-type and estrogen receptor-deficient mice. Increases in vascular medial area and smooth muscle cell proliferation were quantified following vascular injury in ovariectomized mice treated with vehicle or with physiologic levels of 17 beta-estradiol. Surprisingly, in both wild-type and estrogen receptor-deficient mice, 17 beta-estradiol markedly inhibited to the same degree all measures of vascular injury. These data demonstrate that estrogen inhibits vascular by a novel mechanism that is independent of the classic estrogen receptor, ER alpha.

Electrophysiological abnormalities and arrhythmias in alpha MHC mutant familial hypertrophic cardiomyopathy mice.

A new mouse cardiac electrophysiology method was used to study mice harboring an alpha-myosin heavy chain Arg403Gln missense mutation (alpha-MHC403/+), which results in histological and hemodynamic abnormalities characteristic of familial hypertrophic cardiomyopathy (FHC) and sudden death of uncertain etiology during exercise. Wild-type animals had completely normal cardiac electrophysiology. In contrast, FHC mice demonstrated (a) electrocardiographic abnormalities including prolonged repolarization intervals and rightward axis; (b) electrophysiological abnormalities including heterogeneous ventricular conduction properties and prolonged sinus node recovery time; and (c) inducible ventricular ectopy. These data identify distinct electrophysiologic abnormalities in FHC mice with a specific alpha-myosin mutation, and also validate a novel method to explore in vivo the relationship between specific genotypes and their electrophysiologic phenotypes.

Estrogen inhibits the response-to-injury in a mouse carotid artery model.

The atheroprotective effects of estrogen are well documented, but the mechanisms responsible for these effects are not well understood. To study the role of physiologic (nanomolar) estrogen levels on the arterial response-to-injury, we applied a mouse carotid artery injury model to ovariectomized C57BL/6J mice. Mice were treated with vehicle (-E2, n = 10) or 17 beta-estradiol (+E2, n = 10) for 7 d, subjected to unilateral carotid injury, and 14 d later contralateral (normal = NL) and injured carotids from -E2 and +E2 animals were pressure fixed, harvested, and analyzed by quantitative morphometry. E2 levels in +E2 mice were consistently in the nanomolar range (2.1-2.5 nM) at days 0, 7, and 14. At 14 d, measures of both intimal and medial area were markedly increased in the -E2 group: (-E2 vs NL, P < 0.05 for both), but were unchanged from normal levels in the +E2 group (+E2 vs NL, P = NS and +E2 vs -E2, P < 0.05 for both). Cellular proliferation, as assessed by bromodeoxyuridine (BrdU) labeling, was significantly increased over NL in the -E2 mice, but this increase was markedly attenuated in the estrogen replacement group (total BrdU positive cells/section: NL = 6.4 +/- 4.5; -E2 = 113 +/- 26, +E2 = 40 +/- 3.7; -E2 vs NL, P < 0.05; +E2 vs NL, P = NS; -E2 vs +E2, P < 0.05). These data (a) demonstrate significant suppression of the mouse carotid response-to-injury by physiologic levels of estrogen replacement; (b) support the utility of this model in the study of the biologic effects of estrogen on the vascular-injury response; and (c) suggest a direct effect of estrogen on vascular smooth muscle cell proliferation in injured vessels.

A complex role for the progesterone receptor in the response to vascular injury.

Clinical studies of hormone replacement therapy to prevent cardiovascular diseases have heightened interest in the cardiovascular effects of progestins. However, the role of the progesterone receptor (PR) in vascular biology has not been studied in vivo. We studied ovariectomized female PR knockout (PRKO) mice and their wild-type (WT) littermates using the mouse carotid artery injury model. Placebo-treated PRKO mice showed significantly greater vascular medial hypertrophy and vascular smooth muscle cell (VSMC) proliferation in response to vascular injury than did WT mice. Progesterone had no significant effect in the PRKO mice, but worsened the response to injury in WT mice. VSMCs cultured from PRKO mouse aortae were markedly hyperproliferative, and their growth was not affected by progesterone. In contrast to the in vivo findings, progesterone inhibited proliferation of WT-derived VSMCs. Furthermore, reintroduction of PR into PRKO-derived VSMCs using adenoviral methods restored progesterone-mediated inhibition of proliferation to these cells. This effect was reversed by the PR antagonist, RU 486. Thus, the effects of PR and progesterone differ markedly between cultured VSMCs and intact blood vessels. These data demonstrate a direct role for the PR in regulating the response to vascular injury and VSMC proliferation.

DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model.

Myotonic dystrophy (DM) is the most common form of muscular dystrophy and is caused by expansion of a CTG trinucleotide repeat on human chromosome 19. Patients with DM develop atrioventricular conduction disturbances, the principal cardiac manifestation of this disease. The etiology of the pathophysiological changes observed in DM has yet to be resolved. Haploinsufficiency of myotonic dystrophy protein kinase (DMPK), DM locus-associated homeodomain protein (DMAHP) and/or titration of RNA-binding proteins by expanded CUG sequences have been hypothesized to underlie the multi-system defects observed in DM. Using an in vivo murine electrophysiology study, we show that cardiac conduction is exquisitely sensitive to DMPK gene dosage. DMPK-/- mice develop cardiac conduction defects which include first-, second-, and third-degree atrioventricular (A-V) block. Our results demonstrate that the A-V node and the His-Purkinje regions of the conduction system are specifically compromised by DMPK loss. Importantly, DMPK+/- mice develop first-degree heart block, a conduction defect strikingly similar to that observed in DM patients. These results demonstrate that DMPK dosage is a critical element modulating cardiac conduction integrity and conclusively link haploinsufficiency of DMPK with cardiac disease in myotonic dystrophy.

Effects of estrogen on the vascular injury response in estrogen receptor alpha, beta (double) knockout mice.

The two known estrogen receptors, ERalpha and ERbeta, mediate the effects of estrogen in all target tissues, including blood vessels. We have shown previously that estrogen inhibits vascular injury response to the same extent in female wild-type (WT), ERalpha knockout (ERalphaKO(CH)), and ERbeta knockout (ERbetaKO(CH)) mice. We generated mice harboring disruptions of both ERalpha and ERbeta genes (ERalpha,betaKO(CH)) by breeding and studied the effect of 17beta-estradiol (E2) on vascular injury responses in ovariectomized female ERalpha,betaKO(CH) mice and WT littermates. E2 inhibited increases in vascular medial area following injury in the WT mice but not in the ERalpha,betaKO(CH) mice, demonstrating for the first time that the two known estrogen receptors are necessary and sufficient to mediate estrogen inhibition of a component of the vascular injury response. Surprisingly, as in WT littermates, E2 still significantly increased uterine weight and inhibited vascular smooth muscle cell (VSMC) proliferation following injury in the ERalpha,betaKO(CH) mice. These data support that the role of estrogen receptors differs for specific components of the vascular injury response in the ERalpha,betaKO(CH) mice. The results leave unresolved whether E2 inhibition of VSMC proliferation in ERalpha,betaKO(CH) mice is caused by a receptor-independent mechanism, an unidentified receptor responsive to estrogen, or residual activity of the ERalpha splice variant reported previously in the parental ERalphaKO(CH) mice. These possibilities may be resolved by studies of mice in which ERalpha has been fully disrupted (ERalphaKO(St)), which are in progress.

Left ventricular diastolic collapse in regional left heart cardiac tamponade. An experimental echocardiographic and hemodynamic study.

OBJECTIVES: This study was designed to describe the hemodynamic abnormalities associated with the appearance of left ventricular diastolic collapse in the setting of regional left heart cardiac tamponade. BACKGROUND: Cardiac tamponade after heart surgery is frequently associated with localized pericardial effusion. Although right ventricular diastolic collapse and right atrial collapse are reliable echocardiographic findings in patients with circumferential pericardial effusion and tamponade, they are often not present in postoperative patients with localized pericardial effusion and regional left heart tamponade. Left ventricular diastolic collapse has been described in such patients, but the degree of hemodynamic alteration that exists with this finding is not known. METHODS: Acute regional left heart tamponade was produced 14 times in seven spontaneously breathing anesthetized dogs by infusing fluid into an isolated compartment created in the pericardial space adjacent to the left ventricular free wall. Continuous echocardiographic imaging and hemodynamic monitoring of left ventricular, systemic arterial, right atrial, pulmonary capillary wedge and pericardial pressures were performed. Measurements at baseline were compared with those made at the onset of left ventricular diastolic collapse and at decompensated tamponade. RESULTS: Left ventricular diastolic collapse was noted in all 14 episodes of regional tamponade. It occurred when pressure in the left pericardial compartment exceeded left ventricular diastolic pressure by 3.0 +/- 1.9 mm Hg. At the onset of left ventricular diastolic collapse, cardiac output and mean arterial pressure were significantly reduced from the control value (p < 0.05). Systolic hypotension was noted only twice at this stage, respiratory variation in systolic pressure > 10 mm Hg only once. The appearance of this sign was also associated with elevated left heart filling pressures. CONCLUSIONS: Left ventricular diastolic collapse is a reliable sign of regional left ventricular tamponade and is associated with a reduction in cardiac output. This echocardiographic finding usually occurs before the development of arterial hypotension and pulsus paradoxus. Thus, left ventricular diastolic collapse is potentially more reliable than hypotension or pulsus paradoxus in the diagnosis of regional left ventricular tamponade.

Nuclear magnetic resonance spectroscopy of rat ventricles following supravalvar aortic banding. A model of left ventricular hypertrophy.

Left ventricular hypertrophy produced by supravalvar aortic banding in infant rats was studied by proton magnetic resonance spectroscopy. Weight gain at 11 weeks of age in the 11 male Sprague-Dawley rats with aortic bands placed at three weeks was similar to that of the 14 controls. The left ventricle of banded rats hypertrophied, increasing the ratio of left ventricle plus septum to body weight (LV + S/BW) by more than 50% (P less than .00001). Right ventricular weight (RV/BW) increased slightly (P less than .03). T1 and T2 relaxation times of LV + S, RV, and thigh muscle (Th) from the banded and control rats were compared. The T2 value distinguished hypertrophied from control LV + S (P less than .003), but not between RV or Th from the two groups. For banded rats only, the T2 value distinguished each muscle type: LV + S from RV, LV + S from Th, and RV from Th (P less than .00001 for each). For control rats, cardiac muscle was distinguished from Th (P less than .00001), but LV + S and RV were similar. The T1 value did not distinguish either the banded from the control group or any of the muscle types. Percent water content was similar for all tissues. Any correlation between water content and T1 or T2 was inconsistent or weak.

Magnetic resonance imaging in ischemic injury after heart transplantation in rats.

Magnetic resonance imaging with and without gadolinium (Gd)-DTPA has been shown to enable detection of coronary occlusive ischemic injury and heart transplant rejection. This study was performed to examine findings on magnetic resonance images associated with ischemic injury after heart transplantation in rats. Magnetic resonance imaging was performed immediately before death in 22 rats, between 1 and 90 days after isogeneic (Lewis grafts, Lewis host; or Fischer graft, Fischer host) heterotopic heart transplantation. Ischemic injury, characterized histologically by cellular infiltration or myocyte necrosis, correlated inversely with graft duration. It was graded as moderate to severe in 5 of 5 rats killed at 1 to 2 days, and in 0 of 9 animals killed at greater than or equal to 30 days. T2-weighted myocardial signal intensity (TR = 2.3 seconds; TE = 90 milliseconds) correlated inversely with graft duration and was significantly greater in grafts with moderate or severe histologic abnormalities than in grafts with absent or minimal changes. GD-DTPA-induced myocardial enhancement was judged on T1-weighted images (TR = 0.5 seconds, TE = 25 milliseconds). Areas of intense enhancement were present in all seven grafts with severe histologic abnormalities, but in only 3 of 15 grafts with absent to moderate histologic abnormalities. In conclusion, after heart transplantation in rats, ischemic injury causes increased T2-weighted signal intensity and Gd-DTPA-induced T1-weighted signal enhancement--findings similar to those described in transient coronary occlusive ischemia and in graft rejection. Abnormalities seen on magnetic resonance images during the first few posttransplant weeks may represent ischemic injury rather than rejection.

Effects of atrial cardioplegia on the ischemic right ventricle after acute coronary artery occlusion and reperfusion.

Right atrial cardioplegia has been advocated as a simple method of delivering retrograde cardioplegia. Passive distention of the right heart inherent with right atrial cardioplegia has been shown to impair right ventricular function in a canine model of global ischemia. This study was designed to compare right ventricular performance after right atrial cardioplegia administered intermittently (n = 5) and continuously (n = 5) with coronary sinus retrograde cardioplegia (n = 5) and aortic root cardioplegia (n = 8) in a canine model of acute right ventricular ischemia and reperfusion. Right ventricular performance was assessed using the load-independent relationship of end-systolic pressure versus dimension (myocardial fiber length). Right ventricular performance was well preserved after reperfusion in those dogs protected with intermittent right atrial cardioplegia (95% of control). Results with continuous right atrial cardioplegia (66% of control) and coronary sinus retrograde cardioplegia (40% of control) demonstrated diminished postreperfusion right ventricular performance. Right ventricular performance in the group protected with aortic root cardioplegia was significantly impaired after reperfusion when compared with all retrograde groups (34% of control, p less than 0.05). In this model, postreperfusion right ventricular performance was preserved in the right atrial cardioplegia groups despite passive ventricular distention. All methods of retrograde cardioplegia resulted in superior preservation of right ventricular performance when compared with standard aortic root cardioplegia.

Familial hypertrophic cardiomyopathy mice display gender differences in electrophysiological abnormalities.

Genetically-manipulated mice harboring an alpha-myosin heavy chain Arg403Gln missense mutation (alpha-MHC403/+) display a phenotype characteristic of familial hypertrophic cardiomyopathy (FHC). Male and female (30 +/- 8 week old) heterozygous alpha-MHC403/+ mice and litter-mate controls were evaluated using a surface electrocardiogram (ECG) and an in vivo cardiac electrophysiology study (EPS). Wild type animals had normal intracardiac electrophysiology, with no significant differences between male and female control mice during EPS. The female wild-type mice did have slower heart rates and longer ECG intervals than their male wild-type counterparts. The female alpha-MHC403/+ mice had similar ECG's, cardiac conduction times, and refractory periods compared with female wild-type mice. In contrast, male FHC mice had distinctive ECG and electrophysiologic abnormalities including right axis deviation, prolonged ventricular repolarization and prolonged sinus node recovery times. During programmed ventricular stimulation, 62% of male alpha-MHC403/+ mice and 28% of female alpha-MHC403/+ mice had inducible ventricular tachycardia. These studies identify gender-specific electrophysiologic abnormalities in alpha-MHC403/+ FHC mice, concordant with the histological and hemodynamic derangements previously reported.

Assessment of atrioventricular nodal physiology in the mouse.

Transgenic mice are increasingly being utilized for understanding cardiac electrophysiologic abnormalities. However, little is known about the normal atrioventricular nodal and infraHisian physiology in the mouse because of the prior inability to record a His-bundle deflection. We present the first comprehensive examination of the murine atrioventricular nodal and His-Purkinje systems employing His-bundle recordings. Normal, healthy, male C57BL/6J mice (n = 48) underwent an in vivo electrophysiology study using a 2 F octapolar electrode catheter. Effective refractory periods were determined during premature atrial and ventricular stimulation. The PR interval measured 44 +/- 6 ms with a mean sinus cycle length of 185 +/- 42 ms. Baseline AH intervals were 36 +/- 5 ms and HV intervals were 10 +/- 2 ms. At a pacing cycle length of 140 ms the atrioventricular nodal effective refractory period (AVNERP) and atrial effective refractory period (AERP) were 86 +/- 19 ms and 57 +/- 17 ms, respectively. The mean AV Wenckebach and 2:1 paced cycle length were 103 +/- 14 ms and 84 +/- 13 ms, respectively. Premature atrial stimulation curves were asymptotic without discontinuity. A subset of nine mice was studied after administration of isoproterenol. The sinus cycle length, AVNERP and AERP decreased significantly from baseline measurements. This method establishes a practical and feasible technique to record in vivo His-bundle electrograms in the mouse to assess atrioventricular nodal and infraHisian physiology. Use of this model will allow for the examination of abnormalities of atrioventricular nodal and infraHisian conduction in transgenic murine models.

A new platinum balloon-expandable stent (Angiostent) mounted on a high pressure balloon: acute and late results in an atherogenic swine model.

BACKGROUND: Randomized studies have proven the efficacy and safety of stent placement to treat de novo coronary stenosis. However, the poor radio-opacity and the use of an additional high-pressure balloon to fully expand the stent are the major limitations of the currently clinically-approved stents. OBJECTIVE: We evaluated the safety, efficacy, angiographic and histologic effect of a new platinum balloon expandable stent mounted on a high-pressure balloon in Yucatan miniature swine fed high cholesterol diet. METHODS: Fifteen Angiostents (NuMED, Inc., Hopkinton, NY and Angiodynamics, Glens Falls, NY) (coronary stent was 3, 3.5, or 4 mm in diameter and 12 mm long; renal and carotid stents were 5 mm in diameter and 13 mm long) mounted on a high-pressure balloon were placed percutaneously in blood vessels of 10 pigs [5 in circumflex (CX), 2 in left anterior descending (LAD), 5 in renal and 3 in carotid arteries]. The stent was 10-20% larger than the native vessel diameter. All animals received 5000 I.U. of heparin during the procedure and were maintained on 325 mg aspirin daily. Follow-up angiography and histology in the animals was performed at 2, 4, 12, 20, 26 and 52 weeks. RESULTS: The stents were easily visualized with fluoroscopy and placed in all animals without episodes of balloon rupture or embolization. There was no episode of acute thrombosis. Follow-up angiography in the animals revealed patency of all renal and carotid stents, however, 2/7 coronary stents in the animals revealed angiographic lumen narrowing (> 20%) at 20 and 52 weeks. Histologic examination revealed neointimal formation at the stent site with an average neointimal thickness ranging from 325-650 microns. CONCLUSION: This stent was safe in this animal model, easily deployed, had excellent radio-opacity and with good short-term patency without anticoagulation. Clinical trials and experience is underway.

Successful placement and re-expansion of a new balloon expandable stent to maintain patency of the ductus arteriosus in a newborn animal model.

OBJECTIVE: We performed this study in order to evaluate the usefulness of a new balloon expandable stent for maintaining ductal patency in a neonatal piglet model and to evaluate the ability to re-expand the stent weeks following initial implantation. BACKGROUND: Maintaining patency of the ductus arteriosus without administration of Prostaglandin E has been reported previously using balloon dilation and stent implantation techniques. However, the experience is limited and the currently available stents are not modified for neonates. METHODS: 14 newborn piglets all at age 12 days and median weight 3.6 Kg (range 2.7-4.3 Kg), underwent initial balloon dilation of the ductus arteriosus. Angiography after dilation demonstrated no significant left to right shunt. All piglets underwent successful stent (3.5 mm x 17 mm) placement in the ductus arteriosus. RESULTS: Percutaneous ductal stent implantation via the arterial route was successful in all piglets with angiographic demonstration of a significant left to right shunt. Follow-up studies at weekly intervals with color flow Doppler were used to confirm patency of the stents. In 3 piglets the stent was not patent at initial follow-up and autopsy revealed sub-optimal stent placement. In two animals the stent was later re-expanded to 4 mm at 22 days, in one to 4 mm at 30 days and in one to 6 mm at 15 days, maintaining flow for an additional period of 15 to 34 days.(ABSTRACT TRUNCATED AT 250 WORDS)

A new low profile balloon atrial septostomy catheter: initial animal and clinical experience.

OBJECTIVE: To evaluate the safety and efficacy of a new low profile balloon septostomy catheter in neonatal animals as well as in one newborn infant. BACKGROUND: Balloon atrial septostomy remains one of the most commonly performed palliative procedures in pediatric cardiology. The currently available septostomy catheter requires a large introducer sheath (6 or 7F), does not have an end hole for confirmation of position or pressure measurement and is limited in patients with a small left atrium due to its large balloon inflated diameter. METHODS: Four neonatal piglets (average weight 3.9 kg) underwent percutaneous balloon atrial septostomy using the new balloon catheter inflated to 1 cc via a 5F sheath in the femoral vein. Two other piglets (average weight 4.9 kg) underwent septostomy with the conventional catheter inflated to 3.5 cc via a 6 or 7F sheath in the femoral vein. All animals underwent transthoracic echocardiography pre and post septostomy. All animals were sacrificed after the procedure and the size of the atrial defect created was measured. One neonate with Taussig-Bing anomaly underwent septostomy with the new balloon catheter. RESULTS: The left atrium was entered in all piglets. It was easier to enter the left atrium with an end hole catheter which was exchanged over a wire with the septostomy catheter. Septostomy was performed with the new or conventional catheters without complications. Echocardiography demonstrated a very small patent foramen ovale prior to the procedure and a large atrial defect after septostomy. The average size of the defect created by the new catheter was 11.3 x 10 mm in diameter and 11 x 10 mm using the conventional catheter. A 10 x 10 mm atrial communication was created in the neonate. CONCLUSIONS: This study demonstrates the safety and efficacy of this new catheter. This catheter will be of potential importance in patients with a small left atrium and in small neonates with congenital heart disease requiring septostomy.

Effects of chronic in utero hypoxia on the pulmonary vasculature of the newborn guinea pig.

This report analyzes the effect on pulmonary vascular structure and function in the newborn guinea pig of chronic fetal hypoxemia, induced by maternal hypobaric hypoxia (380-420 torr) without direct interference with the utero-placental blood flow. Six pregnant guinea pigs were maintained in hypobaric chambers, 10 newborns from their litters being the hypoxic group. Twenty newborns from the litters of 10 pregnant guinea pigs maintained in air were the control group. After spontaneous delivery catheters were placed in the left carotid and the main pulmonary arteries of the newborns. Oxygen consumption was measured, pressures recorded from the pulmonary artery, right ventricle, and right atrium, oxygen saturation and hemoglobin concentration estimated on blood from systemic arteries, pulmonary artery, and right atrium, and cardiac output calculated (Fick principle). All data were normalized per kilogram body weight. Morphometric analysis of the pulmonary vasculature after injection of the pulmonary arteries showed no difference between the groups. Contrary to expectation chronic hypoxemia in utero did not cause pulmonary hypertension or the precocious muscularization of the precapillary unit found in human cases of persistent pulmonary hypertension: it caused growth retardation, a feature not typical of the human syndrome.

Effects of chronic in utero hypoxemia on rat neonatal pulmonary arterial structure.

Idiopathic persistent pulmonary hypertension of the newborn infant (PPHN) is characterized by intrauterine structural remodeling of the pulmonary arterial bed, consisting of precocious development of muscle in intraacinar arteries, proliferation of adventitial connective tissue, and sometimes medial hypertrophy of preacinar arteries. To evaluate whether gestational hypoxemia causes these changes, we studied pulmonary arterial structure in two groups of newborn rats: one control, the other exposed to hypoxemia produced by maternal hypoxia during the second half of gestation. Morphometric analysis of the pulmonary arterial bed was performed after barium injection into the pulmonary arteries and formol saline expansion of the air spaces. Birth weight was similar in each group. Hematocrit was elevated in the hypoxemia group (51% +/- 1.0% vs 46% +/- 0.8%, P less than 0.005). The structure of preacinar and intraacinar arteries was similar and normal in both groups. Chronic fetal hypoxemia in the rat does not produce the pulmonary arterial structural changes identified in fatal cases of PPHN in human infants.

Effects of indomethacin in utero on the pulmonary vasculature of the newborn guinea pig.

The clinical syndrome of persistent pulmonary hypertension of the newborn results from failure of the normal perinatal vascular adaptation, and functionally is characterized by persistent right to left shunting of blood through the foramen ovale and ductus arteriosus. Exposure of the fetus to drugs that inhibit prostaglandin synthesis and cause closure of the ductus arteriosus has been suggested as one cause of persistent pulmonary hypertension of the newborn. We attempted to produce a functional and structural model of persistent pulmonary hypertension of the newborn by administration of indomethacin, a cyclooxygenase inhibitor, to pregnant guinea pigs. Five pregnant guinea pigs received 3.5 mg/kg indomethacin intravenously twice each day for the 12 to 19 days before delivery and seven controls received saline. Hemodynamic studies were performed in eight "treated" newborns and in 12 controls. After sacrifice, the ductus was ligated and, for morphometric studies, the pulmonary arteries were distended with barium/gelatin. The treated animals did not show the intraacinar structural or hemodynamic changes of persistent pulmonary hypertension of the newborn. It seems that the indomethacin did cross the placenta because lung structure was modified. The radical alveolar count and alveolar/artery ratio were increased and the preacinar arteries dilated, with more increase in muscle mass. This could be explained by increased pulmonary blood flow because of ductal constriction but direct effect of indomethacin cannot be excluded.