Reperfusion, compared with ischemia alone, promotes the rapid accumulation of leukocytes in the coronary microvasculature of dogs.

ABSTRACT. Cardiac effects of the neuropeptide pituitaryAbbreviations adenylate cyclase activating p o l y p e p t i d e -(~~~i~) have not previously been reported. W e investigated the influence of PACAP, vasoactive intestinal polypeptide (68% homology with PACAP) and the B-adrenergic receptor agonist isoproterenol on contractile function and coronary vascular tone in isolated piglet hearts (1 to 5 d of age). Paced (180 beatslmin) isovolumically beating hearts underwent retrograde aortic perfusion a t constant coronary flow (approximately 3 mL. min-' . g-') with an erythrocyte-enriched PACAP, pituitary adenylate cyclase activating polypeptide VIP, vasoactive intestinal polypeptide ISP, isoproterenol IBMX, isobutylmethylxanthine dP/dt,,, maximum rate of change of systolic pressure with respect to time (+), positive (-), negative (hematocrit 15 to 20%)~solution ( 3 7 "~) . ~g o n i s t s were injected into the aortic root of hearts, and the positive (+) and negative (-) changes in maximum rate of change of systolic pressure with respect to time (dP/dtma,) and in PACAP is a newly discovered neuropcptide isolated from the coronary perfusion pressure (that reflected alterations in ovine hypothalamus (1). PACAP is present in two forms: one vascular tone) were measured. PACAP (n = 8,O.l and 0.5 with 27 and the other with 38 N-terminal amino acid residues nmol) increased (+) dP/dt,, from 944 + 59 to 1519 f 206 (2). PACAP has a 68% sequence homology with VIP and appears mm ~g / s and from 867 2 40 to 2010 +: 226 mm ~g / s ( p to be more potent than VIP in stimulating adenylate cyclase in < 0.05); increased (-1 dpldt,, from 11 14 41 to 14-39 + pituitary cells (2). PACAP also has been shown to increase cAMP 9 5 mm ~g and from 999 f 37 to 1668 + 145 mm H~/ S levels in the human neuroblastoma cell line NB-OK (3), the rat ( p < 0.05); and decreased perfusion pressure from 61.4 2 pancreatic acinar cell line AR 4-25 (4), and rat liver cell mem-3.1 to 48.9 2 2.3 mm 1 1~ and from 60.5 + 2.4 to 43.9 branes ( 5 ) . Moreover, high affinity binding sites for PACAP have 2.3 mm H~ (p < 0.05), respectively. comparison, vase-been identified in several organ systems, including the rat lung active intestinal polypeptide (n = 6, 0.1 and 0.5 nmol) (6) and h m a n brain (7). increased (+) dP/dtmn, from 767 +. 53 to 806 + 37 mm Hg/ The ~h~s i o l o g i c role of PACAP has not been elucidated, and from 829 2 94 to 942 8 5 mm ~g /~ (NS); increased although it has been suggested that this peptide may be involved (-) dp/dtma, from 883 2 73 to 926 45 ,,,,,, ~g /~ and in the regulation of vascular smooth muscle tone, in addition to from 923 + 8 2 to 1054 f 78 mm Hg/s (NS); and decreased its presumed role as a hypothalamic, hypophysiotropic hormone perfusion pressure from 57.9 + 4.9 to 50.0 +. 3.6 mm H~ (8 VIP, have been demonstrated in the myocardium and coronary duced positive inotropic, luisitropic, and coronary vasodil-arteries of several adult species (12). The present study, therefore, effects in piglet which may make a was undertaken to inv...

Milrinone, a selective inhibitor of phosphodiesterase (PDE), was examined in neonatal hearts and in ventricular myocytes. Isolated, paced (180 beats/min), isovolumically beating hearts from pigs, less than 3 days of age, were perfused with an erythrocyte-enriched solution. In one group (control, n = 6), milrinone was studied at perfusate concentrations of 1, 10, and 100 micrograms/ml. In a second group (postischemia, n = 10), hearts were subjected to 30 minutes of no-flow ischemic arrest, prior to the addition of milrinone. Left ventricular peak systolic pressure (PSP) and end-diastolic pressure, coronary flow (CF), heart rate (HR), and myocardial oxygen consumption (MVO2) were measured. The PSP averaged approximately 100 mmHg during the baseline periods for both groups and decreased to approximately 85 mmHg in those hearts subjected to ischemic arrest. In both groups, PSP increased approximately 14% at the 1 micrograms/ml concentration of milrinone. No additional increases in PSP were observed in the control group at the higher concentrations. However, PSP increased 28% and 41% (p less than 0.05), in the postischemia group at the 10 and 100 micrograms/ml concentrations, respectively. The CF averaged approximately 3 ml/min/g during the baseline periods of both groups and increased significantly at each milrinone concentration. The HR in both groups increased to approximately 200 and approximately 250 beats/min at the 10 and 100 micrograms/ml concentrations, respectively. Additionally, milrinone's effects in intact hearts were found to be comparable to those of isobutylmethyl xanthine (IBMX), a nonspecific PDE inhibitor. In isolated myocytes, however, milrinone produced only modest increases in cAMP levels, compared to IBMX.(ABSTRACT TRUNCATED AT 250 WORDS)

ABSTRACf. We investigated the influence of exogenously administered acetylcholine, nitric oxide, ADP, ATP , bradykinin, and substance P on coronary vascular tone in isolated , neonatal pig hearts (s4 d). Paced (180 bpm), isovolumically beating hearts underwent retrograde aortic perfusion , with an erythrocyte-enriched solution (hematocrit 0.15-0.20) at constant coronary flow (~2.5 mL/min/g) corresponding to a perfusion pressure of~60 mm Hg. Agonists were injected into the aortic root, and the peak change in coronary perfusion pressure from baseline and left ventricular pressure development were assessed. Nitric oxide (3 JLL), ADP (30 nmol), ATP (30 nmol), bradykinin (125 ng), and substance P (50 ng) decreased the perfusion pressure (vasodilatation) by 16.9 ± 1.2, 25.3 ± 4.4, 18.3 ± 1.2, 18.9 ± 1.4, and 7.1 ± 1.6 mm Hg, respectively. Acetylcholine (0.5 and 1.0 nmol) produced a modest decrease in perfusion pressure (vasodilatation) of 4.2 ± 0.8 and 3.8 ± 0.5 mm Hg, respectivel y, whereas acetylcholine (5, 20, and 100 nmol) increased the perfusion pre ssure (vasoconstriction) by 16.7 ± 2.7, 48.2 ± 8.2, and 85.3 ± 15.1 mm Hg, respectively. Acetylcholine also decreased left ventricular peak systolic pres sure from 108.7 ± 5.0 to 69.2 ± 4.6, 56.3 ± 6.1, and 48.2 ± 6.4 mm Hg, for the 5, 20, and 100 nmol doses, respectively. Responses to acetylcholine were abolished by atropine (50 nmol). In a separate group of hearts, indomethacin (10-6 M) reduced the peak change in perfusion pressure for the 5, 20, and 100 nmol doses of acetylcholine by 87% ,66%, and 48%, respectively. In other hearts, the calcium channel antagonist, nisoldipine (10-7 M), reduced the peak change in perfusion pre ssure for the 5,20, and 100 nmol doses of acetylcholine by 87 %, 77%, and 56%, respectivel y. In summary, acetylcholine causes predominantly coronary vasoconstrictive and negative inotropic effects in neonatal pig hearts; both actions are muscarinic receptor mediated. Our data also indicate that a cyclooxygenase product may, in part, be involved in this vasoconstriction, and that an extracellular source of calcium contributes to the vasoconstrictive process. (Pediatr Res 32: 236-242, 1992) Abbreviations ACh, acet ylcholine EDRF, endothelium-derived relaxing factor BK, brad ykinin sub P, substance P NO , nitric oxide PSP, peak systolic pressure dP/dt, change in pressure per unit time Some 30 years ago, Cassin et al. (I) showed that ACh dilates the normally high tone pulmonary vasculature of the fetus. More recently, ACh has been shown to be a potent dilator of precontra cted, isolated systemic and pulmon ary arteries from neonates of several species (2). As originally demonstrated by Furchgott and Zawadzki (3), the vasorelaxation produced by ACh requires the presence of a functionally intact end othel ium and involves the produ ction of an EDRF. ACh has also been shown to relax precontracted, epicardial coro nary arteries isolated from several species, mo st notably the dog (4). It has becom e apparent, however, that the se results cannot b...

ABSTRACT. We performed intracardiac electrophysioactivity, either in the surface ECG or in the His or right logic studies of the effects of vasoactive intestinal peptide ventricular electrode catheter (VIP, 0.125 pg/kg/min) on sinus and atrioventricular (AV) nodal function, intracardiac conduction, and myocardial refractoriness in two groups of neonatal dogs (aged 6-16 d). Group in autonomic physiology, f 4% (mean f SD), after exposure to 0.1-0.5 nmol of VIP ( p < 0.001). In nine other newborns (aged 4-16 days), the VIP is one o f these neuropeptides that has been identified effect of selective a,-and a2-adrenergic receptor blockade throughout the autonomic nervous system. It is a 28-amino acid on the positive c~ronotrop~c effect of VIP was evaluated. peptide that. within the heart, appears to be most highly localized ~h~ effect of VIP on sinus cycle length was not altered by in the regions o f the sinus and AV nodes and atrial myocardium. the a,-adrenergic receptor blocker prazosin or by the ,,-It is believed that VIP is most likely colocalized with acetylchoadrenergic receptor blocker yohimbine. These data indicate line within cardiac postganglionic parasympathetic nerves ( 1 ). It that, in the neonatal dog, VIP shortens sinus cycle length has been suggested that VIP may be ~hysiologically active as a and AV nodal conduction time but has no effect on infra-neurotransmitter because it has been shown to increase intrinsic nodal conduction or myocardial refractoriness. We find no cardiac pacemaker rate. enhance AV nodal conduction, and evidence that VIP's chronotropic effect is modified by a-shorten myocardial refractoriness it1 lvil8o and it1 vitro in adult adrenergic receptor blockade. V I P may play a role in the dogs (1-5). Although the effects o f VIP in the adult heart have neural modulation of heart rate and AV nodal conduction been well described. there has been little or no information in the neonate. (Pediatr Res 35: 244-249, 1994) regarding the actions o f VIP in the developing heart. At least one study reported that the effect o f VIP on heart rate may be very Abbreviations different in the early neonatal period compared with later in life VIP, vasoactive intestinal peptide (6). This study also suggested that there might be a link between AV, atrioventricular the cardiovascular effects o f VIP and tu-adrenergic receptor activ-AH interval, the time from the onset of the atrial elecwo-ity in the newborn (6). This is o f significance because developgram to the onset of the His bundle electrogram in the mentally determined differences in cardiac chronotropic reHis electrode catheter sponses and in intracellular signal transduction in response to tu-PA interval, the time from the onset of the P wave on the adrenergic stimulation have been previously well documented surface ECG to the onset of the atrial electrogram in the (7-10). Therefore. the purpose o f our study was to characterize His electrode catheter the effects o f VIP on the electrophysiologic properties o f the H V interval, the time from t...