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Pulmonary Vasodilator Action of Tolazoline

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Pulmonary Vasodilator Action of Tolazoline Pediat. Res. 13: 942-944 (1979 Histamine pulmonary vasodilator action newborn tolazoline Pulmonary Vasodilator Action of Tolazoline BOYD W. GOETZMAN AND JAY M. MILSTEIN Department of Pediatrics, University of California. Davir, School of Medicine, Davis, California, USA Summary PpA; mean left atrial pressure, P1.A; and mean aortic pressure, Pi\,, and airway pressure wa_s monitored and end expiratory pre_ssure The pulmonary vasodilator action of tolazoline in newborn lambs was maintained below PI.A PVR was calculated as (PPA- PI.A)/ was shown to be mediated via histamine receptors. Maximal Q,,. The units of pressure measurement were mm Hg and the flow changes in pulmonary vascular resistance, APVR, were calculated measurements were measured as ml/min and then standardized as percents of the base line value, %APVR. The mean %APVR per kg of body, ml/min/kg, for the resistance calculations. after tolazoline, 1 mg/kg, was -25 + 4% for eight lambs. Four Intermittent arterial blood gas analysis was performed to assess lambs then received the histamine tIl receptor antagonist, diphen- acid-base and oxygenation status. Rectal temperature was main- f hydramine, and the mean %APVR due to tolazoline was - 12 tained at 38.540°C. 4%. Four lambs received the ]Iz receptor antagonist, metiamide, Pharmacologic agents were administered in boluses via the and the mean R'APVR due to tolazoline was -18 + 5%. After both inferior vena cava cannula in the following doses: tolazoline Ill and [I2 antagonists, the mean %APVR due to tolazoline was (Priscoline, CIBA Pharmaceuticals, Summit, NJ), I mg/kg; di- +6 8%. + Therefore, both histamine 11, and 112 receptors were phenhydramine (HI receptor antagonist) 5 mg/kg; and metiamide involved in the vasodilator response to tolazoline. (kindly supplied by John G. Paul of Smith, Kline, and French Laboratories, Philadelphia, PA) (Hz receptor antagonist), 5 mg/ Speculation kg. Initially, the effect of tolazoline, 1 mg/kg, on PVR was If the puln~onaryvasodilator action of tolazoline is n~ediatedby determined before the administration of antagonists in all eight histamine receptors in human infants, as it is in newborn lambs, it lambs. In lambs 14, the effect of tolazoline on PVR was then may be possible to select a more specific therapeutic agent for evaluated after HI receptor blockade with diphenhydramine and infants with pulmonary vasospasm. liistamine, 2-methylhistamine, in lambs 5-8 the effect of tolazoline was evaluated after Hz a specific Iil agonist, or 4-methylhistamine, a specific 112 agonist, receptor blockade with metiamide. Finally, the effect of tolazoline may be such agents in certain situations. on PVR was evaluated in all eight lambs after both HI and H2 receptor blockade. In lambs 3-7, before administration of any histamine antago- Tolazoline hydrochloride has been reported to reduce the ele- nists, the PVR was elevated by ventilating the lambs with an 8- vated pulmonary vascular resistance seen in primary pulmonary 10% oxygen mixture balanced with nitrogen. The effect of tola- hypertension (7, 8), mitral stenosis (5), congenital heart disease (4, zoline on the increased PVR due to alveolar hypoxia was then I I), cystic fibrosis (12). respiratory distress syndrome of the new- evaluated. born (6), and "persistence of the fetal circulation" (10, 13). In four additional lambs, tachyphylaxis to tolazoline was eval- Tolazoline is classified pharmacologically as an a-adrenergic uated by the administration of four consecutive 1 mg/kg doses of blocking agent. In addition, it has direct actions on cardiac and tolazoline at 10-min intervals with the determination of fall in smooth muscle which are described as sympathomimetic. para- PVR after each dose. No histamine antagonists were used in these sympathomimetic, and "histamine-like" (15). Dual histamine re- animals. ceptors, called HI and Ha receptors, have recently been described For purposes of analysis, maximal changes in PVR after tola- (3). Tolazoline has been shown to interact with histamine H2 zoline administration, APVR, were calculated as percents of the receptors in gastric mucosa and cardiac atria to produce its hista- base line value, %APVR. Means of %APVR, before and after mine-like effect (16, 19). however, the blood vessels of the lung histamine receptor antagonists, were then compared using the have not been studied in this regard. In the pulmonary circulation Student's t test. of adult animals, histamine HI receptors mediate vasoconstriction and Hz receptors mediate vasodilatation (IS), whereas in the fetus RESULTS both receptors may mediate pulmonary vasodilatation (18). f The pirpose of the present study was to demonstrate that the The mean SD base line values for the eight lambq studied pulmonary vasodilator action of tolazoline is mediated via hista- were = 37.9 -t 8.6 mm HE, P1.A = 4.5 f 2.5 mm HE. Qp = 287 mine receptors. f 60 ml/kg/min, and PVR-= 0.1 1 + 0.4 mm ~~/uml;k~/min (Table 1). EXPERIMENTAL METHOD After 'the administration of tolazoline, 1 mg/kg, the mean %APVR f SD for all eight lambs was -25 -t 4%. In lambs 14,in Newborn lambs, 0- to 3-days-old, weighing 3.1-5.4 kg, were the presence of the HI receptor antagonist, diphenhydramine, the anesthetized with a a-chloralose, tracheotomized, and ventilated mean %APVR f SD produced by tolazoline was -12 f 4%. In with a Harvard small animal ventilator. Cannulae were placed in lambs 5-8, in the presence of the Ha receptor antagonist, metiam- the aorta and inferior vena cava from a femoral approach. The ide, the mean %APVR f SD produced by tolazoline was - 18 f heart and great vessels were exposed through a left lateral thora- 6%. The mean %APVR + SD produced by tolazoline after admin- cotomy and the ductus arteriosus was ligated. Cannulae were istration of both HI and Hz antagonists to all eight lambs was +6 inserted into the left atrium and pulmonary artery. All cannulae +- 8% (Table 2). The mean %APVR's due to tolazoline after the were connected to pressure transducers and appropriate electronic administration of each single histamine antagonist as well as the amplifiers. The following were recorded on a strip chart recorder: combined HI and H2 antagonists were significantly different from Mean pulmonary blood flow, Q,,; mean pulmonary artery pressure, the mean %APVR produced by tolazoline alone (P < 0.01). Lambs 9 PULMONARY VASODlLATOR ACTION OF TOLAZOLINE 943 I and 5 appeared to have considerably less Hz receptor activity In the four additional lambs receiving four consecutive doses of than HI receptor activity (Table 2). tolazoline, 1 mg/kg, at 10-min intervals, no tachyphylaxis in the The duration of action of tolazoline on the pulmonary circula- PVR response to tolazoline was observed. The fall in PVR consis- tion varied from 40-210 sec with a mean of 122 sec. tently slightly increased with consecutive doses of tolazoline, with Lambs 3-7 were ventilated with 8-10% Oz (resultant arterial the means of %APVR of -21% on the fourth dose being similar to PaOz (17-29 torr) and the PVR rose from a mean of 0.133 + 0.044 the initial %APVR of -26% for lambs 1-8. to 0.186 f 0.052 mm Hg/ml/kg/min (Table 3). The administration of tolazoline, 1 mg/kg, lowered the mean PVR to 0.139 k 0.049 DISCUSSION mm Hg/ml/kg/min, not statistically different from the base line mean PVR before alveolar hypoxia. The duration of action of These results demonstrate that the pulmonary vasodilator effect tolazoline during alveolar hypoxia was similar to that for the of tolazoline in the newborn lamb is mediated by both histamine HI and Hp receptors. Work in our laboratory (unpublished) with nonhypoxic state. histamine and specific HI and Hy receptor antagonists has dem- Table I. Base line hemodynamic measurements for 0- to 3-day-old onstrated that both HI and Hy receptors mediate pulmonary lambs vasodilatation in newborn lambs, 0- to 3-days-old. This finding is compatible with those of Woods et al. (18) that both HI and H:! PVR receptors mediate pulmonary vasodilatation in the sheep fetus. (mm Hg/ml/ However, HI receptors appear to mediate pulmonary vasoconstric- Lamb kg/rnin) tion and Hz receptors to mediate pulmonary vasodilatation in 0.088 adult dogs (17). Thus, tolazoline may not be an effective pulmo- 0.067 nary vasodilator in the older animals. 0.214 The increase in PVR produced by tolazoline after histamine HI 0.145 and H2 receptor blockade in this study may be due to the un- 0.1 14 masking of an adrenergic vasoconstrictor action. Benfey and 0.096 Varma (2) have previously demonstrated such an adrenergic 0.09 1 vasoconstrictor action of tolazoline in the peripheral circulation 0.149 of cats treated with reserpine. It should be noted that, unlike tolazoline, histamine, 0.5-1.0 pg/kg, continues to have a pulmo- Mean 37.9 f 8.6 4.5 rt 2.5 287 c 60 0.1 10 f 0.064 nary vasodilator effect after administration of both HI and Hz blocking agents. A non-HI-Hz receptor effect has been postulated at these large histamine doses (9). Table 2. Effect of tolazoline on PVR before and after histamine Our findings, that the pulmonary vasodilator action of tolazo- antagonists line is due to its histamine-like effect and not its cx-adrenergic % Change in PVR after blocking effect are in agreement with the findings of MacKinnon tolazoline, I mg/kg et al. (14) that another adrenergic blocking agent, hydergine. when injected directly into the pulmonary artery had no significant NO HI H2 HI + H2 effect on pulmonary hemodynamics regardless of the initial level Lamb antagonist antagonist antagonist antagonist of total PVR.
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