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PubMed1976

Inhibition of prostaglandin E2 secretion. Failure to abolish autoregulation in the isolated dog kidney.

We studied the role of renal prostaglandins in the regulation of glomerular filtration rate (GFR) and renal blood flow (RBF) in the isolated dog kidney. Indomethacin or meclofenamate, 2 mg/kg of body weight, suppressed renal prostaglandin E2 (PGE2) secretion, measured by radioimmunoassay, to zero within 20 minutes; the effect persisted for the duration of the study. When renal arterial pressure (PRA) was maintained at 104 mm Hg both drugs caused a sharp decrease in sodium excretion and RBF with redistribution of flow from inner to outer cortes we examined autoregulation of GFR and RBF over the pressure ranges of 150-100 and 150-75 mm Hg, respectively, after inhibition of PGE2 secretion and under control conditions. deltaGFR/deltaPRA (ml/min per mm Hg) was 0.020 +/- 0.017 in the indomethacin group, 0.152 +/- 0.055 in the meclofenamate group, and 0.086 +/- 0.017 in the control group. The change in GFR for the indomethacin group was significantly less than that for meclofenamate (P less than 0.01) and control groups (P less than 0.025); the latter two groups were not statistically different from each other (P greater than 0.1). There was no significant difference (P greater than 0.1) between the three groups with respect to deltaRBF/deltaPRA, which measured 0.288 +/- 0.046, 0.370 +/- 0.112, and 0.438 +/- 0.123 ml/min per mm Hg in the indomethacin, meclofenamate and control groups, respectively. Renal was lowered from 150 to 75 mm Hg. The observation that inhibition of prostaglandin synthesis promotes a redistribution of RBF from inner to outer cortex suggests that renal prostaglandins may participate in the regulation of medullary blood flow. However, since autoregulation of GFR and RBF remained intact despite inhibition of prostaglandin secretion, these data argue against a role for renal prostaglandins in regulating whole kidney GFR and RBF.

Animals↗
PubMed1976

Inhibition of hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs.

The role of a transmembrane calcium influx in hypoxic pulmonary vasoconstriction was studied in isolated, blood-perfused, rat lungs. We reasoned that, if the influx of extracellular calcium mediated the hypoxic mechanism, pressor responses to alveolar hypoxia (2.5% O2) would be susceptible to inhibition by the calcium antagonists verapamil (2 X 10(-5) to 2 X 10(-1) mM) and SKF 525A (2.6 to 260 mM). Susceptibility of hypoxic pressor responses to inhibition by these calcium antagonists was contrasted to that of pressor responses elicited by the humoral vasoconstrictors angiotensin II(1 or 0.5 mug) and prostaglandin F2alpha (10 myg). Since neither saralasin (0.5 muM), a competitive antagonist of angiotensin II, nor meclofenamate (6.8 muM), an inhibitor of prostaglandin synthesis, depressed hypoxic pressor responses, it was concluded that these humoral transmitters were not directly involved in the hypoxic mechanism, and therefore served as independent reference agonists. The order of susceptibility of pulmonary pressor responses to inhibition by verapamil was hypoxia greater than angiotensin II greater than prostaglandin F2alpha. SKF 525A also reduced pressor responses to hypoxia more readily than those to angiotensin II. The greater inhibition of hypoxic pulmonary vasoconstriction by both calcium antagonists suggested that the hypoxic mechanism was critically dependent on the transmembrane influx of extracellular calcium. Mediation of the hypoxic response by this type of excitation-contraction coupling is consistent with the idea that hypoxia has a direct depolarizing effect on the vascular smooth muscle. It also provides a unifying explanation for inhibition of the hypoxic mechanism by various agents that have depressant or stabilizing actions on membranes in addition to other pharmacological effects.

Angiotensin II↗
PubMed1976

Inhibition of adrenergic neurotransmission in canine vascular smooth muscle by histamine: mediation by H2-receptors.

Histamine depressed the contractions of dog saphenous vein strips caused by stimulation of their sympathetic nerves. This was due to a decrease in the release of norepinephrine which appears to be mediated by histamine H2-receptors. The evidence for this is as follows: (1) Contractions of the strips caused by activating the nerve endings electrically or by depolarization with potassium ions were depressed by histamine, whereas contractions caused by tyramine and norepinephrine were either unchanged or augmented. (2) Strips were incubated with norepinephrine[7-3H] and mounted for superfusion and isometric tension recording. The perfusate was collected for estimation of total radioactivity and for column chromatographic separation of norpinephrine and its metabolites. Histamine (0.9 muM) depressed the release of norepinphrine[7-3H] during contractions caused by electric stimulation, whereas the release of radioactive compounds caused by tyramine was unaffected. (3) The depression by histamine of the contractions and the efflux of radioactive compounds caused by electric stimulation were inhibited by an H2-receptor antagonist (metiamide), but were unaffected by an H1-receptor antagonist (pyrilamine). (4) Contractions caused by electric stimulation were inhibited by an H2-receptor agonist (4-methylhistamine) and augmented by an H1-receptor agonist (2-methylhistamine). These findings suggest the possibility that histamine, which is abundant in sympathetic nerves, might have a regulatory role in the release of the neurotransmitter.

Animals↗
PubMed1977

Influence of inhibitors of prostaglandin synthesis on renal vascular resistance and on renal vascular responses to vasopressor and vasodilator agents in the cat.

We determined the effects of indomethacin and meclofenamate, two inhibitors of prostaglandin synthesis, on renal vascular resistance and on renal responses to nerve stimulation, pressor and depressor hormones in the in situ feline kidney under conditions of controlled blood flow. Both inhibitors produced a gradual rise in renal vascular resistance which became maximal 15-20 minutes after administration. The increase in renal resistance after indomethacin was not attenuated during intrarenal infusion of either phentolamine or SQ 20881. Pretreatment with propranolol, in a dose sufficient to inhibit renin secretion, also did not attenuate the increase in renal resistance produced by indomethacin. However, infusion of [Sar1-, Ala8]angiotensin II, an angiotensin II antagonist, did attenuate the indomethacin-induced increase in renal vascular resistance. After indomethacin, the vasoconstrictor response to norepinephrine was enhanced, whereas responses to nerve stimulation and angiotensin were unaffected. Although meclofenamate enhanced renal vascular resistance, its effects on vasoconstrictor responses were inconsistent. After indomethacin, the renal dilator response to bradykinin was enhanced; however, dilator responses to nitroglycerin were unaltered. The present data indicate that the increase in renal vascular resistance after indomethacin does not depend on the adrenergic system but may be dependent on the renin-angiotensin system. The inconsistent effect of the inhibitors of synthesis on renal constrictor responses to nerve stimulation suggests that endogenous prostaglandins do not serve to modulate the effects of the sympathetic nervous system on the feline renal vascular bed. These results also indicate that renal dilator responses to bradykninin are not mediated by prostaglandins in the cat.

Animals↗
PubMed1978

Modulation by prostaglandin synthesis inhibitors of the action of exogenous angiotensin II on glomerular ultrafiltration in the rat.

We studied the effects of angiotensin II (A II) infusion, with and without inhibition of prostaglandin (PG) synthesis, on the determinants of glomerular ultrafiltration in 27 plasma volume-expanded Munich-Wistar rats. The effects of PG inhibition alone and infusion of vehicle alone also were investigated. With a pressor dose of A II single nephron (SN) GFR and total GFR did not change significantly, despite declines in both glomerular plasma flow rate (QA) and the ultrafiltration coefficient (Kf), due to an offsetting rise in the transcapillary hydraulic pressure difference (deltaP). Afferent and efferent arteriolar resistances (RA and RE) increased by approximately 100% above control during A II infusion. Inhibition of PG synthesis alone and infusion of vehicle alone similarly failed to affect SNGFR and total GFR, and only slight changes occurred in the determinants of glomerular ultrafiltration in these rats. When A II infusion was accompanied by inhibition of PG synthesis, however, profound declines in SNGFR and total GFR were seen, due to further reductions in QA and 2-fold greater increases in RA and RE than occurred with the same dose of A II alone. The A II-induced fall in Kf was not affected by simultaneous PG inhibition. Thus, endogenous PGs attenuate the vasoconstrictor actions of A II on the superficial renal microvasculature and minimize changes in QA, SNGFR, and total GFR. It is likely that an interaction between A II and PG may be important in pathophysiological conditions in which endogenous A II levels are elevated.

Angiotensin II↗
PubMed1979

Prostaglandin control of the renal circulation in response to hypoxemia in the fetal lamb in utero.

We studied the effects of 10-minute periods of hypoxemia in unanesthetized fetal lambs in utero instrumented for measurements of arterial pressure and renal and iliac blood flows. Fetal hypoxemia, induced by delivering a hypoxic gas mixture to the ewe, was characterized by a reduction in fetal PaO2 from 20.1 +/- 1.4 to 8.8 +/- 1.0 mm Hg (mean +/- SE). The fetus responded with bradycardia and persistent vasoconstriction in the iliac bed throughout the 10-minute period. In contrast, renal resistance rose significantly only at the end of the hypoxemic period. After 5-7 minutes of hypoxemia, when iliac flow had fallen by 40 +/- 4% and iliac resistance had risen by 86 +/- 13%, renal flow and resistance were not changed significantly from control; in fact, we found that renal flow rose substantially at this time in several fetal lambs. After blockade of prostaglandin synthesis with either indomethacin or meclofenamate, renal flow fell after 5-7 minutes of hypoxemia by 36 +/- 5%. The reduction in renal flow and increases in renal resistance were significantly greater than was observed prior to blockade of prostaglandin synthesis. Thus, fetal hypoxemia elicits bradycardia and intense peripheral vasoconstriction reflected by the changes in the iliac bed, with relative sparing of the reanl bed. The relative protection of the renal bed during fetal hypoxemia appears to be related to a mechanism involving prostaglandins, since after blockade of prostaglandin synthesis, hypoxemia results in intense renal vasoconstriction.

Animals↗
PubMed1980

Effects of indomethacin and meclofenamate on renin release and renal hemodynamic function during chronic sodium depletion in conscious dogs.

We studied the control of renin release and renal hemodynamic function by administering prostaglandin synthetase inhibitors to conscious sodium-depleted dogs with blockade of the adrenergic nervous system induced by bilateral renal denervation and propranolol administration. Indomethacin (10 mg/kg) reduced plasma renin activity (PRA) by 59% from a high sodium-depleted value, but PRA was still 3 times the normal sodium-repleted level. Arterial pressure, CCr, CPAH, urine flow, and potassium excretion fell strikingly. Similar results were obtained with meclofenamate. When SQ 14,225 was given to another group of conscious, sodium-depleted dogs with adrenergic nervous system blockade, PRA increased from the high sodium-depleted level of 5.7 to 29.3 ng of Angiotensin I (AI)/ml per hour; indomethacin (10 mg/kg) appeared to reduce PRA (0.05 less than P less than 0.1) but to only 12.1 ng of AI/ ml per hour, which is 17 times the normal level. This high level of PRA after blockade of the adrenergic nervous system and injection of indomethacin suggests that important mechanisms other than norepinephrine and renal prostaglandins control renin release; it is proposed that both the renal vascular receptor and the macula densa are involved. The marked decreases in CCr and CPAH in response to indomethacin emphasize the important role of renal prostaglandins in the control of renal hemodynamic function during sodium depletion.

Animals↗
PubMed1980

Role of medullary hemodynamics in the natriuresis of drug-induced renal vasodilation in the rat.

In contrast to most renal vasodilators, such as acetylcholine (ACh), secretin increases renal blood flow in the dog without a marked effect on sodium excretion (UNaV). To investigate this observation, we studied the relationship between renal vasodilation, UNaV, and papillary plasma flow (PPF) in rats, infused either with ACh or secretin into the aorta at the level of both renal arteries. ACh significantly increased GFR, PAH clearance, and UNaV (delta + 0.35 ml/min, + 2.11 ml/min and + 1.77 muEq/min, respectively; P < 0.05). PPF rose from 50 +/- 2.6 ml/min 100 g (mean +/- SE) in control rats to 91 +/- 4.7 ml/min 100 g after ACh (p < 0.001). Despite a similar increase in PAH clearance after secretin (+ 2.21 ml/min; P < 0.01), UNaV remained unchanged and PPF was only slightly, although significantly, increased (from 50 +/- 2.6 ml/min 100 g to 65 +/- 2.75 ml/min 100 g; P < 0.05). Both total kidney and papillary vasodilation, and the increase in UNaV after ACh were blocked by previous administration of meclofenamate (M), a prostaglandin inhibitor. No effect of M in secretin-infused rats was observed. In conclusion, the relationship between a total renal vasodilation and natriuresis was dissociated with secretin, but not with ACh. However, a relationship between the natriuresis and influence on papillary hemodynamics was observed with both vasodilators. Finally, the renal hemodynamic and natriuretic effects of ACh are probably mediated by prostaglandin release.

Acetylcholine↗
PubMed1985

Two distinct effects of oxygen on vascular tone in isolated porcine coronary arteries.

The relation between PO2 and vessel tone was studied in isolated porcine left descending coronary artery rings. Porcine left descending coronary artery mounted isometrically and equilibrated in Krebs-bicarbonate solution (37 degrees C, pH 7.4, when gassed with 95% oxygen + 5% carbon dioxide) exhibited spontaneous basal tone. Decreasing bath PO2 to 40%, 20%, and 12% elicited sustained increases in basal tension which were reversible, ranging between 10% and 20% of the contraction induced by 40 mM potassium chloride. Further decreases in PO2 to near zero (anoxia) resulted in relaxation to baseline. Cyclooxygenase inhibitors indomethacin (5.5 X 10(-6) M), aspirin (5 X 10(-5) M), and meclofenamate (10(-5) M) decreased vascular tone and totally prevented coronary vasoconstriction induced by lowering bath PO2 to 12% or 40% but did not affect anoxic vasorelaxation. Neither basal tone nor the vasoconstriction induced by decreases in bath PO2 were influenced by the antihistaminergic drug pyribenzamine (10(5) M) or by the alpha-adrenergic blocker phentolamine (10(-6]. Isoproterenol (10(-9) to 10(-8) M) or an elevation of the bath potassium concentration from 5.9 to 11 mM significantly augmented coronary vasoconstriction induced by lowering bath PO2 from 95% to 40%. Elevation of the bath potassium chloride concentration to 40 mM further increased isometric force but inhibited the vasoconstriction in response to decreasing PO2 from 95% to 40%. Anoxia relaxed contractions induced by 40 mM potassium chloride, histamine, or ouabain. The data suggest the existence of two distinct oxygen-sensitive mechanisms in porcine coronary arteries, both of which regulate vascular tone. One is activated at relative high PO2 values (10-40%), and the vasoconstriction induced by this mechanism is mediated by vascular prostaglandin synthesis. The other is expressed at low PO2 values (near zero), and the depression of mechanical activity by this mechanism may be related to limitation of oxidative energy metabolism. The first mechanism can be augmented by beta-adrenoceptor stimulation indicative of an interaction between vascular prostaglandin synthesis and beta-adrenergic mechanisms in the coronary artery wall.

Animals↗
PubMed1985

Decreased pressor reactivity to angiotensin II in cirrhotic rats. Evidence for a post-receptor defect in angiotensin action.

We used a model of cirrhosis in the rat, produced by inhalation of carbon tetrachloride for 6 weeks, to investigate the mechanism of resistance to the pressor effects of angiotensin II. The pressor response to angiotensin II was significantly lower in conscious cirrhotic animals than in controls. On the other hand, cirrhotic animals had normal pressor responses to norepinephrine, indicating that a generalized defect in vascular reactivity does not cause the decreased pressor response to angiotensin II. Enhanced baroreceptor activity was not the cause of the decreased pressor response to angiotensin II, since baroreflex control of heart rate after angiotensin II was similar in cirrhotics and controls. Pretreatment with either the converting enzyme inhibitor captopril to reduce circulating angiotensin II or the prostaglandin synthesis inhibitor meclofenamate failed to normalize the response to angiotensin II. Thus, neither prior occupancy of receptors with endogenous angiotensin II nor the production of vasodilatory prostaglandins was responsible for the decreased angiotensin II response. Studies of angiotensin II binding by mesenteric artery smooth muscle particles showed that, in cirrhotic animals, receptor affinity for angiotensin II, was significantly lower than in controls (kd: cirrhosis 1.11 +/- 0.09 nM, control 0.94 +/- 0.13 nM; P less than 0.02), whereas receptor number was significantly increased (cirrhosis 315 +/- 42 fmol/mg protein, control 277 +/- 43 fmol/mg protein, P less than 0.01). However, total binding of AII by vascular receptors from cirrhotics was no different than in controls, since the decrease in affinity negated the increase in receptor number.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1986

Prostaglandins contribute to cardiovascular reflexes evoked by static muscular contraction.

The purpose of this study was to determine the contribution of prostaglandins to the reflex cardiovascular responses induced by static contraction of the hind limb in cats, i.e., the exercise reflex. To accomplish this, the cardiovascular responses to hind limb contraction induced by electrical stimulation of spinal cord ventral roots L6-7 and S1 were compared before and after inhibition of prostaglandin synthesis (indomethacin, 2-6 mg/kg i.v., n = 5, or sodium meclofenamate, 2-6 mg/kg i.v., n = 5) or after injection of prostaglandin E2 into the hind limb arterial blood supply. Treatment with indomethacin attenuated the contraction-induced increase in mean arterial pressure and left ventricular dP/dt by 76% and 86%, respectively. Heart rate and average developed triceps surae muscle tension were unchanged. After administering sodium meclofenamate, the reflex response was attenuated to a similar degree. In the indomethacin-treated animals, injection of exogenous prostaglandin E2 (PGE2) partially restored the pressor and myocardial contractile responses. In 6 animals, treatment with exogenous PGE2 without prior inhibition of prostaglandin synthesis did not significantly augment the contraction-induced cardiovascular response. Using the radioactive microsphere technique, we measured skeletal muscle blood flow during contraction before and after treatment with indomethacin (n = 6) to determine if an indomethacin-induced alteration in blood flow could account for the attenuated contraction-induced cardiovascular response. Blood flow during static muscle contraction was not significantly altered by indomethacin. We conclude that prostaglandins contribute to the exercise reflex through an action on afferent nerve endings rather than through a regional vascular effect.

Animals↗
PubMed1987

Selective antagonism of hormone-induced vasoconstriction by synthetic atrial natriuretic factor in the rat microcirculation.

Synthetic atrial natriuretic factor (ANF) was either added to suffusate solutions (30 nM) or infused into the jugular vein (0.1 nanomol/min/100 g) of anesthetized rats. Steady-state blood flow was calculated from arteriolar diameter and red blood cell velocity measurements using video microscopy in the intestinal or skeletal muscle microcirculation. Arterioles demonstrated spontaneous vasomotor tone by dilating to topical adenosine, but topical or intravenous ANF did not cause vasodilation. Either angiotensin, norepinephrine, or vasopressin was added to the suffusates in the presence or absence of a cyclooxygenase inhibitor (30 microM, meclofenamate or indomethacin) because each agonist is known to stimulate vasoactive prostanoid synthesis. In the intestine, angiotensin (500 nM) caused 40 +/- 2% blood flow decreases during intravenous saline but only 23 +/- 6% during intravenous ANF. Angiotensin (162 nM) and a cyclooxygenase inhibitor caused 19 +/- 4% blood flow decreases but only 8 +/- 5% decreases with cyclooxygenase inhibitor and topical ANF. In contrast, norepinephrine (2-5 microM) caused vasoconstriction that was not altered by topical or intravenous ANF, either alone or in combination with cyclooxygenase inhibitors. In the spinotrapezius muscle, angiotensin (1-2 nM) plus a cyclooxygenase inhibitor caused 40-60% blood flow decreases but only 20-30% decreases during intravenous or topical ANF. Topical or intravenous ANF did not alter the vasoconstriction evoked by arginine vasopressin (0.5-1.0 nM) or by norepinephrine (40-230 nM). Thus, supraphysiologic concentrations of ANF produced no direct vasodilation in the intestinal or skeletal muscle microcirculation.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1989

Role of prostaglandins in proximal tubule sodium reabsorption: response to elevated renal interstitial hydrostatic pressure.

Previous studies have shown that the elevation of renal interstitial hydrostatic pressure by the direct expansion of renal interstitial volume increases urinary sodium excretion. The objective of the present study was to investigate whether proximal tubules respond to the elevated renal interstitial hydrostatic pressure and whether the inhibition of prostaglandin synthesis would alter the effect of elevated renal interstitial hydrostatic pressure on proximal sodium reabsorption. Expansion of renal interstitial volume by injecting 100 microliters of 2.5% albumin solution through a chronically implanted matrix increased renal interstitial hydrostatic pressure similarly in control rats (n = 8) and in indomethacin (n = 8) or meclofenamate-treated (n = 7) rats. In the absence of prostaglandin synthesis inhibition, renal interstitial volume expansion significantly increased the fractional delivery of sodium at the superficial late proximal tubules from 56.5 +/- 6.1 to 67.0 +/- 6.5% (p less than 0.01) with an accompanying increase in fractional excretion of sodium from 2.1 +/- 0.5 to 3.0 +/- 0.4% (p less than 0.01). In the presence of indomethacin or meclofenamate, renal interstitial volume expansion failed to augment the fractional delivery of sodium and the fractional excretion of sodium. In summary, these studies demonstrate that the synthesis of prostaglandins plays a role in the regulation of sodium reabsorption by the proximal tubules in response to elevated renal interstitial hydrostatic pressure.

Animals↗
PubMed1990

Effect of protein intake on regional vascular resistance and reactivity to angiotensin II in the rat.

Male Sprague-Dawley rats (200-250 g) were fed low protein (6%) diets (LP rats), high protein (50%) diets (HP rats), or regular rat chow (approximately 16% protein) (control rats) and studied under anesthesia after 2 weeks. Dietary protein intake did not affect mean arterial pressure, but renal blood flow was increased in the HP rats and decreased in the LP rats compared with the control rats. Mesenteric blood flow was not significantly different in the three diet groups. Captopril (10 mg.kg-1 i.v.) had no effect on renal vascular resistance in the HP rat but did reduce the elevated renal vascular resistance seen in the LP rat. Meclofenamate (5 mg.kg-1 i.v.) did not significantly affect renal hemodynamics in either HP or LP rats. Finally, the HP rat exhibited resistance to the systemic pressor, renal, and mesenteric vasoconstrictor effects of angiotensin II. Captopril restored the systemic pressor and the mesenteric vasoconstrictor response but not the renal vasoconstrictor response to angiotensin II. Meclofenamate, on the other hand, restored both the systemic pressor response and the renal vasoconstrictor response. Thus, in the LP rat, the vascular response to angiotensin II remains intact, and renal vasoconstriction appears to be mediated by angiotensin II. In contrast, in the HP rat, the renovascular response to angiotensin II is blunted apparently because of enhanced renal prostaglandin production. However, neither increased renal prostaglandin synthesis nor blunting of the renovascular response to angiotensin II appears to account for the chronic vasodilation seen in the HP rat.

Angiotensin II↗
PubMed1997

Endotoxin impairs agonist-induced calcium mobilization in rat mesangial cells.

We hypothesized that endotoxin would impair agonist-induced calcium (Ca2+) mobilization in rat mesangial cells, owing to the induction of nitric oxide synthase (NOS) and augmented nitric oxide (NO) synthesis. We measured basal and bradykinin-induced peak free cytosolic Ca2+ concentrations through microspectrofluorimetry with fura-2 in confluent mesangial cells, and assayed conditioned medium for nitrite accumulation. Prior to measurement, cells were incubated overnight in serum-supplemented medium, with or without endotoxin, 1-arginine, indomethacin, meclofenamate, or N omega-nitro-L-arginine methyl ester (L-NAME). Endotoxin (1 mg/ml) decreased bradykinin-induced peak Ca2+ responses by 35 to 60% (p < 0.0001) and increased nitrite accumulation > 6-fold (p < 0.01). Arginine supplementation further (> 9-fold, p < 0.0001) increased nitrite accumulation without changing the effect on Ca2+. Inhibition of NOS abolished increments in nitrite concentration but had no effect on impaired Ca2+ responses. Cyclooxygenase (COX) inhibitors, present during incubation with endotoxin, but not afterward, normalized bradykinin-stimulated calcium responses. Thrombin-stimulated Ca2+ responses were similarly affected. We conclude that neither NO nor prostaglandins act directly to impair agonist-induced Ca2+ mobilization following endotoxin exposure; however, this effect may be an indirect effect of COX products, including reactive oxygen intermediates.

Animals↗
PubMed1990

Effects of pulmonary vascular obstruction on right ventricular afterload.

We compared the effects of three forms of vascular obstruction: positive end-expiratory pressure (PEEP), ensnarement of the left main pulmonary artery (SN), and pulmonary thromboembolism (EMB) on right ventricular afterload. We measured right ventricular and pulmonary arterial pressures and flow in open-chested dogs under anesthesia (n = 8). Pulmonary artery input impedance (Zin) was calculated by Fourier analysis of the pressure and flow waves. Characteristic impedance (Zc) and pulmonary arterial compliance (Ca) were estimated from Zin with a lumped parameter model. Although PEEP, SN, and EMB all increased mean pulmonary arterial pressure, PEEP, had negligible effect on Zc and Ca, whereas SN increased Zc but decreased Ca (+24% and -49%, respectively), and EMB decreased both Zc and Ca (-33% and -39%, respectively). These changes of Zc affect wave reflection and alter the energy transmission ratio, which is the ratio of hydraulic power output in the measured and forward waves (Wm/Wf). Under control conditions, Wm/Wf was 62% and was not affected significantly by SN (59%) or by PEEP (46%), but it fell significantly to 30% after EMB. Simulation of these experiments in a mathematical model suggested that the increase of Zc with SN was due to an active neurohumoral effect; all other responses were consistent with passive mechanical effects. In additional experiments, we tested the effects of meclofenamate (n = 6) and ketanserin (n = 6) and of atropine and vagotomy (n = 5) on the response to SN and EMB. The serotonin antagonist, ketanserin, blunted the increase of Zc to SN, but none of the interventions significantly affected the response of Zc or Ca to EMB.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗