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Biomedical subjects

D M Rodman

Publications and source records attributed to D M Rodman.

At least 55 records · Page 3Linked to original sources
PubMed1992

Endothelin-1 increases the pulmonary microvascular pressure and causes pulmonary edema in salt solution but not blood-perfused rat lungs.

Endothelin-1 (ET-1) is a potent vasoactive peptide that has been reported to cause lung edema. This study tested if the edemagenic effect of ET-1 is due to preferential venoconstriction and, if so, whether the site of resistance is similar with salt solution (PSS) and more physiologic blood perfusate. ET-1 caused concentration-dependent contraction of pulmonary arterial and venous rings, with an EC50 of 1.3 nM in artery and 0.6 nM in vein (p less than 0.05). In PSS-perfused lungs, 5 nM ET-1 caused a 7.0 +/- 0.8 torr pressor response that was associated with a 5.0 +/- 0.3 torr increase in microvascular pressure and a 530 +/- 20 mg increase in lung weight within 10 min. In contrast, KCl-treated lungs had an equivalent pressor response (7.4 +/- 1.1 torr), yet the microvascular pressure increased by only 2.5 +/- 0.4 torr (p less than 0.05 from ET-1) and the lung weight was unchanged. Meclofenamate did not prevent the effect of ET-1 on microvascular pressure or lung weight. In blood-perfused lungs, ET-1 caused a 7.3 +/- 0.1 torr pressor response but only a 2.0 +/- 0.5 torr increase in microvascular pressure and no increase in lung weight. ET-1 had no effect on permeability either of cultured endothelial cell monolayers or in the pulmonary microvasculature in vivo. We conclude that the edemagenic effect of ET-1 in PSS-perfused lungs is mediated through venoconstriction and an increase in microvascular pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Role of ATP-sensitive potassium channels in ovine fetal pulmonary vascular tone.

To study the potential role of ATP-sensitive K+ (K+ATP) channels in fetal pulmonary vasoregulation, we studied the effect of a K+ATP channel agonist, lemakalim, and antagonist, glibenclamide, on the fetal pulmonary circulation in nine chronically instrumented late-gestation fetal lambs. Left pulmonary artery (LPA) blood flow was measured with an electromagnetic flow transducer. Brief (10 min) infusions of lemakalim at 3, 10, and 30 micrograms/min into the LPA produced dose-dependent increases in flow from 68 +/- 7 to 96 +/- 11, 160 +/- 15, and 204 +/- 34 ml/min, respectively. The duration of pulmonary vasodilation after the 10-min infusions of lemakalim at 3, 10, and 30 micrograms/min was 20 +/- 3, 47 +/- 10, and 55 +/- 15 min, respectively. Pulmonary blood pressure and flow did not change with intrapulmonary infusion of glibenclamide (10 mg), a K+ATP channel antagonist. Lemakalim-induced pulmonary vasodilation was not affected by nitro-L-arginine (10 mg), a competitive inhibitor of endothelium-dependent relaxing factor, but was blocked by glibenclamide. Prolonged (2 h) intrapulmonary infusions of lemakalim (2-6 micrograms/min) increased pulmonary blood flow by 137%. The increase in pulmonary blood flow was sustained throughout the infusion. Systemic and pulmonary arterial pressures decreased during prolonged infusion. We conclude that K+ATP channels are present in the fetal pulmonary circulation, but do not participate in the regulation of basal pulmonary vascular tone. K+ATP channel activation produces sustained vasodilation that is not mediated by endothelium-derived relaxing factor. We speculate that birth-related stimuli activate K+ATP channels to enhance the pulmonary vasodilation that occurs at birth.

Adenosine Triphosphate↗
PubMed1992

Chronic hypoxia selectively augments rat pulmonary artery Ca2+ and K+ channel-mediated relaxation.

The initiating event in hypoxic pulmonary hypertension is felt to be sustained hypoxic vasoconstriction, ultimately leading to vascular remodeling and fixed pulmonary hypertension. During the initial vasospastic phase endogenous vasodilatory pathways may serve to ameliorate the development of pulmonary hypertension. However, various studies in the systemic and pulmonary circulations have shown that chronic hemodynamic stress alters both endothelial and smooth muscle cell function. The effect of chronic hypoxia in rats was therefore tested on three major vasodilatory pathways: 1) endothelium-dependent relaxation (using endothelium-derived relaxing factor agonists and antagonists); 2) smooth muscle cell cyclic nucleotide-mediated relaxation [using guanosine and adenosine 3',5'-cyclic monophosphate (cGMP and cAMP) agonists]; and 3) ion channel-dependent relaxation (using K+ channel agonists and Ca2+ channel antagonists). It was found that short-term exposure (72 h) to hypoxia caused augmentation of K+ and Ca2+ channel-dependent relaxation with no effect on endothelium-dependent or cyclic nucleotide-mediated relaxation. More prolonged exposure (4-5 wk) was additionally associated with inhibition of endothelium-dependent relaxation and smooth muscle cell cGMP-mediated relaxation. There was no effect on either basal modulation of tone by the endothelium, cAMP-mediated relaxation, or systemic vessel relaxation. It is concluded that an early response to hemodynamic stress in the pulmonary circulation is alteration in smooth muscle cell ion channel function and/or Ca2+ homeostasis.

Animals↗
PubMed1991

The cystic fibrosis heterozygote--advantage in surviving cholera?

Cystic fibrosis (CF) is the most common fatal genetic disorder of caucasians. While it has been hypothesized that there is a CF heterozygote advantage which allowed the gene to achieve such high prevalence, the nature of that advantage remains a mystery. The recent identification and sequencing of the CF gene has increased the probability that the CF heterozygote advantage will be discovered. In this hypothesis we review the information which is known about the selection of the CF mutation and its cellular consequences, and present evidence which suggests that resistance to cholera may have been the environmental factor which selected CF heterozygotes over their 'normal' homozygote cohort. Future lines of experimentation and possible clinical applicability to therapy of secretory diarrhea are presented.

Chloride Channels↗
PubMed1991

Paradoxical constriction to platelets by arteries from rats with pulmonary hypertension.

We recently described the early appearance of pulmonary hypertension in the fawn-hooded rat (FHR), an animal with platelet storage pool disease also known to develop systemic hypertension at later ages. Since mediators released from aggregating platelets influence vascular tone, we hypothesized that platelet-mediated pulmonary vascular responses in FHR may be abnormal and potentially linked to the mechanism of pulmonary hypertension. To test this we examined reactivity of isolated pulmonary arteries (PA) and thoracic aortas (Ao) from young FHR with moderately severe pulmonary hypertension but normal systemic pressures. These vessels were compared with PA and Ao from control Sprague-Dawley rat (SDR). Aggregating platelets (1,000-40,000 platelets/mm3) from FHR caused dilation of SDR PA and Ao but constriction of FHR PA and Ao. Qualitatively similar responses were also observed with platelets isolated from SDR implying that abnormal responses were not simply due to the storage pool deficiency in FHR. Response to the platelet-derived endothelium-dependent vasodilator ADP was markedly impaired in FHR PA and mildly impaired in FHR Ao. Endothelium-dependent dilation to acetylcholine, but not to A23187, was mildly impaired in FHR PA while responses to both dilators were normal in FHR Ao. Endothelium-independent dilation to sodium nitroprusside was normal in both FHR PA and Ao. Constrictor sensitivity to serotonin, but not to the thromboxane A2 mimetic U-46619, was increased in FHR PA while responses to both constrictors were normal in FHR Ao. In summary, PAs from FHR with spontaneous pulmonary hypertension exhibit paradoxical constriction to both normal and storage pool deficient platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Effects of inhibitors of EDRF and EDHF on vasoreactivity of perfused rat lungs.

Recent studies indicate that the endothelium of isolated rat pulmonary arteries releases two different factors, endothelium-derived relaxing factor (EDRF) and hyperpolarizing factor (EDHF), which participate in histamine- and acetylcholine-induced relaxation. There is evidence for EDRF vasoreactivity in perfused lungs, but a role for EDHF, which hyperpolarizes vascular smooth muscle by activating membrane K+ channels, has not been reported. We used the inhibitors of EDRF, 20 microM hemoglobin, 200 microM NG-mono-methyl-L-arginine, and 2 mM L-canavanine, the nonselective blocker of K+ channels, 10 mM tetraethylammonium (TEA), and the inhibitor of ATP-sensitive K+ channels, 20 microM glibenclamide, to compare the roles of EDRF and EDHF in the vasoregulation of meclofenamate-treated, salt solution-perfused rat lungs. The three EDRF inhibitors had little or no effect on baseline perfusion pressure, but each potentiated the peak pressor response to airway hypoxia. Neither of them inhibited the pulmonary vasodilation to 5 microM histamine. TEA, but not glibenclamide, increased baseline pressure and potentiated the peak hypoxic response. Both K+ channel blockers, but not the EDRF inhibitors, also prolonged the hypoxic response by reducing the rate of spontaneous vasodilation. TEA, but not glibenclamide, inhibited histamine vasodilation. These results suggest roles for both EDRF and EDHF in the control of rat pulmonary vascular reactivity. EDRF is apparently not responsible for the low vascular tone of the normoxic lung and does not mediate the vasodilation to histamine, but it does modulate the hypoxic pressor response. The exact role of EDHF is uncertain, but it may also modulate hypoxic vasoconstriction and mediate at least part of the histamine vasodilation.

Analysis of Variance↗
PubMed1991

Maturational changes in endothelium-derived relaxing factor activity of ovine pulmonary arteries in vitro.

To examine mechanisms underlying fetal pulmonary vascular vasodilator responses and maturational changes in endothelial function, we studied effects of endothelium-dependent (acetylcholine, ACh: adenosine diphosphate, ADP; and A23187) and -independent (sodium nitroprusside, SNP) vasodilators on tone of small (third generation) pulmonary artery rings isolated from late-gestation fetal, newborn, and adult sheep. Changes in isometric force of phenylephrine-contracted rings were measured after the cumulative addition of vasodilators in baths aerated with 21% O2 and 5% CO2. Pulmonary artery rings from fetal lambs demonstrated minimal relaxation to ACh, ADP, and A23187, achieving only 17 +/- 3, 14 +/- 5, and 23 +/- 8% relaxation, respectively. In contrast, fetal rings relaxed completely (100%) to SNP. Rings from newborn and adult animals had significantly greater maximal relaxation in response to ACh. ADP, and A23187 than fetal rings (at least P less than 0.05 for each comparison with fetal rings), but responses to SNP were not different. Hemoglobin (10(-5) M), an inhibitor of endothelium-derived relaxing factor, caused less augmentation of phenylephrine contraction in fetal than adult pulmonary artery rings (11 +/- 4% vs. 49 +/- 8%; P less than 0.01). We conclude that in comparison with pulmonary artery rings from postnatal animals, fetal pulmonary artery rings have diminished endothelium-derived relaxation factor activity. We speculate that maturational changes in endothelial cell function contribute to ontogenetic differences in pulmonary vasoreactivity.

Acetylcholine↗
PubMed1991

Effects of K+ channel blockers on vascular tone in the perfused rat lung.

To learn more of the role of K+ channel activity in the regulation of pulmonary vascular tone, we compared the pressor effects of the differential blockers of numerous K+ channels, tetraethylammonium chloride and 4-aminopyridine, and the inhibitor of ATP-sensitive K+ channels glibenclamide in meclofenamate-treated salt solution-perfused rat lungs. Tetraethylammonium (1 to 20 mM) and 4-aminopyridine (1 to 10 mM), but not glibenclamide (1 to 20 microM) caused vasoconstriction in the normoxic lung. The Ca++ channel blocker nifedipine (0.1 microM) and the alpha adrenoceptor antagonist phentolamine (10 microM) inhibited the 4-aminopyridine response by about 50% and reduced slightly the smaller tetraethylammonium response. 4-Aminopyridine and, to a lesser extent, tetraethylammonium, but not glibenclamide, also potentiated peak vasoconstriction to angiotensin II and airway hypoxia. Nifedipine, but not phentolamine, inhibited hypoxic vasoconstriction and prevented the potentiation by 4-aminopyridine. These results suggest that Ca(++)- and/or voltage-activated (not ATP-sensitive) K+ channels may be important in maintaining low pulmonary vascular tone.

Angiotensin II↗
PubMed1991

Difference in effect of inhibitors of energy metabolism on endothelium-dependent relaxation of rat pulmonary artery and aorta.

Previous studies have suggested that systemic artery endothelial cell production of the nitrovasodilator endothelium-derived relaxing factor (EDRF) is dependent upon oxidative energy production. This study was undertaken to test if pulmonary artery (PA) EDRF has a similar requirement for oxidative phosphorylation. The effects of inhibitors of oxidative phosphorylation and glycolysis on endothelium-dependent relaxation were studied in rat aortic and PA rings. In aortic rings, 0.1 microM rotenone and 0.1 microM antimycin A, and, to a lesser extent, 50 mM 2-deoxyglucose, inhibited endothelium-dependent relaxation to acetylcholine and adenosine diphosphate. Relaxation to the receptor-independent calcium ionophore A23187 was less severely affected, and relaxation to the direct smooth muscle dilator sodium nitroprusside was unaffected. The inhibitors had much less effect on PA relaxation, decreasing the potency but not the efficacy of the endothelium-dependent dilators. These results suggest that the dependence on oxidative energy production for endothelium-dependent relaxation may differ between the systemic and pulmonary vascular beds, and that in pulmonary arterial endothelium, oxidative energy production may not be required for receptor-mediated production and/or release of EDRF. The resistance of PA endothelium to decreases in oxidative energy production may contribute to the normally low tone maintained in this circuit in vivo.

Animals↗
PubMed1990

Endothelin 1 causes pulmonary vasodilation in rats.

Endothelin 1 (ET-1), a peptide produced by endothelial cells, causes transient dilation of some systemic vascular beds. To test whether low concentrations of ET-1 could also dilate the pulmonary vascular bed, we examined its effects in isolated blood- and salt solution-perfused rat lungs and in conscious catheterized rats. In blood-perfused lungs undergoing hypoxic (3% O2) vasoconstriction, repeated additions of 0.5 nM ET-1 to the perfusate elicited transient partial vasodilations. The higher concentration of 5 nM caused a larger transient vasodilation followed by vasoconstriction. In nine conscious rats exposed to 8% O2, intravenous ET-1 (0.2 nmol/kg) reversed the hypoxic pressor response by 63 +/- 8% without affecting cardiac output. In eight salt solution-perfused lungs vasoconstricted with 25 mM KCl, 0.5 nM ET-1 caused a maximum vasodilation of 35 +/- 3% with a half-life of 10.7 +/- 1.1 min. The vasodilation was not inhibited by blockers of cyclooxygenase (3.1 microM meclofenamate), platelet-activating factor receptors (10 microM Web 2086), histamine H1 receptors (50 microM chlorpheniramine), or endothelium-derived relaxing factor activity (10 microM hemoglobin and 50 microM methylene blue). However, it was reduced by approximately 50% with the K+ channel blockers, tetraethylammonium chloride (10 mM) and glybenclamide (10 microM), and the inhibitor of Na(+)-K+ pumping, ouabain (0.1 mM). These results indicate that ET-1 is a potent dilator of the pulmonary vascular bed of the rat and that the mechanism of dilation may involve activation of ATP-sensitive K+ channels and membrane hyperpolarization.

Animals↗
PubMed1990

Effects of hypoxia on endothelium-dependent relaxation of rat pulmonary artery.

We have previously reported that the isolated rat branch pulmonary artery (PA) contracts when made hypoxic and that the contraction is dependent in large part on the presence of a functioning endothelium. This study tested if the hypoxic contraction was caused by reduced endothelium-derived relaxing factor (EDRF) activity. To do so we tested if chemical inhibitors of EDRF mimicked the effect of hypoxia, if PA guanosine 3',5'-cyclic monophosphate (cGMP) fell during hypoxic contraction, and if stimulation of smooth muscle cGMP attenuated hypoxic contraction. We found that the EDRF inhibitors hemoglobin and methylene blue caused a concentration-dependent increase in PA force that equaled that produced by hypoxia. PA cGMP decreased in endothelium-intact rings from 105 +/- 14 pM/g (wet wt) during normoxia to 41 +/- 9 pM/g during hypoxia. In endothelium-denuded rings normoxic cGMP was reduced to 32 +/- 10 pM/g with no further decrease during hypoxia. The endothelium-independent stimulators of cGMP, nitric oxide, and 8-bromo-cGMP, reduced maximum hypoxic contraction by 80 +/- 11 and 93 +/- 3%, respectively, whereas the endothelium-dependent stimulator acetylcholine did not. PA adenosine 3',5'-cyclic monophosphate (cAMP) fell only slightly during hypoxia and cAMP inhibitors failed to mimic the hypoxic contraction. We conclude that the hypoxic contraction of isolated rat PA is caused largely by decreased EDRF activity.

Acetylcholine↗
PubMed1990

Successful treatment of sarcoidosis-associated pulmonary hypertension with corticosteroids.

We report a case of sarcoidosis presenting with cor pulmonale of a greater severity than would be expected from the degree of hypoxia and pulmonary fibrosis. Right heart catheterization revealed that mean pulmonary artery pressure was markedly increased (42 mm Hg), was not reduced by supplemental oxygen, but was reduced significantly (25 mm Hg) after 16 weeks of therapy with corticosteroids. Improvement in symptoms and pulmonary function was maintained for an 18-month period of observation after cessation of corticosteroid therapy.

Adult↗
PubMed1989

Comparative pharmacology of rat and porcine endothelin in rat aorta and pulmonary artery.

Endothelins are potent vasoactive polypeptides produced by endothelial cells. This study compared the potency and efficacy of porcine and rat endothelin in rat aortic and pulmonary artery rings. We found that porcine endothelin was 25 to 55 times more potent than rat endothelin in both endothelium-intact and -denuded rings. Removal of the endothelium augmented and acetylcholine reduced contraction by either endothelin. We conclude that porcine endothelin is intrinsically more potent than rat endothelin and that the endothelium modulates the contraction of both endothelins.

Animals↗
PubMed1989

Hypoxic contraction of isolated rat pulmonary artery.

This study was undertaken to test if isolated rat pulmonary artery (PA) rings contract in response to hypoxia, if the response behaves similarly to previously described physiologic and pharmacologic features of hypoxic pulmonary vasoconstriction (HPV) in the isolated perfused rat lung and if the endothelium is necessary for the response. Rings (2-3 mm wide) cut from the main extrapulmonary PA branches were studied. Hypoxic contractions of up to 80 mg (mean +/- S.E. 34 +/- 5 mg, n = 20) were seen in resting rings. The contraction was more reproducible and was potentiated in rings prestimulated with either phenylephrine, norepinephrine, KCl, angiotensin II or the thromboxane mimetic U46619. The magnitude of the hypoxic contraction was proportional to the level of prestimulation and the severity of the hypoxia, with maximum hypoxic contraction seen during exposure to 0% oxygen. The hypoxic dose response showed a threshold bath pO2 of between 30 and 60 Torr, was potentiated by BAY K8644 (10(-7) M), was inhibited by both nifedipine (10(-7) M) and cooling to 29 degrees C and was not inhibited by meclofenamate (1.6 x 10(-6) M). All these characteristics are comparable to previously described features of HPV in the isolated perfused rat lung. Removal of the endothelium resulted in a 48-80% reduction in maximum PA hypoxic contraction. Similar hypoxic contraction was seen in precontracted aortic rings. We conclude that the hypoxic contraction of isolated rat PA may be a useful in vitro model of HPV, that both the endothelium and smooth muscle may be involved in the sensing of PO2 and that the direct hypoxic response is not unique to pulmonary arteries.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1988

Pulmonary vascular reactivity.

The pulmonary vasculature responds to a multitude of constrictor and dilator mediators, but the exact physiologic and pathologic significance of such responsiveness is unknown. Further careful studies with specific mediator receptor blockers and synthesis inhibitors are required to determine if dilators play a role in maintaining the low vascular tone of the normal pulmonary circulation and if constrictors contribute to either the onset or the maintenance of the pulmonary hypertension associated with chronic airway hypoxia, lung injury, and pulmonary microembolism. It would be a mistake to summarily dismiss the possible involvement of vasoconstrictors in chronic pulmonary hypertension, but the apparent difficulty in establishing their importance emphasizes that mediators of vascular cell migration, proliferation, synthesis, and secretion may be at least as important in the etiology of the increased vascular resistance as the mediators of vascular tone.

Animals↗
PubMed1987

Tracheostomy tube failure in obstructive sleep apnea.

In our institutions we routinely do posttracheostomy sleep studies on patients being treated for obstructive sleep apnea. We have identified several patients who failed to show objective evidence of improvement after tracheostomy. From our studies we have found that both mechanical obstruction and concomitant respiratory control dysfunction caused this failure. A unique tracheostomy tube was constructed to treat the subset of patients with internal collapse of the tracheostomy tube.

Adult↗