Polymorphism of 5' regulatory region of ovine FSHR gene and its association with litter size in Small Tail Han sheep.

Single nucleotide polymorphisms of 5' regulatory region of follicle-stimulating hormone receptor (FSHR) gene were detected in two high prolificacy sheep breeds (Small Tail Han and Hu sheep) and two low prolificacy sheep breeds (Corriedale and Chinese Merino sheep) by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). The results indicated that there were three genotypes (AA, AB and BB) detected by primer 1 in Hu sheep while only one genotype (AA) in other three sheep breeds, and frequencies of AA, AB and BB genotypes in Hu sheep were 0.700, 0.225 and 0.075, respectively. There were three genotypes (EE, EF and EG) detected by primer 3 in Small Tail Han sheep while only EE genotype occurred in other three sheep breeds, and frequencies of EE, EF and EG genotypes in Small Tail Han sheep were 0.775, 0.200 and 0.025, respectively. No polymorphism was detected in four sheep breeds by primer 2 and primer 4. The sequencing results showed that there were two nucleotide mutations (g. -681T>C and g. -629C>T) in genotype BB compared with AA for primer 1. As for primer 3, two mutations (g. -197G>A and g. -98T>C) in genotype EF compared with EE and two mutations (g. -200G>A and g. -197G>A) in genotype EG compared with EE. The heterozygous ewes with EG or EF had 0.89 (P < 0.05) or 0.42 (P < 0.05) lambs more than homozygous ewes (EE genotype) in Small Tail Han sheep, respectively, while there was no significant difference on litter size between EG and EF ewes.

Peroxynitrite does not impair pulmonary and systemic vascular responses.

The effects of peroxynitrite (ONOO-) on vascular responses were investigated in the systemic and hindquarters vascular bed and in the isolated perfused rat lung. Intravenous injections of ONOO- decreased systemic arterial pressure, and injections of ONOO- into the hindquarters decreased perfusion pressure in a dose-related manner. Injections of ONOO- into the lung perfusion circuit increased pulmonary arterial perfusion pressure. Responses to ONOO- were rapid in onset, short in duration, and repeatable without exhibiting tachyphylaxis. Repeated injections of ONOO- did not alter systemic, hindquarters, or pulmonary responses to endothelium-dependent vasodilators or other vasoactive agonists and did not alter the hypoxic pulmonary vasoconstrictor response. Injections of sodium nitrate or nitrite or decomposed ONOO- had little effect on vascular pressures. Pulmonary and hindquarters responses to ONOO- were not altered by a cyclooxygenase inhibitor in a dose that attenuated responses to arachidonic acid. These results demonstrate that ONOO- has significant pulmonary vasoconstrictor, systemic vasodepressor, and vasodilator activity; that short-term repeated exposure does impair vascular responsiveness; and that responses to ONOO- are not dependent on cyclooxygenase product release.

[Topological research of Kováts indices for amines].

A novel connectivity index(mQ) is defined as mQ = sigma (ti.tj.tk....)-0.5 in this paper. 0Q and 3Q have very good correlation for Kováts indices of 22 amines on three stationary phases(OV-101, OV-225 and NGA). Their linear regression equations are proposed as follows: IOV-101 = 118.341 + 197.854 x 0Q + 448.773 x 3Q, r = 0.9733; IOV-225 = 249.218 + 1,815.760 x 3Q + 343.222 x 1Q, r = 0.9746; INGA = 382.196 + 2,004.277 x 3Q + 318.416 x 1Q, r = 0.9734. These models can better elucidate the change rule of Kováts indices for the amines. Furthermore, a modified Jackknife's test was performed to validate the model robustness.

Analysis of responses of garlic derivatives in the pulmonary vascular bed of the rat.

Allicin, an extract from garlic, has been shown to be a systemic and pulmonary arterial vasodilator that acts by an unknown mechanism. In the present experiments, pulmonary vascular responses to allicin (10-100 microg), allyl mercaptan (0.3-1 mg), and diallyl disulfide (0.3-1 mg) were studied in the isolated lung of the rat under constant-flow conditions. When baseline tone in the pulmonary vascular bed of the rat was raised to a high-steady level with the thromboxane A(2) mimic U-46619, dose-related decreases in pulmonary arterial pressure were observed. In terms of the mechanism of action of allicin vasodilator activity in the rat, responses to allicin were not significantly different after administration of the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester, the K(ATP)(+) channel antagonist U-37883A, or the cyclooxygenase inhibitor sodium meclofenamate, or when lung ventilation was interrupted. These data show that allicin has significant vasodilator activity in the pulmonary vascular bed of the rat, whereas allyl mercaptan and diallyl disulfide produced no significant changes in pulmonary arterial perfusion pressure. The present data suggest that pulmonary vasodilator responses to allicin are independent of the synthesis of nitric oxide, ATP-sensitive K(+) channels, activation of cyclooxygenase enzyme, or changes in bronchomotor tone in the pulmonary vascular bed of the rat.

Responses to propofol in the pulmonary vascular bed of the rat.

BACKGROUND: Although a great deal is known about responses to propofol, controversy remains about its mechanism of action. The present study was undertaken to investigate the direct effects of 2,6-diisopropyl phenol, disodium edetate, and its intralipid emulsion in the rat pulmonary vascular bed and to better understand the mechanisms involved in propofol-mediated responses. METHODS: The effects of N omega-l-nitro-l-arginine benzyl ester (L-NABE), an inhibitor of nitric oxide synthase, of the cyclooxygenase blocker, meclofenamate, and the K + ATP channel antagonist, U-37883A, an ATP-sensitive potassium channel antagonist, on responses to propofol, acetylcholine, nitroglycerin, and isoproterenol were investigated in the isolated blood-perfused rat lung under low tone and high steady-state tone. RESULTS: Propofol produced a dose-dependent decrease in pulmonary arterial perfusion pressure. L-NABE significantly reduced vasodilator responses to acetylcholine, whereas the nitric oxide synthase inhibitor had no significant effect on responses to propofol. Meclofenamate significantly reduced vasodilator responses to arachidonic acid without effecting responses to propofol. Responses to propofol were not significantly changed in the presence of U-37883A, whereas U-37883A reduced vasodilator responses to levcromakalim. Additionally, 2,6-diisopropylphenol in a pure preparation as well as an intralipid preparation similar to propofol emulsion had no significant effect while disodium edetate had a dose-dependent depressor effect under high steady-state tone. CONCLUSION: Propofol has significant vasodilator activity in the pulmonary vascular bed of the rat but responses to propofol are not mediated or modulated by the release of nitric oxide, opening of K + ATP channels, or the release of vasodilator cyclooxygenase products.

EMG analysis of voluntary elbow movements in subjects with spasticity.

Surface electromyography (EMG) signals were measured from the biceps brachii (BIC), the brachioradialis (BRD) and the triceps brachii (TRI) of seven young adults with pure spastic quadriplegia and eight normal individuals. The signals were analyzed in both the time domain and the frequency domain. The subjects sat in an adjustable chair and were asked to perform two voluntary tasks involving the elbow joint. For task A, the subjects moved the hand from the proximal target plate to the distal target plate and then back to the proximal one along the table plane. For task B, the subject followed the sound of a metronome (0.5 Hz), perform 5 elbow flexion/extension cycles in the vertical plane. Certain quantitative parameters were identified as statistically significant in describing quantitatively the condition of spasticity. Compared to the normal subjects, the spastic subjects showed significantly higher EMG activities for both the elbow flexors and extensor. The stretch/shortening (S/S) ratios for BRD and TRI were significantly different from those of the normal subjects. The power spectra analysis showed higher mean power frequency (MPF). MPF of BIC and TRI were uncorrelated for normal subjects, but correlated for the spastic subjects. It is speculated that low motor unit discharge rate and fiber type abnormalities may account for these differences.

Pulmonary vasodilation by ketamine is mediated in part by L-type calcium channels.

UNLABELLED: We studied the effects of ketamine in the isolated rat lung under conditions of increased pulmonary arterial pressure using the thromboxane A2 mimic, U46619, and in response to ventilatory hypoxia. Ketamine caused dose-dependent vasodilation, and possible mechanisms were evaluated using verapamil, meclofenamate, N(omega)-L-nitro-L-arginine benzyl ester (an inhibitor of nitric oxide synthase), and U-38883A (an ATP-sensitive potassium channel antagonist) in the isolated blood-perfused rat lung. Under increased tone conditions, N(omega)-L-nitro-L-arginine benzyl ester, meclofenamate, and U-38883A had no significant effect in attenuating ketamine-induced vasodilator responses. In a final series of experiments, verapamil significantly attenuated ketamine-induced vasodilator responses. These data suggest that ketamine has significant vasodilator activity in the pulmonary vascular bed of the rat, which seems to be mediated by an L-type calcium channel-sensitive pathway. These responses are not mediated or modulated by the release of nitric oxide, the activation of K+ ATP channels, or the release of vasodilator cyclooxygenase products. IMPLICATIONS: In this study, we examined the mechanism of the vasodilator effects of ketamine in the blood-perfused rat lung. The results of the present study suggest that ketamine-induced vasodilator responses are mediated by an L-type calcium channel-sensitive pathway.

Three-dimensional motion analysis of the voluntary elbow movement in subjects with spasticity.

The purpose of this study was to quantitatively compare the difference in voluntary upper extremity movements between subjects with and without spasticity. Eight normal subjects (mean 26.7 +/- 2.8 years, four males and four females) and seven subjects with spasticity (mean 25.9 +/- 4.3 years, three males and four females) were involved in this study. The subjects sat in an adjustable chair and performed two voluntary tasks involving the elbow joint. Task A was to move the hand between two touch-plates which were mounted 28 cm apart on the surface of the table. Task B was to flex and extend the elbow joint in the sagittal plane with the forearm in neutral position. Reflective markers were attached on the shoulder, the elbow and the wrist. A Peak5 video-based motion analysis system was used to record the positions of the markers in the three-dimensional (3-D) space during the movement tasks. A set of quantitative parameters were used to document the elbow movement. The results revealed that in comparison to normal subjects, subjects with spasticity exhibited a higher average jerk, a larger standard deviation of the coordinates of the markers along the movement path, a larger standard deviation of the angle between the plane of the elbow joint and the horizontal plane, and a longer 3-D path length. The characteristics of spastic elbow movement and the usage of quantitative parameters were discussed.

Effects of charybdotoxin on responses to nitrosovasodilators and hypoxia in the rat lung.

This study investigated the effects of the Ca2+-sensitive K+ channel antagonist charybdotoxin on responses to the nitrosovasodilators nitroglycerin and sodium nitroprusside and on pulmonary pressor responses to ventilatory hypoxia in the isolated blood-perfused rat lung. Injections of nitroglycerin and sodium nitroprusside induced dose-related decreases in pulmonary arterial perfusion pressure when tone was increased with U-46619, whereas ventilatory hypoxia (3% O2-5% CO2-balance N2) increased pulmonary arterial perfusion pressure in a reproducible manner. After administration of charybdotoxin, the pressor response to ventilatory hypoxia was significantly increased, whereas charybdotoxin significantly decreased vasodilator responses to nitroglycerin and sodium nitroprusside but had no effect on the vasodilator responses to albuterol or to isoproterenol when tone was increased with U-46619. The results of the present study show that charybdotoxin enhances the pressor response to ventilatory hypoxia and significantly decreases responses to nitric oxide-donating vasodilator agonists in a selective manner. These data suggest that the response to ventilatory hypoxia is modulated by alterations in Ca2+-sensitive K+ channel activity and suggest that vasodilator responses to the nitric oxide donors nitroglycerin and sodium nitroprusside are dependent on the opening of large-conductance Ca2+-sensitive K+ channels in the pulmonary vascular bed of the rat.

Analysis of responses to bradykinin in the rat hindquarters vascular bed.

The mechanism by which bradykinin (BK) decreases vascular resistance was investigated in the hindquarters vascular bed of the rat. Under conditions of controlled blood flow, BK produced dose-related decreases in hindquarters perfusion pressure when injected into the perfusion circuit in doses of 0.1-1.0 pg. Responses to BK were reproducible with respect to time, and HOE-140 (D-Arg, [Hyp3,Thi5,D-Tic7,Oic8] -BK), a kinin B2 receptor antagonist, decreased hindquarters vasodilator responses to the peptide. HOE-140 had no significant effect on responses to vasodilator agents, which act by a variety of pharmacologically distinct mechanisms. Nitric oxide synthase inhibitors N(omega)-nitro-L-arginine methyl ester or N(omega)-nitro-L-arginine benzyl ester did not decrease responses to BK in doses that decreased hindquarters vasodilator responses to acetylcholine. The cyclooxygenase inhibitors meclofenamate and indomethacin had no effect on responses to BK in doses that attenuated vasodilator responses to the prostaglandin precursor, arachidonic acid. Clotrimazole or 5,8,11,14-eicosatetraynoic acid (ETYA), cytochrome P-450 arachidonic acid metabolism inhibitors, in doses that attenuated vasodilator responses to arachidonic acid, had no effect on responses to BK. Glybenclamide or U-37883A (4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl), K+-ATP channel antagonists, in doses that attenuated responses to lemakalim, had no significant effect on responses to BK. Finally, des-Arg9-BK, a reported kinin B1 receptor agonist, decreased hindquarters perfusion pressure when injected in doses of 3-30 microg, and responses to the B1 agonist were attenuated by HOE-140. The observation that des-Arg9-BK, in high doses, induces modest HOE-140-sensitive responses suggests that kinin B1 receptors are not normally expressed in the hindquarters vascular bed of the rat. The present results indicate that BK dilates the hindquarters vascular bed by a kinin B2 receptor mechanism that is independent of the release of nitric oxide, cyclooxygenase, or P-450 metabolites of arachidonic acid or the activation of K+-ATP channels.

Effects of captopril on responses to bradykinin in the hindquarters vascular bed of the rat.

The effects of captopril, and angiotensin converting enzyme (ACE) inhibitor, on responses to bradykinin (BK), to angiotensin (Ang) I and II, and to other agonists were investigated in the hindquarters vascular bed of the rat. Under conditions of controlled flow, intra-arterial (i.a.) injections of BK in doses of 0.1-1.0 microgram, produced dose related decreases in hindquarters perfusion pressure and evoked decreases in systemic arterial pressure. Intra-arterial injections of Ang I and II produced dose-related increases in hindquarters perfusion pressure. Following administration of captopril in a dose of 2 mg/kg i.v., vasodilator responses to i.a. injections of BK were only slightly enhanced in the hindquarters vascular bed, whereas the evoked systemic vasodepressor responses to i.a. injections of BK were markedly enhanced by the ACE inhibitor. Captopril significantly reduced vasoconstrictor responses to i.a. injections of Ang I, whereas vasoconstrictor responses to i.a. injections of Ang II were significantly enhanced. The ACE inhibitor did not significantly alter vasodilator responses to i.a. injections of acetylcholine, nitroglycerin, nitric oxide, albuterol, or pinacidil. The present data show that BK has potent vasodilator activity in the hindquarters vascular bed of the rat and suggest that the site of action is most likely upstream from the site of inactivation, whereas the site of action of Ang I is at or near the site of conversion to Ang II in the hindquarters vascular bed. The observation that the evoked systemic vasodepressor responses to i.a. injections of BK were greatly enhanced, suggest that the lung is the major site of inactivation of BK.

Analysis of vancomycin in the hindlimb vascular bed of the rat.

Previously, studies have demonstrated that the effects of both a laboratory-produced vancomycin and a clinically available vancomycin were mediated, in part, by activation of both H(1) and H(2) receptors; however, other mechanisms may play a role in the vascular changes associated with vancomycin, since neither H(1) and H(2) receptor blockade has completely abolished the vasodilator responses to vancomycin in any model system. To study the mechanisms of vancomycin interactions in the hindlimb vascular bed of the rat, responses of two types of vancomycin preparations were studied. Vancomycin prepared for either clinical or laboratory use produced an initial short-lived period of vasoconstriction followed by a prolonged period of vasodilation in the hindlimb vascular bed. Responses to both the vancomycins and histamine on systemic arterial vasodilation were significantly decreased after administration of both the H(1)-receptor antagonist diphenhydramine and the H(2)-receptor antagonist famotidine. Verapamil, an L-type calcium channel blocker, significantly reduced the vasopressor responses to clinical vancomycin but not the vasopressor responses to laboratory vancomycin. Enalaprilat, and angiotensin-converting enzyme blocker, significantly reduced the vasodilator responses but not the vasoconstrictor responses of clinical vancomycin and significantly reduced the vasoconstrictor responses but not the vasodilator responses to laboratory vancomycin. Meclofenamate, a cyclo-oxygenase inhibitor, and N(omega)-L-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthetase inhibitor, had no significant effect on the biphasic responses with either vancomycin preparations. Atropine, an anticholinergic-antimuscarinic receptor antagonist, and propranolol, a beta adrenergic blocker, had no significant effect on vancomycin responses. Finally, ondansetron, a serotonin receptor blocker, and HOE 140, a bradykinin receptor blocker, also had no significant effect on vancomycin responses. These data suggest that both vancomycin preparations (clinically available and laboratory prepared) caused biphasic responses that differed from the dose-dependent vasodilation elicited by histamine. Both vancomycin preparations' vasodilator responses appear to be modulated, in part, by a histamine receptor--sensitive mechanism, while vancomycin-induced vasoconstrictor responses appear to be modulated, in part, by angiotensin-converting enzyme and L-type calcium channel--sensitive mechanisms in the rat hindlimb vascular bed. These data also suggest that the vascular responses of vancomycin are preparation dependent.

Pulmonary vasodilator responses to adrenomedullin are reduced by NOS inhibitors in rats but not in cats.

Responses to and the mechanism of action of adrenomedullin (ADM), the carboxy-terminal fragments of ADM, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the pulmonary vascular bed of the rat. Under conditions of elevated tone and controlled pulmonary blood flow in the isolated blood-perfused rat lung, injections of ADM, the 15-52 amino acid carboxy-terminal ADM analogue (ADM15-52), and CGRP caused dose-related decreases in pulmonary arterial perfusion pressure. In contrast, the carboxy-terminal 22-52 and 40-52 amino acid fragments had no consistent vasodilator activity. After administration of the nitric oxide synthase inhibitors, N omega-nitro-L-arginine benzyl ester or N omega-nitro-L-arginine methyl ester (L-NAME), pulmonary vasodilator responses to ADM, to ADM15-52, to CGRP, to acetylcholine, and to bradykinin were significantly decreased in the rat, whereas vasodilator responses to isoproterenol and nitroglycerin were not changed. However, in the pulmonary vascular bed of the cat, L-NAME had no significant effect on vasodilator responses to ADM in doses that attenuated vasodilator responses to acetylcholine and bradykinin. L-NAME had no effect on responses to isoproterenol or nitric oxide. When the relative vasodilator activity of the active peptides was compared, ADM15-52 was approximately three-fold less potent than ADM, and ADM was threefold less potent than CGRP in decreasing pulmonary vascular resistance in the rat lung. When vasodilator responses were compared in the rat and cat, ADM was threefold more potent in decreasing pulmonary vascular vascular resistance in the cat than in the rat, and vasodilator responses to ADM were independent of the intervention used to raise tone in the rat. The present data demonstrate that ADM and ADM15-52 have significant vasodilator activity in the pulmonary vascular bed of the rat, and that responses to ADM, ADM15-52, and CGRP are dependent on the release of nitric oxide in the rat. The present results indicate that pulmonary vasodilator responses to ADM are not dependent on the release of nitric oxide in the cat and suggest that responses to the peptide are mediated by different mechanisms in the pulmonary vascular bed of the rat and cat.

Influence of protein kinase C inhibitors on vasoconstrictor responses in the pulmonary vascular bed of cat and rat.

The effects of staurosporine and calphostin C, two different protein kinase C (PKC) inhibitors, on pressor responses were studied in the pulmonary vascular bed of the intact chest anesthetized cat and the isolated rat lung. Under conditions of constant lobar blood flow in the cat, injections of the angiotensin peptides, norepinephrine (NE), serotonin, and U-46619 into the lobar arterial perfusion circuit caused dose-related increases in lobar arterial pressure and responses were reproducible with respect to time. Infusion of staurosporine into the perfused lobar artery at 1-2 micrograms/kg for 10 min reduced the pressor response to the angiotensin peptides and to NE; however, staurosporine did not alter pressor responses to serotonin or to the thromboxane mimic U-46619. In a separate series of experiments, the effects of calphostin C were investigated and infusion of the PKC inhibitor into the perfused lobar artery at 1-5 micrograms/kg for 10 min also reduced pressor responses to the angiotensin peptides and to NE and did not alter pressor responses to serotonin or to U-46619. In the isolated rat lung, the inhibitory effects of staurosporine on pulmonary pressor responses were investigated and injections of angiotensin II, NE, and serotonin produced dose-related increases in pulmonary arterial perfusion pressure that were decreased after administration of 20 micrograms ia of the PKC inhibitor staurosporine. (ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of responses of allicin, a compound from garlic, in the pulmonary vascular bed of the cat and in the rat.

Allicin, diallyl disulfide-oxide, an active ingredient released from garlic is a systemic vasodilator that acts by an unknown mechanism. In the present experiments, pulmonary vascular responses to allicin (0.1-1.0 mg) were studied in the intact-chest anesthetized cat and in the isolated lung of the rat under constant flow conditions. When baseline tone in the pulmonary vascular bed of the cat was raised with U46619 (11 alpha,9 alpha-epoxymethano-9 alpha,11 beta-dideoxyprostaglandin F2 alpha), intralobar injections of allicin produced dose-related decreases in pulmonary arterial pressure without changing left atrial pressure indicating that allicin had significant vasodilator activity in the pulmonary vascular bed when tone was increased experimentally. Allicin also decreased systemic arterial pressure in a dose-related manner. In terms of relative vasodilator activity in the cat, allicin was 100-fold less potent than sodium nitroprusside and many orders of magnitude less potent than isoproterenol. In the cat, vasodilator responses to allicin were unchanged by methylene blue or N omega-nitro-L-arginine methyl ester. Allicin also significantly diminished the pulmonary pressor response to ventilatory hypoxia in the isolated perfused rat lung. These data show that allicin has significant vasodilator activity in the pulmonary vascular bed of the cat and the rat. The present data suggest that pulmonary vasodilator responses to allicin are independent of the synthesis of endothelial-derived relaxing factor or the activation of soluble guanylate cyclase.

Analysis of responses to ANG IV: effects of PD-123319 and DuP-753 in the pulmonary circulation of the rat.

Pulmonary vasoconstrictor responses to angiotensin (ANG) IV, the 3-8 amino acid fragment of ANG II, were compared with responses to ANG I, ANG II, and ANG III and to other vasoactive peptides in the isolated blood perfused rat lung. In terms of relative activity, ANG IV was similar in potency to bradykinin and serotonin but was approximately 100-fold less potent than ANG I, ANG II, and ANG III. PD-123319, an AT2-receptor antagonist, enhanced pressor responses to the four angiotensin peptides and to bradykinin but did not significantly change the pressor response to serotonin or to ventilatory hypoxia. DuP-753, an AT1-receptor antagonist, significantly decreased pressor responses to the four angiotensin peptides and enhanced the pressor responses to bradykinin but not to serotonin. Captopril and enalaprilat increased the pressor response to ANG IV. Meclofenamate and N omega-nitro-L-arginine methyl ester shifted the dose-response curve for ANG IV to the left in a manner similar to that observed with ANG II and ANG III. These data show that ANG IV has significant vasoconstrictor activity and suggest that responses are mediated by the activation of AT1 receptors and that vasopressor responses of the angiotensin peptides may be modulated by activation of AT2 receptors. These results also suggest that responses to ANG IV are modulated by the release of vasodilator prostaglandins and nitric oxide and that AT2 receptors have little, if any, role in mediating or modulating the pressor response to ventilatory hypoxia.

Analysis of thromboxane receptor-mediated responses in the feline pulmonary vascular bed.

OBJECTIVE: Current evidence suggests that thromboxane plays a role in pathophysiologic processes in the lung. Efforts to find effective, specific therapy to modify these effects have led to the development of a new class of thromboxane receptor blockers. This present investigation examined the selectivity and duration of the inhibitory effects of one of these novel agents in the pulmonary vascular bed of anesthetized cats. DESIGN: Prospective, randomized, controlled study with repeated measures. SETTING: University research laboratory. SUBJECTS: Twenty-nine adult cats obtained from the Tulane University School of Medicine vivarium. INTERVENTIONS: The effects of GR32191, a thromboxane receptor antagonist, were investigated under constant-flow conditions in the intact-chest cat, using a triple-lumen, 6-Fr, balloon perfusion catheter that was placed by means of fluoroscopic guidance. Data were analyzed using a paired or unpaired t-test or analysis of variance. A p < .05 was considered statistically significant. MEASUREMENTS AND MAIN RESULTS: Aortic, left atrial, and left lobar arterial pressures were measured. After administration of GR32191 (0.25 and 1.0 mg/kg iv), pulmonary vasoconstrictor responses to U46619, a thromboxane mimic, were significantly decreased. Blockade was overcome with higher doses of the thromboxane mimic. GR32191 was without significant effect on the responses to prostaglandin (PG) D2, PGF2 alpha, serotonin, the calcium-channel agonist BAY K8644, or norepinephrine. Additionally, GR32191 did not alter baseline vascular pressures. Responses to U46619 returned to 50% of control value 90 mins after administration of 0.25 mg/kg of U46619. Responses to GR32191 returned to 50% of control value 180 mins after administration of 1.0 mg/kg of GR32191. These data suggest that GR32191 selectively blocks thromboxane A2 receptor-mediated responses in a competitive and reversible manner in the pulmonary vascular bed of the cat. CONCLUSIONS: These results are consistent with the hypothesis that discrete thromboxane A2 receptors, unrelated to receptors activated by PGF2 alpha or PGD2, are present in the feline pulmonary vascular bed. Specific thromboxane receptor antagonists, such as GR32191, could be useful therapeutic agents in the treatment of pulmonary hypertensive and thromboembolic disorders.

Analysis of aprotinin on the mean arterial pressure, carotid artery blood flow, and hindlimb vascular resistance in the live rat, and pulmonary vascular resistance in the isolated perfused rat lung.

The effects of aprotinin on mean arterial pressure, carotid artery blood flow, pulmonary vascular resistance, and systemic vascular resistance have not been well documented. Therefore, the responses of aprotinin on the mean arterial pressure, carotid artery blood flow and the changes in pulmonary and hindlimb vascular resistances were investigated in the rat using ultrasonic flow probe analysis, and in two isolated vascular bed preparations. In studies on cardiac output using ultrasonic flow analysis, injections of aprotinin, in doses of 70-7000 KIU intravenously (iv), resulted in no changes in carotid artery ultrasonic flow, suggesting no changes in cardiac output. In isolated blood-perfused lung studies under conditions of controlled pulmonary blood flow, aprotinin, in doses of 7-7000 KIU intra-arterially (ia), caused no significant changes in pulmonary arterial perfusion pressure. Aprotinin, in doses of 7-240 KIU, was injected iv into the hindquarters perfusion circuit, and hindquarters arterial perfusion pressure did not change. Additionally, in the hindquarters perfusion preparation, aprotinin, in doses of 70-7000 KIU, ia resulted in no changes in mean arterial pressure. The present data demonstrate aprotinin has no significant response in MAP, carotid artery blood flow, pulmonary vascular resistance, or hindlimb vascular resistance in the rat.

Comparative effects of adrenomedullin, an adrenomedullin analog, and CGRP in the pulmonary vascular bed of the cat and rat.

Responses to synthetic human adrenomedullin (ADM), a novel hypotensive peptide initially isolated from human pheochromocytoma cells, an ADM analog (ADM15-52), and a structurally related peptide, calcitonin gene-related peptide (CGRP), were compared in the pulmonary vascular bed of the cat and rat under constant flow conditions. When tone was increased with U46619, intraarterial injections of ADM (0.03-0.3 nmol), ADM15-52 (0.03-0.3 nmol), and of CGRP (0.03-0.3 nmol) caused dose-related decreases in pulmonary arterial perfusion pressure. When the relative vasodilator activity of the peptides was compared on a nmol basis, ADM was approximately 10-fold more potent in the cat than in the rat, whereas vasodilator responses to CGRP were very similar in both species. CGRP was slightly more potent than ADM in the rat, whereas ADM was slightly more potent than CGRP in the cat. ADM and ADM15-52 had similar pulmonary vasodilator activity in the cat, whereas the full sequence peptide was slightly more potent than ADM15-52 in the rat. The present data demonstrate that ADM has significant vasodilator activity in the pulmonary vascular beds of the cat and of the rat, and that the relative potency of the vasodilator effects of ADM and ADM15-52 are different in the two species.

Analysis of responses to vancomycin in carotid blood flow in the male rat.

Vancomycin is known to cause vasodilation, and hypotension secondary to histamine release. We studied the actions of two forms of vancomycin, a clinically available preparation, clinical vancomycin, and a research grade preparation, laboratory vancomycin, in the presence of an H1 receptor blockade and during H2 receptor blockade with Doppler flow probe analysis of carotid artery flow rate. Clinical vancomycin, laboratory vancomycin, and histamine, increased the mean carotid artery blood flow from baseline in a dose-dependent manner. Diphenhydramine, H1 receptor antagonist, attenuated the increase in mean carotid artery blood flow for the highest dose of clinical vancomycin and for each dose of histamine. Famotidine, H2 receptor antagonist, significantly attenuated the increase in mean carotid artery blood flow for the highest dose of clinical vancomycin, the two higher doses of laboratory vancomycin, and with each dose of histamine. Both diphenhydramine and famotidine attenuated the increase of mean carotid artery blood flow with clinical vancomycin, laboratory vancomycin, and histamine. These data suggest that the change in carotid flow produced by vancomycin, is dependent, in part, on either H1 or H2 receptor activation.