Effects of IV and aerosol administration of 5-hydroxytryptamine (5-HT) on ventilation, pulmonary mechanics values, pulmonary arterial pressure, and heart rate were investigated in healthy unsedated Friesian calves. Minute volume increased significantly, mainly because of an increase in respiratory rate. Except for total pulmonary resistance after bolus injection, continuous administration of 5-HT given by either route caused significant alterations of lung dynamic compliance and total pulmonary resistance, the former decreasing to one-fifth of its baseline value and the latter increasing twofold. Pulmonary arterial pressure increased significantly, whatever the speed or route of administration. Administration of a bolus did not affect heart rate, whereas continuous iv administration of 5-HT as well by perfusion or by aerosol resulted in sustained tachycardia. It was concluded that 5-HT induces reversible bronchoconstriction and pulmonary vasoconstriction in healthy unsedated calves, 5-HT-induced functional alterations depend on the speed of administration, and excess of 5-HT production or depression in uptake by the lungs during bovine respiratory tract diseases could contribute to pulmonary dysfunction.

peer reviewed

peer reviewed | OBJECTIVE: To characterize the cardiovascular response to i.v. administration of serotonin (5-hydroxytryptamine [5-HT]) in calves. ANIMALS: 5 healthy unsedated Friesian calves. PROCEDURE: 41 5-HT administrations were performed: II slow infusions (duration, 5 minutes) and 30 bolus infusions (duration, 5 seconds). Cardiovascular function values were recorded before, during, and after the infusion. RESULTS: Slow infusion of 5HT first resulted in a brief period of severe bradycardia, then in sustained tachycardia with a concomitant increase in cardiac output. Systemic initial hypotension concomitant with bradycardia, then a pressor phase associated with an increase in systemic vascular resistance, and finally, a long-lasting hypotensive phase associated with decreased systemic vascular resistance. Pulmonary hypertension was associated with increased pulmonary vascular resistance, reflecting intense pulmonary vasoconstriction. Bolus infusion at increasing dosages resulted in dose-dependent bradycardia and systemic hypotension, followed by dose-dependent systemic hypertension. Unlike with slow infusion, neither the second tachycardiac nor the third systemic hypotensive phases were evident. CONCLUSIONS: 5-HT induces dose-dependent cardiovascular responses, including a reflex response followed by pulmonary and systemic vasoconstriction, in healthy calves. CLINICAL RELEVANCE: Determining the type of serotonergic receptors responsible for these responses may help to determine whether 5-HT is involved in the mechanisms underlying brisket disease in cattle.

The beige (bgJ/bgJ) mouse is a well-described murine model of Chediak-Higashi syndrome. Platelet function was examined in normal and beige mice to better characterize the defective aggregation response in platelets from mice with Chediak-Higashi syndrome. Platelet aggregation after collagen, thrombin, and phorbol-12-myristate 13-acetate stimulation was significantly (P < 0.025) decreased in platelets from beige mice, relative to platelets from normal mice. Compared with beige and normal mice, those heterozygous for the bg trait had intermediate responses to collagen and thrombin, but not phorbol-12-myristate 13-acetate. The defect(s) in aggregation of platelets from beige mice was associated with a dense granule storage pool deficiency and decreased stores of serotonin and adenine nucleotides in platelets. Mice heterozygous for the bg trait had normal platelet serotonin and adenine nucleotide concentrations. Platelets from beige mice were approximately 10 times more sensitive to prostacyclin inhibition of collagen-induced aggregation than were platelets from control mice. However, a significant difference in platelet cyclic AMP concentration was not apparent between beige and normal mice after prostacyclin stimulation. Platelet endoperoxide synthesis measured by quantification of thromboxane B2, was normal in beige mice. Protein phosphorylation patterns in mouse platelets were similar to those seen in human platelets. Thrombin and collagen-induced [32P] phosphorylation of 40- and 20-kD proteins in platelets from normal and beige mice was similar. Results indicate that the biochemical defect(s) in platelet function in beige mice is partially attributable to storage pool deficiency and does not result in an absolute defect in phosphorylation of 40- and 20-kD proteins.

Ticlopidine hydrochloride was evaluated for its effectiveness in inhibiting platelet aggregation and serotonin release in 5 laboratory Beagles before and after heartworm implantation with 7 adult Dirofilaria immitis, and after embolization with 7 dead heartworms to mimic what happens after heartworm adulticide treatment. Five other laboratory Beagles, similarly implanted and embolized with heartworms, were used as nonmedicated controls. During the heartworm-negative stage, the dosage of ticlopidine that inhibited adenosine diphosphate (ADP)-induced platelet aggregation in 5 dogs by at least 50% after 5 days of treatment was 62 mg/kg of body weight once a day. In the same dogs implanted with 7 adult heartworms 21 days previously, mean (+/- SD) ticlopidine dosage required to obtain similar results was 71 (+/- 13) mg/kg given once daily. During the 21 days after dead heartworms were implanted in heartworm-infected dogs, mean ticlopidine dosage was 108 (+/- 35) mg/kg (range, 62 to 150 mg/kg). Ticlopidine treatment was associated with increased platelet numbers in all 5 dogs during the heartworm-negative stage and in 4 of 5 dogs during the heartworm implantation and heartworm embolization stages. Mean platelet volume tended to decrease as platelet numbers increased. At necropsy, gross and histologic pulmonary lesions were less severe in ticlopidine-treated dogs than in nonmedicated control dogs.

The in vitro reactivity of vasoconstrictive mediators that are implicated in acute laminitis was determined in palmar and plantar digital arteries and veins obtained from healthy horses and in palmar digital vessels of horses with early laminitis (Obel grade I). To obtain baseline reactivity data, 3 experiments were conducted, using healthy horses: (1) the reactivity of palmar and plantar digital arteries and veins to angiotensin II, norephinephrine, and 5-hydroxytryptamine (serotonin) were compared; (2) the direct effects of bacterial endotoxin on vascular reactivity were assessed; and (3) the reactivity of palmar digital arteries and veins to angiotensin II, norepinephrine, prostaglandin F2 alpha (PGF2 alpha), sertonin, and a thromboxane-endoperoxide analog (U46619) were determined. The vascular reactivity of these same 5 vasoconstrictors then was determined in horses with early laminitis and was compared with data from healthy (control) horses. Obel grade-I laminitis was experimentally induced in horses using carbohydrate overload. Dose responses were conducted for each agent at concentrations between 10(-8)M and 10(-4)M. The potency of a drug was defined as the mean effective concentration necessary to induce 50% of maximal contraction (EC50). There were no differences in EC50 concentrations and in maximal contractions between forelimb and hind limb arteries and veins for angiotensin II, norepinephrine, and serotonin. Incubation with endotoxin had no effect on the reactivity of arteries and veins to angiotension II, norepinephrine, and serotonin. In healthy horses, serotonin and U46619 were more potent arterial constrictors than were norepinephrine PGF2 alpha, and angiotensin II. In veins, serotonin, U46619, and angiotension II were similar in potency, and all were significantly (P less than 0.05) more potent than were norepinephrine and PGF2 alpha. Serotonin induced greater arterial constriction than did all other agents tested. There were no differences in the maximal venoconstriction induced by norepinephrine, PGF2 alpha, serotonin, and U46619. Angiotensin II induced the least amount of arterial and venous constriction. Maximal contractions were significantly (P less than 0.05) greater for veins than for arteries for all agents evaluated, except for angiotensin II. In horses with early laminitis, angiotensin II and serotonin were the most potent (smallest EC50 values) constricting agents for the arterial and venous segments and norepinephrine and PGF2 alpha were the least potent. Serotonin and norepinephrine induced significantly (P less than 0.05) greater venoconstriction than did the other agents. Angiotensin II induced the least arterial and venous contraction. For all agonists except angiotensin II, the mean EC50 values for vessels from horses with early laminitis were either similar or greater than those for vessels from control horses. The EC50 values for norepinephrine and the thromboxane analog were significantly (P less than 0.05) greater for vessels from horses with early laminitis, compared with those from control horses. The mean maximal contractions for all vasoconstrictors, except angiotensin II, were significantly (P less than 0.05) less for vessels from horses with early laminitis. Significantly greater venous-to-arterial maximal contraction ratios were found for norepinephrine and serotonin in horses with laminitis, compared with those ratios in control horses. These data suggested that the digital vasculature of horses with early laminitis was not more sensitive to the vasoconstrictor substances tested and that the vessels were significantly less repsonsive than was vasculature from the control horses. However, the venous-to-arterial contraction ratios were either the same or significantly (P less than 0.05) greater in horses with laminitis.

Objective: To determine the isometric responses of isolated intrapulmonary bronchioles from cats with and without adult heartworm infection. Animals: 13 purpose-bred adult cats. Procedures: Cats were infected with 100 third-stage larvae or received a sham inoculation, and the left caudal lung lobe was collected 278 to 299 days after infection. Isometric responses of intrapulmonary bronchiolar rings were studied by use of a wire myograph. Three cycles of contractions induced by administration of 10μM acetylcholine were followed by administration of the contractile agonists acetylcholine, histamine, and 5-hydroxy-tryptamine. To evaluate relaxation, intrapulmonary bronchiolar rings were constricted by administration of 10μM 5-hydroxytryptamine, and concentration-response curves were generated from administration of sodium nitroprusside, isoproterenol, and substance P. Results: Compared with tissues from control cats, contractile responses to acetylcholine and 5-hydroxytryptamine were reduced in tissues from heartworm-infected cats. Relaxation to isoproterenol was significantly reduced in tissues from heartworm-infected cats. Relaxation to substance P was increased in tissues from heartworm-infected cats, but relaxation to sodium nitroprusside was unchanged. Conclusions and Clinical Relevance: Results suggested that despite increased bronchiolar wall thickness in heartworm-infected cats, a hyperreactive response of the bronchiolar smooth muscle is not the primary mechanism of respiratory tract clinical signs. Reduced response of the airway to isoproterenol may indicate refractoriness to bronchiolar relaxation in heartworm-infected cats.

The tricyclic antidepressant, clomipramine, is an effective treatment for canine compulsive disorder (canine CD). This disorder is a clinical syndrome of abnormal conflict behaviors and its pathophysiology is unknown. However, because clomipramine is an effective treatment, information about the drug's neurochemical effect could enhance the understanding of canine CD. The following experiment used 6 behaviorally normal dogs to assess the effect of clomipramine (3 mg/kg, q24h, PO) on the central turnover of 3 monoamines (serotonin, dopamine, and norepinephrine) as measured by the concentrations of their respective metabolites in cerebrospinal fluid (CSF). In a randomized, placebo-controlled, AB-BA crossover experiment, cisternal CSF was taken after 1, 2, 4, and 6 wk on each treatment. No effect of clomipramine was detected. This contrasts with human studies that have suggested that clomipramine affects the concentrations of monoamine metabolites in lumbar CSF. However, those papers do not address methodological assumptions, such as (i) metabolites in CSF originate only from the brain, and (ii) concentrations of metabolites in cisternal/lumbar CSF reflect the concentrations in local areas of the brain. Notwithstanding the small sample size, our results suggest that more localized sampling techniques (e.g. microdialysis) are needed when examining the effect of drugs on central monoamine metabolites. Clomipramine's efficacy for canine CD indicates the need for neurobiological research and, to our knowledge, our study is the first of its kind in dogs. The resulting data are preliminary but they can inform optimal neurobiological studies of canine CD.