Differential effects of clonidine, dopamine, dobutamine, and dopexamine on basal and acid-stimulated mucosal blood flow in the rat stomach.
OBJECTIVE
To analyze the effects of clonidine, dopamine, dobutamine, and dopexamine on gastric mucosal blood flow (GMBF) at baseline and after stimulation by acid back diffusion through a disrupted gastric mucosal barrier.


METHODS
Prospective, randomized, unblinded study.


METHODS
University research laboratory.


METHODS
Adult Sprague-Dawley rats.


METHODS
Mean arterial blood pressure (MAP) and heart rate (HR) were recorded from a carotid artery of the phenobarbital-anesthetized animals. A jugular vein was cannulated for continuous infusion of saline and intravenous drug administration. The stomach was prepared for luminal perfusion and for recording GMBF with the hydrogen gas clearance technique. Gastric mucosal vascular conductance (GMVC) was calculated as GMBF divided by MAP.


RESULTS
Clonidine (37.5 and 112.5 nmol x kg(-1)) lowered MAP and HR and caused gastric vasodilation as shown by a rise of GMVC. The 2.5-fold increase in GMVC elicited by gastric perfusion with HCl (0.15 M) plus ethanol (25%) was depressed by clonidine. All cardiovascular effects of clonidine were prevented by the alpha2-adrenoceptor antagonist idazoxan (2 micromol x kg(-1)). Infusion of dopamine (15 and 45 micromol x kg(-1) x hr(-1)), dobutamine, or dopexamine (each at 5 and 15 micromol x kg(-1) x hr(-1)) caused tachycardia. GMVC at baseline was attenuated by the higher dose of dopamine and dopexamine, but not dobutamine. In contrast, the acid-induced vasodilation in the gastric mucosa was depressed by dobutamine and dopexamine, but not dopamine.


CONCLUSIONS
Clonidine, dobutamine, and dopexamine at high dosage suppress the gastric mucosal vasodilator response to acid back diffusion, which is an important defense mechanism. Although the dose equivalence between rats and humans is not known, the antivasodilator effects highlight an adverse action whereby large doses of dobutamine, dopexamine, and clonidine may compromise gastric mucosal homeostasis and facilitate stress ulcer formation. Dopamine lacks this detrimental activity.
Department of Experimental and Clinical Pharmacology, University of Graz, Graz, Austria. peter.holzer@kfunigraz.ac.at
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D000316:Adrenergic alpha-Agonists / Q000009:adverse effects*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000009:adverse effects*; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000009:adverse effects*; D003000:Clonidine / Q000009:adverse effects*; D004280:Dobutamine / Q000009:adverse effects*; D004298:Dopamine / Q000009:adverse effects* / Q000031:analogs & derivatives*; D018491:Dopamine Agonists / Q000009:adverse effects*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D019329:Idazoxan / Q000494:pharmacology; D007262:Infusions, Intravenous; D007413:Intestinal Mucosa / Q000098:blood supply* / Q000187:drug effects*; D008833:Microcirculation / Q000187:drug effects*; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000009:adverse effects*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D018491:Dopamine Agonists; D014665:Vasodilator Agents; C046318:dopexamine; D004280:Dobutamine; D003000:Clonidine; D004298:Dopamine; D019329:Idazoxan