[Effects of octreotide on experimental orthostatic neurogenic hypotension].
The synthetic somatostatin analogue, octreotide, has recently been proposed for the treatment of both postprandial and orthostatic hypotension (OH) in humans with autonomic failure related to multiple system atrophy (MSA) or diabetes mellitus. However, pharmacodynamic data are not still available in experimental models of orthostatic hypotension. We investigated in a model of neurogenic orthostatic hypotension, obtained by chronic sinoaortic denervation (SAD) in chloralose-anaesthetized dogs, the effects of octreotide (0.1 mg/kg, subcutaneous route) during a double-blind cross-over study vs placebo. Blood pressure (BP) and heart rate (HR) average values, SBP and HR short-term variabilities (using fast Fourier transformation) in both low (LF: 50-150 mHz) and high frequency range (respiratory rate +/- 50 mHz) and plasma noradrenaline (NA) levels (HPLC) were measured in supine position and during head-up tilt test (HUT: 80 degrees, 10 min) before and 45 min after drug administration. In controls, as expected, head-up tilt test induced a significant increase in DBP (+14 +/- 8 mmHg), HR (+36 +/- 21 beat/min), NA (296 +/- 118 vs 141 +/- 63 pg/ml), SBP-LF (25 +/- 5 vs 14 +/- 3%) whereas HR-HF significantly decreased. The changes during head-up tilt test were not modified after placebo or octreotide administration. In SAD dogs, head-up tilt test elicited a dramatic fall in SBP (-74 +/- 39 mmHg), DBP (-20 +/- 15 mmHg) without any significant change in HR (-5 +/- 12 beat/min), NA (708 +/- 213 vs 606 +/- 331 pg/ml), SBP-LF (16 +/- 3 vs 16 +/- 3%), HR-HF (8 +/- 2 vs 7 +/- 1%). Octreotide or placebo failed to significantly modify any of the measured parameters during head-up tilt test performed 45 min after drug administration. At the dose used, octreotide elicited a 80% decrease in insulin plasma levels after 45 min in both normal and SAD dogs. These results suggest that 1) this experimental model of orthostatic hypotension in SAD dogs is reproductible and can be used to investigate the pharmacological effects of antihypotensive drugs, 2) cardiovascular and biochemical characteristics of the SAD model are similar to those observed in MSA and 3) octreotide, in these experimental conditions, is not able to correct the BP fall during head-up tilt test.
Verwaerde
P
P
Laboratoire de pharmacologie médicale et clinique, INSERM U317, faculté de médecine de Toulouse.
Bordet
R
R
Portolan
G
G
Tran
M A
MA
Marques
M A
MA
Montastruc
J L
JL
Sénard
J M
JM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002395:Catecholamines / Q000097:blood; D003714:Denervation; D004195:Disease Models, Animal; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects*; D007024:Hypotension, Orthostatic / Q000188:drug therapy* / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D015282:Octreotide / Q000494:pharmacology / Q000627:therapeutic use; D010919:Placebos; D013564:Sympathetic Nervous System / Q000187:drug effects*; D018667:Tilt-Table Test; D017211:Treatment Failure
D002395:Catecholamines; D007328:Insulin; D010919:Placebos; D015282:Octreotide
Effets de l'octréotide sur l'hypotension orthostatique neurogène expérimentale.