LACK OF EFFECT OF OCTREOTIDE ON EXPERIMEN TAL ORTHOSTATIC HYPOTENSIONIN SINOAORTIC DENERVATED DOGS

The synthetic somatostatin analogue, octreotide, has recently been pro posed for the treatment of both postprandial and orthostatic hypotensi on (OH) in humans with autonomic failure related to multiple system at rophy (MSA) or diabetes mellitus. However, pharmacodynamic data are no t still available in experimental models of orthostatic hypotension. W e investigated in a model of neurogenic orthostatic hypotension, obtai ned by chronic sinoaortic denervation (SAD) in chloralose-anaesthetize d dogs, the effects of octreotide (0.1 mg/kg, subcutaneous route) duri ng a double-blind cross-over study vs placebo. Blood pressure (BP) and heart rate (HR) average values, SEP and HR short-term Variabilities ( using fast Fourier transformation) in both low (LF: 50-150 mHz) and hi gh frequency range (respiratory rate+/-50 mHz) and plasma noradrenalin e (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 ad ministration. In controls, as expected, head-up tilt test induced a si gnificant 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 no t modified after placebo or octreotide administration. In SAD dogs, he ad-up tilt test elicited a dramatic fall in SEP (-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-H F (8+/-2 vs 7+/-1%). Octreotide or placebo failed to significantly mod ify any of the measured parameters during head-up tilt test performed 49 min after drug administration. At the dose used, octreotide elicite d a 80% decrease in insulin plasma levels after 49 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 experimen tal conditions, is not able to correct the BP fall during head-up tilt test.