The Serotonin 5-Hydroxytryptaphan_1A Receptor Agonist, (+)8-Hydroxy-2-(di-n-propylamino)-tetralin, Stimulates Sympathetic-Dependent Increases in Venous Tone during Hypovolemic Shock

Abstract

Adjuvant treatment of hypovolemic shock with vasoconstrictors is controversial due to their propensity to raise arterial resistance and exacerbate ischemia. A more advantageous therapeutic approach would use agents that also promote venoconstriction to augment perfusion pressure through increased venous return. Recent studies indicate that 5-hydroxytryptophan (5-HT) 1A receptor agonists increase blood pressure by stimulating sympathetic drive when administered after acute hypotensive hemorrhage. Given that venous tone is highly dependent upon sympathetic activation of ␣ 2 -adrenergic receptors, we hypothesized that the 5-HT 1A receptor agonist, (ϩ)8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), would increase venous tone in rats subject to hypovolemic shock through sympathetic activation of ␣ 2 -adrenergic receptors. Systemic administration of 8-OH-DPAT produced a sustained rise in blood pressure (ϩ44 Ϯ 3 mm Hg 35 min after injection, P Ͻ 0.01 versus saline) and mean circulatory filling pressure (ϩ4.2 Ϯ 0.7 mm Hg, P Ͻ 0.01 versus saline) in conscious rats subjected to hypovolemic shock. An equipressor infusion of epinephrine failed to influence mean circulatory filling pressure (MCFP). Ganglionic blockade, ␣ 1 -, or peripheral ␣ 2 -adrenergic receptor blockade prevented the rise in MCFP observed with 8-OH-DPAT, but only ␣ 1 -adrenergic receptor blockade diminished the pressor effect of the drug (P Ͻ 0.01). 8-OH-DPAT raises blood pressure in rats in hypovolemic shock through both direct vascular activation and sympathetic activation of ␣ 1 -adrenergic receptors. The sympathoexcitatory effect of 8-OH-DPAT contributes to elevated venous tone through concurrent activation of both ␣ 1 -and ␣ 2 -adrenergic receptors. The data suggest that 5-HT 1A receptor agonists may provide an advantageous alternative to currently therapeutic interventions used to raise perfusion pressure in hypovolemic shock.

The 5-Hydroxytryptamine1A Receptor Agonist, (+)-8-Hydroxy-2-(di-n-propylamino)-tetralin, Increases Cardiac Output and Renal Perfusion in Rats Subjected to Hypovolemic Shock

“…Here, we demonstrated that a single bolus dose of 8-OH-DPAT increased CO throughout the 15-min postinjection recording period. In our prior study, 8-OH-DPAT increased arterial and mean circulatory filling pressure for the duration of a 35-min postinjection recording period (Tiniakov and Scrogin, 2006). Hematocrit and plasma protein levels were not affected by drug treatment in either the previous or present studies, indicating that increases in mean circulatory filling pressure and CO were most likely the result of altered venous tone and not differences in capillary refill.…”

“…Evidence from the present study supports these findings by demonstrating that 8-OH-DPAT promotes increased cardiac output. Previous studies indicated that venoconstriction is, in part, responsible for the rise in venous return (Tiniakov and Scrogin, 2006). However, additional studies suggested that 8-OH-DPAT may also increase cardiac output by virtue of its ability to stimulate epinephrine release (Bagdy et al, 1989a,b).…”

“…The choice of 8-OH-DPAT dose used in these studies was based on evidence demonstrating it to be the half-maximal dose necessary to delay the rapid hypotensive response to blood loss in unanesthetized rats (Scrogin et al, 2000). The same dose has since been proven to produce reliable and significant increases in blood pressure in rats subjected to either acute hemorrhage or hemorrhage sufficient to produce circulatory shock (Osei-Owusu and Scrogin, 2004;Tiniakov and Scrogin, 2006).…”

“…More recent work indicates that the pressor effect of the relatively selective 5-HT 1A receptor agonist, 8-OH-DPAT, is due, in large part, to a sympathetic-dependent increase in venous tone (Tiniakov and Scrogin, 2006). Increased venous tone should lead to increased venous return in the absence of a change in right atrial pressure.…”

“…For instance, our previous studies indicated that the pressor effect of 8-OH-DPAT in acutely hemorrhaged animals is primarily mediated by central activation of the sympathetic system, most likely through 5-HT 1A receptors (Scrogin, 2003;OseiOwusu and Scrogin, 2004). However, the pressor response to 8-OH-DPAT observed in animals subjected to more severe hemorrhagic shock are also due, in large part, to direct vascular ␣ 1 -adrenergic receptor activation (Tiniakov and Scrogin, 2006). In contrast, a similar dose of 8-OH-DPAT causes hypotension and inhibition of renal sympathetic drive in the anesthetized, euvolemic cat (Ramage et al, 1992).…”