Enhanced Contraction to 5-Hydroxytryptamine Is Not Due to “Unmasking” of 5-Hydroxytryptamine _1B Receptors in the Mesenteric Artery of the Deoxycorticosterone Acetate–Salt Rat

Abstract

Abstract-5-Hydroxytryptamine 1B (5-HT 1B ) receptors have been implicated in mediating arterial contraction to 5-HT.Additionally, the 5-HT 1B receptor has been reported to be "unmasked" by depolarizing stimuli. We hypothesized that 5-HT 1B receptors in arteries from hypertensive animals, arteries reported to have a depolarized resting membrane potential in smooth muscle cells, are unmasked and participate in the supersensitivity observed to 5-HT in hypertension. We used the isolated tissue bath apparatus and examined the response of superior mesenteric arteries from normotensive sham and hypertensive deoxycorticosterone acetate (DOCA)-salt rats. The 5-HT 1B agonists CP93129 and sumatriptan (10 Ϫ9 to 10 Ϫ5 mol/L) caused a maximal contraction (50Ϯ12% of phenylephrine [10 Ϫ5 mol/L] contraction) in arteries from DOCA-salt rats; no contraction was observed in arteries from normotensive rats. The 5-HT 1B receptor antagonist GR55562 (100 nmol/L) inhibited both the 5-HT-(4-fold rightward shift) and CP93129-induced (11-fold rightward shift) contractions in mesenteric arteries from hypertensive DOCA-salt rats. In other experiments, arteries from normotensive rats were incubated with 15 mmol/L KCl, as a depolarizing stimulus, and then exposed to 5-HT and CP93129. In the presence of KCl, a small leftward shift to 5-HT was observed. However, the presence of a depolarizing stimulus was unable to produce changes in the 5-HT maximal response to resemble that of arteries from DOCA-salt rats, nor was contraction to CP93129 observed. These data support the conclusions that 5-HT 1B receptors mediate contraction in mesenteric arteries from hypertensive rats and that this enhanced response to 5-HT is not due to membrane depolarization alone. Key Words: serotonin Ⅲ mesenteric arteries Ⅲ vasoconstriction Ⅲ deoxycorticosterone S erotonin (5-hydroxytryptamine, 5-HT) is a molecule that has generated much interest and controversy in cardiovascular research. A finding that is common, but not absolute, is that arteries from animals with hypertension demonstrate supersensitivity to 5-HT. 1,2 Under normotensive conditions, the 5-HT 2A receptor has been implicated as the predominant receptor involved in mediating 5-HT-induced contraction in many arteries. 3,4 Recently, 5-HT 1B receptors have also been implicated as mediators of 5-HT-induced vasoconstriction. The 5-HT 1B receptor has been shown to mediate contraction in human pulmonary artery, 5 rat pulmonary artery, 6 human coronary artery, 7 human cerebral artery, 8 rabbit carotid artery, 9 rabbit ear artery, 10 rabbit renal artery, 11 and rat tail artery. 12 The 5-HT 1B receptor appears to be the predominant receptor mediating 5-HT-induced contraction in the human cerebral arteries. 8 This receptor is a G protein-coupled receptor, using G i and G o to couple negatively with cAMP modulatory pathways. [13][14][15] Unlike other serotonin receptors, the 5-HT 1B receptor has been described as a receptor that can be "unmasked" to mediate its contractile effects. 10 This unmasking of a functionally ...

Upregulation of Arterial Serotonin 1B and 2B Receptors in Deoxycorticosterone Acetate-Salt Hypertension

“…The role of 5-HT 2B and 5-HT 1B receptors in mediating 5-HT-induced contraction and hyperreactivity in arteries from Sprague-Dawley DOCA-salt hypertensive rats has been previously established. [3][4][5][6] We used Western analysis and antibodies to 5-HT 1B and 5-HT 2B receptors to determine whether the change in contractility to 5-HT 1B receptor and 5-HT 2B receptor agonists was due to an increase in the levels of the receptor protein. 5-HT 1B and 5-HT 2B receptor proteins were upregulated Ϸ2-fold in aortas from Sprague-Dawley DOCA-salt hypertensive rats compared with aortas from control rats (Figure 1).…”

“…1,2 Recently, in deoxycorticosterone acetate (DOCA)-salt hypertensive rats, 5-HT 2B and 5-HT 1B receptors have been implicated as mediators of 5-HT contractile hyperresponsiveness. [3][4][5][6] 5-HT 2B and 5-HT 1B receptors do not appear to be involved in mediating contraction to 5-HT under conditions of normal blood pressure. The 5-HT 2B receptor has also been implicated as a mediator of 5-HT-induced contraction in the mesenteric arteries of Wistar and Wistar-Furth rats, which undergo the DOCA-salt protocol.…”

5-Hydroxytryptamine Receptors as Targets for Drug Therapies of Vascular-Related Diseases

“…14,15) 5-HT 1B receptors also exist on the smooth muscle membrane of blood vessels and mediate 5-HT-induced vasoconstriction in human coronary artery, 16) human pulmonary artery, 17) human cerebral artery, 18) and various blood vessels in humans and other species. 2,10,19) 5-HT 1B receptors can mediate vasoconstriction of intra-and extracranial arteries, therefore, selective 5-HT 1B(/1D) agonists, generally called triptans, are used as antimigraine agents. This matter is discussed in greater detail in the next chapter.…”

Serotonin (5-HT) in Veins: Not All in Vain

“…For instance, the 5-HT 1B agonist CP93129 failed to induce contraction in rat aorta, although the 5-HT 1B receptor was expressed (Banes and Watts, 2003). On the other hand, we observed that CP93129 and sumatriptan induced contraction of rat mesenteric artery from hypertensive but not from normotensive rats (Banes and Watts, 2001).…”