Subthreshold stimulation of a serotonin 5-HT3 reflex attenuates cardiovascular reflexes

Abstract

Volume-sensitive and chemosensitive cardiopulmonary reflexes modulate volume homeostasis via renal sympathetic nerve activity (RSNA). Blunting of volume-sensitive cardiopulmonary reflexes is associated with volume retention, e.g., in hypertension, whereas the role of chemosensitive cardiopulmonary reflexes is largely unknown. To elucidate the possible role of chemosensitive cardiopulmonary reflexes in control of volume homeostasis, we investigated whether subthreshold stimulation of 5-HT3 receptors modulates the control of RSNA by volume-sensitive cardiopulmonary reflexes or the arterial baroreceptor reflex in rats. Phenyl biguanide (PBG) was infused intravenously to stimulate 5-HT3 receptors. Higher doses of PBG lowered RSNA, but a dose of 6 micrograms/min, given as a background infusion throughout the experiment, did not change arterial pressure, heart rate (HR), or RSNA. Ten minutes after beginning the 6 micrograms/min PBG infusion, a 15-min volume expansion (0.9% saline, 5 or 10% body weight) was started to stimulate volume-sensitive cardiopulmonary reflexes. In separate experiments, 5-min ramp infusions of methoxamine and nitroglycerin to stimulate the arterial baroreceptor reflex (evaluated by a 4-parameter logistic regression) were performed 15 min after beginning the PBG background infusion (6 micrograms/min). During PBG infusion, the RSNA responses to volume expansions were significantly impaired (5% body weight: PBG -6 +/- 6%, n = 7 vs. control -39 +/- 9%, n = 6, P < 0.001; 10% body weight: PBG -33 +/- 6%, n = 8 vs. control -52 +/- 5%, n = 7, P < 0.05). The 5-HT3 receptor antagonist odansetron (GR-38032F) abolished these effects of PBG. The maximum HR gain of the arterial baroreceptor reflex was impaired but the arterial baroreceptor control of RSNA was unaffected by PBG background infusion. We conclude that 5-HT3-serotonergic cardiopulmonary chemoreceptors blunt the RSNA decrease to volume loading. This mechanism may facilitate volume retention when cardiac serotonin is increased.

Serotonin 5-HT3 receptors on mechanosensitive neurons with cardiac afferents

“…First, they support the in vivo observation that the control of RSNA by mechanosensitive cardiopulmonary reflexes stimulated with a saline volume load was considerably impaired in rats preinfused with subthreshold doses of the serotonin 5-HT 3 receptor agonist PBG (30). In this respect, our findings allow for the hypothesis that serotonin 5-HT 3 receptors on cardiac afferent axons contained within the vagal nerve may directly influence the mechanosensitivity of these neural pathways.…”

“…Our in vivo experiments (30) did not more precisely reveal in which way stimulated 5-HT 3 receptors (16) can interfere with the mechanosensitive properties of the afferent portion of the cardiorenal reflex. One mechanism could be that the stimulation of serotonin 5-HT 3 receptors on afferent cardiac fibers decreases mechanosensitivity.…”

Cardiopulmonary Reflex Impairment in Experimental Diabetes in Rats

“…It was demonstrated that subthreshold stimulation of cardiopulmonary receptors by the 5-HT3 receptor agonist phenylbiguanide may attenuate cardiovascular reflexes. 26 The cardiovascular responses to stimulation of chemosensitive cardiac receptors were grossly preserved in diabetic rats. The interpretation of these results needs some considerations: (1) most ventricular afferents exhibit some degree of both mechanosensitivity and chemosensitivity.…”

Neural Control of Kidney Function

“…This effect was attributed to increased cardiac prostaglandin levels acting on cardiac afferent nerve fibers [65,66]. On the other hand, in normal rats the renal sympathoinhibitory response to a volume expansion with saline was severely blunted if accompanied by an infusion with a serotonin 5-HT 3 receptor agonist in a dose that itself could not elicit a cardiorenal reflex response [67]. Hence, in heart disease and hypertension, serotonin and other substances might further worsen the neurogenic control of renal sympathetic nerve activity, when afferent nerve fibers of the heart already respond with a decreased sensitivity to mechanical stimuli.…”