Ramelteon attenuates age‐associated hypertension and weight gain in spontaneously hypertensive rats

Abstract

The neuroendocrine theory of aging suggests the common mechanisms of developmental (prereproductive) and aging (postreproductive) processes and identified a cluster of conditions (hypertension, obesity, dyslipidemia, type 2 diabetes, menopause, late onset depression, vascular cognitive impairment, impairment of immune defense, and some forms of cancer) as age-associated neuroendocrine disorders (AAND). Obesity, dyslipidemia, hypertension, and type 2 diabetes were later described as metabolic syndrome (MetS). Because melatonin attenuated development of MetS is age-dependent, that is, in young and old, but not in middle-aged rats, we studied the effect of the selective melatonin agonist, Ramelteon, on the two core symptoms of MetS/AAND: hypertension and body weight gain in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto male rats (WKY). SHR rats developed hypertension at the time of maximal weight gain that coincided with the onset of reproductive activity (8-10 weeks old). Chronic (but not acute) administration of Ramelteon (in drinking water, 8 mg/kg/day, from 4 to 12 weeks of age) attenuated age-associated increase of systolic blood pressure (tail-cuff method) by 45%, and age-associated body weight gain by 30%. Acute and chronic Ramelteon did not affect blood pressure and body weight in normotensive WKY rats. Ramelteon-induced attenuation of age-associated hypertension and weight gain suggests that Ramelteon might attenuate the other symptoms of MetS/AAND and might be useful in the treatment of MetS/AAND during puberty, menopause, and old age.

Weight Considerations in Psychotropic Drug Prescribing and Switching

“…63,64 Ramelteon prevented age-associated weight gain and hypertension in spontaneously hypertensive rats. 65 In a double-blind, placebo-controlled, 8-week pilot study 66 of patients with schizophrenia, ramelteon improved some laboratory and radiologic measures of adiposity but not standard anthropometric measures.…”

Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders

“…administration of melatonin agonists, e.g., Ramelteon that attenuates age-associated hypertension and body weigh gain (Oxenkrug and Summergrad 2010). …”

Melatonin and the Metabolic Syndrome: Physiopathologic and Therapeutical Implications

“…To what extent the new melatonergic agents approved by the US Food and Drug Administration or the European Medicines Agency (ramelteon, agomelatine) or those that are in the process of being approved (tasimelteon) share the protective activity of melatonin in MS remains to be defined. A recent study indicates that ramelteon given in drinking water (8 mg/kg/day) for 8 weeks to spontaneously hypertensive Wistar-Kyoto male rats significantly attenuated age-associated increase of systolic blood pressure and age-associated body weight gain [69]. …”

“…As melatonin is a short-lived molecule having a limited duration of action (half-life 0.54–0.67 h), analogs with a high affinity for melatonin receptors and a longer duration of action have been synthesized with a potential therapeutic efficacy to treat circadian disorders [69]. To what extent the new melatonergic agents approved by the US Food and Drug Administration or the European Medicines Agency (ramelteon, agomelatine) or those that are in the process of being approved (tasimelteon) share the protective activity of melatonin in MS remains to be defined.…”