Evidence for a noradrenergic mechanism causing hypertension and abnormal glucose metabolism in rats with relative deficiency of γ‐melanocyte‐stimulating hormone

Abstract

A close association between salt-sensitive hypertension and insulin resistance has been recognized for more than two decades, although the mechanism(s) underlying this relationship have not been elucidated. Recent data in mice with genetic disruption of the γ-melanocytestimulating hormone (γ-MSH) system suggest that this system plays a role in the pathophysiological relationship between hypertension and altered glucose metabolism during ingestion of a high-sodium diet (8% NaCl, HSD). We tested the hypothesis that these two consequences of interrupted γ-MSH signalling were the result of sympathetic activation by studying rats treated with the dopaminergic agonist bromocriptine (5 mg kg −1 i.p., daily for 1 week; Bromo) to cause relative γ-MSH deficiency. Bromo-treated rats fed the HSD developed hypertension and also exhibited fasting hyperglycaemia (P < 0.005) and hyperinsulinaemia (P < 0.025). Furthermore, Bromo-treated rats on the HSD had impaired glucose tolerance and blunted insulin-mediated glucose disposal. Intravenous infusion of γ 2 -MSH, or of the α-adrenergic receptor antagonist phentolamine, to Bromo-HSD rats lowered both mean arterial pressure (MAP) and blood glucose to normal after 15 min (P < 0.001 versus control), but had no effect in rats receiving vehicle and fed the HSD; γ 2 -MSH infusion also reduced the elevated plasma noradrenaline to control levels in parallel with the reductions in MAP and blood glucose concentration. Infusion of hydralazine to Bromo-HSD rats lowered MAP but had only a trivial effect on blood glucose. We conclude that rats with relative γ-MSH deficiency develop abnormal glucose metabolism, with features of insulin resistance, in association with hypertension when ingesting the HSD. Elevated plasma noradrenaline concentration in Bromo-HSD rats is normalized by γ 2 -MSH infusion, suggesting that an adrenergic mechanism may link the salt-sensitive hypertension and the impaired glucose metabolism of relative γ-MSH deficiency.

The natriuretic mechanism of Gamma-Melanocyte-Stimulating Hormone

“…The findings presented here are consistent with the notion that the natriuretic effect of γ-MSH, like the vasodepressor effect, involves suppression of central neural pathways, possibly limiting sympathetic outflow to kidney tubules, which normally maintain a tonic level of renal salt absorption [7]. Indeed, recent evidence demonstrates that intravenous infusion of γ-MSH normalizes the elevated plasma noradrenaline levels in γ-MSH-deficient rats [21], consistent with the role of the γ-MSH/MC3-R pathway serving as an adrenergic brake mechanism.…”

Cardiovascular effects of melanocortins

“…Thus, the development of salt-sensitive hypertension after one week’s treatment with bromocriptineis perhaps surprising given these reports of its hypotensive action, and is an indicator of the importance of the accompanying γ-MSH deficiency coupled with the high sodium diet in blood pressure regulation. Male rats fed the high sodium diet and treated with bromocriptine had fasting hyperglycemia (blood glucose 116±4 vs 102±2 mg/dL, p <0.01) and hyperinsulinemiaas well as hype rtension (133±3 vs 103±3 mm Hg, p <0.001) (Ni et al, 2009; Van Dijk et al, 2006), paralleling the results in the PC2−/− and Mc3r−/− mouse models. This result too is surprising, since bromocriptine has been shown to ameliorate glucose metabolism and increase insulin sensitivity in obese humans (Kok et al, 2006; Pijl et al, 2000)and the obese Syrian hamster (Luo et al, 1999).…”

“…This was not the case when the peripheral vasodilator hydralazine (0.1 μg/kg/min) was used to lower blood pressure. As with the studies infusing γ 2 -MSH and phentolamine, hydralazine lowered pressure to the same level as vehicle -treated rats but had no significant effect on blood glucose concentration after 15 min; after 60 min blood pressure remained stable, and blood glucose concentration had fallen only trivially (Ni et al, 2009) (Fig. 5).…”

“…Third, the hyperinsulinemia in bromocriptine-treated rats ingesting the high sodium diet could itself be a stimulus for increased sympathetic outflow via a central mechanism (Muntzel et al, 2007; Muntzel et al, 1994). Consistent with increased sympathetic nerve activity is the observation that plasma noradrenaline concentration was twice as high in bromocriptine-treated rats eating the high sodium diet as in the other groups; infusion of γ 2 -MSHa t a low rate (0.4 pmol/min) lowered plasma noradrenaline concentration from 184±37 to 98±17 pg/ml as blood pressure fell from 131±3 to 104 ±3 mm Hg (Ni et al, 2009). Peripheral vasoconstriction and sympathetically-and insulin -mediated increase sin tubular sodium reabsorption (Baum, 1987; DeFronzo et al, 1975; DiBona and Kopp, 1997)could both contribute to the hypertension.…”

“…Its primary use in clinical medicine has been to suppress release of prolactin, and studies in both rats and humans indicate that it does cause reductions in plasma prolactin concentration (Kok et al, 2006; Mannelli et al, 1984; Nagahama et al, 1984; 1985; Ni et al, 2009; Stier et al, 1982). Prolactin infusion leads to natriuresis in the rat through an inhibition of proximal tubular Na, K-ATPase, an effect blocked by a dopamine D1 receptor antagonist (Ibarra et al, 2005).…”