Hypertension is a major cause of premature death worldwide. Inflammatory macrophages play a key role in the pathogenesis of hypertension. Our lab has observed that nicotinic acetylcholine receptors (nAChR) activation potentiates salt-sensitive hypertension in Spontaneously Hypertensive Rats (SHR). Cholinergic receptor activation causes infiltration of CD68
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macrophages into the renal cortex/medulla junction and results in enhanced expression of renal sodium-potassium chloride cotransporter (NKCC2). To determine whether or not NKCC2 plays a role in the activation of inflammatory pathway furosemide, a selective pharmacologic blocker of NKCC2, was used to block NKCC2 expression in SHR in current study. Young pre-hypertensive SHR, receiving nicotine infusion (15mg/kg/day), were fed HSD (4% NaCl) and treated with either saline or furosemide (20mg/kg/day) intraperitoneal injections. There was a 16% increase (158.5±7.3 mmHg to 183.6±7.0 mmHg) in the systolic blood pressure in SHR that received saline injections, compared to no increase in SHR that received furosemide (155±6.0 mmHg to 148±3.6 mmHg) (p<0.0016). There was over a two-fold increase in fractional excretion of sodium (FENa, p=0.03) in the furosemide group, compared to saline controls. Although furosemide injections did not alter renal NKCC2 expression, there was nearly 50% reduction in phosphorylated p38 MAPK (p=0.0002) and a 25% decrease in renal infiltration of inflammatory CD68
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macrophages in SHR receiving furosemide injections, compared to saline controls. Interestingly, there was also a significant reduction in urinary albumin in response to furosemide injections (14.7±5.7 control vs 3.3±0.9 furosemide, p=0.027). Based on these findings, we conclude that furosemide results in cessation of the development of hypertension via interruption of a p38-MAPK dependent inflammatory pathway.
Central Acetylcholine Receptors in Spontaneously Hypertensive Rats
