Functional alterations of mesenteric small resistance arteries in Milan hypertensive and normotensive rats

Abstract

The Milan hypertensive rat strain (MHS) is a genetic strain in which cardiovascular phenotypes seem to be dependent, at least in part, on adducin gene polymorphisms. The aim of our study was to evaluate the structure, contractile responses and endothelium-dependent vasodilation in mesenteric small resistance arteries in 12-week-old MHS, (n¼7), age-matched Milan normotensive rats (MNS, n¼7) and congenic strains in which the DNA segments carrying the a-adducin locus from the MHS have been introgressed into the MNS (MNA, n¼7). Systolic blood pressure (tail cuff) and left ventricular weight to body weight were measured. Mesenteric small arteries were dissected and mounted on a micromyograph; the media:lumen ratio was then calculated. Concentration-response curves to acetylcholine and to norepinephrine (NE) were created. Systolic blood pressure was significantly increased in the MHS and MNA strains compared with the MNS. No significant difference in mesenteric small resistance artery structure was observed among the groups; however, a slightly more elevated media:lumen ratio was observed in MNA compared with the MNS. In contrast, left ventricular weight to body weight was significantly increased and ACH-induced dilatation was significantly impaired in the MHS and in MNA compared with MNS. The concentration-response curve to NE in the MHS showed significantly reduced sensitivity to NE; however, maximum contraction was increased in the MHS vs. the other groups. The MHS presents cardiac (but not vascular) remodeling, endothelial dysfunction and a peculiar contractile response to NE, compared with the other groups. The systolic blood pressure increase and trend to vascular remodeling in MNA support the pathogenic role of a-adducin.

Reduced vasorelaxation to estradiol and G-1 in aged female and adult male rats is associated with GPR30 downregulation

“…In contrast, there were no differences in ACh relaxation. Whereas other hypertensive animal models exhibit a decrease in endothelium-dependent vasodilation (30,31), mesenteric vessels from transgenic (mRen2)27 rats, the predecessor of the congenic mRen2 rats, do not show any evidence of endothelial dysfunction (29). Likewise, we show for the first time that mesenteric artery endothelial function is preserved in both male and female congenic mRen2.Lewis rats.…”

Upregulation of Na+/Ca2+exchanger and TRPC6 contributes to abnormal Ca2+homeostasis in arterial smooth muscle cells from Milan hypertensive rats

“…Arterial hypertension in MHS rats has been associated with functional alterations of small resistance arteries including increased contractility (62). As intracellular Ca 2ϩ plays a fundamental role in the genesis and maintenance of arterial tone (39,65,81), alterations of vascular Ca 2ϩ signaling might be pivotal events for the development and maintenance of adducin-dependent hypertension.…”

“…Recent findings indicate that adducin polymorphisms are associated not only with renal dysfunction (18,64,78) but also with functional alterations in rat mesenteric small resistance arteries (62). Augmented Ca 2ϩ signaling plays a key role in the vascular dysfunction associated with arterial hypertension.…”

“…The Milan hypertensive strain (MHS) of rats is a genetic model of hypertension in which cardiovascular phenotypes seem to be dependent, at least in part, on adducin gene polymorphisms (11,62). In the MNS ϫ MHS F2 hybrid population, the mutation of the Add1 gene accounts for the 50% of the blood pressure (BP) difference between MHS and its normotensive counterpart (MNS) (9, 11).…”

“…The ␣-, ␤-, and ␥-subunits of adducin are encoded by genes (ADD1, ADD2, and ADD3 or Add1, Add2, and Add3 in humans and rats, respectively) that map to different chromosomes (29, 50). The polymorphism of ADD1 (G460W/S586C) alone (or in combination with those of ADD2) and angiotensin-converting enzyme is associated with either essential hypertension (18,45,78) or with the related cardiovascular and renal complications (51,54,60,70,75).The Milan hypertensive strain (MHS) of rats is a genetic model of hypertension in which cardiovascular phenotypes seem to be dependent, at least in part, on adducin gene polymorphisms (11,62). In the MNS ϫ MHS F2 hybrid population, the mutation of the Add1 gene accounts for the 50% of the blood pressure (BP) difference between MHS and its normotensive counterpart (MNS) (9, 11).…”