Mechanisms of Hypertension Induced by Nitric Oxide (NO) Deficiency: Focus on Venous Function

Abstract

Loss of endothelial cell-derived nitric oxide (NO) in hypertension is a hallmark of arterial dysfunction. Experimental hypertension created by the removal of NO, however, involves mechanisms in addition to decreased arterial vasodilator activity. These include augmented endothelin-1 (ET-1) release, increased sympathetic nervous system activity, and elevated tissue oxidative stress. We hypothesized that increased venous smooth muscle (venomotor) tone plays a role in Nomega-nitro-L-arginine (LNNA) hypertension through these mechanisms. Rats were treated with the NO synthase inhibitor LNNA (0.5 g/L in drinking water) for 2 weeks. Mean arterial pressure of conscious rats was 119 +/- 2 mm Hg in control and 194 +/- 5 mm Hg in LNNA rats (P<0.05). Carotid arteries and vena cava were removed for measurement of isometric contraction. Maximal contraction to norepinephrine was modestly reduced in arteries from LNNA compared with control rats whereas the maximum contraction to ET-1 was significantly reduced (54% control). Maximum contraction of vena cava to norepinephrine (37% control) also was reduced but no change in response to ET-1 was observed. Mean circulatory filling pressure, an in vivo measure of venomotor tone, was not elevated in LNNA hypertension at 1 or 2 weeks after LNNA. The superoxide scavenger tempol (30, 100, and 300 micromol kg(-1), IV) did not change arterial pressure in control rats but caused a dose-dependent decrease in LNNA rats (-18 +/- 8, -26 +/- 15, and -54 +/- 11 mm Hg). Similarly, ganglionic blockade with hexamethonium caused a significantly greater fall in LNNA hypertensive rats (76 +/- 9 mm Hg) compared with control rats (35 +/- 10 mm Hg). Carotid arteries, vena cava, and sympathetic ganglia from LNNA rats had higher basal levels of superoxide compared with those from control rats. These data suggest that while NO deficiency increases oxidative stress and sympathetic activity in both arterial and venous vessels, the impact on veins does not make a major contribution to this form of hypertension.

Sympathetic activation in rats with L-NAME-induced hypertension

“…Acute inhibition of the SNS in this model has been shown to produce either a substantial fall or a small change in blood pressure, particularly in the initial phase of hypertension. However, a progressive increase in sympathetic tone was reported by others (8,20,21) . This discrepancy may be related to methodological reasons, such as the dose and duration of L-NAME treatment and the use of anesthesia.…”

Leptin and mechanisms of endothelial dysfunction and cardiovascular disease

“…Various vasoactive compounds have been suggested as potential mechanisms for endothelial dysfunction in hypertension including endothelial-derived nitric oxide (NO) [14], endothelin-1 [15], and others. However, the focus of this article is on recently described mechanisms of endothelial dysfunction in obesity that are potentially mediated by leptin.…”

Chemistry and Antihypertensive Effects of Tempol and Other Nitroxides

“…When recorded, the HR was reduced with intravenous tempol in six of seven hypertensive rat models (Table 1, Studies in hypertensive rats with intravenous tempol ) including one study in which NOS was blocked (Thakali et al, 2006). Four studies in normotensive models reported a modest increase in HR with intravenous tempol (Table 1, Studies in normotensive rats with intravenous tempol ).…”