Cardiovascular responses to long-term blockade of nitric oxide synthesis.

Abstract

The goal of this study was to determine if there is a basal release of nitric oxide that affects long-term arterial pressure regulation in dogs. Studies were conducted over a 23-day period in eight conscious dogs with indwelling catheters. Nitric oxide synthesis was blocked by continuous intravenous infusion of nitro-L-arginine-methyl ester at 37.1 nmol/kg per minute for 11 days. Arterial pressure increased to 120±4% of control on the first day, decreased for a few days, and then increased to a maximum value of 122±6% of control on day 7. Bradycardia was sustained throughout the entire nitro-arginine period. Blockade of nitric oxide synthesis was evidenced by attenuated pressure and flow responses to systemic acetylcholine infusion. The pressor response to phenylephrine was increased for only 1 day, and the hypotensive effects of nitroprusside were enhanced. Also, the variability of arterial pressure was significantly increased during nitro-arginine. Sodium and water balances were positive the first day of nitro-arginine infusion but were unchanged for the entire nitro-arginine period. In conclusion, the data suggest that blockade of the basal release of nitric oxide in dogs causes an increase in the long-term level of arterial pressure without any sustained sodium or water retention. (Hypertension 1993;22:40-48) KEY WORDS • endothelium • vasodilation • arginine • nitric oxide • hypertension, essential I n 1980 Furchgott and Zawadzki 1 found that acetyl-choline-induced relaxation of vascular strips or rings was dependent on the presence of an intact endothelium. A substance released from the endothe-lium, later known as endothelium-derived relaxing factor (EDRF), was primarily responsible for this relaxation. Furchgott 2 later suggested that EDRF was nitric oxide (NO), and Ignarro et al 3 speculated that EDRF might be NO or a related compound. Other investigators have confirmed that NO is an integral part of EDRF, and specific NO synthesis inhibitors have been successfully developed. 4 The two major inhibitors of NO production are JV G-monomethyl L-arginine (L-NMMA) and Af G-nitro-L-arginine-methyl ester (L-NAME), and they both act by competitive inhibition of NO synthase. This inhibition prevents the conversion of L-arginine to NO. Of these two inhibitors, L-NAME is much more potent and causes acute vasoconstriction in a number of vascular beds, whereas D-NAME does not. 5 Most experiments on NO synthesis blockade have been performed in vitro on vascular rings. However, more recently, administration of NO synthesis blockers resulted in acute increases in arterial pressure in rats, 6 ' 7 guinea pigs, 8 and rabbits. 9 In addition, studies by Gar-diner et al 5 and Baylis et al 10 showed that administration of L-NAME for several hours to conscious rats resulted in increases in arterial pressure. More recently, several longer experiments have been performed in which NOson, MS 39216-4505 (Dr Manning). synthesis inhibitors were administered to rats orally for periods lasting between 9 hours and 6 months, and mean arter...

Effectiveness of Angiotensin-Converting Enzyme Inhibitor or Angiotensin II Receptor Blocker on Atrial Natriuretic Peptide

“…In our experiment, administration of L-NNA to normotensive rats induced a marked increase in blood pressure. Moreover, administration of the NO precursor L-arginine in combination with an NO inhibitor slows the rise in blood pressure, 12 thus demonstrating that treatment with substances related to NO secretion produces changes in blood pressure. When blood pressure is altered by treatment with an NO inhibitor, positive and negative feedback mechanisms involving other vasoactive substances are also activated within the body in order to regulate blood pressure.…”

Hypertension inl-NAME-treated diabetic rats depends on an intact sympathetic nervous system

“…Endogenous NO plays an important role in the maintenance of normal blood flow and arterial pressure under normal conditions (19,30,49), but the role of changes in the NO system in mediating hemodynamic disturbances associated with diabetes is unclear. This study confirms our previous observation that induction of diabetes in L-NAME-treated rats causes a significant, progressive increase in MAP that does not occur in normal diabetic rats (15) and also shows that 1) the hypertensive response is significantly attenuated in rats with chronic ␣-and ␤-adrenergic receptor blockade, and 2) hypertension in L-NAME-treated diabetic rats is related to increased renin-angiotensin system activity and to an attenuation of diabetes-associated hyperfiltration.…”

A Large Blood Pressure–Raising Effect of Nitric Oxide Synthase Inhibition in Humans

“…[1][2][3][4][5][6] Although this experimental NOdeficient hypertension at first was attributed solely to inhibition of endothelium-dependent vasodilation, 1,7 there is increasing evidence of an important sympathetic neural component. 5,6,8 -12 The concept is that neuronally produced NO is part of the signal transduction pathway involved in the restraint of brainstem sympathetic vasomotor outflow and that inhibition of such restraint leads to neurogenic hypertension.…”