ABSTRACT
Long-term inhibition of nitric oxide synthase (NOS) by substituted arginine analogues has previously been shown to induce systemic hypertension in several animal species; however, the precise mechanisms for the elevated blood pressure remain unclear. We hypothesized that a portion of the hypertensive response to arginine analogues was due to direct inhibition of endothelial NOS and resultant functional alterations in the vasculature that contribute to elevated systemic resistance. Adult Sprague-Dawley rats were treated for 2 weeks with an arginine analogue, N omega Nitro-L-arginine (L-NNA), alone or in combination with the angiotensin converting enzyme (ACE) inhibitor quinapril. Next, thoracic aortas were removed, cut into rings and suspended in isolated tissue baths for measurement of contractile force in response to vasoactive drugs. Our results showed that oral L-NNA treatment significantly elevated systolic blood pressure in rats that was completely prevented by quinapril. Furthermore, L-NNA treatment increased endothelium-dependent and -independent contractility and attenuated endothelium-dependent vasodilation in the thoracic aorta. These functional alterations were also attenuated by quinapril treatment. Therefore, long-term L-NNA-induced hypertension in rats is associated with enhanced vascular reactivity due both to direct inhibition of endothelial NOS and to stimulation of the renin-angiotensin system.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/pharmacology , Hypertension/prevention & control , Isoquinolines/pharmacology , Nitroarginine/pharmacology , Tetrahydroisoquinolines , Vasomotor System/drug effects , Animals , Aorta/drug effects , Blood Pressure/drug effects , Body Weight/drug effects , Hypertension/chemically induced , In Vitro Techniques , Male , Quinapril , Rats , Rats, Sprague-DawleyABSTRACT
Reductions in cortical and trabecular bone mass have been documented in young women with hyperprolactinemic amenorrhea. It is unknown whether trabecular osteopenia is progressive or reversible with treatment of hyperprolactinemia. In addition, it is not known whether clinical or hormonal variables can predict trabecular bone density (BD) changes. Therefore, we investigated prospectively trabecular BD by computed tomography in 52 hyperprolactinemic women and 41 controls. The mean follow-up interval was 1.8 +/- 0.1 (SEM) yr. Patient groups were defined as follows: group 1, amenorrhea during the entire study; group 2, restoration of menses during the study by treatment of hyperprolactinemia; group 3, regular menses despite hyperprolactinemia, with no history of prior amenorrhea; group 4, history of prior amenorrhea, but menses restored with treatment of hyperprolactinemia before study entry; and group 5, oligomenorrhea. Groups 1, 2, and 4 had significant (P = 0.0006) initial spinal osteopenia [mean BD 141 +/- 7 (SEM), 144 +/- 9, and 151 +/- 5 mg/cc K2HPO4, respectively] compared with controls or with group 3 (170 +/- 4 and 173 +/- 8 mg/cc K2HPO4, respectively). Group 5 had an initial mean BD which was midway between that of the amenorrheic and eumenorrheic women (156 +/- 13 mg/cc K2HPO4). Group 1 had a significant (P = 0.04) decrease in mean BD to 132 +/- 8 mg/cc K2HPO4 over 1.7 +/- 0.2 yr, with BD in 42% of the group more than 2 SD below the control mean at the final study point. The mean BD in group 2 increased to 155 +/- 9 mg/cc K2HPO4, approaching significance (P = 0.07) when compared with the initial BD. Five of the nine patients in this group (56%) had an increase in BD greater than the variation expected for the computed tomography technique. However, 44% of the group 2 patients had a spinal BD which remained more than 1 SD below the normal mean. There was no change in BD in the other groups.(ABSTRACT TRUNCATED AT 400 WORDS)
