S-Nitrosocaptopril: In vitro characterization of pulmonary vascular effects in rats

1 On rat isolated pulmonary arteries, vasorelaxation by S-nitrosocaptopril (SNOcap) was compared with S-nitrosoglutathione (GSNO) and nitroprusside, and inhibition by SNOcap of contractions to angiotensin I was compared with the angiotensin converting enzyme (ACE) inhibitor, captopril. 2 SNOcap was equipotent as a vasorelaxant on main (i.d. 2-3 mm) and intralobar (i.d. 600 mum)pulmonary arteries (pIC(50) values: 5.00 and 4.85, respectively). Vasorelaxant responses reached equilibrium rapidly (2-3 min). 3 Pulmonary vasorelaxant responses to SNOcap, like GSNO, were (i) partially inhibited by the soluble guanylate cyclase inhibitor, ODQ (1H-(1,2,4) oxadiazolo(4,3-a)-quinoxalin-1-one; 3 muM) whereas responses to nitroprusside were abolished and (ii) potentiated by hydroxocobalamin (HCOB; NO. free radical scavenger; 100 muM) whereas responses to nitroprusside were inhibited. 4 The relative potencies for pulmonary vasorelaxation compared with inhibition of platelet aggregation were: SNOcap 7: 1; GSNO 25: 1; nitroprusside > 2000:1. 5 SNOcap, like captopril, concentration-dependently and time-dependently increased the EC50 for angiotensin I but not angiotensin II. The dependence on incubation time was independent of the presence of tissue but differed for SNOcap and captopril. This difference reflected the slow dissociation of SNOcap and instability of captopril, and precluded a valid comparison of the potency of the two drugs. After prolonged incubation (greater than or equal to 5.6 h) SNOcap was more effective than captopril. 6 Thus, in pulmonary arteries SNOcap (i) possesses NO donor properties characteristic of S-nitrosothiols but different from nitroprusside and (ii) inhibits ACE at least as effectively as captopril. These properties suggest that SNOcap could be valuable in the treatment of pulmonary hypertension.

Vasodilator mechanisms in the dorsal aorta of the giant shovelnose ray, Rhinobatus typus (Rajiformes; Rhinobatidae)

This study investigated the nature of vasodilator mechanisms in the dorsal aorta of the giant shovelnose ray, Rhinobatus typus. Anatomical techniques found no evidence for an endothelial nitric oxide synthase, but neural nitric oxide synthase was found to be present in the perivascular nerve fibres of the dorsal aorta and other arteries and veins using both NADPH-diaphorase staining and immunohistochemistry with a specific neural NOS antibody. Arteries and veins both contained large nNOS-positive nerve trunks from which smaller nNOS-positive bundles branched and formed a plexus in the vessel wall. Single, varicose nNOS-positive nerve fibres were present in both arteries and veins. Within the large bundles of both arteries and veins, groups of nNOS-positive cell bodies forming microganglia were observed. Double-labelling immunohistochemistry using an antibody to tyrosine hydroxylase showed that nearly all the NOS nerves were not sympathetic. Acetylcholine always caused constriction of isolated rings of the dorsal aorta and the nitric oxide donor, sodium nitroprusside, did not mediate any dilation. Addition of nicotine (3 x 10(-4) M) to preconstricted rings caused a vasodilation that was not affected by the nitric oxide synthase inhibitor, L-NNA (10(-4) M), nor the soluble guanylyl cyclase inhibitor, ODQ (10(-5) M). This nicotine-mediated vasodilation was, therefore, not due to the synthesis and release of NO. Disruption of the endothelium significantly reduced or eliminated the nicotine-mediated vasodilation. In addition. indomethacin (10(-5) M), an inhibitor of cyclooxygenases, significantly increased the time period to maximal dilation and reduced, but did not completely inhibit the nicotine-mediated vasodilation. These data support the hypothesis that a prostaglandin is released from the vascular endothelium of a batoid ray, as has been described previously in other groups of fishes. The function of the nitrergic innervation of the blood vessels is not known because nitric oxide does not appear to regulate vascular tone. (C) 2003 Elsevier Inc. All rights reserved.

Increased calcium influx mediates increased cardiac stiffness in hyperthyroid rats

Cardiac remodeling (hypertrophy and fibrosis) and an increased left ventricular diastolic stiffness characterize models of hypertension such as the SHR and DOCA-salt hypertensive rats. By contrast, hyperthyroidism induces hypertrophy and hypertension, yet collagen expression and deposition is unchanged or decreased, whereas diastolic stiffness is increased. We determined the possible role of increased calcium influx in the development of increased diastolic stiffness in hyperthyroidism by administering verapamil (15 mg/[kg(.)d] orally) to rats given triiodothyronine (T-3) (0.5 mg/[kg.d] subcutaneously for 14 d). Administration of T3 significantly increased body temperature (control: 36.7 +/- 0.2 degrees C; T-3: 39.6 +/- 0.2 degrees C), left ventricular wet weight (control: 2.09 +/- 0.02 mg/kg; T-3 3.07 +/- 0.07 mg/kg), systolic blood pressure (control: 128 +/- 5 mmHg; T-3: 156 +/- 4 mmHg), and left ventricular diastolic stiffness (control: 20.6 +/- 2.0; T-3: 28.8 +/- 1.4). Collagen content of the left ventricle was unchanged. Contractile response to noradrenaline in thoracic aortic rings was reduced. Relaxation in response to acetylcholine (ACh) was also reduced in T-3-treated rats, whereas sodium nitroprusside response was unchanged. Verapamil treatment of hyperthyroid rats completely prevented the increased diastolic stiffness and systolic blood pressure while attenuating the increased body temperature and left ventricular weight; collagen content remained unchanged. ACh response in thoracic aortic rings was restored by verapamil. Thus, in hyperthyroid rats, an increased calcium influx is a potential mediator of the increased diastolic stiffness independent of changes in collagen.

Platelet nitric oxide responsiveness - A novel prognostic marker in acute coronary syndromes

Objectives - Nitric oxide (NO) is critically important in the regulation of vascular tone and the inhibition of platelet aggregation. We have shown previously that patients with acute coronary syndromes (ACS) or stable angina pectoris have impaired platelet responses to NO donors when compared with normal subjects. We tested the hypotheses that platelet hyporesponsiveness to NO is a predictor of (1) cardiovascular readmission and/or death and (2) all-cause mortality in patients with ACS (unstable angina pectoris or non-Q-wave myocardial infarction). Methods and Results - Patients (n = 51) with ACS had evaluation of platelet aggregation within 24 hours of coronary care unit admission using impedance aggregometry. Patients were categorized as having normal (>= 32% inhibition of ADP-induced aggregation with the NO donor sodium nitroprusside; 10 mu mol/L; n = 18) or impaired (>= 32% inhibition of ADP-induced aggregation; n = 33) NO responses. We then compared the incidence of cardiovascular readmission and death during a median of 7 years of follow-up in these 2 groups. Using a Cox proportional hazards model adjusting for age, sex, index event, postdischarge medical treatment, revascularization status, left ventricular systolic dysfunction, concurrent disease states, and cardiac risk factors, impaired NO responsiveness was associated with an increased risk of the combination of cardiovascular readmission and/or death (relative risk, 2.7; 95% CI, 1.03 to 7.10; P = 0.041) and all-cause mortality (relative risk, 6.3; 95% CI, 1.09 to 36.7; P = 0.033). Conclusions - Impaired platelet NO responsiveness is a novel, independent predictor of increased mortality and cardiovascular morbidity in patients with high-risk ACS.

Improved cardiovascular function with aminoguanidine in DOCA-salt hypertensive rats

1 The ability of aminoguanidine (AG), an inhibitor of collagen crosslinking, to prevent changes in cardiac and vascular structure and function has been determined in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat as a model of the cardiovascular remodelling observed in chronic human hypertension. 2 Uninephrectomized rats (UNX) administered DOCA (25 mg every fourth day s.c.) and 1% NaCl in drinking water for 28 days developed cardiovascular remodelling shown as systolic hypertension, left ventricular hypertrophy, increased thoracic aortic and left ventricular wall thickness, increased left ventricular inflammatory cell infiltration together with increased interstitial collagen and increased passive diastolic stiffness, impaired contractility, prolongation of the action potential duration and vascular dysfunction. 3 Treatment with AG (0.05-0.1% in drinking water; average 182 +/- 17 mg kg(-1) day(-1) in DOCA-salt rats) decreased blood pressure (DOCA-salt 176 +/- 4; + AG 144 +/- 5 mmHg; *P < 0.05 vs DOCA-salt), decreased left ventricular wet weights (DOCA-salt 3.17 +/- 0.07; + AG 2.66 +/- 0.08 mg g(-1) body wt*), reduced diastolic stiffness constant (DOCA-salt 30.1 +/- 1.2; + AG 24.3 +/- 1.2* (dimensionless)), improved cardiac contractility (DOCA-salt 1610 +/- 130; + AG 2370 +/- 100 mmHg s(-1)*) and vascular reactivity (3.4-fold increase in maximal contractile response to noradrenaline, 3.2-fold increase in maximal relaxation response to acetylcholine, twofold increase in maximal relaxation response to sodium nitroprusside) and prolonged the action potential duration at 50% repolarization without altering collagen content or inflammatory cell infiltration. 4 Thus, cardiovascular function in DOCA-salt hypertensive rats can be improved by AG independent of changes in collagen content. This suggests that collagen crosslinking is an important cause of cardiovascular dysfunction during cardiovascular remodelling in hypertension.