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Tetrahydrobiopterin (BH 4 ) is an essential cofactor for nitric oxide synthases (NOS). This study investigated the effect of increasing BH 4 levels on hypoxia-induced pulmonary vasoconstriction (HPV).Sprague Dawley rats and hph-1 (BH 4 deficient) mice were given BH 4 before and during HPV in an isolated perfused lung preparation. BH 4 inhibited HPV in a concentration-dependent manner and increased NO metabolites in the perfusate. Bradykinin-induced reductions in HPV were blunted in hph-1 mice and pre-administration of BH 4 restored the response. The effect of BH 4 was attenuated by L-NAME (NOS inhibitor), PTIO (NO scavenger), and catalase (H 2 O 2 catalyser) administered prior to HPV but enhanced by MnTMPyP (superoxide dismutase mimetic). The effect of BH 4 on HPV was partially recapitulated by NH 4 , a stereoisomer that shares antioxidant properties with BH 4 but is not a NOS cofactor.The bioavailability of BH 4 is an important determinant of the pulmonary vascular response to hypoxia. Its effects are mediated via nitric oxide, hydrogen peroxide and its antioxidant properties, and are attenuated by oxidant stress. Pharmacological administration of BH 4 may have therapeutic potential in pulmonary hypertension.

Endothelial nitric oxide synthase (eNOS) plays a major role in maintaining pulmonary vascular homeostasis. Tetrahydrobiopterin (BH 4 ), an essential cofactor that stabilizes the dimerization of eNOS and balances nitric oxide (NO) and superoxide production, may have therapeutic potential in pulmonary hypertension. In the isolated perfused lung, we demonstrated a direct effect of exogenous administration of BH 4 on pulmonary NO production, leading to acute vasorelaxation during the plateau phase of hypoxia-induced pulmonary vasoconstriction. In the chronic hypoxia-induced pulmonary hypertension rat model, chronic BH 4 oral administration attenuated the pressor response to hypoxia (mean pulmonary artery pressure AE standard error of the mean, 31.8 AE 0.5 mmHg at 100 mg/kg/day; placebo group, 36.3 AE 0.6 mmHg; P < 0.05). During telemetric monitoring, right ventricular systolic pressure was reduced by approximately 50% after 1 week of BH 4 treatment at 100 mg/kg/day. BH 4 at 100 mg/kg/day reduced right ventricular hypertrophy (from 0.55 AE 0.01 to 0.50 AE 0.01; P < 0.05) and pulmonary vascular muscularization (from 79.2% AE 2% to 65.2% AE 3%; P < 0.01). BH 4 treatment enhanced lung eNOS activity and reduced superoxide production, with a net increase in cyclic guanosine monophosphate levels. BH 4 is effective in attenuating pulmonary hypertension in the hypoxic rat model when given as a rescue therapy.

Endothelin-1 (ET-1) exerts its biological actions through two receptor subtypes: endothelin-A (ETA) receptor and endothelin-B (ETB) receptor. We demonstrated previously that ET-1 induces systemic and renal cortical vasoconstriction via ETA whereas ETB mediates medullary vasodilation. Congestive heart failure (CHF) is characterized by increased vascular resistance and impaired renal hemodynamic and excretory function. While the pathophysiological effects of ET-1 in CHF are well established, the status of ETA and ETB in the kidney is poorly characterized. The present study examined the immunostaining and localization of ETA and ETB in the renal cortex and medulla of rats with experimental CHF induced by aorto-caval fistula. Rats with CHF were further subdivided, based on their daily urinary sodium excretion, into rats with compensated (urinary sodium excretion > 1200 microEq/day) and decompensated CHF (urinary sodium excretion < 200 microEq/day). ETA is predominantly localized to the cortex mainly in the peritubular capillaries, and is upregulated in rats with compensated and decompensated CHF compared with sham controls. In contrast, ETB is preferentially expressed in the outer and inner medulla, mainly in the vasa recta, the thick ascending limb of Henle's loop and the collecting duct. While compensated CHF is associated with upregulation of ETB in the collecting duct and vasa recta, decompensated CHF is accompanied with enhanced ETB abundance in the vasa recta and remarkable downregulation of this receptor subtype in the collecting duct. The findings suggest that upregulation of ETA may lead to a decrease in cortical blood flow while upregulation of ETB in the vasa recta probably contributes to the preservation of medullary blood flow. Furthermore, downregulation of ETB in the collecting duct, only in rats with decompensated CHF, could contribute to sodium retention in that subgroup.

Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac and renal hemodynamic changes and impaired excretory function in congestive heart failure. It has previously been demonstrated that acute administration of ABT-627 (endothelin-A blocker) abolished systemic and renal vasoconstriction in controls and rats with congestive heart failure induced by a surgically created aortocaval fistula (Abassi et al. Clin Sci (Lond) 2002;103:S245-S248). In contrast, acute endothelin-B blockade by A-192621 exaggerated the ET-1 induced systemic and renal vasoconstriction. The present study examined the renal and systemic effects of chronically administered ABT-627 (24 mg/kg per day) or A-192621 (72 mg/kg per day) for 7 days via osmotic minipumps inserted intraperitoneally on the day of operation of sham controls and rats with congestive heart failure. Tailcuff measurements revealed that ABT- 627 significantly decreased mean arterial pressure from 108 +/- 2 mmHg to 87 +/- 2 mmHg (P < 0.05), whereas A-192621 significantly increased mean arterial pressure from 110 +/- 3 mmHg to 122 +/- 3 mmHg (P < 0.05) in controls. Despite the hypotensive effect of ABT-627, daily sodium excretion dramatically increased, but to a lesser extent in A-192621-treated controls. Furthermore, chronic administration of ABT-627 to controls attenuated the systemic and renal vasoconstriction induced by ET-1 (1 nmol/kg intravenous), whereas A-192621 augmented these effects. Similarly, chronic treatment with ABT-627 totally abolished the systemic and renal vasoconstriction caused by injected ET-1 in rats with congestive heart failure, whereas A192621 potentiated these effects. Chronic treatment of animals with congestive heart failure with ABT-627 did not influence daily sodium excretion, whereas treatment with A192621 significantly improved daily sodium excretion. Interestingly, treatment with either ABT-627 or A192621 significantly decreased cardiac hypertrophy in rats with congestive heart failure. In conclusion, in sham controls endothelin-B receptor mediated vasodilation and natriuresis, probably as a result of tubular action, whereas in congestive heart failure the excretory contribution of endothelin-B receptor was attenuated, resulting in Na+ retention.

Background Comprehensive geriatric assessment (CGA) has been in use for the last three decades. However, some doubts remain regarding its clinical use. Therefore, we aimed to capture the breadth of outcomes reported and assess the strength of evidence of the use of comprehensive geriatric assessment (CGA) for health outcomes in older persons. Methods Umbrella review of systematic reviews of the use of CGA in older adults searching in Pubmed, Embase, Scopus, Cochrane library and CINHAL until 05 November 2021. All possible health outcomes were eligible. Two independent reviewers extracted key data. The grading of evidence was carried out using the GRADE for intervention studies, whilst data regarding systematic reviews were reported as narrative findings. Results Among 1,683 papers, 31 systematic reviews (19 with meta-analysis) were considered, including 279,744 subjects. Overall, 13/53 outcomes were statistically significant (P &lt; 0.05). There was high certainty of evidence that CGA reduces nursing home admission (risk ratio [RR] = 0.86; 95% confidence interval [CI]: 0.75–0.89), risk of falls (RR = 0.51; 95%CI: 0.29–0.89), and pressure sores (RR = 0.46; 95%CI: 0.24–0.89) in hospital medical setting; decreases the risk of delirium (OR = 0.71; 95%CI: 0.54–0.92) in hip fracture; decreases the risk of physical frailty in community-dwelling older adults (RR = 0.77; 95%CI: 0.64–0.93). Systematic reviews without meta-analysis indicate that CGA improves clinical outcomes in oncology, haematology, and in emergency department. Conclusions CGA seems to be beneficial in the hospital medical setting for multiple health outcomes, with a high certainty of evidence. The evidence of benefits is less strong for the use of CGA in other settings.

The present study examined the effects of two highly selective endothelin-1 (ET-1) receptor antagonists, ABT-627 (ET(A) blocker) and A-192621 (ET(B) blocker), on the systemic and renal haemodynamic effects of ET-1 in normal rats and in rats with experimental congestive heart failure (CHF) produced by aortocaval fistula. Intravenous injection of ET-1 (1.0 nmol x kg(-1) of body weight) to anaesthetized normal rats produced sustained decreases in renal blood flow (RBF) (assessed by ultrasonic flowmetry) and glomerular filtration rate (GFR), and significant increases in renal vascular resistance (RVR) and mean arterial pressure (MAP). Pretreatment with ABT-627 (1 mg x h(-1) x kg(-1) of body weight) abolished the pressor response to ET-1 without affecting the depressor phase, and significantly impaired the renal vasoconstriction. The systemic and renal vasoconstrictive effects of ET-1 in normal rats were significantly augmented by pretreatment with 3.0 mg x h(-1) x kg(-1) of A-192621. Baseline RBF and GFR in rats with CHF were reduced significantly compared with control rats, whereas RVR was elevated. The hypertensive effect of ET-1 was attenuated in rats with CHF. In the presence of ET(A) blockade, the pressor response to ET-1 was completely abolished in CHF rats. Furthermore, pretreatment with ABT-627 enhanced the recovery from ET-1- dependent vasoconstriction and remarkably reversed the ET-1-induced hypofiltration. Blockade of ET(B) receptors in rats with CHF further exposed the exaggerated ET-1-induced renal vasoconstriction. Our data demonstrate that experimental CHF is associated with altered responsiveness to ET(A)- and ET(B)-mediated systemic and renal effects of ET-1. Furthermore, in CHF, as in control rats, the ET(B)-mediated vasodilatory response may serve as an important compensatory counterbalance to the adverse ET(A)-mediated effects.

Summary Purpose Pulmonary Hypertension (PH) is complex disease which is associated with endothelial and cardiac dysfunction. Tetrahydrobiopterin (BH4) regulates endothelial nitric oxide synthase (eNOS) to produce nitric oxide rather than superoxide which maintains normal endothelial and cardiac function. This study explores the therapeutic potential of BH4 in experimental PH. Methods Monocrotaline‐induced PH in rats and Hph‐1 deficiency in mice were used for animal experiments. Hemodynamic measurements using pressure transducers were conducted for pulmonary and cardiac pressures, and Langendorff apparatus was used for isolated heart experiments; preventive as well as rescue treatment protocols were conducted; tissues were collected for histological and biochemical studies. Results In vivo acute BH4 administration reduced pulmonary artery pressure (PAP) only in the MCT rat. In a Langendorff preparation, BH4 increased right ventricular systolic pressure (RVSP) in right ventricular hypertrophy (RVH) but not in control. In “prevention” therapy, BH4 (10 and 100 mg/kg) attenuated the development of PH in rat MCT model. eNOS protein levels in lung homogenates were maintained and cGMP levels were increased. In “rescue” therapy, BH4 (10 and 100 mg/kg) ameliorated pulmonary vascular muscularization in a dose‐dependent manner. RVSP was reduced in RVH and pulmonary vascular muscularization was attenuated. BH4 at 10 mg/kg reduced RV myocyte diameter while BH4 at 100 mg/kg reversed it to control level. BH4 restored normal levels of eNOS protein and in a dose of 100 mg/kg enhanced lung tissue levels of BH4, cGMP, and NO compared to placebo. Conclusion The current study provides scientific evidence for a therapeutic potential of BH4 in PH and invites further investigation.