RESUMO
Dialysis requiring renal failure is a silent epidemic. Despite an annual mortality of 24% the dialysis population has increased by 1-4% per annum. Regardless of the initial injury, tubulointerstitial fibrosis is a feature of the renal pathology and it inversely correlates with declining renal function. Current agents display little efficacy against tubulointerstitial fibrosis. Clearly, therapies effective against tubulointerstitial fibrosis and able to preserve kidney function are needed. Vasoactive intestinal peptide (VIP) has been shown to reverse pre-existing cardiac fibrosis. We sought to determine whether VIP is effective in tubulointerstitial fibrosis. Spontaneous hypertensive rats (SHR) on a 2.2% salt diet were randomised to zero time control, 4 week infusion of VIP (5 pmol/kg/min) or vehicle control infusion. A fourth group, to match the blood pressure reduction achieved in the VIP infused group was included. Fibrosis was quantitated by computerised histomorphometry, changes in pro-fibrotic mediators were measured by quantitative rt-PCR and macrophage activation assessed by cyclic adenosine monophosphate (c-AMP) response to incubation with VIP. Tubulointerstitial fibrosis in the VIP treated rats was significantly lower than the zero time control (P < 0.0005), the vehicle infused control (P < 0.0005) and the blood pressure matched group (P < 0.01). Although all six profibrotic mediators increased over the 4 week experimental period VIP infusion only decreased tumour necrosis alpha (TNFα) expression significantly (P < 0.001). Incubation of RAW264 macrophages with VIP significantly increased c-AMP (P < 0.01). We conclude that VIP infusion reversed existing tubulointerstitial fibrosis suggesting a possible therapeutic role for a VIP based therapy in chronic kidney disease.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Nefrite Intersticial/tratamento farmacológico , Peptídeo Intestinal Vasoativo/uso terapêutico , Animais , AMP Cíclico/farmacologia , Fibrose , Expressão Gênica/efeitos dos fármacos , Infusões Intravenosas , Rim/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Nefrite Intersticial/genética , Nefrite Intersticial/patologia , Células RAW 264.7 , Ratos , Ratos Endogâmicos SHR , Sódio na Dieta , Fator de Necrose Tumoral alfa/biossíntese , Peptídeo Intestinal Vasoativo/administração & dosagemRESUMO
Congestive cardiac failure has become one of the major health challenges of the 21st century and new therapies are needed to address this problem. The concentration of vasoactive intestinal peptide (VIP) in the heart has been shown to decrease as fibrosis (the pathology leading to heart failure) increases and to become undetectable in end stage cardiomyopathy. We sought to determine whether replenishment of myocardial VIP might treat myocardial fibrosis and therefore represent a new therapeutic target. Wistar Kyoto rats on a high (4.4%) salt diet were randomised to zero time control, 4 week infusion of VIP (5â¯pmol/kg/min) or vehicle control infusion. Myocardial VIP concentration was measured by radioimmunoassay, fibrosis was quantitated by computerised histomorphometry and changes in pro-fibrotic mediators were measured by quantitative rt-PCR. Myocardial VIP increased significantly in VIP treated rats compared with vehicle treated controls (Pâ¯<â¯0.01) while fibrosis in the VIP treated rats was significantly lower than in both the zero time control (Pâ¯<â¯0.05) and the vehicle infused control (Pâ¯<â¯0.0005). Although all six profibrotic mediators which were measured increased over the 4 week experimental period VIP infusion only affected angiotensinogen (Agt) and angiotensin receptor type 1a (AT1a) expression. In both instances VIP caused a significant decrease in messenger rna expression (Agt Pâ¯<â¯0.01 and At1a Pâ¯<â¯0.01) compared with vehicle infused controls. We conclude that VIP infusion increased myocardial VIP concentration and was able to reverse existing myocardial fibrosis suggesting a possible therapeutic role for a VIP based therapy in cardiac failure.
Assuntos
Cardiomiopatias/tratamento farmacológico , Miocárdio/patologia , Peptídeo Intestinal Vasoativo/administração & dosagem , Angiotensinogênio/análise , Angiotensinogênio/metabolismo , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Cardiomiopatias/diagnóstico , Cardiomiopatias/etiologia , Modelos Animais de Doenças , Fibrose , Humanos , Infusões Intravenosas , Masculino , Miocárdio/metabolismo , Ratos , Ratos Endogâmicos WKY , Receptor Tipo 1 de Angiotensina/análise , Receptor Tipo 1 de Angiotensina/metabolismo , Sódio na Dieta/efeitos adversos , Peptídeo Intestinal Vasoativo/análise , Peptídeo Intestinal Vasoativo/metabolismoRESUMO
We have shown previously that the concentration of Vasoactive Intestinal Peptide (VIP) in the heart is inversely correlated with the degree of fibrosis in a number of experimental models of early myocardial fibrosis. Vasopeptidase inhibition and angiotensin converting enzyme inhibition both decrease myocardial fibrosis. In this study, we sought to determine whether this myocardial protective effect might reflect increased VIP concentrations in the heart. We compared the effects of 4 weeks treatment of the vasopeptidase inhibitor omapatrilat and the angiotensin converting enzyme inhibitor enalapril on the degree of fibrosis and the concentration of VIP in the heart in salt sensitive hypertension induced by treatment with L-nitro-omega-methylarginine (L-NAME). Systolic blood pressure decreased in both treatment groups compared with control (omapatrilat P<0.005; enalapril P<0.001). Myocardial fibrosis was less for omapatrilat than control (P<0.0005) and enalapril (P<0.0005) groups. Myocardial VIP was greater in omapatrilat than in controls (P<0.005) and enalapril-treated rats (P<0.05). We conclude that vasopeptidase inhibition exerts a greater myocardial protective effect than angiotensin converting enzyme inhibition. Further, this myocardial protective effect is associated with increased VIP in the heart suggesting a pathogenetic role for VIP depletion in the development of fibrosis in the heart.
Assuntos
Hipertensão/enzimologia , Miocárdio/enzimologia , Peptídeo Hidrolases/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Enalapril/farmacologia , Enalapril/uso terapêutico , Fibrose , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Masculino , Miocárdio/patologia , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Ratos Endogâmicos WKY , Tiazepinas/farmacologia , Tiazepinas/uso terapêuticoRESUMO
BACKGROUND: Twenty-four hour ambulatory blood pressure thresholds have been defined for the diagnosis of mild hypertension but not for its treatment or for other blood pressure thresholds used in the diagnosis of moderate to severe hypertension. We aimed to derive age and sex related ambulatory blood pressure equivalents to clinic blood pressure thresholds for diagnosis and treatment of hypertension. METHODS: We collated 24 hour ambulatory blood pressure data, recorded with validated devices, from 11 centres across six Australian states (n=8575). We used least product regression to assess the relation between these measurements and clinic blood pressure measured by trained staff and in a smaller cohort by doctors (n=1693). RESULTS: Mean age of participants was 56 years (SD 15) with mean body mass index 28.9 (5.5) and mean clinic systolic/diastolic blood pressure 142/82 mm Hg (19/12); 4626 (54%) were women. Average clinic measurements by trained staff were 6/3 mm Hg higher than daytime ambulatory blood pressure and 10/5 mm Hg higher than 24 hour blood pressure, but 9/7 mm Hg lower than clinic values measured by doctors. Daytime ambulatory equivalents derived from trained staff clinic measurements were 4/3 mm Hg less than the 140/90 mm Hg clinic threshold (lower limit of grade 1 hypertension), 2/2 mm Hg less than the 130/80 mm Hg threshold (target upper limit for patients with associated conditions), and 1/1 mm Hg less than the 125/75 mm Hg threshold. Equivalents were 1/2 mm Hg lower for women and 3/1 mm Hg lower in older people compared with the combined group. CONCLUSIONS: Our study provides daytime ambulatory blood pressure thresholds that are slightly lower than equivalent clinic values. Clinic blood pressure measurements taken by doctors were considerably higher than those taken by trained staff and therefore gave inappropriate estimates of ambulatory thresholds. These results provide a framework for the diagnosis and management of hypertension using ambulatory blood pressure values.
Assuntos
Determinação da Pressão Arterial/normas , Hipertensão/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea/fisiologia , Monitorização Ambulatorial da Pressão Arterial/normas , Ritmo Circadiano , Feminino , Humanos , Hipertensão/fisiopatologia , Hipertensão/terapia , Masculino , Pessoa de Meia-Idade , Postura , Valores de Referência , Adulto JovemRESUMO
In this study we sought to determine whether early myocardial fibrosis is associated with depletion of vasoactive intestinal peptide (VIP) in the heart, thereby suggesting a possible pathogenetic role for depletion of myocardial VIP levels in the development of fibrosis in the heart. Spontaneously hypertensive rats (SHRs) and normotensive control Wistar-Kyoto rats (WKYs) were assigned randomly to low, intermediate or high sodium diets and their blood pressure was recorded twice weekly for 4 weeks. At the end of this period the rats were anaesthetised, blood was sampled for plasma VIP concentration and the hearts were harvested for histology and determination of the concentration of VIP in the heart. The degree of myocardial fibrosis increased with increasing dietary sodium intake in both the WKYs (P < 0.001) and the SHRs (P < 0.01). Myocardial VIP concentration decreased with increasing dietary sodium intake in the WKYs (P < 0.01) and in the SHRs (P < 0.01). There was a negative correlation between myocardial VIP concentration and the degree of myocardial fibrosis in both the WKYs (P < 0.0005) and the SHRs (P < 0.005). Dietary sodium intake induces myocardial fibrosis in a dose-dependent manner. Further, in early myocardial fibrosis resulting from increasing dietary sodium intake in both normotensive and hypertensive rats the concentration of VIP in the heart was negatively correlated with the degree of fibrosis. This suggests a possible role for depletion of VIP in the myocardium in the pathogenesis of myocardial fibrosis.