Abnormal Vascular Reactivity in Growth Hormone Deficiency

Abstract

Background-The reason why patients with growth hormone (GH) deficiency (GHD) are at increased risk for premature cardiovascular death is still unclear. Although a variety of vascular risk factors have been identified in GHD, little is known regarding vascular reactivity and its contribution to premature arteriosclerosis. Methods and Results-We assessed vascular function in 7 childhood-onset, GH-deficient nontreated patients (age 22Ϯ3 years, body mass index [BMI] 25Ϯ1 kg/m 2 ) and 10 healthy subjects (age 24Ϯ0.4 years, BMI 22Ϯ1 kg/m 2 ) by using strain gauge plethysmography to measure forearm blood flow in response to vasodilatory agents. The increase in forearm blood flow to intrabrachial infusion of the endothelium-dependent vasodilator acetylcholine was significantly lower in GH-deficient nontreated patients than in control subjects (PϽ0.05). Likewise, forearm release of nitrite and cGMP during acetylcholine stimulation was reduced in GH-deficient nontreated patients (PϽ0.05 and PϽ0.002 versus controls). The response to the endothelium-independent vasodilator sodium nitroprusside was also markedly blunted in GH-deficient patients compared with control subjects (PϽ0.005). To confirm that abnormal vascular reactivity was due to GHD, we also studied 8 patients with childhood-onset GHD (age 31Ϯ2 years, BMI 24Ϯ1 kg/m 2 ) who were receiving stable GH replacement therapy. In these patients, the response to both endothelium-dependent and -independent vasodilators, as well as forearm nitrite and cGMP, release was not different from that observed in normal subjects. Peak hyperemic response to 5-minute forearm ischemia was significantly reduced in GH-deficient nontreated patients (17.2Ϯ2.6 mL ⅐ dL Ϫ1 ⅐ min Ϫ1 , PϽ0.01) but not in GH-treated patients (24.8Ϯ3.3 mL ⅐ dL Ϫ1 ⅐ min Ϫ1 ) compared with normal subjects (29.5Ϯ3.2 mL ⅐ dL Ϫ1 ⅐ min Ϫ1 ). Conclusions-The

Growth hormone-induced blood pressure decrease is associated with increased mRNA levels of the vascular smooth muscle KATP channel

“…In the present study, GH did not increase plasma nitrate levels, arguing against a major role of increased nitric oxide production for the observed blood pressure effect. Several studies have shown that GH, or IGF-I, may cause vasorelaxation through endothelium-independent mechanisms (Hasdai et al 1998, Capaldo et al 2001. In line with these data, our finding of increased vascular Kir6·1 mRNA levels by GH supports the notion of an endotheliumindependent vasodilatory mechanism activated by GH.…”

“…Besides affecting cardiac structure and contractility (Fazio et al 1997, Longobardi et al 2000, Barreto-Filho et al 2002, both experimental and clinical GH deficiency has been associated with increased systemic vascular resistance (Fazio et al 1997, Longobardi et al 2000 and abnormal vascular reactivity (Rossoni et al 1999, Evans et al 2000, Capaldo et al 2001. Accordingly, an increased prevalence of hypertension (Barreto-Filho et al 2002) and atherosclerotic disease (Pfeifer et al 1999) has been reported among patients with GH deficiency, and hypopituitary patients show increased cardiovascular morbidity and mortality (Rosen & Bengtsson 1990).…”

“…Accordingly, an increased prevalence of hypertension (Barreto-Filho et al 2002) and atherosclerotic disease (Pfeifer et al 1999) has been reported among patients with GH deficiency, and hypopituitary patients show increased cardiovascular morbidity and mortality (Rosen & Bengtsson 1990). GH treatment in GH deficient states has been shown to normalize systemic vascular resistance (Boger et al 1996, Longobardi et al 2000, arterial stiffness (Smith et al 2002), endothelial and/or endothelium-independent vasodilation (Rossoni et al 1999, Evans et al 2000, Capaldo et al 2001, and may reverse markers of early atherosclerosis (Pfeifer et al 1999).…”

GH and IGF-I regulate the expression of endothelial nitric oxide synthase (eNOS) in cardiovascular tissues of hypophysectomized female rats

“…These patients demonstrate normal blood pressure, hypotension or hypertension (for review see (2)). They also have endothelial dysfunction (3) and decreased nitric oxide (NO) formation (4). Several studies have shown the clinical benefits of GH therapy on cardiovascular function in these patients, such as unchanged or decreased systolic and diastolic blood pressure (BP), increased cardiac output (CO), increased heart rate (HR) (4,5), increased NO formation (4) and decreased vascular resistance (5).…”

The prolactin family hormones regulate vascular tone through NO and prostacyclin production in isolated rat aortic rings

“…In the human endothelial cell line, EAht926, high concentrations of GH regulate eNOS expression and NO production [26] , effects that also occur in human aortic endothelial cells [29] . Based on these findings, the loss of GH in humans decreases both blood flow and NO levels, whereas GH replacement restores these vascular responses [27,30,31] , indicating that patients with GH deficiency are at increased cardiovascular risk [32] .…”