Dysfunction of Soluble Guanylyl Cyclase in Aorta and Kidney of Goto–Kakizaki Rats: Influence of Age and Diabetic State

doi:10.1006/niox.2001.0363

Nitric Oxide

Volume 6, Issue 1, February 2002, Pages 85-95

https://doi.org/10.1006/niox.2001.0363 Get rights and content

Abstract

Type 2 diabetes mellitus is frequently associated with arterial hypertension. The mechanisms involved in this association are not known in detail, but endothelial dysfunction and a blunted vascular response to endogenous vasodilators are thought to play a role. In the present study we investigated the in vitro activity of vascular and renal soluble guanylyl cyclase in type 2 diabetic Goto–Kakizaki rats aged 5, 15, and 30 weeks, in comparison with age-matched Wistar controls. Blood pressure was monitored by radiotelemetry, and serum glucose and insulin concentrations were measured by standard assays. Goto–Kakizaki rats of all age groups had serum glucose concentrations significantly higher than those of corresponding Wistar controls. Serum insulin was unchanged until 15 weeks of age and was elevated in the 30-week-old diabetic rats. Blood pressure in Goto–Kakizaki rats was significantly higher than that in Wistar controls, and heart rate was significantly lower. Mesenteric arteries of diabetic rats showed a blunted relaxation in response to acetylcholine and sodium nitroprusside. In aortic tissue from Wistar rats an age-dependent increase was found in nitric oxide-stimulated cGMP formation, which was absent in the diabetic animals. Moreover, the maximum activity of soluble guanylyl cyclase was significantly lower in Goto–Kakizaki rats in all age groups studied. In renal tissue no differences were found between diabetic and control rats, except at 30 weeks of age when Goto–Kakizaki rats showed a significant reduction in basal and stimulated guanylyl cyclase activity. In conclusion, the present study shows a persistent reduction in vascular nitric oxide-sensitive guanylyl cyclase in Goto–Kakizaki rats, which occurred shortly after weaning and may contribute to the elevation in blood pressure in this strain of genetically diabetic rats.

References (29)

S.B. Williams et al.
Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus
J. Am. Coll. Cardiol.
(1996)
L.J. Ignarro et al.
Activation of purified guanylate cyclase by arachidonic acid requires absence of enzyme-bound heme
Biochim. Biophys. Acta
(1987)
K. Jacke et al.
Contribution of the renin–angiotensin system to subsensitivity of soluble guanylyl cyclase in TGR(mREN2)27 rats
Eur. J. Pharmacol.
(2000)
A.O. Phillips et al.
Association of prolonged hyperglycemia with glomerular hypertrophy and renal basement membrane thickening in the Goto Kakizaki model of non-insulin-dependent diabetes mellitus
Am. J. Kidney Dis.
(2001)
T.W. Gress et al.
Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus
N. Engl. J. Med.
(2000)
M.T. Johnstone et al.
Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus
Circulation
(1993)
G.E. McVeigh et al.
Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus
Diabetologia
(1992)
G.F. Watts et al.
Impaired endothelium-dependent and independent dilation of forearm resistance arteries in men with diet-treated non-insulin-dependent diabetes: Role of dyslipidaemia
Clin. Sci. (Colch.)
(1996)
P.S. Yuen et al.
A new form of guanylyl cyclase is preferentially expressed in rat kidney
Biochemistry
(1990)
Y. Goto et al.
The spontaneous-diabetes rat: A model of noninsulin dependent diabetes mellitus
Proc. Jpn. Acad.
(1981)

B. Portha et al.

Beta-cell insensitivity to glucose in the GK rat, a spontaneous nonobese model for type II diabetes

Diabetes

(1991)

C.G. Östenson et al.

Abnormal insulin secretion and glucose metabolism in pancreatic islets from the spontaneously diabetic GK rat

Diabetologia

(1993)

N. Atef et al.

Changes in islet blood flow in rats with NIDDM

Diabetologia

(1994)

R.V. Farese et al.

Insulin-induced activation of glycerol-3-phosphate acyltransferase by a chiro-inositol-containing insulin mediator is defective in adipocytes of insulin-resistant, type II diabetic, Goto–Kakizaki rats

Proc. Natl. Acad. Sci. USA

(1994)

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Although these findings are not sufficient, the influence on the sGC heme redox state in blood vessels may vary depending on the duration and/or type of hypertension. Diabetes is accompanied by a decrease in DEA/NO [NO donor]-stimulated cGMP accumulation but not by a change in protoporphyrin IX [porphyrin]-stimulated cGMP accumulation in thoracic aortas of Goto-Kakizaki rats [79]. Similarly, a study using a streptozotocin-induced diabetes model in rats found that the relaxant response of thoracic aortas to DEA/NO [NO donor] is attenuated by diabetes, whereas the response to HMR-1766 [sGC activator] remains unchanged; the former is arguably caused by the scavenging of NO, but not by a shift in the sGC heme redox balance [80].
Soluble guanylate cyclase (sGC) plays an important role in maintaining vascular homeostasis, as an acceptor for the biological messenger nitric oxide (NO). However, only reduced sGC (with a ferrous heme) can be activated by NO; oxidized (ferric heme) and apo (absent heme) sGC cannot. In addition, the proportions of reduced, oxidized, and apo sGC change under pathological conditions. Although diseased blood vessels often show decreased NO bioavailability in the vascular wall, a shift of sGC heme redox balance in favor of the oxidized/apo forms can also occur. Therefore, sGC is of growing interest as a drug target for various cardiovascular diseases. Notably, the balance between NO-sensitive reduced sGC and NO-insensitive oxidized/apo sGC in the body is regulated in a reversible manner by various biological molecules and proteins. Many studies have attempted to identify endogenous factors and determinants that influence this redox state. For example, various reactive nitrogen and oxygen species are capable of inducing the oxidation of sGC heme. Conversely, a heme reductase and some antioxidants reduce the ferric heme in sGC to the ferrous state. This review summarizes the factors and mechanisms identified by these studies that operate to regulate the sGC heme redox state.
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Evidence from animal models suggests that the severity of vascular dysfunction increases in aged diabetic animals with respect to those only diabetic or only aged. Old type 2 diabetic rats show an exacerbated reduction of endothelium-dependent relaxations in aorta, mesenteric artery and corpus cavernosum (Gür et al., 2005; Miyata et al., 1992; Witte et al., 2002). With respect to age-matched lean non-diabetic (LETO) rats, endothelial vasodilation is significantly reduced in obese diabetic (OLETF) rats at 20 weeks and further reduced at 40 weeks of age, an impairment that was prevented by performing physical activity (Bunker et al., 2010).
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Diabetes mellitus, a chronic metabolic disorder, is recognized as a root cause of cardiovascular disorders. A long-term and uncontrolled diabetes mellitus coincides with the cardiovascular signalling alteration, resulting in inadequacy of maintaining the cardiovascular physiology. Nitric oxide (NO) is an imperative mediator of cardiovascular physiology as its signalling is known to mediate vasodilatory, anti-platelet, anti-proliferative, and anti-inflammatory actions in vessels. In 1998, Robert Furchgott, Louis Ignarro and Ferid Murad received the Nobel Prize in Medicine or Physiology for their great discoveries concerning the role of NO (originally identified as endothelium-derived relaxing factor, EDRF) as a key signalling molecule in regulating cardiovascular physiology. The activation of phosphatidylinositol 3-kinase (PI3-K) further activates protein kinase B (PKB/Akt), which subsequently enhances eNOS activation and vascular NO generation. However, in recent studies a marked impairment in PI3-K/Akt–eNOS–NO signalling has been demonstrated in the condition of diabetes mellitus. Therefore, the defective PI3-K–Akt–eNOS–NO signalling pathways could make diabetic patients more vulnerable to cardiovascular disease pathology concerning the key functions of NO. Adenosine produced by cardiac cells has abilities to attenuate the proliferation of cardiac fibroblasts, inhibit collagen synthesis, and defend the myocardium against ischemia–reperfusion injury. However, diabetes mellitus is associated with enhanced unidirectional uptake of interstitial adenosine and reduced ability to release adenosine by cardiac cells during ATP deprivation. The reduced myocardial extracellular availability and increased uptake of adenosine could make diabetic subjects more susceptible to myocardial abnormalities. This review throws lights on diabetes mellitus-associated cardiovascular signalling alterations and their possible contribution to cardiovascular disease pathology.
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Thus, it is possible that the reported efficacy was still mediated by direct VPAC2-mediated neuroprotection, although “by passing” those systemic side effects that led to brain hemorrhage in our study. Although no side effects of Bay 55-9837, except at very high doses, were reported by Tsutsumi et al. (Tsutsumi et al., 2002), the high rate of mortality and hemorrhages in our study could possibly be attributed to the combination of the following factors: the diabetic GK rats develop severe endothelial dysfunction over time, which leads to decreased arterial relaxation (Kazuyama et al., 2009) and increased blood pressure (Witte et al., 2002). GK rats have been reported to exhibit significant alterations in cerebral vasculature (Beauquis et al., 2010), which-together with the above hypertension–may underlie their increased propensity for hemorrhagic transformations after stroke (Ergul et al., 2007).
VPAC2 receptor is a potential target for the treatment of type 2 diabetes and may also convey neuroprotective effects. The aim of this study was to determine the potential efficacy of the VPAC2 receptor agonist Bay 55-9837 against stroke in type-2 diabetic Goto-Kakizaki (GK) rats. GK rats were treated intravenously once daily for 7 days with 0.25 or 0.025 nmol/kg Bay 55–9837 or vehicle before inducing stroke by transient middle cerebral artery occlusion. Treatments were then continued for 7 further days. The glycemic effects of Bay 55-9837 were assessed by measuring fasting blood glucose and oral glucose tolerance. The severity of stroke was measured by assessing ischemic volume. The results show that Bay 55-9837 is not effective in lowering fasting glycemia and does not facilitate glucose disposal. The highest dose of Bay 55-9837 (0.25 nmol/kg) led to increased mortality and brain hemorrhage when compared to control. The lower dose of Bay 55-9837 (0.025 nmol/kg) did not increase mortality rate but caused a threefold increase of the ischemic lesion size with signs of brain hemorrhages as compared to control.
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Regular ArticleDysfunction of Soluble Guanylyl Cyclase in Aorta and Kidney of Goto–Kakizaki Rats: Influence of Age and Diabetic State

Abstract

J. Am. Coll. Cardiol.

Biochim. Biophys. Acta

Eur. J. Pharmacol.

Am. J. Kidney Dis.

Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus

N. Engl. J. Med.

Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus

Circulation

Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus

Diabetologia

Impaired endothelium-dependent and independent dilation of forearm resistance arteries in men with diet-treated non-insulin-dependent diabetes: Role of dyslipidaemia

Clin. Sci. (Colch.)

A new form of guanylyl cyclase is preferentially expressed in rat kidney

Biochemistry

The spontaneous-diabetes rat: A model of noninsulin dependent diabetes mellitus

Proc. Jpn. Acad.

Beta-cell insensitivity to glucose in the GK rat, a spontaneous nonobese model for type II diabetes

Diabetes

Abnormal insulin secretion and glucose metabolism in pancreatic islets from the spontaneously diabetic GK rat

Diabetologia

Changes in islet blood flow in rats with NIDDM

Diabetologia

Insulin-induced activation of glycerol-3-phosphate acyltransferase by a chiro-inositol-containing insulin mediator is defective in adipocytes of insulin-resistant, type II diabetic, Goto–Kakizaki rats

Proc. Natl. Acad. Sci. USA

Regular Article
Dysfunction of Soluble Guanylyl Cyclase in Aorta and Kidney of Goto–Kakizaki Rats: Influence of Age and Diabetic State