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Biomedical subjects

R Clinton Webb

Publications and source records attributed to R Clinton Webb.

49 records · Page 3Linked to original sources
PubMed2003

Tamoxifen, a selective estrogen receptor modulator, reduces ischemic damage caused by middle cerebral artery occlusion in the ovariectomized female rat.

Previous work has demonstrated that physiological concentrations of 17beta-estradiol can protect the female rat brain against middle cerebral artery occlusion (MCAO)-induced ischemic damage. The present study examined whether therapeutic doses of the clinically relevant selective estrogen receptor modulator (SERM), tamoxifen, can similarly protect the female rat brain against ischemic stroke damage. Adult female rats were bilaterally ovariectomized and implanted subcutaneously with either a placebo or tamoxifen time-release pellet (0.1, 0.8 or 2.4 mg/kg/day). One week later, the animals underwent permanent MCAO to assess the protective ability of the different tamoxifen doses on brain infarct size. As expected, MCAO produced a large infarct ( approximately 53%) of the affected cerebral hemisphere in placebo (control) animals. The 0.1 mg/kg/day dose of tamoxifen did not exhibit any significant protective effects, however; the 0.8 and 2.4 mg/kg/day doses of tamoxifen, which are in the therapeutic range, dramatically reduced infarct of the affected cerebral hemisphere ( approximately 70% reduction) as compared to the controls. The reduction of infarct size was primarily due to protection of two major structures, the cerebral cortex and striatum. Laser Doppler analysis further revealed that tamoxifen had no significant effect on cerebral blood flow either before or after MCAO, suggesting that tamoxifen protection is independent of cerebral blood flow changes. Further studies showed that tamoxifen pellets implanted at the time of MCAO did not reduce infarct size, suggesting that pretreatment with tamoxifen is necessary to observe a protective effect. These studies suggest that clinically important SERMs may have an additional unrecognized beneficial effect of protection of the female brain.

Animals↗
PubMed2003

Inhibition of the tonic contraction in the treatment of erectile dysfunction.

Erectile dysfunction (ED) reduces the quality of life. It is estimated that 52% of men have some degree of ED, which is associated with ageing. While it is clear that there are a variety of current treatment options for ED, each of these has drawbacks and contraindications. A better understanding of the physiological mechanisms involved in penile erection will provide new ways to treat ED. This review not only focuses on the vasoconstrictors and vasodilators that control the state of contraction and relaxation of the corpora cavernosa smooth muscle, but also presents a novel Ca(2+)-sensitising pathway that contributes to maintaining the penis in the non-erect state. Studies have shown that inhibition of the RhoA/Rho-kinase signalling pathway induces penile erection. Further understanding of this RhoA/Rho-kinase pathway may provide a novel alternative treatment for ED.

Adrenergic Agonists↗
PubMed2002

Adeno-associated viral gene transfer of dominant negative RhoA enhances erectile function in rats.

We previously reported the inhibition of Rho-kinase to result in increased intracavernosal pressure (ICP) in an in vivo rat model of erection. Expression of an upstream activator of Rho-kinase, RhoA, has been demonstrated in the penile vasculature; however, the functional role of RhoA in the regulation of erection remains unknown. We used adeno-associated viral gene transfer of a dominant negative RhoA mutant (T19NRhoA) into rat cavernosum to test the hypothesis that RhoA activation is physiologically important for maintenance of the non-erect state and inhibition of this pathway leads to erection. Anesthetized, male, Sprague-Dawley rats transfected with the T19NRhoA mutant exhibited an elevated baseline ICP/mean arterial pressure (MAP) and nerve stimulation-induced ICP/MAP as compared with beta-galactosidase-transfected controls. The novel findings of this study demonstrate a functional role of RhoA in maintaining the flaccid penis and provide support for the inhibition of RhoA as a potential therapy for the enhancement of erectile function.

Animals↗
PubMed2002

Nitric oxide inhibits RhoA/Rho-kinase signaling to cause penile erection.

The RhoA/Rho-kinase pathway mediates vasoconstriction in the cavernosal circulation. Inhibition of this pathway leads to penile erection in the in vivo rat model. These studies examined the hypothesis that nitric oxide (NO) inhibits RhoA/Rho-kinase signaling as part of normal erection. The results show that NO causes increased intracavernosal pressure and that this response is potentiated by prior treatment with a threshold dose of the Rho-kinase inhibitor, (+)-(R)-trans-4-(1-Aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride, monohydrate (Y-27632). These results support the hypothesis that NO inhibits Rho-kinase-induced cavernosal vasoconstriction during erection.

Amides↗
PubMed2002

Microtubule depolymerization facilitates contraction of rat aorta via activation of Rho-kinase.

This study tests the hypothesis that microtubule (MT) depolymerization facilitates contraction of rat aorta via activation of Rho-kinase. Aortic rings from Sprague-Dawley rats were placed in a muscle bath for the measurement of isometric force generation. Bath temperature was decreased from 37 to 10-20 degrees C (30 min), inducing MT depolymerization. Some vessels were treated with nocodazole (10(-5) M) or colchicine (10(-8)-10(-5) M) to stabilize the MTs in the depolymerized state, and the remaining vessels were treated with dimethyl sulfoxide (DMSO: vehicle). Warming of vessels to 37 degrees C induced a significantly greater contraction in nocodazole- and colchicine-treated vessels as compared with controls, and this increase was blocked by pretreatment with taxol (10(-5) M; a MT stabilizing agent) [force (mg): NOC 1159 +/- 93; COL 1138 +/- 69; DMSO 578 +/- 14; TAX + NOC 526 +/- 43; TAX + COL 538 +/- 90]. Following the sustained contraction in response to rewarming, Rho-kinase inhibition with Y-27632 (10(-5) M) relaxed nocodazole- and colchicine-treated rings to a significantly greater extent as compared to DMSO-treated vessels (percent relaxation: NOC 64 +/- 2; COL 65 +/- 5; DMSO 33 +/- 5). These results support the hypothesis that MT depolymerization facilitates contraction of rat aorta via activation of Rho-kinase.

Analysis of Variance↗
PubMed2002

Nitric oxide induces dilation of rat aorta via inhibition of rho-kinase signaling.

NO induces vasodilation through cGMP-dependent protein kinase--dependent and --independent mechanisms. A recent study demonstrated that recombinant cGMP-dependent protein kinase can phosphorylate the small G protein, RhoA, thus inhibiting its activity. Additionally, sodium nitroprusside was found to reverse the phenylephrine-induced translocation of RhoA, which is further indicative of the inhibition of RhoA activity. RhoA is known to be involved in the Ca(2+) sensitization of vascular smooth muscle through the actions of one of its downstream effectors, Rho-kinase. This study examined whether NO endogenously induces the relaxation of intact rat aorta via the inhibition of the Rho-kinase--mediated Ca(2+)-sensitizing pathway. Endogenous Rho-kinase inhibitor activity was inhibited by the selective compound Y-27632. Treatment of endothelium-intact rat aorta with Y-27632 (1 micromol/L) resulted in an attenuation of maximal force generated in response to phenylephrine. In endothelium-denuded rings, however, 1 micromol/L Y-27632 was ineffective at inhibiting the phenylephrine-induced contraction. Additionally, 1 micromol/L Y-27632 was significantly less effective at inhibiting the phenylephrine-induced contraction of endothelium-intact rings in the presence of inhibitors of NO synthase or guanylate cyclase (N(omega)-nitro-L-arginine and 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, respectively). Interestingly, sodium nitroprusside restored the ability of 1 micromol/L Y-27632 to attenuate phenylephrine-induced contraction. Rho-kinase inhibition was also found to increase the sensitivity of the endothelium-denuded aorta to sodium nitroprusside. These data demonstrate that NO inhibits Rho-kinase activity in the intact rat aorta, supporting the hypothesis that endogenous NO-mediated vasodilation occurs through the inhibition of Rho-kinase constrictor activity in the intact rat aorta.

Amides↗
PubMed2002

Impaired vasodilation and nitric oxide synthase activity in glucocorticoid-induced hypertension.

Synthetic glucocorticoids are among the most widely prescribed medications by physicians. Although they have a vast array of beneficial effects such as immunosuppression and anti-inflammation, excess glucocorticoids can lead to iatrogenic Cushing's syndrome, which includes hypertension and cardiovascular disease. The exact mechanism by which glucocorticoids elevate blood pressure is not completely understood, but it appears to be a complex pathology that involves increased responsiveness to vasoconstrictors and decreased vasodilator production. Nitric oxide is a vasodilator that plays a key role in blood pressure regulation, and previous studies have shown that a reduction in nitric oxide production or bioavailability contributes to hypertension. Tetrahydrobiopterin, a necessary cofactor for nitric oxide synthase activity, can affect nitric oxide production and bioavailability, with low levels causing decreased nitric oxide production. However, little is known about the interaction between glucocorticoids and tetrahydrobiopterin levels. In this review, the roles of nitric oxide and tetrahydrobiopterin in the pathogenesis of glucocorticoid hypertension will be discussed. Furthermore, the authors propose that glucocorticoids exert a genomic effect to decrease guanosine triphosphate cyclohydrolase I, the rate-limiting enzyme in the production of tetrahydrobiopterin. In the future, tetrahydrobiopterin supplementation in patients with iatrogenic Cushing's syndrome may prove to be beneficial and decrease mortality attributed to cardiovascular disease.

Antioxidants↗
PubMed2002

[Inhibition of tonic contraction of smooth muscle: a new approach to achieve erection dysfunction].

It has shown that vasoconstriction in the cavernosal circulation is mediated by the RhoA/Rho-kinase calcium sensitization pathway. Inhibition of Rho-kinase activity in cavernosal smooth muscle with Y-27632 resulted in an erectile response marked by elevated intracavernosal pressure (ICP) without a significant change in men arterial pressure (MAP). To explain how erection can occurred in the presence of this strong vasoconstrictive signal, we have hypothesized that nitric oxide (NO) induces vasodilation leading to erection by directly inhibiting activity of the RhoA/Rho-kinase pathway, thereby reducing vasoconstriction. Administration of Y-27632 restored erectile function in rat models of hypogonadism and hypertension, suggesting that Rho-kinase inhibition may have potential clinical value. In addition, our results show that topical application of Y-27632 may be an effective mode of treatment for erectile dysfunction.

Amides↗
PubMed2001

Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway.

Relaxation of the smooth muscle cells in the cavernosal arterioles and sinuses results in increased blood flow into the penis, raising corpus cavernosum pressure to culminate in penile erection. Nitric oxide, released from non-adrenergic/non-cholinergic nerves, is considered the principle stimulator of cavernosal smooth muscle relaxation, however, the inhibition of vasoconstrictors (that is, norepinephrine and endothelin-1, refs. 5-9) cannot be ignored as a potential regulator of penile erection. The calcium-sensitizing rho-A/Rho-kinase pathway may play a synergistic role in cavernosal vasoconstriction to maintain penile flaccidity. Rho-kinase is known to inhibit myosin light chain phosphatase, and to directly phosphorylate myosin light-chain (in solution), altogether resulting in a net increase in activated myosin and the promotion of cellular contraction. Although Rho-kinase protein and mRNA have been detected in cavernosal tissue, the role of Rho-kinase in the regulation of cavernosal tone is unknown. Using pharmacologic antagonism (Y-27632, ref. 13, 18), we examined the role of Rho-kinase in cavernosal tone, based on the hypothesis that antagonism of Rho-kinase results in increased corpus cavernosum pressure, initiating the erectile response independently of nitric oxide. Our finding, that Rho-kinase antagonism stimulates rat penile erection independently of nitric oxide, introduces a potential alternate avenue for the treatment of erectile dysfunction.

Animals↗
PubMed2001

Heme oxygenase-1 protects against vascular constriction and proliferation.

Heme oxygenase (HO-1, encoded by Hmox1) is an inducible protein activated in systemic inflammatory conditions by oxidant stress. Vascular injury is characterized by a local reparative process with inflammatory components, indicating a potential protective role for HO-1 in arterial wound repair. Here we report that HO-1 directly reduces vasoconstriction and inhibits cell proliferation during vascular injury. Expression of HO-1 in arteries stimulated vascular relaxation, mediated by guanylate cyclase and cGMP, independent of nitric oxide. The unexpected effects of HO-1 on vascular smooth muscle cell growth were mediated by cell-cycle arrest involving p21Cip1. HO-1 reduced the proliferative response to vascular injury in vivo; expression of HO-1 in pig arteries inhibited lesion formation and Hmox1-/- mice produced hyperplastic arteries compared with controls. Induction of the HO-1 pathway moderates the severity of vascular injury by at least two adaptive mechanisms independent of nitric oxide, and is a potential therapeutic target for diseases of the vasculature.

Animals↗
PubMed2001

Decreased vascular glucose transporter expression and glucose uptake in DOCA-salt hypertension.

OBJECTIVE: Because glucose uptake and metabolism can affect vascular smooth muscle cell function, we proposed that animals with hypertension might develop alterations in glucose transporter expression in vascular smooth muscle cells that were responsible for some of the vascular abnormalities characteristic of hypertension. DESIGN AND METHOD: Male Sprague-Dawley rats (250-300 g) were left uni-nephrectomized and either implanted or not with deoxycorticosterone acetate (DOCA, 200 mg/kg) impregnated silastic. All animals were fed normal rat chow. The DOCA-implanted rats were given water supplemented to 1% NaCl and 0.2% KCl for 7, 14 or 28 days. RESULTS: The insulin-response glucose transporter (GLUT4) polypeptide levels were depressed several-fold in aortae and carotid arteries from DOCA-salt hypertensive rats compared with sham rats. Uptake of the glucose analog, 2-deoxyglucose (2-DOG), was also reduced 53% in hypertensive compared with sham aortae. There were no changes in GLUT4 expression in other tissues in the DOCA-salt animals, nor were there significant changes in aortae from spontaneously hypertensive rat/stroke prone animals. As previously demonstrated, carotid arteries from DOCA-salt animals exhibited a significant increased contractile sensitivity to ergonovine. Inhibition of glucose metabolism with 2-DOG in sham arteries caused a marked enhancement of contractile responsiveness to ergonovine, whereas 2-DOG had no effect on the already enhanced contractility of DOCA-salt arteries, suggesting that reduction in glucose uptake and metabolism substantially increases the contractile response of DOCA-salt arteries. CONCLUSIONS: Alterations in glucose uptake and metabolism in vascular smooth muscle cells may participate in the contractile abnormalities characteristic of certain forms of hypertension.

Animals↗
PubMedDate not supplied

Vasorelaxing effects of propranolol in rat aorta and mesenteric artery: a role for nitric oxide and calcium entry blockade.

1. Propranolol has been prescribed successfully to patients with cardiovascular diseases, but the exact mechanisms by which it reduces peripheral vascular resistance have been poorly investigated. 2. The present study was designed to investigate the relaxing effects of propranolol in the rat isolated aorta and mesenteric artery, focusing on the contribution of the nitric oxide (NO)-cGMP pathway and calcium entry blockade. Relaxation responses to propranolol were obtained in precontracted rat aortic and mesenteric artery rings. 3. DL-Propranolol (10-100 micromol/L) produced concentration-dependent relaxations in the aorta and mesenteric artery rings with intact endothelium. The isomers D- and L-propranolol produced relaxation responses that were equipotent to the racemic mixture. 4. Metoprolol (10-100 micromol/L) produced slight relaxations, whereas atenolol (10-100 micromol/L) had no relaxant activity. 5. The NO inhibitor N(G)-nitro-L-arginine methyl ester (100 micromol/L) and the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (1 micromol/L), as well as removal of the endothelium, significantly reduced the relaxation responses induced by the lower concentrations of propranolol without affecting maximal responses. In addition, DL-propranolol markedly increased cGMP levels in endothelium-intact preparations. 6. In Ca(2+)-free Krebs' solution, DL-propranolol (10-100 micromol/L) caused marked rightward shift in the concentration-response curves to CaCl(2), with a decrease of maximal responses in tissues with either intact or denuded endothelium. Nifedipine (1 micromol/L) in combination with DL-propranolol virtually abolished the CaCl(2)-induced contractile responses. 7. The relaxation responses induced by DL-propranolol were significantly reduced in aortic and mesenteric rings precontracted with phorbol-12,13-dibutyrate (1 micromol/L). 8. In conclusion, DL-propranolol relaxes arterial smooth muscle by mechanisms involving activation of the NO-cGMP pathway and calcium influx blockade, independent of beta-adrenoceptor blockade.

Animals↗