Growth factors mediate intracellular signaling in vascular smooth muscle cells through protein kinase C-linked pathways.

Intracellular Ca2+ and pH are potent modulators of growth factor-induced mitogenesis and contraction. This study examined platelet-derived growth factor-(PDGF-BB) and insulin-like growth factor (IGF-1)-mediated signal transduction in primary cultured unpassaged vascular smooth muscle cells (VSMC) from mesenteric arteries of Sprague-Dawley rats. Intracellular free Ca2+ concentration ([Ca2+]i) and intracellular pH (pHi) were measured by fluorescence digital imaging using fura-2 AM and 2'7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein, respectively.

Cardiac type-1 angiotensin II receptor status in deoxycorticosterone acetate-salt hypertension in rats.

The regulation of angiotensin II (Ang II) receptors and Ang II-induced modulation of intracellular Ca2+ concentration in cardiac cells from hearts of experimentally induced hypertensive deoxycorticosterone acetate (DOCA)-salt and control unilaterally nephrectomized (Uni-Nx) Sprague-Dawley rats was assessed. Ang II receptor density and intracellular Ca2+ concentration measurements were examined in adult ventricular myocytes and fibroblasts by radioligand binding assay and digital imaging using fura 2 methodology, respectively. Four-week DOCA-salt treatment induced hypertension associated with cardiac hypertrophy.

Time course and localization of endothelin-1 gene expression in a model of renal disease progression.

Experimental and human proteinuric glomerulopathies are associated with tubulo-interstitial injury that correlates with the decline of renal function even better than glomerular lesions do. Mechanism(s) leading to tubulo-interstitial damage are unknown. It has been proposed that excessive reabsorption of filtered proteins activates renal cells to produce vasoactive and inflammatory molecules including endothelin-1.

Angiotensin II regulates vascular smooth muscle cell pH, contraction, and growth via tyrosine kinase-dependent signaling pathways.

Angiotensin II (Ang II), a potent vasoactive peptide with mitogenic potential, influences vascular smooth muscle cell contraction and growth through receptor-linked pathways that increase intracellular free Ca2+ concentration ([Ca2+]i) and pH (pHi). Activation of these second messengers by Ang II may involve tyrosine kinase-dependent signaling pathways. This study determined the role of tyrosine kinases in Ang II-stimulated pHi, and in simultaneously measured contractile and [Ca2+]i responses, as well as growth in cultured vascular smooth muscle cells from mesenteric arteries of Wistar-Kyoto rats.

Abnormal adrenal and vascular responses to vasopressin mediated by a V1-vasopressin receptor in a patient with adrenocorticotropin-independent macronodular adrenal hyperplasia, Cushing's syndrome, and orthostatic hypotension.

The elucidation of gastric inhibitory polypeptide-dependent Cushing's syndrome suggested that ectopic expression or increased responsiveness of other adrenal hormone receptors may underlie ACTH-independent macronodular adrenal hyperplasia (AIMAH) or adrenocortical tumors. We studied a 36-yr-old woman with Cushing's syndrome, AIMAH, and orthostatic hypotension. During upright posture, cortisol and aldosterone were stimulated despite suppression of ACTH and renin.

Immune modulation of blood leukocytes in humans by lactic acid bacteria: criteria for strain selection.

Lactic acid bacteria in food can transiently colonize the intestine and exert beneficial effects (probiotic). Survival during intestinal transit or adhesion to epithelium or both seem to be important for modifying the host's immune reactivity. Because Lactobacillus acidophilus strain La1 is adherent to enterocytes in vitro, we hypothesize that contact with immune cells may occur in vivo.

Effect of AT1 angiotensin-receptor blockade on structure and function of small arteries in SHR.

The structure and function of small arteries of different vascular beds in spontaneously hypertensive rats (SHRs) are altered relative to Wistar-Kyoto (WKY) control rats, and these differences may be blunted under treatment with angiotensin-converting enzyme inhibitors. To determine whether this effect of angiotensin-converting enzyme inhibitors was caused by the interruption of the renin-angiotensin system, our experiments were conducted with an AT1 angiotensin-receptor antagonist to evaluate its ability to induce regression of hypertrophy of resistance arteries in SHRs. The result of treatment of SHRs with losartan, an orally active selective angiotensin AT1 receptor antagonist was examined at a low (20 mg/kg/day) and a high (60 mg/kg/day) oral dose in SHRs once blood pressure had been elevated for some time.

Clinical significance of endothelin in cardiovascular disease.

Endothelins are ubiquitously produced 21-amino-acid peptides that were discovered as an endothelial product and may play important roles in cardiovescular physiology and pathophysiology. The main endothelin produced by the endothelium is endothelin-1. The vasoconstrictor role of endothelins may participate in blood pressure elevation and vascular hypertrophy in salt-dependent models of hypertension (deoxycorticosterone acetate-salt hypertensive rats, spontaneously hypertensive rats treated with deoxycorticosterone, acetate and salt, and Dehl salt-sensitive rats), and in stroke-prone spontaneously hypertensive rats.

Effect of chronic ETA-selective endothelin receptor antagonism on blood pressure in experimental and genetic hypertension in rats.

1. Chronic treatment with a combined ETA/ETB endothelin receptor antagonist has been shown to reduce blood pressure in experimental rat models of hypertension in which endothelin-1 gene overexpression occurs in the walls of blood vessels, particularly small, resistance-sized arteries, but not in those genetic or experimental models of hypertension in which there is no overexpression of vascular endothelin-1. Failure of some experimental models of hypertension to respond to treatment with the combined ETA/ETB endothelin antagonist may be due in part to blockade of vasorelaxant endothelial ETB receptors which could in theory reduce the efficacy of endothelin antagonism.

How to assess vascular remodelling in small and medium-sized muscular arteries in humans.

The study of vascular wall changes in humans has generated great interest with the increasing realization that, independently of the potential contribution to mechanisms involved in blood pressure elevation, these structural alterations (remodelling) or functional changes may contribute to the complications of elevated blood pressure. Moreover, some of these changes may be corrected partially or totally by administration of antihypertensive agents and other drugs. This has fuelled interest in the techniques used to evaluate changes in the vascular wall in humans, which are reviewed critically here with a focus on human studies in hypertension.

Tissue targeting of angiotensin peptides.

Angiotensin II (Ang II) is an octapeptide generated by the sequential proteolytic action of renin and angiotensin converting enzyme on the glycoprotein angiotensinogen. While numerous mammalian tissues have been shown to express some or all of the components of the renin-angiotensin system (RAS), the function of most of these tissue RAS remains a matter of conjecture. To test for tissue-specific functions of Ang II and as an alternative to co-expressing all the components of RAS, we have engineered a fusion protein that leads to direct Ang II release within specific tissues.

The effects of atenolol and zofenopril on plasma atrial natriuretic peptide are due to their interactions with target organ damage of essential hypertensive patients.

The effects of 10 weeks of treatment with atenolol (n = 9) or the converting enzyme inhibitor zofenopril (n = 25) on plasma atrial natriuretic peptide (ANP) were studied in 34 essential hypertensive patients. After 4 weeks on placebo, pretreatment ANP, 56 +/- 7 pg/ml, was slightly but not significantly higher than that of 29 controls (41 +/- 4) and correlated with age (r = 0.44), ECG score for left ventricular hypertrophy (LVH) (r = 0.

Effect of magnesium on vascular tone and reactivity in pressurized mesenteric resistance arteries from spontaneously hypertensive rats.

This study examines the effects of magnesium on vascular tone and reactivity in mesenteric resistance arteries from 17-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Third-order branches of mesenteric arteries were mounted in a pressurized flow chamber and studied with constant flow and transmural pressure. The mesenteric arteries were perfused extra- and intra-luminally with physiological salt solution containing a normal (1.

Cyclic GMP inhibits a pharmacologically distinct Na+/H+ exchanger variant in cultured rat astrocytes via an extracellular site of action.

There is growing evidence that cyclic GMP (cGMP) plays important roles in the brain. In cultured rat astrocytes, we observed that the cGMP-inducing C-type natriuretic peptide (CNP) and cGMP analogues caused a decrease in intracellular pH (pHi). To examine whether this effect was due to inhibition of an Na+/H+ exchanger (NHE), we acidified cells by replacing extracellular Na+ by choline and examined the kinetics of the pHi recovery that occurred on reintroduction of Na+ in the extracellular medium.

Effect of pressurization on mechanical properties of mesenteric small arteries from spontaneously hypertensive rats.

The mechanical properties of the wall of isolated perfused arterial segments of mesenteric small arteries from 17-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar Kyoto rats (WKY) were investigated. Third-order branches of mesenteric arteries were mounted in a pressure myograph chamber and pressurized from 1 to 140 mm Hg. Under isobaric conditions, the outer diameter and the lumen of small arteries studied were smaller in SHR than in WKY, whereas media width, media cross-sectional area and media-lumen ratio were greater in SHR.

Vascular endothelin-1 gene expression and effect on blood pressure of chronic ETA endothelin receptor antagonism after nitric oxide synthase inhibition with L-NAME in normal rats.

Background: Vascular expression of the endothelin-1 gene may be associated with severe vascular hypertrophy. Because in rats, inhibition of NO synthase with the L-arginine analogue N omega-nitro-L-arginine methyl ester (L-NAME) induces blood pressure elevation associated with little cardiovascular hypertrophy, we studied vascular endothelin-1 gene expression in L-NAME-treated rats and the effects of chronic endothelin antagonism.

Methods And Results: Sprague-Dawley rats received 100 mg.

Resistance arteries as endpoints in hypertension.

Resistance arteries are small vessels measuring less than 400 microm which present alterations in their structure and function in hypertension. These alterations correlate with the severity of elevation of blood pressure, and include a smaller lumen which increases resistance to blood flow and an elevated media to lumen ratio, which may amplify responses to vasoconstrictors. The endothelium of these arteries has a reduced ability to induce vascular relaxation due to an impaired response or increased inactivation of endothelium-derived nitric oxide.

Structure and function of small arteries of essential hypertensive patients following chronic treatment with once-a-day nifedipine.

In view of the important impact of small-artery structural and functional abnormalities on complications of hypertension and recent data suggesting that some antihypertensive agents may correct some of these abnormalities, a study of resistance artery structure and function in 20 well-controlled essential hypertensive patients who had received for a prolonged period of time monotherapy with the once-a-day extended release formulation of the calcium channel antagonist nifedipine (nidefipine GITS) or with the beta-blocker atenolol is reviewed. Resistance-size small arteries (standardized lumen diameter of 247 +/- 8 microns) were studied after dissection from a gluteal subcutaneous biopsy. Small arteries were investigated on a wire myograph and as pressurized vessels.

Enhanced expression of endothelin-1 gene in resistance arteries in severe human essential hypertension.

Background: Endothelins are potent vasoconstrictors, and may also act as mitogens and hypertrophic agents. Expression of a member of this family of peptides, endothelin-1, is enhanced in the endothelium of blood vessels of rats with severe forms of hypertension, even in the absence of elevated plasma endothelin levels. In some of these hypertensive models enhanced endothelin-1 gene expression may contribute to vascular hypertrophy of small arteries and to elevation of blood pressure.

Effect of short-term treatment of SHR with the novel calcium channel antagonist mibefradil on function of small arteries.

Treatment of spontaneously hypertensive rats (SHR) and Wistar-Kyoto control rats (WKY) for at least 12 weeks with calcium channel antagonists is associated with regression of structural hypertensive changes in the heart and in conduit and small arteries. To establish whether structural or functional changes of small arteries could be corrected with shorter periods of specific antihypertensive treatment, SHR and WKY were treated for 4 weeks with the novel calcium channel blocker mibefradil. Blood pressure rise was significantly reduced by mibefradil treatment in SHR to 165 +/- 1 mm Hg compared to a systolic blood pressure of 183 +/- 2 mm Hg in untreated SHR (P <.

Effect of antihypertensive treatment and N omega-nitro-L-arginine methyl ester on cardiovascular structure in deoxycorticosterone acetate-salt hypertensive rats.

Background: Deoxycorticosterone acetate (DOCA)-salt hypertensive rats exhibit a very severe degree of cardiovascular hypertrophy, which may in part be mediated by overexpression of the endothelin-1 gene.

Objective: To examine the effects of the angiotensin I converting enzyme inhibitor cilazapril and of the calcium channel antagonist mibefradil, both of which may affect potential mechanisms responsible for hypertrophy of cardiovascular structures, and that of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), which may exert a paradoxical inhibitory effect on cardiovascular growth, on the severe cardiovascular hypertrophy of DOCA-salt hypertensive rats and on arterial expression of the endothelin-1 gene.

Methods: Small-artery structure was examined on a wire myograph and endothelin-1 messenger RNA (mRNA) was quantified by Northern blot analysis.

Intracellular Ca2+ modulation by angiotensin II and endothelin-1 in cardiomyocytes and fibroblasts from hypertrophied hearts of spontaneously hypertensive rats.

The vasoactive peptides angiotensin II (Ang II) and endothelin-1 (ET-1) have been implicated in cardiac hypertrophy. This study investigates Ang II and ET-1 effects on intracellular free calcium concentration and the receptor subtype through which agonist-induced calcium responses are mediated in isolated cardiomyocytes and fibroblasts from hypertrophied hearts of spontaneously hypertensive rats (SHR). We measured intracellular free calcium concentration by fura 2 methodology and determined receptor status by radioligand binding assays.

Angiotensin II and vasopressin modulate intracellular free magnesium in vascular smooth muscle cells through Na+-dependent protein kinase C pathways.

Vasoactive peptides mobilize cytosolic free Mg2+ in vascular smooth muscle cells. It is unknown whether angiotensin II and arginine vasopressin, potent vasoconstrictor agents, influence intracellular Mg2+. The effects of angiotensin II and vasopressin on intracellular free Mg2+ concentrations ([Mg2+]i) were therefore investigated in primary cultured unpassaged vascular smooth muscle cells (VSMC) from mesenteric arteries of Wistar Kyoto rats, and in an established cell line of rat thoracic aorta cells (A10 cells).

Structure and function of resistance arteries of hypertensive patients treated with a beta-blocker or a calcium channel antagonist.

Objective: To investigate the effects on resistance artery structure and function of monotherapy with the beta-blocker atenolol or the calcium channel antagonist nifedipine in its once a day form or gastrointestinal therapeutic system (GITS).

Subjects: Twenty well-controlled essential hypertensive patients matched for age, body mass index, duration and severity of hypertension. Normotensive subjects and untreated hypertensives served as the reference groups.