The present study evaluated the effects and mechanisms of action of endothelin-1 (ET-1) on medullary and cortical blood flow (MBF and CBF, respectively). CBF and MBF were measured simultaneously by laser-Doppler flowmetry in anesthetized male Wistar rats. Bolus injection of ET-1 (1.0 nmol/kg iv) produced a sustained decrease in CBF (delta = -30%) and a transient increase in MBF (delta = +35%). The medullary vasodilation induced by ET-1 was observed with doses lower than that required to produce cortical vasoconstriction; was completely blocked by bosentan, a mixed ETA/B-receptor antagonist; and was mimicked by IRL-1620, a specific ETB-receptor agonist. In contrast, BQ-123, an ETA-receptor antagonist, failed to inhibit the ET-1-dependent medullary vasodilation but effectively blocked the cortical vasoconstriction induced by the peptide. Finally, inhibition of nitric oxide (NO) synthase completely abolished, whereas cylooxygenase inhibition attenuated, the effect of ET-1 on MBF. The data demonstrate that ET-1 exerts opposite effects on renal cortical and medullary circulation, i.e., ETA-receptor-mediated cortical vasoconstriction and ETB-mediated medullary vasodilation. Furthermore, the medullary vasodilation induced by ET-1 is dependent on the NO system and, to a lesser extent, on prostaglandin generation.
The purpose of this study was to determine the accuracy of CT angiography using a multidetector scanner in the evaluation of patients with peripheral vascular disease.Eighteen patients with peripheral vascular disease who were referred for elective digital subtraction angiography (DSA) also underwent CT angiography. We scanned patients from the level of the superior mesenteric artery to the pedal arteries in a single helical scan. CT angiograms were produced using maximum-intensity-projection reconstructions. Findings were graded according to six categories: 1, normal (0% stenosis); 2, mild (1-49% stenosis); 3, moderate (50-74% stenosis); 4, severe (75-99% stenosis); 5, occluded; and 6, nondiagnostic. CT angiography findings were compared with DSA findings for each arterial segment.We found agreement for the degree of stenosis in 77.7% of the arteries and discrepancy for 22.3% of the arteries when all categories were considered. Grouping the six categories according to the threshold for treatment (categories 1 and 2 as one group and categories 3, 4, and 5 as the second group) resulted in an agreement of 91.95%. Compared with DSA, CT angiography yielded a sensitivity of 90.9% and a specificity of 92.4%.Multidetector CT angiography is an accurate, noninvasive technique for the imaging of peripheral vascular disease.
The regional hemodynamic effects of endothelin-1 (ET-1) were studied in Wistar-Kyoto rats. Endothelin-1 caused a transient increase in blood flow in the carotid and femoral arteries but a decrease in flow in the renal and mesenteric arteries. The resistance in the carotid and femoral beds decreased while it increased in the renal and mesenteric beds. Subsequently there was a variable increase in resistance in all vascular beds with a maximal increase in the renal bed. Thus, ET-1 initially causes a selective vasorelaxation in musculocutaneous beds but not in visceral beds; the cause of this selectivity is unknown. Am J Hypertens 1990;3:789-791
Hypertension is the most common risk factor for cardiovascular disease, constituting the most common cause of death in industrialized countries. Therefore, the task of blood pressure reduction has significant importance in reducing vascular damage, myocardial infarctions, kidney damage and incidence of cerebrovascular accidents. The renin-angiotensin-aldosterone system (RAAS) plays a central role in control and function of the cardiovascular and renal systems, and is deeply involved in the pathophysiology of diseases of vasculature, heart, kidneys and others. Therefore, blockade of RAAS by angiotensin converting enzyme (ACE) inhibitors and blockers of angiotensin II type AT1 receptors (ARBs) is widely utilized by clinicians. Indeed, it has long been known that ACE inhibitors and ARBs protect different targets of angiotensin II, due to impedance of the negative effects of the hormone and the inhibition of aldosterone production, which contributes both directly and indirectly to the damages, independent of angiotensin II. Despite this, the morbidity and mortality resulting from the progression of cardiovascular diseases in patients treated with ACE inhibitors or ARBs remain high. As such, over the years, much effort has been dedicated to the development of direct inhibitors of renin. The earliest renin inhibitors, developed 30 years ago were not effective due to their protein nature, which prevents their oral administration and limited their clinical use. In the last decade, several non-protein renin inhibitors which could be given orally were developed, of which Aliskiren is the most well known representative. Due to the fact that neutralization of the RAAS by ACE inhibitors and ARBs has been reviewed at length many times, this review will focus on the renewed subject of renin inhibition. The earliest research, both in humans as well as in animal models, show that Aliskiren has therapeutic potential in treatment of patients with hypertension, cardiovascular disease and renal disease. However, the efficacy of Aliskiren in treating systolic and diastolic hypertension in patients was not better than that obtained using ACE inhibitors or ARBs. Even so, there is no need to lower levels of optimism for potential therapy using direct inhibitors of renin. Current research is still in its early stages and there is a need to remember that it took many years to prove the clinical usefulness of ACE inhibitors, which are now central to treatment of cardiovascular and renal diseases, including hypertension.
Vasopressin, or anti-diuretic hormone, is a peptide hormone that plays an important role in the regulation of extracellular volume and its osmolarity. Increased plasma osmolarity and hypovolemia are the principal physiological stimuli for vasopressin release. The biological effects of vasopressin on its target organs are mediated by two receptors: V1 and V2. V2 is localized to renal tissue and its activation leads to upregulation of aquaporin-2 in the collecting duct allowing the reabsorption of large volumes of water. In contrast, V1 is expressed mainly in blood vessel walls, and its activation results in vascoconstriction. Besides the physiological importance of the vasopressin system, it also plays a crucial role in the pathogenesis of various diseases, including congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone secretion. These clinical syndromes are characterized by enhanced plasma levels of vasopressin, which correlate with the severity of the disease and largely contribute to the development of edema and hyponatremia. Great efforts have been invested in attempting to develop selective and long lasting vasopressin antagonists. However, general medicine and particularly nephrology, suffered from the absence of non-peptide vasopressin blockers that could be taken orally. The last few years have witnessed the development of numerous selective vasopressin antagonists with high bioavailability and long half-lives. Administration of these antagonists to patients with congestive heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion substantially enhanced free water excretion and moderately increased serum sodium concentrations. No side effects, except for mild increased thirst sensation, were observed. The present review focuses on the recent developments in vasopressin research, with special emphasize on the development of selective non-peptide antagonists and their clinical use.
To test the hypothesis that the pituitary gland has a role in modulating the release of atrial natriuretic peptide (ANP) from atrial myocytes, we applied different stimuli of both acute and chronic nature to rats 8-10 days after hypophysectomy (Hypx). Acute rapid cardiac pacing at a rate of 500 beats/min in anesthetized rats caused a marked increase in plasma levels of ANP (from 76 +/- 7 to 237 +/- 60 pg/ml, P less than 0.05) despite a marked decrease of blood pressure. This response was similar to that of paced control rats, but because the basal levels were lower in Hypx rats, the relative increase in ANP was larger in the experimental group. Studies were also done in a chronic model of high-output congestive heart failure produced by an aortocaval fistula in hydrocortisone-supplemented rats. Although these rats had low blood pressure 2-3 days after surgery, there were marked increases in right atrial pressures associated with high plasma levels of ANP (194 +/- 24 pg/ml) that were not significantly different from controls (221 +/- 26 pg/ml, P greater than 0.05). These results indicate that the role of the pituitary in ANP release is indirect, and no specific hypophyseal factor is required for this response. Hemodynamic parameters are the important determinants of ANP secretion, even in hypophysectomized rats.
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