High blood pressure. Causes, symptoms, treatments

In vitro activities of eight macrolide antibiotics and RP-59500 (quinupristin-dalfopristin) against viridans group streptococci isolated from blood of neutropenic cancer patients.

2017-04-11

The angiotensin-converting enzyme (ACE) profile in urine of hypertensive patients and spontaneously hypertensive rats (SHR; 90- and 65-kDa N-domain ACEs) is different from that of healthy subjects and Wistar rats (190 and 65 kDa). In addition, four ACE isoforms were purified from mesangial cells (MC) of Wistar rats in the intracellular compartment (130 and 68 kDa) and as secreted forms (130 and 60 kDa). We decided to characterize ACE forms from SHR MC in culture. Analysis of the ACE gene showed that SHR MC are able to express ACE mRNA. The concentrated medium and cell homogenate were separately purified by gel filtration and then subjected to lisinopril-Sepharose chromatography. The molecular masses of purified enzymes, 90 kDa for ACEm1A and 65 kDa for ACEm2A (secreted enzymes) and 90 kDa for ACEInth1A and 65 kDa for ACEInth2A (intracellular), were different from those of Wistar MC. The purified enzymes are Cl- dependent, inhibited by enalaprilat and captopril, and able to hydrolyze AcSDKP. Immunofluorescence and cell fractionation followed by Western blotting showed predominant immunoreaction of the 9B9 antiserum for N-domain ACE in the nuclei. The N-domain ACE was localized in the glomerulus from Wistar rats and SHR. ANG II and ANG-(1-7) were localized in the cell cytoplasm and nuclei. The 90-kDa N-domain ACE, described recently as a possible genetic marker of hypertension, was found inside the cell nuclei of SHR MC colocalized with ANG II and ANG-(1-7). The presence of ANG II in the cell nuclei could suggest an important role for this peptide in the transcription of new genes.

ACE-inhibitors enalaprilat and benazepril (both 10(-5) M) did not change ciliary vascular tone nor flow of perfused porcine eyes. However, enalaprilat or benazepril enhanced the relaxation of ciliary arteries to bradykinin (P < 0.02). In the perfused porcine eye, enalaprilat (10(-5) M) augmented vasodilation to bradykinin (P < 0.02). The bradykinin antagonist Hoe 140 (3 x 10(-7) M) prevented the relaxation of ciliary arteries to bradykinin (P < 0.001), but not to acetylcholine. In perfused eyes, Hoe 140 reduced the vasodilation to bradykinin (P < 0.01). Ang II (10(-8) to 10(-6) M) evoked a contraction of ciliary arteries and was more potent than Ang I. Enalaprilat abolished the effect of Ang I. The AT1-receptor antagonist, valsartan (10(-9) to 10(-5) M; 30 minutes) inhibited the response of ciliary arteries to Ang II, whereas the AT2-receptor ligand CGP 42112 B (10(-7) to 10(-8) M) was ineffective. In the perfused porcine eye, valsartan restored the decrease in flow to Ang II.

IgA nephropathy (IgAN) is characterized by mesangial deposition of polymeric IgA1, and podocyte injury plays an important role in glomerulosclerosis of the disease. Our previous study indicated that medium of mesangial cells co-incubated with aggregated IgA1 (aIgA1), isolated from IgAN patients, down-regulated nephrin expression. Yet the mechanism remains unclear.

Angiotensin converting enzyme (ACE) inhibitor prevents the inactivation of bradykinin by inhibiting ACE activity, leading to side effects such as dry cough and angioedema. KD3-671 is a novel nonpeptide angiotensin II antagonist which is expected to exhibit persistent hypotensive action without these side effects. In this study, we investigated the relationship between the pharmacokinetics and cough-inducing effect of this drug in guinea-pig, compared with that of an ACE inhibitor, enalaprilat. KD3-671 was not significantly different from the vehicle treatment in the ability to induce coughing, whereas enalaprilat significantly enhanced coughing compared with the vehicle treatment. Thus, as expected from its mechanism of pharmacological action, KD3-671 did not induce coughing. We suggest that the citric acid-induced guinea pig coughing model will be useful in preclinical studies to examine the effect of drug on pulmonary function.

Angiotensin II maintains extracellular volume homeostasis, in part, by regulating proximal tubule transport. Physiological doses of angiotensin II stimulate volume and solute transport in the proximal tubule independent of changes in the glomerular filtration rate. Stimulation of bicarbonate transport primarily occurs via increasing activity of the sodium/hydrogen exchanger and the sodium/bicarbonate cotransporter. The effects of circulating angiotensin II are mediated by angiotensin II receptors on the basolateral membrane of the proximal tubule. Recently, the proximal tubule was found to synthesize and secrete angiotensin II into the lumen. The luminal membrane contains angiotensin II receptors and luminal angiotensin II levels are 100 to 200-fold higher than that found in plasma. Luminal angiotensin II receptor blockade or luminal inhibition of angiotensin II synthesis both significantly diminish proximal tubule transport, consistent with stimulation of proximal tubule transport by endogenously produced and luminally secreted angiotensin II. These data provide evidence for an autocrine/paracrine role for angiotensin II that functions independent of circulating angiotensin II.