Induction Of Acute Hypertension Research Articles

Matrix Metalloproteinase-7 and ADAM-12 (a Disintegrin and Metalloproteinase-12) Define a Signaling Axis in Agonist-Induced Hypertension and Cardiac Hypertrophy

Excessive stimulation of Gq protein-coupled receptors by cognate vasoconstrictor agonists induces a variety of cardiovascular processes, including hypertension and hypertrophy. Here, we report that matrix metalloproteinase-7 (MMP-7) and a disintegrin and metalloproteinase-12 (ADAM-12) form a novel signaling axis in these processes. In functional studies, we targeted MMP-7 in rodent models of acute, long-term, and spontaneous hypertension by 3 complementary approaches: (1) Pharmacological inhibition of activity, (2) expression knockdown (by antisense oligodeoxynucleotides and RNA interference), and (3) gene knockout. We observed that induction of acute hypertension by vasoconstrictors (ie, catecholamines, angiotensin II, and the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester) required the posttranscriptional activation of vascular MMP-7. In spontaneously hypertensive rats, knockdown of MMP-7 (by RNA interference) resulted in attenuation of hypertension and stopped development of cardiac hypertrophy. Quantitative reverse-transcription polymerase chain reaction studies in mouse models of MMP-7 knockdown (by RNA interference) and gene knockout revealed that MMP-7 controlled the transcription of ADAM-12, the major metalloproteinase implicated in cardiac hypertrophy. In mice with angiotensin II-induced hypertension and cardiac hypertrophy, myocardial ADAM-12 and downstream hypertrophy marker genes were overexpressed. Knockdown of MMP-7 attenuated hypertension, inhibited ADAM-12 overexpression, and prevented cardiac hypertrophy. Agonist signaling of both hypertension and hypertrophy depends on posttranscriptional and transcriptional mechanisms that involve MMP-7, which is transcriptionally connected with ADAM-12. Approaches targeting this novel MMP-7/ADAM-12 signaling axis could have generic therapeutic potential in hypertensive disorders caused by multiple or unknown agonists.

Control of the Na+,K(+)-ATPase under normal and pathological conditions.

The Na+,K(+)-ATPase is an important enzyme in determining the ionic milieu of the cerebromicrovasculature and neurons. The effect of hypertension or aging on this enzyme, as well as its susceptibility to regulation by fatty acids or aluminum, is the focus of this study. A significant increase (34%) in the apparent affinity constant (KD) but no change in the maximum binding capacity (Bmax) for [3H]ouabain binding to the cerebromicrovascular Na+,K(+)-ATPase occurs after induction of acute hypertension. In addition, long chain unsaturated fatty acids stimulate the binding of [3H]ouabain to the enzyme in microvessels from normotensive and hypertensive rats. The synaptosomal Na+,K(+)-ATPase is sensitive to aluminum. AlCl3 (1-100 microM) inhibits the K(+)-dependent-p-nitrophenylphosphatase (K(+)-NPPase) activity of the Na+,K(+)-ATPase in a dose-dependent manner. AlCl3 (100 microM) decreases the Vmax by 14% but does not alter the KM, suggestive of non-competitive inhibition. The enzyme from aged brain displays a greater Vmax, but shows the same susceptibility to AlCl3 as the enzyme from younger brain. In summary, disruption of the Na+,K(+)-ATPase may underlie, at least in part, abnormalities of nerve and vascular cell function in disorders where elevated concentrations of fatty acids or metal ions are involved.

Arterial CO2 Tension and Cerebral Vascular Reactivity During the Induction of Acute Hypertension and Hypotension in the Awake Human

The CO2 reactivity was calculated at mean arterial blood pressure (MABP) values ranging from 40 to 140 mm Hg in 15 normotensive volunteers and in 7 patients with chronic arterial hypertension. The cerebral vascular reactivity (CVR) was estimated from indirect measurements of cerebral blood flow (CBF) by the arteriovenous oxygen saturation method. In all subjects but one of the hypertensive patients, there was a significant linear correlation of CVR with PaCO2 over the total range of MABP. The median CO2 reactivity in the volunteers and in the hypertensive patients was 2.7 and 2.8% CBF/0.1 kPa, respectively (NS). At MABP values corresponding to the plateau of CBF autoregulation (baseline MABP +/- 20%), the median CO2 reactivity was 3.0% CBF/0.1 kPa in both groups. During a cross-sectional correlation analysis of the pooled data from all volunteers, the CO2 reactivity increased with increasing MABP in the range of 50-110 mm Hg. Outside this range there was no correlation of CVR with PaCO2. In conclusion, our results confirmed that during acute hypo- and hypertension, the influence of PaCO2 on the CVR is reduced. The full CO2 reactivity of the cerebral vessel exists only at the plateau of CBF autoregulation.

Inositol Phosphate Production in the Left Ventricle following Induction of Acute Hypertension

Inositol Phosphate Production in the Left Ventricle following Induction of Acute Hypertension

Hyperplastic growth response of vascular smooth muscle cells following induction of acute hypertension in rats by aortic coarctation.

This study examines the growth response of vascular smooth muscle cells following induction of acute hypertension in rats by partial ligation of the abdominal aorta between the renal arteries. Systolic blood pressures proximal to the ligature increased dramatically within 3 days (from 135 +/- 3 to 195 +/- 7 torr) of surgery while pressures distal to the ligature were reduced from control values. The frequency of smooth muscle cells undergoing DNA replication was increased 25-fold in thoracic aortas of coarctation rats compared to sham-operated controls 9 days post-coarctation, while no differences were observed in cells in abdominal aortic segments 1 cm distal to the ligature. A small but significant increase in the frequency of tetraploid smooth muscle cells was observed in thoracic aortas of coarctation rats, but this increase accounted for less than 2% of the increase in medial DNA content. By far, the major growth response was hyperplasia, as evidenced by a 25% increase in thoracic aortic medial smooth muscle cell number without a change in mean cellular volume (micron3/cell) or mass (ng/cell). Whereas no evidence of endothelial denudation was observed in thoracic aortas of coarctation rats by scanning electron microscopy, endothelial cell turnover rates were increased 23-fold compared to controls, indicating that some form of endothelial "injury" or dysfunction was present. Consistent with this, morphological changes indicative of endothelial injury (e.g., subendothelial edema) were observed by light and transmission electron microscopy. The marked contrast between results of this study and our previous studies showing that aortic medial hypertrophy in spontaneously hypertensive and Goldblatt hypertensive rats was due to cellular hypertrophy and hyperploidy without hyperplasia, clearly demonstrates that the growth response of smooth muscle cells within a given blood vessel can be quite different, depending on the model of hypertension. It is suggested that a non-denuding form of endothelial "injury" may play an important role in the proliferative growth response of smooth muscle cells following induction of coarctation hypertension.

Increased prolyl hydroxylase activity in the aorta and heart in rat after induction of acute hypertension

Increased prolyl hydroxylase activity in the aorta and heart in rat after induction of acute hypertension

Increased prolyl hydroxylase activity in the aorta and heart in rat after induction of acute hypertension.

Increased prolyl hydroxylase activity in the aorta and heart in rat after induction of acute hypertension.