Concordance of murine quantitative trait loci for salt-induced hypertension with rat and human loci.

To investigate the genetic control of salt-induced hypertension, we performed a quantitative trait locus analysis on male mice from a reciprocal backcross between the salt-sensitive C57BL/6J and the normotensive A/J inbred mouse strains after they were provided with water containing 1% salt for 2 weeks. Genome-wide scans performed on these mice and analyzed with a combination of conventional marker-based regressions and a novel simultaneous search for pairs revealed six significant quantitative trait loci associated with salt-induced blood pressure, two of which were interacting loci. These six loci, named Bpq1-6 for blood pressure quantitative trait loci, mapped to D1Mit334, D1Mit14, D4Mit164, D5Mit31, D6Mit15, and D15Mit13. Furthermore, five of these six loci were concordant with hypertension loci in rats, and four were concordant with hypertension loci in humans, suggesting that quantitative trait loci mapping in model organisms can be used to guide the search for human blood pressure genes.

Role of alpha(2)-adrenergic receptor subtypes in the acute hypertensive response to hypertonic saline infusion in anephric mice.

Experimental evidence suggests that the acute hypertensive response induced in anephric animals by infusion of a hypertonic saline solution is mediated by disinhibition of the presynaptic sympathoinhibitory alpha(2)-adrenergic receptors (alpha(2)-AR) of the central nervous system. The purpose of the present experiments was to dissect the role of the 3 distinct alpha(2)-AR subtypes (alpha(2A)-, alpha(2B), - and alpha(2C)-AR) in this response. Groups of genetically engineered mice deficient in each one of these alpha(2)-AR subtype genes were submitted to bilateral nephrectomy followed by a 0.4-mL infusion of 4% saline over a 2-hour period, with constant direct blood pressure (BP) monitoring. The alpha(2A)-AR-deficient and alpha(2C)-AR-deficient mice responded with significant BP elevations (by 11.8+/-2.5 and 16.7+/-1.7 mm Hg, respectively), and so did their wild-type counterparts (17.8+/-2.5 and 11.8+/-2.0 mm Hg, respectively) and the wild-type alpha(2B) +/+ (13.1+/-2.4 mm Hg). However, the alpha(2B)-AR-deficient mice were unable to raise their BP and had a slightly lowered BP (by -3.0+/-4. 0 mm Hg) at the end of the infusion period. All 6 groups exhibited elevated plasma norepinephrine levels ranging between 0.8 and 1.8 ng/mL at the end of the infusion. In all cases, the alpha(2)-AR-deficient groups tended to have higher norepinephrine levels than their wild-type counterparts. Surprisingly, this difference was significant only in the alpha(2B)-AR-deficient mice, which, despite the elevated norepinephrine, were unable to raise their BP. The data suggest that a full complement of the alpha(2B)-AR is needed to mediate the hypertensive response to acute saline load, even though its absence does not prevent the release of norepinephrine under these conditions.

Sympathoinhibitory function of the alpha(2A)-adrenergic receptor subtype.

Presynaptic alpha(2)-adrenergic receptors (alpha(2)-AR) are distributed throughout the central nervous system and are highly concentrated in the brain stem, where they contribute to neural baroreflex control of blood pressure (BP). To explore the role of the alpha(2A)-AR subtype in this function, we compared BP and plasma norepinephrine and epinephrine levels in genetically engineered mice with deleted alpha(2A)-AR gene to their wild-type controls. At baseline, the alpha(2A)-AR gene knockouts (n=11) versus controls (n=10) had higher systolic BP (123+/-2.5 versus 115+/-2.5 mm Hg, P<0. 05), heart rate (730+/-15 versus 600+/-18 b/min, P<0.001), and norepinephrine (1.005+/-0.078 versus 0.587+/-0.095 ng/mL, P<0.01), respectively. When submitted to subtotal nephrectomy and given 1% saline as drinking water, both alpha(2A)-AR gene knockouts (n=14) and controls (n=14) became hypertensive, but the former required 15. 6+/-2.5 days versus 29.3+/-1.4 days for the controls (P<0.001). End-point systolic BP was similar for both at 155+/-2.1 versus 152+/-5.2 mm Hg, but norepinephrine and epinephrine levels were twice as high in the knockouts at 1.386+/-0.283 and 0.577+/-0.143 versus 0.712+/-0.110 and 0.255+/-0.032 ng/mL, respectively, P<0.05 for both. We conclude that the alpha(2A)-AR subtype exerts a sympathoinhibitory effect, and its loss leads to a hypertensive, hyperadrenergic state.

Role of the alpha2B-adrenergic receptor in the development of salt-induced hypertension.

Salt sensitivity is a common trait in patients with essential hypertension and seems to have both an inherited and an acquired component (eg, is influenced by aging and renal insufficiency). Experimental evidence suggests that salt loading induces hypertension via a neurogenic mechanism mediated by the alpha2-adrenergic receptors (alpha2-AR). To explore the alpha2-AR subtype involved in this mechanism, we studied 2 groups of mice genetically engineered to be deficient in one of the 3 alpha2-AR subtype genes (either alpha2B-AR +/- or alpha2C-AR -/- knockout mice) compared with their wild-type counterparts. The mice (n=10 to 14 in each group) were submitted to subtotal nephrectomy and given 1% saline as drinking water for up to 35 days. Blood pressure (BP) was monitored by tail-cuff readings and confirmed at the end point by direct intra-arterial BP recording. The alpha2B-AR-deficient mice had an attenuated BP response in this protocol (baseline 101.8+/-2.7 versus end point 109.9+/-2.8 mm Hg), whereas the BP of their wild-type counterparts went from a baseline 101.9+/-2.3 to an end point 141.4+/-7.1 mm Hg. The other 2 groups had BP increases of 44. 6+/-5.17 and 46.7+/-7.01 mm Hg, with no difference between the mice deficient in the alpha2C-AR gene subtype versus their wild-type counterparts. Body weight, renal remnant weight, and residual renal function were no different among groups. These data suggest that a full complement of alpha2B-AR genes is necessary to raise BP in response to dietary salt loading, whereas complete absence of the alpha2C-AR subtype does not preclude salt-induced BP elevation. It is unclear whether the mechanism(s) involved in this process are of central origin (inability to increase sympathetic outflow), vascular origin (inability to vasoconstrict), or renal origin (inability to retain excess salt and fluid).

Alpha1-adrenergic plus angiotensin receptor blockade reduces atherosclerosis in apolipoprotein E-deficient mice.

-We have used the apolipoprotein E (apoE)-deficient mouse model to determine whether both the angiotensin II type 1 (AT1) and the alpha1-adrenergic receptors influence arteriosclerotic changes in this hyperlipidemic animal model. Mice were treated with antihypertensive drugs beginning at 9 weeks of age, and aortic atherosclerosis was measured after 12 weeks of treatment. Systolic blood pressure in the untreated apoE-deficient mouse averaged 104 mm Hg throughout the treatment period. Prazosin at a dose of 7.5 mg. kg-1. d-1 was ineffective in attenuating atherosclerosis and did not significantly reduce blood pressure. Losartan, at dosages of either 20 or 30 mg. kg-1. d-1, also did not influence atherosclerosis and had only a slight blood pressure-lowering effect. However, combined treatment with both prazosin and losartan markedly reduced atherosclerotic lesion development from an average lesion size per section of 2.6 to 1.5x10(5) microm2 (P<0.001) and significantly reduced blood pressure to 85+/-5 mm Hg. Treatment with NG-nitro-L-arginine methyl ester (40 mg. kg-1. d-1) produced significant elevations of blood pressure (127+/-3.8 mm Hg) but had no effect on the development of atherosclerosis. None of the treatments used affected plasma cholesterol throughout the 12-week period. These studies suggest that the vascular changes associated with atherosclerosis are influenced by a combination of AT1 and alpha1-adrenergic receptor activation.

Myocardial salvage by the use of reperfusion and intraaortic balloon pump: experimental study.

BACKGROUND: Thrombolytic therapy improves left ventricular ejection fraction and survival. The study was undertaken to evaluate the effects of intraaortic balloon pump used in conjunction with reperfusion in reducing infarct size. METHODS: Twenty-two dogs were subjected to proximal left anterior descending coronary artery occlusion. In group 1 (n = 7) occlusion lasted for 6 hours. In group 2 (n = 6) 2 hours of occlusion was followed by reperfusion. In group 3 (n = 9) after 2 hours of occlusion the dogs were assisted with the intraaortic balloon pump throughout the 4 hours of reperfusion. At the end of 6 hours the infarcted myocardium of the left ventricle was determined and expressed as percentage of the myocardium at risk. RESULTS: In group 1, the infarcted myocardium was 79.3 +/- 9.9% of the myocardium at risk, in group 2, 59.0 +/- 19.9% (p < 0.05 versus group 1), and in group 3, 37.1 +/- 16.7% (p < 0.001 versus group 1 and p < 0.05 versus group 2). Endocardial viability ratio was increased by the intraaortic balloon pump; in group 1 it was 1.02 +/- 0.14, in group 2, 1.25 +/- 0.24, and in group 3, 1.47 +/- 0.31 (p < 0.001 versus group 1 and p < 0.02 versus group 2). CONCLUSIONS: Reperfusion and intraaortic balloon pump increased salvage of the ischemic myocardium over that achieved by reperfusion alone in a canine occlusion-reperfusion model.