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The authors wish to add the following information. Table 1: The doses of antagonists used to treat wild-type and RGS2-knockout mice were hexamethonium at 5 mg/kg i.v., prazosin at 200 µg/kg i.v., and candesartan at 100 µg/kg i.v. Effective ganglionic blockade by hexamethonium was established as described previously, whereas blockade by prazosin or candesartan was demonstrated by the inability of a subsequent infusion of phenylephrine (10 µg/kg i.v.) or angiotensin II (1 µg/kg i.v.) to increase blood pressure of wild-type or RGS2-knockout mice. Figure 3:Blood pressure responses were determined using anesthetized mice as described in Methods. In Figure 3a, the doses of vasoconstrictors used to treat wild-type and RGS2-knockout mice were 1 µg/kg i.v. for angiotensin II and 10 µg/kg i.v. for phenylephrine. These doses were determined empirically, as were those that elicited a near-maximal (>75%) increase in blood pressure (determined by dose-response experiments such as those shown in Figure 4a for phenylephrine). In Figure 3b, candesartan (100 µg/kg i.v.) was infused into wild-type and RGS2-knockout mice over a period of 10 seconds, after which blood pressure was recorded continuously over the time period indicated. In Figure 3c, the same dose of angiotensin II (1 µg/kg iv) was used to treat wild-type and RGS2-knockout mice in order to increase systolic blood pressure to similar absolute levels (160-170 mmHg) prior to antagonist infusion (candesartan, 100 µg/kg i.v.). This approach was established by the results shown in Figure 3a, in which MAP of wild-type mice increased from a resting value (prior to agonist infusion) of ∼85 mmHg to a value of ∼135 mmHg after angiotensin II infusion, and the MAP of RGS2-knockout mice increased from a resting value of ∼135 mmHg to ∼140 mmHg by the same treatment. After a maximal effect of angiotensin II on blood pressure was achieved (∼1 minute), candesartan (100 µg/kg i.v.) was infused over 10 seconds, and decreases in blood pressure were recorded continuously over the time period indicated.

Signaling by hormones and neurotransmitters that activate G protein–coupled receptors (GPCRs) maintains blood pressure within the normal range despite large changes in cardiac output that can occur within seconds. This implies that blood pressure regulation requires precise kinetic control of GPCR signaling. To test this hypothesis, we analyzed mice deficient in RGS2, a GTPase-activating protein that greatly accelerates the deactivation rate of heterotrimeric G proteins in vitro. Both rgs2+/– and rgs2–/– mice exhibited a strong hypertensive phenotype, renovascular abnormalities, persistent constriction of the resistance vasculature, and prolonged response of the vasculature to vasoconstrictors in vivo. Analysis of P2Y receptor–mediated Ca2+ signaling in vascular smooth muscle cells in vitro indicated that loss of RGS2 increased agonist potency and efficacy and slowed the kinetics of signal termination. These results establish that abnormally prolonged signaling by G protein–coupled vasoconstrictor receptors can contribute to the onset of hypertension, and they suggest that genetic defects affecting the function or expression of RGS2 may be novel risk factors for development of hypertension in humans

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NaCl-sensitive spontaneously hypertensive rats (SHR-S) were used to test the hypotheses that dietary Ca2+ supplementation 1) prevents NaCl-sensitive hypertension via a sympatholytic mechanism, and 2) increases diuretic and natriuretic responses to acute volume loading. SHR-S and control WKY rats were begun on one of four diets at age 8 wk: control, high NaCl, high Ca2+, or high NaCl and high Ca2+. In SHR-S, dietary Ca2+ supplementation prevented the NaCl-induced increases in blood pressure and plasma norepinephrine concentrations, the reductions in anterior hypothalamic norepinephrine stores and turnover, and the secondary increases in alpha 2 adrenoceptor number. Thus, Ca2+ prevented NaCl-sensitive hypertension in SHR-S by increasing noradrenergic input to the anterior hypothalamus. High-NaCl-fed SHR-S had impaired diuretic and natriuretic responses to an isotonic volume load; Ca2+ enhanced the ability of these animals to adjust fluid volume rapidly via diuresis and natriuresis. This alteration in renal function may contribute to the hypotensive effect of a high Ca2+ diet in NaCl-sensitive hypertension.