Central hypotensive action of clonidine requires nitric oxide.

Background- Clonidine has an antihypertensive effect by its action in the brain and, because we observed that the tonic production of nitric oxide (NO) in the brain is required to maintain blood pressure at its low, normotensive level, the current study was designed to determine whether the hypotensive action of clonidine resulted from its stimulation of excess NO in the brain. Methods and Results- Porphyritic microsensors were used to quantify NO concentration in the nucleus tractus solitarius (NTS) in vitro in brain slices and in vivo in the anesthetized rat. In both preparations, the basal production of NO in the NTS was 15+/-3 nmol/L. In vitro stimulation of the NTS with clonidine (50 nmol/L) resulted in an increase in the NO concentration to 84+/-7 nmol/L. In vivo, the intracerebroventricular (ICV) infusion of clonidine (0.03 microgram) caused an increase in NO concentration in the NTS to 128+/-17 nmol/L. This ICV injection of clonidine caused a fall in mean arterial pressure of -22+/-1 mm Hg and a decrease of heart rate of -18+/-2%. The blockade of NO production with N(G)-nitro-L-arginine-methyl ester (2 micromol; delivered ICV, 30 minutes before the clonidine) reduced responses to clonidine for both mean arterial pressure and heart rate (-3+/-1 mm Hg and -2+/-1% change, respectively). Conclusion- The stimulation of the release of NO in the brain by clonidine contributes to its central antihypertensive action.

Vascular reactivity in the spontaneously hypertensive stroke-prone rat. Effect of antihypertensive treatment.

This study investigated vascular responsiveness in stroke-prone spontaneously hypertensive rats (SHRSP) and the effect of antihypertensive treatment on this responsiveness. Weanling (4-week-old) male and female SHRSP and Wistar-Kyoto rats (WKY) received either the antihypertensive combination treatment of hydralazine plus hydrochlorothiazide in drinking water or tap water alone (controls) for 15 weeks. Whereas the antihypertensive combination prevented the development of hypertension in treated SHRSP (SHRSP-T), blood pressure remained unchanged in treated WKY (WKY-T). Femoral arterial smooth muscle responsiveness to KCl, norepinephrine, and calcium (in the presence of either 40 mM KCl or 1 microM norepinephrine) was not altered in SHRSP when compared with WKY. A significant increase in the sensitivity of femoral arteries to KCl and calcium (in the presence of 40 mM KCl) was seen, however, in SHRSP-T and WKY-T. An increased sensitivity to norepinephrine and calcium (in the presence of 1 microM norepinephrine) was seen only in SHRSP-T. Isoproterenol-induced relaxation was significantly attenuated in both SHRSP and SHRSP-T. Relaxation induced by sodium nitroprusside and calcium (membrane stabilization) was not different between the four groups. These results show that femoral arterial smooth muscle responsiveness to vasoconstrictor stimuli is not altered in SHRSP but that beta-adrenergic-mediated relaxation is attenuated. Antihypertensive treatment resulted in an enhanced responsiveness to these vasoconstrictor stimuli but had no effect on the relaxation properties of femoral arterial smooth muscle.

Calcium-related abnormalities in lymphocytes from genetically hypertensive rats.

We examined the effect of various external calcium concentrations on net potassium efflux and net sodium influx in lymphocytes from spontaneously hypertensive rats (SHR), stroke-prone spontaneously hypertensive rats (SHRSP), and Wistar-Kyoto rats (WKY). Net potassium efflux was greater in lymphocytes from SHRSP than in those from WKY at external calcium concentrations of 0.1, 0.3, 1.0, and 3.0 mM but not at 0 mM (14.9 +/- 0.8 vs 13.0 +/- 0.7 mmol per kilogram of dry weight per hour, respectively). Net sodium influx in lymphocytes from SHRSP was greater than in those from WKY at all external calcium concentrations tested (0, 0.1, 1.0, and 3.0 mM). In contrast to lymphocytes from WKY, net potassium efflux and net sodium influx in lymphocytes from SHRSP were not significantly higher at 0 than at 0.1 mM external calcium concentration. Lymphocytes from SHRSP had elevated intracellular free calcium concentrations (173.6 +/- 7.4 nM, n = 8), as compared with lymphocytes from WKY (98.1 +/- 9.1 nM, n = 8). These data suggest that the interaction of calcium with the lymphocyte plasma membrane directly affects monovalent ion permeability and is altered in lymphocytes from SHRSP, as compared with those from WKY. Our findings support the hypothesis that in hypertension there is a generalized increase in cell membrane permeability to calcium and monovalent ions, which may result from a reduced number of calcium-binding sites on the plasma membrane.

Structural and functional changes in cerebral arteries from spontaneously hypertensive rats.

Segments of basilar arteries from both spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied in vitro utilizing a microvessel apparatus. At similar levels of passive force, basilar arteries from SHR developed less force in response to depolarizing solution (130 mM K+) compared to basilar arteries from WKY. Arterial segments from the hypertensive animals required less stretch to achieve each level of passive force. Basilar arteries from SHR but not WKY typically displayed both phasic and tonic spontaneous activity which was inhibited in a reversible manner by washing the tissues in physiological salt solution without added Ca++ (EGTA, 1 mM). There was a significant shift to the left in the EC50 of serotonin and a greater maximal response to this agonist in basilar arteries from SHR compared to those from WKY (p less than 0.01). The EC50 to Ca++ (added to a depolarizing solution) was shifted to the right in the arteries from SHR compared to the normotensive controls (p less than 0.05). There was no difference between the arteries from the two groups of animals in the relaxation response produced by isoproterenol. However, contracted basilar arteries from SHR were less sensitive to the relaxant effects of elevated Ca++ than contracted basilar arteries from WKY (p less than 0.05). These results demonstrate the existence of both structural and functional difference between cerebral vessels of SHR and WKY. Our findings also demonstrate the complex nature of the changes in calcium dynamics in blood vessels from hypertensive animals.

Role of endothelium in the response to endothelin in hypertension.

The relation between endothelin and acetylcholine (ACh) was examined and compared in aortas from Wistar-Kyoto (WKY) rats and from stroke-prone spontaneously hypertensive rats (SHRSP). The relaxation produced by ACh in an endothelin-induced contraction was less in aortas from WKY rats than in those from SHRSP. In aortas from WKY rats but not in those from SHRSP, the contraction produced by endothelin was augmented when the intact aortic rings were treated with methylene blue (10(-5) M). This augmentation was also found in preparations of the WKY rat aortic rings in which the endothelium had been removed. The augmentation was not present in SHRSP aortic rings that had been similarly denuded. Treatment with indomethacin (5 x 10(-6) M) had no effect on endothelin-induced contraction in either WKY rat or SHRSP aortic rings. Our findings indicate that endothelin and ACh have in common the ability to release endothelium-derived relaxing factor (EDRF) in WKY rat aortic rings. The reduced endothelium-dependent relaxation in response to ACh in the WKY rat probably reflects the fact that endothelin had already released the EDRF in rings from this strain of rats. The release of EDRF by endothelin is less in SHRSP than it is in WKY rats. Because of this failure of endothelin to release EDRF in SHRSP, endothelin may contribute to the increase in total peripheral resistance in this form of hypertension.

Calcium sensitivity of Ca2(+)-activated K+ channels in spontaneously hypertensive stroke-prone rats.

In previous studies, we measured a greater intracellular free calcium concentration and net potassium efflux, possibly calcium activated, in lymphocytes from spontaneously hypertensive stroke-prone rats (SHRSP) as compared with Wistar-Kyoto (WKY) rats. In this study, we addressed two related questions: 1) Can the greater intralymphocytic calcium concentration of the SHRSP account for the greater net potassium efflux? 2) Is the calcium sensitivity of calcium-activated potassium channels in lymphocytes from SHRSP different as compared with that of those from WKY rats? Ionomycin, a calcium ionophore, caused a concentration-dependent and proportional increase in net potassium efflux and intracellular free calcium concentration in lymphocytes from both strains of rat. Based on the relations between net potassium efflux and intracellular free calcium concentration established with ionomycin, the resting net potassium efflux of lymphocytes from SHRSP is greater than would be predicted based on the resting intracellular free calcium concentration. Using the patch clamp technique, we were able to identify and characterize a calcium-activated potassium channel in the plasma membrane of lymphocytes from both strains of rat. Potassium currents were recorded that had a slope conductance of 18.1 +/- 1.49, n = 6, and 18.5 +/- 1.44, n = 7, in WKY rat and SHRSP thymocytes, respectively. The channel exhibited rectification of the outward current in both strains of rat. Channels tended to appear in clusters of two or more per patch and were recorded in 30-50% of the patches examined. Calcium sensitivity of the channels was similar; maximum activation occurred at 700 nM free calcium concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental hypertension.

Several interventions are used to induce hypertension in the experimental animal. The three most used interventions are renal ischemia, mineralocorticoid excess, and genetic manipulation. The sequence of events leading from these initiating manipulations to the elevated arterial pressure is being explored to define the mechanism responsible for hypertension. The following mechanisms are currently extensively evaluated: Pressor and depressor factors of renal origin, neurogenic regulation, circulating humoral factors, vessel wall hypertrophy, and membrane transport abnormality. The experimental models of hypertension hold great promise in providing an understanding of the mechanisms and developing effective treatment in clinical hypertension.

Lymphocyte abnormalities in three types of hypertension in the rat.

Lymphocyte number and weight and their sodium and potassium contents and net passive fluxes were measured in spontaneously hypertensive stroke-prone rats, deoxycorticosterone acetate-treated rats, and two-kidney, one clip renal hypertensive rats. Wistar-Kyoto rats were used as controls for the spontaneously hypertensive stroke-prone rats, and normal intact Sprague-Dawley rats were used as controls for the others. Blood lymphocyte count was higher and lymphocyte weight was lower in the hypertensive rats. Intralymphocytic sodium content (millimoles per kilogram of dry weight) was elevated in the three forms of hypertension as compared with control values (spontaneously hypertensive stroke-prone rats, 43.0 +/- 1.7 vs Wistar-Kyoto rats, 37.3 +/- 1.3; deoxycorticosterone acetate-treated rats, 44.4 +/- 3.1 vs Sprague-Dawley rats, 36.1 +/- 1.7; one-kidney, one clip rats, 50.5 +/- 3.7 vs Sprague-Dawley rats, 38.9 +/- 2.0). Intralymphocytic potassium content was not significantly altered in any of the forms of hypertension. Lymphocytes from spontaneously hypertensive stroke-prone rats and deoxycorticosterone acetate-treated rats exhibited elevated net sodium fluxes (millimoles per kilogram of dry weight per hour) as compared with those of controls (spontaneously hypertensive stroke-prone rats, 7.00 +/- 0.99 vs Wistar-Kyoto rats, 4.89 +/- 0.63; deoxycorticosterone acetate-treated rats, 7.58 +/- 0.97 vs Sprague-Dawley rats, 5.6 +/- 0.64). Net potassium fluxes were significantly elevated only in the spontaneously hypertensive stroke-prone rats (14.07 +/- 1.70 vs 8.23 +/- 1.04 in Wistar-Kyoto rats). Sodium and potassium fluxes in lymphocytes from two-kidney, one clip rats and Sprague-Dawley rats were not significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelial function in hypertension: the role of superoxide anion.

Much attention has been focused on the role of nitric oxide in hypertension and cardiovascular disease. More recently, the role of superoxide anion and its interaction with nitric oxide has been investigated in this context. This review will concentrate on the role of superoxide in human and experimental hypertension, paying particular attention to the potential sources of superoxide within the vasculature and discussing some of the molecular mechanisms surrounding its production and dismutation. We discuss what is known about the human superoxide dismutase enzymes. We conclude that the balance between nitric oxide and superoxide is more important than the absolute levels of either alone.

Pathophysiology of the vasculature in hypertension.

The vessel wall is thicker in hypertension. Folkow demonstrated that adaptive structural changes occur in vessels in response to the increased wall stress of hypertension. Because the vessel wall thickens and encroaches on the lumen, the adaptive change results in an elevated vascular resistance. It also exaggerates the vasoconstrictor effects of vascular smooth muscle contraction, thereby increasing vascular reactivity to physiologically occurring vasoactive agents. As solid as this information may be, important unanswered questions still remain related to the question "What makes the pressure go up in the first place?" In this brief review, we have examined possible culprits both in the area of extrinsic vascular regulatory systems and in that of intrinsic changes in the vascular smooth muscle cell. Interesting newly described vasoactive agents currently are being evaluated. On the other hand, generalized intrinsic abnormalities in the cell membrane are well documented in hypertension. Many individual transport systems display this abnormality, suggesting that the primary defect may be in the lipid bilayer that influences the function of all integral protein transport systems. Abnormalities also have been found in the cells' signal transduction systems, whereas the energy metabolism and contractile protein system are essentially normal. Functional abnormalities of the vascular smooth muscle cell in hypertension must explain both its increased contraction and its increased growth. It is likely that the same functional abnormality may explain both of these changes.

Immunoreactive atrial natriuretic hormone levels increase in deoxycorticosterone acetate-treated pigs.

Extensive evidence reported here and elsewhere indicates a hormonal role for atrial natriuretic factor. In the light of this evidence, it appears that atrial natriuretic hormone is a more appropriate term for these peptides than atrial natriuretic factor. Plasma levels of immunoreactive atrial natriuretic hormone were measured daily in seven pigs before and 1 week after subcutaneous implantation of deoxycorticosterone acetate (DOCA). Nine other animals underwent daily measurements of mean arterial pressure and central venous pressure during similar treatments. Plasma immunoreactive atrial natriuretic hormone levels rose progressively during the first 3 days after implantation, from a basal level of 60 +/- 9 pmol/L to a peak level of 159 +/- 21 pmol/L (p less than 0.05), and they remained significantly elevated throughout the rest of the 7-day observation period. In two animals that were restudied 6 weeks after DOCA implantation, plasma immunoreactive atrial natriuretic hormone had returned to preimplantation levels. The rise in plasma hormone levels after DOCA implantation closely paralleled the previously reported time course of mineralocorticoid escape. Whether atrial natriuretic hormone plays an important part in the escape phenomenon remains to be determined.

Dietary calcium and cell membrane abnormality in genetic hypertension.

Adult stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats were maintained for 10 weeks on one of two diets: 1.0% calcium content and 2.5% calcium content. At the end of this time rats were anesthetized, and blood pressure was determined by means of aortic cannulation; then the rats were exsanguinated. Lymphocytes were isolated for determination of intracellular sodium and potassium concentrations, net sodium influx, net potassium efflux, and intracellular free calcium concentration. Serum ionized calcium was also measured. The increase in calcium content of their diet had no effect on intracellular sodium and potassium concentrations in lymphocytes from WKY rats and SHRSP. In lymphocytes from WKY rats, none of the parameters was affected by the change in dietary calcium intake. In contrast, in lymphocytes from SHRSP the increase in dietary calcium from 1.0 to 2.5% led to significant decreases in net potassium efflux (13.3 +/- 2.3 vs. 19.7 +/- 1.4 mmol/kg dry wt/hr, p less than 0.05, analysis of variance), intracellular free calcium concentration (114.5 +/- 10.2 vs. 166.2 +/- 11.2 nM, p less than 0.001), and systolic blood pressure (125.3 +/- 13.6 vs. 183.3 +/- 16.6 mm Hg, p less than 0.01). Serum ionized calcium increased in SHRSP (2.40 +/- 0.04 vs. 2.16 +/- 0.03, p less than 0.01) but not in WKY rats (2.34 +/- 0.05 vs. 2.31 +/- 0.05) fed the high calcium diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrolyte and hormonal effects of deoxycorticosterone acetate in young pigs.

Balances of sodium, potassium, and water were studied in the growing male pig as hypertension developed in response to subcutaneous implantation of deoxycorticosterone acetate (DOCA). Serum sodium, potassium, deoxycorticosterone (DOC), aldosterone, and plasma renin activity (PRA) were determined. These variables were observed in a total of 10 experimental and nine control pigs. All animals were uninephrectomized and fed a diet of Purina Pig Chow and tap water ad libitum. No salt was added to the food or water. Serum DOC levels rose dramatically on the day of the implantation, then gradually declined but remained approximately 10 times greater than control levels 40 days after implant. Plasma renin activity was suppressed rapidly and completely, whereas aldosterone fell only slowly to about half its control value. Sodium retention was maximum during the first 24 hours. Therefore an "escape" process became operative, causing sodium balance to return to normal after the third day, at which time the major rise in arterial pressure occurred. A marked increase in water turnover (intake and output) also began after the third day and persisted throughout the experimental period. Water balance remained normal during this period of increased turnover. Hypokalemia developed in the absence of kaliuresis, suggesting that potassium moved into the cells. Except for the potassium retention, these changes parallel the abnormalities seen in other states of mineralocorticoid excess.

Vascular changes in DOCA hypertension. Influence of a low protein diet.

The goal of this study was to characterize the influence of low protein diet on vascular changes induced by deoxycorticosterone acetate (DOCA) hypertension. DOCA hypertensive and control normotensive rats were placed on a low protein (5%) diet for 4 weeks. This intervention blocked the further increase in systolic blood pressure of rats treated with DOCA; systolic blood pressures of control rats were not influenced by the low protein diet. The sensitivity of isolated mesenteric arteries to norepinephrine was increased in DOCA hypertensive rats compared to that in arteries from control rats; arterial strips from rats maintained on the low protein diet were less sensitive to the catecholamine than arteries from their respective control diet group. Vascular sensitivity to calcium was identical in both normotensive and DOCA hypertensive rats, and the low protein diet had no effect on this measure of calcium activation. Calcium-induced relaxation was depressed in arteries from DOCA hypertensive rats, suggesting a decreased stabilizing influence of the cation on the excitable membrane. Arteries from rats maintained on the low protein diet showed enhanced relaxation to calcium compared to those from their respective control diet group. Membrane stores of calcium available for activation by norepinephrine were increased in arteries from DOCA hypertensive rats; the low protein diet decreased the storage capacity of these membrane sites. The total protein content of the aorta was increased in DOCA hypertensive rats and depressed to control level in DOCA rats maintained on low protein diet. No change was observed in actomyosin content nor in the actin-to-myosin ratio during the DOCA hypertension or the addition of a low protein diet. Since one action of DOCA is to increase cellular protein synthesis, the attenuation of these vascular changes in DOCA rats maintained on a protein-deficient diet is probably due to a decrease in available substrate.

Adrenergic neurotransmission in tail arteries from two-kidney, one clip, renal hypertensive rats.

The goal of this study was to determine if increased vascular smooth muscle sensitivity to norepinephrine in two-kidney, one clip (2K1C) hypertensive rats is the result of a decrease in adrenergic nerve function. Vascular sensitivity to norepinephrine was measured in isolated tail artery strips from 2K1C hypertensive and normotensive rats and in various arterial stripe preparations from normotensive rats that exhibit varying degrees of adrenergic innervation. In each case, the characteristic of the vascular smooth muscle response in the vessel with the least amount of adrenergic innervation simulated the response of the vascular smooth muscle from the 2K1C hypertensive rats. Release or displacement of endogenous norepinephrine by electrical stimulation, tyramine, potassium-free solution, and potassium excess, and measurement of tissue content of norepinephrine suggest that the blood vessels of 2K1C hypertensive animals are depleted of catecholamine stores. Based on these observations it is concluded that the increased sensitivity of vascular smooth muscle to norepinephrine in 2K1C hypertensive rats is the result of a diminished adrenergic innervation. This increased sensitivity of the vasculature may be a response of the smooth muscle cells to a decrease in innervation or the consequence of vascular wall hypertrophy leading to an increased number of smooth muscle cells that are remote from their adrenergic supply.

Nitroprusside-induced vascular relaxation in DOCA hypertensive rats.

Vascular responsiveness to nitroprusside and to norepinephrine was examined in two different preparations from DOCA hypertensive and normotensive control Sprague-Dawley rats. The blood-perfused renal vasculatures of DOCA hypertensive rats were significantly more sensitive than those of normotensive controls to the vasodilator action of low doses of nitroprusside. At high doses, responses in DOCA hypertensive and normotensive rats were similar. Since basal "structural" vascular resistances were greater in the hypertensive rats, It is possible that further vasodilation with nitroprusside was impeded more in DOCA-treated than in control rats. Nitroprusside produced a greater degree of vascular smooth muscle relaxation in tail artery strips from DOCA hypertensive rats than in those from normotensive controls. The current study is the first characterization of the effects of a vasodilator in mineralocorticoid hypertension. The two preparations gave divergent results with respect to vascular sensitivity to norepinephrine. When compared with control rats, the DOCA hypertensive rats showed a greater sensitivity to norepinephrine in tail arteries but a lesser renal vascular reactivity. It is evident that one must take a number of variables into consideration when characterizing changes in vascular responses that occur in a given model of hypertension: 1) the region of the vasculature (renal vs caudal artery);2) the level of the arterial tree (conduit vs resistance vessels);3) the technique employed for measurement of vascular changes (smooth muscle contraction vs vascular resistance changes);4) the initial vasoconstrictor tone of the preparation; and 5) the agonist used (nitroprusside vs norepinephrine).

Lipid bilayer in genetic hypertension.

Membrane microviscosity, phospholipid composition, and turnover were measured in cultured vascular smooth muscle cells isolated from mesenteric arteries of stroke-prone spontaneously hypertensive and age-matched, normotensive Wistar-Kyoto rats. Membrane microviscosity, measured with fluorescence polarization, revealed greater microviscosity (lower fluidity) of the membranes isolated from smooth muscle cells from hypertensive as compared with those isolated from normotensive rats (p less than 0.01). Preincubation of membranes from hypertensive rats with 5 mM calcium reduced membrane microviscosity in "core" and in "surface" regions of the bilayer toward values observed in Wistar-Kyoto rats. Phospholipid composition did not differ between intact aortas and cultured mesenteric cells or between those tissues obtained from normotensive and from hypertensive rats. The total lipid-associated radioactivity was significantly lower in cells from stroke-prone spontaneously hypertensive rats than in those from Wistar-Kyoto controls (p less than 0.01). Phosphatidylcholine incorporated 70% and phosphatidylinositol 16% of total lipid-associated radioactivity, with no difference between cells from hypertensive and normotensive animals. Turnover of phosphatidylethanolamine was greater in cells from Wistar-Kyoto rats (p = 0.02), whereas turnover of phosphatidylserine was greater in cells from stroke-prone spontaneously hypertensive rats (p = 0.04). The greater microviscosity of the lipid bilayer in hypertension is a generalized defect of the matrix in which the transport proteins function. We hypothesize that this defect is responsible for the multiple abnormalities of membrane transport systems that have been described in genetic hypertension.

Red blood cell sodium in the DOCA hypertensive pig.

The influence of deoxycorticosterone acetate (DOCA) on the sodium content of the red blood cell was determined in the pig. DOCA (100 mg/kg), impregnated in Silastic, was implanted subcutaneously (s.c.) in six male pigs; seven additional pigs received Silastic implants without the DOCA. Those receiving DOCA had an increase in mean arterial pressure (MAP) that was significant in 48 hours and reached a plateau that was 24 mm Hg greater than that of the controls after 15 days. These animals also developed hypokalemia and polydipsia over approximately the same time course. Red blood cell sodium content increased in DOCA-treated pigs 24 hours after implant (5.57 +/- 0.17 vs 5.23 +/- 0.05, mEq/liter cells). The sodium content continued to rise, reaching a plateau 28% above that of control value by the 5th postimplant day (6.37 +/- 0.40 mEq/liter cells). In vitro tests of possible mechanisms that might have caused the in vivo increase in red blood cell sodium content gave the following results: 1) Incubations of red blood cells in a physiological salt solution (PSS) containing deoxycorticosterone failed to cause an increase in cell sodium content. 2) No ouabain-like factor was demonstrated in plasma from the DOCA hypertensive pigs. 3) An elevation in bicarbonate concentration in the PSS caused an increase in red blood cell sodium content. 4) A decrease in potassium concentration in the PSS also caused an increase in red blood cell sodium content.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic responses to DOCA in young pigs.

Hemodynamic variables were measured in 20 young pigs; thirteen received subcutaneous implantations of desoxycorticosterone acetate (DOCA) impregnated in Silastic strips, seven received implants of Silastic strips alone and served as controls. No salt was added to the standard diet of either group. Mean arterial pressure (MAP) rose in a regular pattern in the DOCA-treated pigs, reaching on the average a level significantly greater than that of the control group 48 hours after the implantation. Pressure continued to rise, reaching a plateau 38% above that of the preimplant value 2 weeks later. In some pigs the MAP elevation was caused by an increase in cardiac output (CO); in others it was caused by an increase in total peripheral resistance (TPR). An increase in central venous pressure occurred in many DOCA-treated pigs regardless of whether the increase in MAP was caused by an increase in CO or in TPR. The results indicate that it is arterial pressure per se that is the regulated variable in this model of mineralocorticoid hypertension. The regulating system, whether it resides in the kidney or in the central nervous system, elevates pressure by effecting increases in either CO or TPR.

Functional evidence for increased sodium permeability in aortas from DOCA hypertensive rats.

We studied the role of increased Na+ permeability on the increased responsiveness to ouabain and to K+-free solution in aortas from DOCA hypertensive rats. Helically cut strips from DOCA hypertensive and normotensive control rats were mounted in a muscle bath for recording isometric force. In response to ouabain, aortas from DOCA hypertensive rats were significantly more sensitive and developed a greater maximal force than aortas from control rats. The rate of force development in response to K+-free solution was significantly faster in aortas from DOCA hypertensive rats as compared to those from control rats. Monensin (10(-5)M), a Na+ ionophore, increased the contractile response to ouabain and the rate of force development in response to K+-free solution in both DOCA hypertensive and control aortas. Amiloride (3 X 10(-5) M), a Na+ channel blocker, decreased the contractile response to ouabain and the rate of force development to a K+-free solution in both the DOCA hypertensive and control aortas, but the magnitude of decrease was greater in aortas from DOCA hypertensive rats. Thus, a Na+ ionophore causes the control aortas to perform like those from DOCA hypertensive rats, and a Na+ channel blocker causes aortas from DOCA hypertensive rats to perform like those from control rats. It is concluded that the difference between the two is that the smooth muscle of aortas from DOCA hypertensive rats is more permeable to Na+ than is that from control rats.