Renal denervation decreases arterial pressure (AP) in hypertensive rats and humans. This procedure destroys both afferent and efferent nerves. Several investigators have proposed that renal afferent nerves contribute to the elevated AP. We developed a procedure to selectively remove renal afferent nerves with capsaicin (1-100 mM) both topically on the nerve and in the renal pelvis. We examined the effects of renal deafferentation on the development of genetic and renal hypertension. We studied spontaneously hypertensive rats (SHR), and a model of renal hypertension, two kidney-one clip (2K1C) in Sprague-Dawley rats. SHR were treated at 3-4 weeks of age with capsaicin. Mean arterial pressure was recorded by tail cuff through 16 weeks of age. On week 17, rats were cannulated, allowed 3 days to recover then had their AP measured directly for 3 days (3 hrs/day). Rats with renal deafferentation (n=11) had lower arterial pressure weeks 9-16 (average reduction AP=10.1±1.4 mmHg, ANOVA, p=0.0049) compared to control (saline treated, n=6) although the final direct recording was not significantly different on week 17 (control AP=184.1±3.4 mmHg vs deafferented AP=173.9±4.3 mmHg, p=0.07). Substance P levels from the kidneys were reduced in deafferented rats compared to control (6.9±1.0 vs 17.3±5.2 pg/g protein, p=0.0009). In contrast, renal NE levels were not altered (307±19 vs 313±20 pg/g protein, p=0.428). In the second study, the left kidney in weanling Sprague-Dawley rats was exposed to capsaicin or saline. Rats were allowed to mature (>250 g BW) then subjected to left renal artery clipping (0.2mm) or sham clip. AP was recorded by tail cuff during development of 2K1C for 6 weeks before direct cannulation to record AP on week 7. Renal deafferentation prevented the development of hypertension in 13 rats compared to 9 saline treated rats (average reduction AP=16.9±2.7 mmHg, ANOVA, p=0.0031). Saline treated rats had a higher AP 7 weeks after clipping (147.1±10.2 vs 130.5±4.2 mmHg direct recording, p=0.02). The left kidney contained 48% SP compared to the right kidney (p=0.04). These data suggest that increased afferent renal nerve activity contributes to the elevation in AP in hypertension and contributes to essential hypertension in humans. Supported by USPHS DA017371.

Neuropeptide W (NPW) is a centrally acting peptide that activates the central melanocortin system and increases arterial pressure in conscious rats. We investigated the mechanism by which NPW evokes hemodynamic responses. Rats were instrumented for recording arterial pressure and for measuring blood flow changes in the abdominal aorta (hindquarters) and the superior mesenteric artery using pulsed Doppler flowmetry. Intracerebroventricular NPW (0.3 nmol and 1 nmol) elicited a pressor response of 9.6±3 and 10.6±4.9 mmHg, respectively, occurring between 90 and 180 seconds after administration. There was a concomitant increase in heart rate (27±10 and 30±12 b/min) and increase in mesenteric vascular resistance (26±8 and 28±10%). Therefore, the increase in arterial pressure due to central administration of NPW is at least partially dependent on increased mesenteric vascular resistance. Hindquarters vascular responses were minimal and highly variable. We conclude that central NPW evokes mesenteric vasoconstriction and tachycardia contributing to a pressor response similar to a classical behavioral stress response. Supported by USPHS DA017371.

Others have reported that the dorsomedial hypothalamus (DMH) mediates certain cardiovascular responses to behavioral stress. We sought to determine whether this variability is strain dependent and whether different stressors are similarly dependent on the DMH. We compared responses to cocaine (5 mg/kg, iv) with startle responses to 1 cm deep ice cold water (CWS) in Brown‐Norway (BN) and Dahl salt sensitive (DSS) rats. BN and DSS rats were instrumented for recording arterial pressure and for measuring blood flow changes in the abdominal aorta (hindquarters or Hq) and the superior mesenteric (Ms) artery using Doppler flowmetry. We calculated changes in vascular resistance (R) in animals. BN rats had greater increases in MsR (visceral) and HqR (skeletal muscle) to cocaine than DSS. In contrast, DSS rats had greater increases in MsR in response to CWS than BN rats. Microinjection of muscimol (80 pmol in 100 nl) in the DMH attenuated the increase in MsR in BN but not DSS rats in response to cocaine but not to CWS. DMH stimulation with kainate (10 pmol in 100 nl) elicited greater Ms vasoconstriction in BN compared to DSS rats. We conclude that there are unique strain‐dependent pathways mediating regional vascular resistance for specific stressors. The BN is more dependent on DMH in mediating cocaine‐induced visceral vasoconstriction. Supported by USPHS DA017371 and HL091440.

We have used the cold pressor test in Sprague Dawley rats to elicit behavioral stress. In this paradigm, ice‐cold water (1 cm deep) is rapidly added to a watertight cage while recording hemodynamic responses. The initial startle response (5 ‐ 10 sec) is characterized by a profound pressor response due to an increase in systemic vascular resistance (SVR). The sustained modest pressor response (15‐60 sec) is characterized by tachycardia. We hypothesized that the sustained response but not the initial startle response is dependent on water temperature. Rats instrumented for cardiac output, mean arterial pressure (MAP) and heart rate determination were acclimated then tested with each temperature in the following order: room temperature (22‐24 °C), warm (33‐36 °C), then cold (2‐4 °C) water. After acclimation, we rapidly added water and recorded the response for one minute. The initial startle response was independent of temperature since all rats responded by increasing MAP and SVR. The sustained responses were highly dependent on water temperature since the modest pressor response and tachycardia observed with cold water were smaller with room temperature water and not observed with warm water. Our results suggest the initial startle response is independent of water temperature whereas the sustained modest pressor response is dependent on cold water. This work was supported by USPHS DA0017371 and HL091440.